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  • Core Concepts  (21)
  • Breast Cancer Special Feature  (19)
  • Electrochemistry Special Feature  (15)
  • National Academy of Sciences  (55)
  • Copernicus
  • 2010-2014  (55)
  • 1995-1999
  • 1980-1984
  • 1945-1949
  • 1925-1929
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  • National Academy of Sciences  (55)
  • Copernicus
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  • 2010-2014  (55)
  • 1995-1999
  • 1980-1984
  • 1945-1949
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  • 1
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    Quasiparticle [Core Concepts] (2014)
    National Academy of Sciences
    Details
    Publication Date: 2014-11-05
    Description: Physicists have identified dozens of different subatomic species in the particle zoo, but most physical and chemical interactions arise from only three: the proton, the neutron, and the electron. There are a lot of those: solids and liquids contain on the order of 1024 particles per cubic centimeter. In February,...
    Keywords: Core Concepts
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  • 2
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    Disruption of bone morphogenetic protein receptor 2 (BMPR2) in mammary tumors promotes metastases through cell autonomous and paracrine mediators [Cell Biology] (2012)
    National Academy of Sciences
    Details
    Publication Date: 2012-02-22
    Description: Bone morphogenetic proteins (BMPs) are members of the TGF-β superfamily of signaling molecules. BMPs can elicit a wide range of effects in many cell types and have previously been shown to induce growth inhibition in carcinoma cells as well as normal epithelia. Recently, it has been demonstrated that BMP4 and BMP7 are overexpressed in human breast cancers and may have tumor suppressive and promoting effects. We sought to determine whether disruption of the BMP receptor 2 (BMPR2) would alter mammary tumor progression in mice that express the Polyoma middle T antigen. Mice expressing Polyoma middle T antigen under the mouse mammary tumor virus promoter were combined with mice that have doxycycline-inducible expression of a dominant-negative (DN) BMPR2. We did not observe any differences in tumor latency. However, mice expressing the BMPR2-DN had a fivefold increase in lung metastases. We characterized several cell autonomous changes and found that BMPR2-DN–expressing tumor cells had higher rates of proliferation. We also identified unique changes in inflammatory cells and secreted chemokines/cytokines that accompanied BMPR2-DN–expressing tumors. By immunohistochemistry, it was found that BMPR2-DN primary tumors and metastases had an altered reactive stroma, indicating specific changes in the tumor microenvironment. Among the changes we discovered were increased myeloid derived suppressor cells and the chemokine CCL9. BMP was shown to directly regulate CCL9 expression. We conclude that BMPR2 has tumor-suppressive function in mammary epithelia and microenvironment and that disruption can accelerate mammary carcinoma metastases.
    Keywords: Breast Cancer Special Feature
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    Homeobox B9 induces epithelial-to-mesenchymal transition-associated radioresistance by accelerating DNA damage responses [Cell Biology] (2012)
    National Academy of Sciences
    Details
    Publication Date: 2012-02-22
    Description: Homeobox 9 (HOXB9), a nontransforming transcription factor overexpressed in breast cancer, alters tumor cell fate and promotes tumor progression and metastasis. Here we show that HOXB9 confers resistance to ionizing radiation by promoting DNA damage response. In nonirradiated cells, HOXB9 induces spontaneous DNA damage, phosphorylated histone 2AX and p53 binding protein 1 foci, and increases baseline ataxia telangiectasia mutated (ATM) phosphorylation. Upon ionizing radiation, ATM is hyperactivated in HOXB9-expressing cells during the early stages of the double-stranded DNA break (DSB) response, accelerating accumulation of phosphorylated histone 2AX, mediator of DNA-damage checkpoint 1, and p53 binding protein 1, at DSBs and enhances DSB repair. The effect of HOXB9 on the response to ionizing radiation requires the baseline ATM activity before irradiation and epithelial-to-mesenchymal transition induced by TGF-β, a HOXB9 transcriptional target. Our results reveal the impact of a HOXB9–TGF-β–ATM axis on checkpoint activation and DNA repair, suggesting that TGF-β may be a key factor that links tumor microenvironment, tumor cell fate, DNA damage response, and radioresistance in a subset of HOXB9-overexpressing breast tumors.
    Keywords: Breast Cancer Special Feature
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  • 4
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    Leukocyte composition of human breast cancer [Immunology] (2012)
    National Academy of Sciences
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    Publication Date: 2012-02-22
    Description: Retrospective clinical studies have used immune-based biomarkers, alone or in combination, to predict survival outcomes for women with breast cancer (BC); however, the limitations inherent to immunohistochemical analyses prevent comprehensive descriptions of leukocytic infiltrates, as well as evaluation of the functional state of leukocytes in BC stroma. To more fully evaluate this complexity, and to gain insight into immune responses after chemotherapy (CTX), we prospectively evaluated tumor and nonadjacent normal breast tissue from women with BC, who either had or had not received neoadjuvant CTX before surgery. Tissues were evaluated by polychromatic flow cytometry in combination with confocal immunofluorescence and immunohistochemical analysis of tissue sections. These studies revealed that activated T lymphocytes predominate in tumor tissue, whereas myeloid lineage cells are more prominant in “normal” breast tissue. Notably, residual tumors from an unselected group of BC patients treated with neoadjuvant CTX contained increased percentages of infiltrating myeloid cells, accompanied by an increased CD8/CD4 T-cell ratio and higher numbers of granzyme B-expressing cells, compared with tumors removed from patients treated primarily by surgery alone. These data provide an initial evaluation of differences in the immune microenvironment of BC compared with nonadjacent normal tissue and reveal the degree to which CTX may alter the complexity and presence of selective subsets of immune cells in tumors previously treated in the neoadjuvant setting.
    Keywords: Breast Cancer Special Feature
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    Comparative oncogenomics identifies breast tumors enriched in functional tumor-initiating cells [Genetics] (2012)
    National Academy of Sciences
    Details
    Publication Date: 2012-02-22
    Description: The claudin-low subtype is a recently identified rare molecular subtype of human breast cancer that expresses low levels of tight and adherens junction genes and shows high expression of epithelial-to-mesenchymal transition (EMT) genes. These tumors are enriched in gene expression signatures derived from human tumor-initiating cells (TICs) and human mammary stem cells. Through cross-species analysis, we discovered mouse mammary tumors that have similar gene expression characteristics as human claudin-low tumors and were also enriched for the human TIC signature. Such claudin-low tumors were similarly rare but came from a number of distinct mouse models, including the p53 null transplant model. Here we present a molecular characterization of 50 p53 null mammary tumors compared with other mouse models and human breast tumor subtypes. Similar to human tumors, the murine p53 null tumors fell into multiple molecular subtypes, including two basal-like, a luminal, a claudin-low, and a subtype unique to this model. The claudin-low tumors also showed high gene expression of EMT inducers, low expression of the miR-200 family, and low to absent expression of both claudin 3 and E-cadherin. These murine subtypes also contained distinct genomic DNA copy number changes, some of which are similarly altered in their cognate human subtype counterpart. Finally, limiting dilution transplantation revealed that p53 null claudin-low tumors are highly enriched for TICs compared with the more common adenocarcinomas arising in the same model, thus providing a unique preclinical mouse model to investigate the therapeutic response of TICs.
    Keywords: Breast Cancer Special Feature
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    Maintenance of hormone responsiveness in luminal breast cancers by suppression of Notch [Medical Sciences] (2012)
    National Academy of Sciences
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    Publication Date: 2012-02-22
    Description: Luminal breast cancers express estrogen (ER) and/or progesterone (PR) receptors and respond to hormone therapies. Basal-like “triple negative” cancers lack steroid receptors but are cytokeratin (CK) 5-positive and require chemotherapy. Here we show that more than half of primary ER+PR+ breast cancers contain an ER−PR−CK5+ “luminobasal” subpopulation exceeding 1% of cells. Starting from ER+PR+ luminal cell lines, we generated lines with varying luminal to luminobasal cell ratios and studied their molecular and biological properties. In luminal disease, luminobasal cells expand in response to antiestrogen or estrogen withdrawal therapies. The phenotype and gene signature of the hormone-resistant cells matches that of clinical triple negative basal-like and claudin-low disease. Luminobasal cell expansion in response to hormone therapies is regulated by Notch1 signaling and can be blocked by γ-secretase inhibitors. Our data establish a previously unrecognized plasticity of ER+PR+ luminal breast cancers that, without genetic manipulation, mobilizes outgrowth of hormone-resistant basal-like disease in response to treatment. This undesirable outcome can be prevented by combining endocrine therapies with Notch inhibition.
    Keywords: Breast Cancer Special Feature
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    The HOXB7 protein renders breast cancer cells resistant to tamoxifen through activation of the EGFR pathway [Medical Sciences] (2012)
    National Academy of Sciences
    Details
    Publication Date: 2012-02-22
    Description: Multiple factors including long-term treatment with tamoxifen are involved in the development of selective estrogen receptor (ER) modulator resistance in ERα-positive breast cancer. Many underlying molecular events that confer resistance are known but a unifying theme is yet to be revealed. In this report, we provide evidence that HOXB7 overexpression renders MCF-7 cells resistant to tamoxifen via cross-talk between receptor tyrosine kinases and ERα signaling. HOXB7 is an ERα-responsive gene. Extended treatment of MCF-7 cells with tamoxifen resulted in progressively increasing levels of HOXB7 expression, along with EGFR and EGFR ligands. Up-regulation of EGFR occurs through direct binding of HOXB7 to the EGFR promoter, enhancing transcriptional activity. Finally, higher expression levels of HOXB7 in the tumor significantly correlated with poorer disease-free survival in ERα-positive patients with breast cancer on adjuvant tamoxifen monotherapy. These studies suggest that HOXB7 acts as a key regulator, orchestrating a major group of target molecules in the oncogenic hierarchy. Functional antagonism of HOXB7 could circumvent tamoxifen resistance.
    Keywords: Breast Cancer Special Feature
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  • 8
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    Quorum sensing [Core Concepts] (2013)
    National Academy of Sciences
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    Publication Date: 2013-02-20
    Description: pnas;110/8/2690/UNFIG01F1unfig01There are enough bacteria in this flask that they sense a “quorum” sufficient to luminesce. Image courtesy of Zach Donnell, Bassler Research Laboratory, Princeton University.When the Hawaiian bobtail squid rises from the sand each evening to hunt, it swims cloaked from detection by predators and prey because it casts no...
    Keywords: Core Concepts
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  • 9
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    Mantle plumes [Core Concepts] (2013)
    National Academy of Sciences
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    Publication Date: 2013-02-13
    Description: pnas;110/7/2435/UNFIG01F1unfig01Mantle plumes can be emitted from the core-mantle boundary region to reach the Earth’s crust. Because of the lateral displacement of the tectonic plates at the surface, the mantle plumes can create a series of aligned hot-spot volcanoes. A mid-ocean ridge and a subducted plate are also shown. Image courtesy...
    Keywords: Core Concepts
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  • 10
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    Nanoelectrodes for ROS and RNS [Chemistry] (2012)
    National Academy of Sciences
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    Publication Date: 2012-07-18
    Description: Reactive oxygen and nitrogen species (ROS and RNS) produced by macrophages are essential for protecting a human body against bacteria and viruses. Micrometer-sized electrodes coated with Pt black have previously been used for selective and sensitive detection of ROS and RNS in biological systems. To determine ROS and RNS inside macrophages, one needs smaller (i.e., nanometer-sized) sensors. In this article, the methodologies have been extended to the fabrication and characterization of Pt/Pt black nanoelectrodes. Electrodes with the metal surface flush with glass insulator, most suitable for quantitative voltammetric experiments, were fabricated by electrodeposition of Pt black inside an etched nanocavity under the atomic force microscope control. Despite a nanometer-scale radius, the true surface area of Pt electrodes was sufficiently large to yield stable and reproducible responses to ROS and RNS in vitro. The prepared nanoprobes were used to penetrate cells and detect ROS and RNS inside macrophages. Weak and very short leaks of ROS/RNS from the vacuoles into the cytoplasm were detected, which a macrophage is equipped to clean within a couple of seconds, while higher intensity oxidative bursts due to the emptying of vacuoles outside persist on the time scale of tens of seconds.
    Keywords: Electrochemistry Special Feature
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    Electron transfer in a molecular shuttle [Chemistry] (2012)
    National Academy of Sciences
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    Publication Date: 2012-07-18
    Description: The kinetics and thermodynamics of intramolecular electron transfer (IET) can be subjected to redox control in a bistable [2]rotaxane comprised of a dumbbell component containing an electron-rich 1,5-dioxynaphthalene (DNP) unit and an electron-poor phenylene-bridged bipyridinium (P-BIPY2+) unit and a cyclobis (paraquat-p-phenylene) (CBPQT4+) ring component. The [2]rotaxane exists in the ground-state co-conformation (GSCC) wherein the CBPQT4+ ring encircles the DNP unit. Reduction of the CBPQT4+ leads to the CBPQT2(•+) diradical dication while the P-BIPY2+ unit is reduced to its P-BIPY•+ radical cation. A radical-state co-conformation (RSCC) results from movement of the CBPQT2(•+) ring along the dumbbell to surround the P-BIPY•+ unit. This shuttling event induces IET to occur between the pyridinium redox centers of the P-BIPY•+ unit, a property which is absent between these redox centers in the free dumbbell and in the 1∶1 complex formed between the CBPQT2(•+) ring and the radical cation of methyl-phenylene-viologen (MPV•+). Using electron paramagnetic resonance (EPR) spectroscopy, the process of IET was investigated by monitoring the line broadening at varying temperatures and determining the rate constant (kET = 1.33 × 107 s-1) and activation energy (ΔG‡ = 1.01 kcal mol-1) for electron transfer. These values were compared to the corresponding values predicted, using the optical absorption spectra and Marcus–Hush theory.
    Keywords: Electrochemistry Special Feature
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  • 12
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    Electrochemistry [Introductions] (2012)
    National Academy of Sciences
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    Publication Date: 2012-07-18
    Description: For this special issue of PNAS, it seems appropriate to begin with a brief commentary on the path(s) leading to where the discipline of electrochemistry is today. The papers in this issue serve as a sampling of the current themes and directions; we thank the authors for their contributions. We should also point to a nice collection of historical perspectives gathered together by Leddy et al. (1).The development of the electrochemistry discipline up to the 1960s was substantially that of the physical principles of describing electrochemical reactions and electrode reactions in which current or working electrode potential was controlled in...
    Keywords: Electrochemistry Special Feature
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  • 13
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    Comparison of dopamine and serotonin release [Neuroscience] (2012)
    National Academy of Sciences
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    Publication Date: 2012-07-18
    Description: Dopamine and serotonin (5-hydroxytryptamine or 5-HT) are neurotransmitters that are implicated in many psychological disorders. Although dopamine transmission in the brain has been studied extensively in vivo with fast scan cyclic voltammetry, detection of 5-HT using in vivo voltammetric methods has only recently been established. In this work we use two carbon-fiber microelectrodes to simultaneously measure dopamine release in the nucleus accumbens and 5-HT release in the substantia nigra pars reticulata, using a common stimulation in a single rat. We find that 5-HT release is profoundly restricted in comparison with dopamine release despite comparable tissue content levels. Using physiological and pharmacological analysis, we find that 5-HT transmission is mostly sensitive to uptake and metabolic degradation mechanisms. In contrast, dopamine transmission is constrained by synthesis and repackaging. Finally, we show that disruption of serotonergic regulatory mechanisms by simultaneous inhibition of uptake and metabolic degradation can have severe physiological consequences that mimic serotonin syndrome.
    Keywords: Electrochemistry Special Feature
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  • 14
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    Hydrogenases as electrocatalysts [Chemistry] (2012)
    National Academy of Sciences
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    Publication Date: 2012-07-18
    Description: The extraordinary ability of Fe- and Ni-containing enzymes to catalyze rapid and efficient H+/H2 interconversion—a property otherwise exclusive to platinum metals—has been investigated in a series of experiments combining variable-temperature protein film voltammetry with mathematical modeling. The results highlight important differences between the catalytic performance of [FeFe]-hydrogenases and [NiFe]-hydrogenases and justify a simple model for reversible catalytic electron flow in enzymes and electrocatalysts that should be widely applicable in fields as diverse as electrochemistry, catalysis, and bioenergetics. The active site of [FeFe]-hydrogenases, an intricate Fe-carbonyl complex known as the “H cluster,” emerges as a supreme catalyst.
    Keywords: Electrochemistry Special Feature
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  • 15
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    Nanopore detection of DNA abasic sites [Chemistry] (2012)
    National Academy of Sciences
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    Publication Date: 2012-07-18
    Description: DNA abasic (AP) sites are one of the most frequent lesions in the genome and have a high mutagenic potential if unrepaired. After selective attachment of 2-aminomethyl-18-crown-6 (18c6), individual AP lesions are detected during electrophoretic translocation through the bacterial protein ion channel α-hemolysin (α-HL) embedded in a lipid bilayer. Interactions between 18c6 and Na+ produce characteristic pulse-like current amplitude signatures that allow the identification of individual AP sites in single molecules of homopolymeric or heteropolymeric DNA sequences. The bulky 18c6-cation complexes also dramatically slow the DNA motion to more easily recordable levels. Further, the behaviors of the AP-18c6 adduct are different with respect to the directionalities of DNA entering the protein channel, and they can be precisely manipulated by altering the cation (Li+, Na+ or K+) of the electrolyte. This method permits detection of multiple AP lesions per strand, which is unprecedented in other work. Additionally, insights into the thermodynamics and kinetics of 18c6-cation interactions at a single-molecule level are provided by the nanopore measurement.
    Keywords: Electrochemistry Special Feature
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  • 16
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    Electrochemical imaging of carbon nanotube [Chemistry] (2012)
    National Academy of Sciences
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    Publication Date: 2012-07-18
    Description: Carbon nanotubes have attracted considerable interest for electrochemical, electrocatalytic, and sensing applications, yet there remains uncertainty concerning the intrinsic electrochemical (EC) activity. In this study, we use scanning electrochemical cell microscopy (SECCM) to determine local heterogeneous electron transfer (HET) kinetics in a random 2D network of single-walled carbon nanotubes (SWNTs) on an Si/SiO2 substrate. The high spatial resolution of SECCM, which employs a mobile nanoscale EC cell as a probe for imaging, enables us to sample the responses of individual portions of a wide range of SWNTs within this complex arrangement. Using two redox processes, the oxidation of ferrocenylmethyl trimethylammonium and the reduction of ruthenium (III) hexaamine, we have obtained conclusive evidence for the high intrinsic EC activity of the sidewalls of the large majority of SWNTs in networks. Moreover, we show that the ends of SWNTs and the points where two SWNTs cross do not show appreciably different HET kinetics relative to the sidewall. Using finite element method modeling, we deduce standard rate constants for the two redox couples and demonstrate that HET based solely on characteristic defects in the SWNT side wall is highly unlikely. This is further confirmed by the analysis of individual line profiles taken as the SECCM probe scans over an SWNT. More generally, the studies herein demonstrate SECCM to be a powerful and versatile method for activity mapping of complex electrode materials under conditions of high mass transport, where kinetic assignments can be made with confidence.
    Keywords: Electrochemistry Special Feature
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    BiVO4 photoelectrode for water splitting [Chemistry] (2012)
    National Academy of Sciences
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    Publication Date: 2012-07-18
    Description: An efficient BiVO4 thin film electrode for overall water splitting was prepared by dipping an F-doped SnO2 (FTO) substrate electrode in an aqueous nitric acid solution of Bi(NO3)3 and NH4VO3, and subsequently calcining it. X-ray diffraction of the BiVO4 thin film revealed that a photocatalytically active phase of scheelite-monoclinic BiVO4 was obtained. Scanning electron microscopy images showed that the surface of an FTO substrate was uniformly coated with the BiVO4 film with 300–400 nm of the thickness. The BiVO4 thin film electrode gave an excellent anodic photocurrent with 73% of an IPCE at 420 nm at 1.0 V vs. Ag/AgCl. Modification with CoO on the BiVO4 electrode improved the photoelectrochemical property. A photoelectrochemical cell consisting of the BiVO4 thin film electrode with and without CoO, and a Pt counter electrode was constructed for water splitting under visible light irradiation and simulated sunlight irradiation. Photocurrent due to water splitting to form H2 and O2 was confirmed with applying an external bias smaller than 1.23 V that is a theoretical voltage for electrolysis of water. Water splitting without applying external bias under visible light irradiation was demonstrated using a SrTiO3∶Rh photocathode and the BiVO4 photoanode.
    Keywords: Electrochemistry Special Feature
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    Topographical and electrochemical imaging [Chemistry] (2012)
    National Academy of Sciences
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    Publication Date: 2012-07-18
    Description: We describe voltage-switching mode scanning electrochemical microscopy (VSM-SECM), in which a single SECM tip electrode was used to acquire high-quality topographical and electrochemical images of living cells simultaneously. This was achieved by switching the applied voltage so as to change the faradaic current from a hindered diffusion feedback signal (for distance control and topographical imaging) to the electrochemical flux measurement of interest. This imaging method is robust, and a single nanoscale SECM electrode, which is simple to produce, is used for both topography and activity measurements. In order to minimize the delay at voltage switching, we used pyrolytic carbon nanoelectrodes with 6.5–100 nm radii that rapidly reached a steady-state current, typically in less than 20 ms for the largest electrodes and faster for smaller electrodes. In addition, these carbon nanoelectrodes are suitable for convoluted cell topography imaging because the RG value (ratio of overall probe diameter to active electrode diameter) is typically in the range of 1.5–3.0. We first evaluated the resolution of constant-current mode topography imaging using carbon nanoelectrodes. Next, we performed VSM-SECM measurements to visualize membrane proteins on A431 cells and to detect neurotransmitters from a PC12 cells. We also combined VSM-SECM with surface confocal microscopy to allow simultaneous fluorescence and topographical imaging. VSM-SECM opens up new opportunities in nanoscale chemical mapping at interfaces, and should find wide application in the physical and biological sciences.
    Keywords: Electrochemistry Special Feature
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    Oxidation of water at interfaces [Chemistry] (2012)
    National Academy of Sciences
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    Publication Date: 2012-07-18
    Description: Photoreduction of [P2W18O62]6-, [S2Mo18O62]4-, and [S2W18O62]4- polyoxometalate anions (POMs) and oxidation of water occurs when water–ionic liquid and water–diethylether interfaces are irradiated with white light (275–750 nm) or sunlight. The ionic liquids (ILs) employed were aprotic ([Bmim]X; Bmim = (1-butyl-3-methylimidazolium,X = BF4,PF6) and protic (DEAS = diethanolamine hydrogen sulphate; DEAP = diethanolamine hydrogen phosphate). Photochemical formation of reduced POMs at both thermodynamically stable and unstable water–IL interfaces led to their initial diffusion into the aqueous phase and subsequent extraction into the IL phase. The mass transport was monitored visually by color change and by steady-state voltammetry at microelectrodes placed near the interface and in the bulk solution phases. However, no diffusion into the organic phase was observed when [P2W18O62]6- was photo-reduced at the water–diethylether interface. In all cases, water acted as the electron donor to give the overall process: 4POM + 2H2O + hν → 4POM- + 4H+ + O2. However, more highly reduced POM species are likely to be generated as intermediates. The rate of diffusion of photo-generated POM- was dependent on the initial concentration of oxidized POM and the viscosity of the IL (or mixed phase system produced in cases in which the interface is thermodynamically unstable). In the water-DEAS system, the evolution of dioxygen was monitored in situ in the aqueous phase by using a Clark-type oxygen sensor. Differences in the structures of bulk and interfacial water are implicated in the activation of water. An analogous series of reactions occurred upon irradiation of solid POM salts in the presence of water vapor.
    Keywords: Electrochemistry Special Feature
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    DNA sensing by electrocatalysis with hemoglobin [Chemistry] (2012)
    National Academy of Sciences
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    Publication Date: 2012-07-18
    Description: Electrocatalysis offers a means of electrochemical signal amplification, yet in DNA-based sensors, electrocatalysis has required high-density DNA films and strict assembly and passivation conditions. Here, we describe the use of hemoglobin as a robust and effective electron sink for electrocatalysis in DNA sensing on low-density DNA films. Protein shielding of the heme redox center minimizes direct reduction at the electrode surface and permits assays on low-density DNA films. Electrocatalysis with methylene blue that is covalently tethered to the DNA by a flexible alkyl chain linkage allows for efficient interactions with both the base stack and hemoglobin. Consistent suppression of the redox signal upon incorporation of a single cytosine-adenine (CA) mismatch in the DNA oligomer demonstrates that both the unamplified and the electrocatalytically amplified redox signals are generated through DNA-mediated charge transport. Electrocatalysis with hemoglobin is robust: It is stable to pH and temperature variations. The utility and applicability of electrocatalysis with hemoglobin is demonstrated through restriction enzyme detection, and an enhancement in sensitivity permits femtomole DNA sampling.
    Keywords: Electrochemistry Special Feature
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    Inhibition of the MRP1-mediated transport [Chemistry] (2012)
    National Academy of Sciences
    Details
    Publication Date: 2012-07-18
    Description: Oxidative stress induced in live HeLa cells by menadione (2-methyl-1,4-napthaquinone) was studied in real time by scanning electrochemical microscopy (SECM). The hydrophobic molecule menadione diffuses through a living cell membrane where it is toxic to the cell. However, in the cell it is conjugated with glutathione to form thiodione. Thiodione is then recognized and transported across the cell membrane via the ATP-driven MRP1 pump. In the extracellular environment, thiodione was detected by the SECM tip at levels of 140, 70, and 35 µM upon exposure of the cells to menadione concentrations of 500, 250, and 125 µM, respectively. With the aid of finite element modeling, the kinetics of thiodione transport was determined to be 1.6 × 10-7 m/s, about 10 times faster than menadione uptake. Selective inhibition of these MRP1 pumps inside live HeLa cells by MK571 produced a lower thiodione concentration of 50 µM in presence of 500 µM menadione and 50 µM MK571. A similar reduced (50% drop) thiodione efflux was observed in the presence of monoclonal antibody QCRL-4, a selective blocking agent of the MRP1 pumps. The reduced thiodione flux confirmed that thiodione was transported by MRP1, and that glutathione is an essential substrate for MRP1-mediated transport. This finding demonstrates the usefulness of SECM in quantitative studies of MRP1 inhibitors and suggests that monoclonal antibodies can be a useful tool in inhibiting the transport of these MDR pumps, and thereby aiding in overcoming multidrug resistance.
    Keywords: Electrochemistry Special Feature
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    Compression of the molecular tunnel barrier [Chemistry] (2012)
    National Academy of Sciences
    Details
    Publication Date: 2012-07-18
    Description: Molecular junctions are essentially modified electrodes familiar to electrochemists where the electrolyte is replaced by a conducting “contact.” It is generally hypothesized that changing molecular structure will alter system energy levels leading to a change in the transport barrier. Here, we show the conductance of seven different aromatic molecules covalently bonded to carbon implies a modest range (  2 eV range). These results are explained by considering the effect of bonding the molecule to the substrate. Upon bonding, electronic inductive effects modulate the energy levels of the system resulting in compression of the tunneling barrier. Modification of the molecule with donating or withdrawing groups modulate the molecular orbital energies and the contact energy level resulting in a leveling effect that compresses the tunneling barrier into a range much smaller than expected. Whereas the value of the tunneling barrier can be varied by using a different class of molecules (alkanes), using only aromatic structures results in a similar equilibrium value for the tunnel barrier for different structures resulting from partial charge transfer between the molecular layer and the substrate. Thus, the system does not obey the Schottky-Mott limit, and the interaction between the molecular layer and the substrate acts to influence the energy level alignment. These results indicate that the entire system must be considered to determine the impact of a variety of electronic factors that act to determine the tunnel barrier.
    Keywords: Electrochemistry Special Feature
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    Mass transfer and the oxygen reduction reaction [Chemistry] (2012)
    National Academy of Sciences
    Details
    Publication Date: 2012-07-18
    Description: Here we report on the effect of the mass transfer rate (kt) on the oxygen reduction reaction (ORR) catalyzed by Pt dendrimer-encapsulated nanoparticles (DENs) comprised of 147 and 55 atoms (Pt147 and Pt55). The experiments were carried out using a dual-electrode microelectrochemical device, which enables the study of the ORR under high kt conditions with simultaneous detection of H2O2. At low kt (0.02 to 0.12 cm s-1) the effective number of electrons involved in ORR, neff, is 3.7 for Pt147 and 3.4 for Pt55. As kt is increased, the mass-transfer-limited current for the ORR becomes significantly lower than the value predicted by the Levich equation for a 4-electron process regardless of catalyst size. However, the percentage of H2O2 detected remains constant, such that neff barely changes over the entire kt range explored (0.02 cm s-1). This suggests that mass transfer does not affect neff, which has implications for the mechanism of the ORR on Pt nanoparticles. Interestingly, there is a significant difference in neff for the two sizes of Pt DENs (neff = 3.7 and 3.5 for Pt147 and Pt55, respectively) that cannot be assigned to mass transfer effects and that we therefore attribute to a particle size effect.
    Keywords: Electrochemistry Special Feature
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    Biphasic water splitting by osmocene [Chemistry] (2012)
    National Academy of Sciences
    Details
    Publication Date: 2012-07-18
    Description: The photochemical reactivity of osmocene in a biphasic water-organic solvent system has been investigated to probe its water splitting properties. The photoreduction of aqueous protons to hydrogen under anaerobic conditions induced by osmocene dissolved in 1,2-dichloroethane and the subsequent water splitting by the osmocenium metal-metal dimer formed during H2 production were studied by electrochemical methods, UV-visible spectrometry, gas chromatography, and nuclear magnetic resonance spectroscopy. Density functional theory computations were used to validate the reaction pathways.
    Keywords: Electrochemistry Special Feature
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    Cyclin-dependent kinase subunit (Cks) 1 or Cks2 overexpression overrides the DNA damage response barrier triggered by activated oncoproteins [Cell Biology] (2012)
    National Academy of Sciences
    Details
    Publication Date: 2012-02-22
    Description: Cyclin-dependent kinase subunit (Cks) proteins are small cyclin-dependent kinase-interacting proteins that are frequently overexpressed in breast cancer, as well as in a broad spectrum of other human malignancies. However, the mechanistic link between Cks protein overexpression and oncogenesis is still unknown. In this work, we show that overexpression of Cks1 or Cks2 in human mammary epithelial and breast cancer-derived cells, as well as in other cell types, leads to override of the intra–S-phase checkpoint that blocks DNA replication in response to replication stress. Specifically, binding of Cks1 or Cks2 to cyclin-dependent kinase 2 confers partial resistance to the effects of inhibitory tyrosine phosphorylation mediated by the intra–S-phase checkpoint, allowing cells to continue replicating DNA even under conditions of replicative stress. Because many activated oncoproteins trigger a DNA damage checkpoint response, which serves as a barrier to proliferation and clonal expansion, Cks protein overexpression likely constitutes one mechanism whereby premalignant cells can circumvent this DNA damage response barrier, conferring a proliferative advantage under stress conditions, and therefore contributing to tumor development.
    Keywords: Breast Cancer Special Feature
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    Mechanistic insight into Myc stabilization in breast cancer involving aberrant Axin1 expression [Cell Biology] (2012)
    National Academy of Sciences
    Details
    Publication Date: 2012-02-22
    Description: High expression of the oncoprotein Myc has been linked to poor outcome in human tumors. Although MYC gene amplification and translocations have been observed, this can explain Myc overexpression in only a subset of human tumors. Myc expression is in part controlled by its protein stability, which can be regulated by phosphorylation at threonine 58 (T58) and serine 62 (S62). We now report that Myc protein stability is increased in a number of breast cancer cell lines and this correlates with increased phosphorylation at S62 and decreased phosphorylation at T58. Moreover, we find this same shift in phosphorylation in primary breast cancers. The signaling cascade that controls phosphorylation at T58 and S62 is coordinated by the scaffold protein Axin1. We therefore examined Axin1 in breast cancer and report decreased AXIN1 expression and a shift in the ratio of expression of two naturally occurring AXIN1 splice variants. We demonstrate that this contributes to increased Myc protein stability, altered phosphorylation at S62 and T58, and increased oncogenic activity of Myc in breast cancer. Thus, our results reveal an important mode of Myc activation in human breast cancer and a mechanism contributing to Myc deregulation involving unique insight into inactivation of the Axin1 tumor suppressor in breast cancer.
    Keywords: Breast Cancer Special Feature
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    Sensitization of BCL-2-expressing breast tumors to chemotherapy by the BH3 mimetic ABT-737 [Medical Sciences] (2012)
    National Academy of Sciences
    Details
    Publication Date: 2012-02-22
    Description: Overexpression of the prosurvival protein BCL-2 is common in breast cancer. Here we have explored its role as a potential therapeutic target in this disease. BCL-2, its anti-apoptotic relatives MCL-1 and BCL-XL, and the proapoptotic BH3-only ligand BIM were found to be coexpressed at relatively high levels in a substantial proportion of heterogeneous breast tumors, including clinically aggressive basal-like cancers. To determine whether the BH3 mimetic ABT-737 that neutralizes BCL-2, BCL-XL, and BCL-W had potential efficacy in targeting BCL-2–expressing basal-like triple-negative tumors, we generated a panel of primary breast tumor xenografts in immunocompromised mice and treated recipients with either ABT-737, docetaxel, or a combination. Tumor response and overall survival were significantly improved by combination therapy, but only for tumor xenografts that expressed elevated levels of BCL-2. Treatment with ABT-737 alone was ineffective, suggesting that ABT-737 sensitizes the tumor cells to docetaxel. Combination therapy was accompanied by a marked increase in apoptosis and dissociation of BIM from BCL-2. Notably, BH3 mimetics also appeared effective in BCL-2–expressing xenograft lines that harbored p53 mutations. Our findings provide in vivo evidence that BH3 mimetics can be used to sensitize primary breast tumors to chemotherapy and further suggest that elevated BCL-2 expression constitutes a predictive response marker in breast cancer.
    Keywords: Breast Cancer Special Feature
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    Integrated molecular profiles of invasive breast tumors and ductal carcinoma in situ (DCIS) reveal differential vascular and interleukin signaling [Medical Sciences] (2012)
    National Academy of Sciences
    Details
    Publication Date: 2012-02-22
    Description: We use an integrated approach to understand breast cancer heterogeneity by modeling mRNA, copy number alterations, microRNAs, and methylation in a pathway context utilizing the pathway recognition algorithm using data integration on genomic models (PARADIGM). We demonstrate that combining mRNA expression and DNA copy number classified the patients in groups that provide the best predictive value with respect to prognosis and identified key molecular and stromal signatures. A chronic inflammatory signature, which promotes the development and/or progression of various epithelial tumors, is uniformly present in all breast cancers. We further demonstrate that within the adaptive immune lineage, the strongest predictor of good outcome is the acquisition of a gene signature that favors a high T-helper 1 (Th1)/cytotoxic T-lymphocyte response at the expense of Th2-driven humoral immunity. Patients who have breast cancer with a basal HER2-negative molecular profile (PDGM2) are characterized by high expression of protumorigenic Th2/humoral-related genes (24–38%) and a low Th1/Th2 ratio. The luminal molecular subtypes are again differentiated by low or high FOXM1 and ERBB4 signaling. We show that the interleukin signaling profiles observed in invasive cancers are absent or weakly expressed in healthy tissue but already prominent in ductal carcinoma in situ, together with ECM and cell-cell adhesion regulating pathways. The most prominent difference between low and high mammographic density in healthy breast tissue by PARADIGM was that of STAT4 signaling. In conclusion, by means of a pathway-based modeling methodology (PARADIGM) integrating different layers of molecular data from whole-tumor samples, we demonstrate that we can stratify immune signatures that predict patient survival.
    Keywords: Breast Cancer Special Feature
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    Mammary epithelial-specific disruption of c-Src impairs cell cycle progression and tumorigenesis [Medical Sciences] (2012)
    National Academy of Sciences
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    Publication Date: 2012-02-22
    Description: The tyrosine kinase c-Src is activated in a large proportion of breast cancers, in which it is thought to play a key role in promoting the malignant phenotype. c-Src activity is also elevated in transgenic mouse models of breast cancer, including the widely used polyomavirus middle-T antigen (PyVmT) model, which provides an opportunity to study the importance of c-Src in mammary tumorigenesis. However, germline c-Src deletion in mammary epithelial and stromal compartments complicates the interpretation of in vivo tumorigenesis studies as a result of severe defects in mammary gland development. We have therefore engineered a mouse strain in which deletion of c-Src can be targeted to the mammary epithelium. We demonstrate that mammary epithelial disruption of c-Src impairs proliferation and tumor progression driven by PyVmT in vivo. Whereas related kinases substitute for c-Src in PyVmT signaling, c-Src ablation impairs cell cycle progression with decreased cyclin expression and elevated expression of cyclin-dependent kinase inhibitors. Our data indicate that c-Src has essential and unique functions in proliferation and tumor progression in this mouse model that may also be important in certain contexts in some human breast cancers.
    Keywords: Breast Cancer Special Feature
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    Subtype and pathway specific responses to anticancer compounds in breast cancer [Systems Biology] (2012)
    National Academy of Sciences
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    Publication Date: 2012-02-22
    Description: Breast cancers are comprised of molecularly distinct subtypes that may respond differently to pathway-targeted therapies now under development. Collections of breast cancer cell lines mirror many of the molecular subtypes and pathways found in tumors, suggesting that treatment of cell lines with candidate therapeutic compounds can guide identification of associations between molecular subtypes, pathways, and drug response. In a test of 77 therapeutic compounds, nearly all drugs showed differential responses across these cell lines, and approximately one third showed subtype-, pathway-, and/or genomic aberration-specific responses. These observations suggest mechanisms of response and resistance and may inform efforts to develop molecular assays that predict clinical response.
    Keywords: Breast Cancer Special Feature
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    Conservation genomics [Core Concepts] (2014)
    National Academy of Sciences
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    Publication Date: 2014-01-15
    Description: The Tasmanian devil, a carnivorous marsupial that prowls the scrublands of the Australian island of Tasmania at night in search of small prey, is often seen as a face of imminent species extinction. Faced with the threat of wipeout, the devils have dwindled in number since the mid-1990s, when a...
    Keywords: Core Concepts
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    Optogenetics [Core Concepts] (2013)
    National Academy of Sciences
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    Publication Date: 2013-10-09
    Description: By selectively inserting opsins—which react to light—into them, neurons can be activated or inactivated for research purposes. Image courtesy of Inbal Goshen and Karl Deisseroth. A story spanning four decades that began with one the most basic of science questions—how microscopic organisms sense light—has changed the way researchers approach brain...
    Keywords: Core Concepts
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    Progress in breast cancer research [Introductions] (2012)
    National Academy of Sciences
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    Publication Date: 2012-02-22
    Description: Breast cancer is a heterogeneous disease composed of multiple different subtypes with distinct molecular features and clinical behavior (1). Gene expression profiling studies have identified at least four major subtypes classified as luminal A, luminal B, HER2+, and basal-like (2). Genome-wide expression profiling of breast tumors has not entered routine clinical practice, but molecular classification according to immunohistochemical assessment of estrogen and progesterone receptors and of HER2 is the basis of individualized therapy that has been guiding the clinical management of patients with breast cancer for the past two decades. Indeed, the first molecular target for cancer therapy was the...
    Keywords: Breast Cancer Special Feature
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    Transducin-like enhancer protein 1 mediates estrogen receptor binding and transcriptional activity in breast cancer cells [Applied Biological Sciences] (2012)
    National Academy of Sciences
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    Publication Date: 2012-02-22
    Description: Estrogen receptor (ER) binds to distal enhancers within the genome and requires additional factors, such as the Forkhead protein FoxA1, for mediating chromatin interactions. We now show that the human Groucho protein, Transducin-like enhancer protein 1 (TLE1), positively assists some ER-chromatin interactions, a role that is distinct from its general role as a transcriptional repressor. We show that specific silencing of TLE1 inhibits the ability of ER to bind to a subset of ER binding sites within the genome, a phenomenon that results in perturbations in phospho-RNA Pol II recruitment. Furthermore, TLE1 is essential for effective ER-mediated cell division. We have discovered a distinct role for TLE1, as a necessary transcriptional component of the ER complex, where it facilitates ER-chromatin interactions.
    Keywords: Breast Cancer Special Feature
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    Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors [Medical Sciences] (2012)
    National Academy of Sciences
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    Publication Date: 2012-02-22
    Description: We examined the effects of an inhibitor of PI3K, XL147, against human breast cancer cell lines with constitutive PI3K activation. Treatment with XL147 resulted in dose-dependent inhibition of cell growth and levels of pAKT and pS6, signal transducers in the PI3K/AKT/TOR pathway. In HER2-overexpressing cells, inhibition of PI3K was followed by up-regulation of expression and phosphorylation of multiple receptor tyrosine kinases, including HER3. Knockdown of FoxO1 and FoxO3a transcription factors suppressed the induction of HER3, InsR, IGF1R, and FGFR2 mRNAs upon inhibition of PI3K. In HER2+ cells, knockdown of HER3 with siRNA or cotreatment with the HER2 inhibitors trastuzumab or lapatinib enhanced XL147-induced cell death and inhibition of pAKT and pS6. Trastuzumab and lapatinib each synergized with XL147 for inhibition of pAKT and growth of established BT474 xenografts. These data suggest that PI3K antagonists will inhibit AKT and relieve suppression of receptor tyrosine kinase expression and their activity. Relief of this feedback limits the sustained inhibition of the PI3K/AKT pathway and attenuates the response to these agents. As a result, PI3K pathway inhibitors may have limited clinical activity overall if used as single agents. In patients with HER2-overexpressing breast cancer, PI3K inhibitors should be used in combination with HER2/HER3 antagonists.
    Keywords: Breast Cancer Special Feature
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    Genome-wide functional screen identifies a compendium of genes affecting sensitivity to tamoxifen [Medical Sciences] (2012)
    National Academy of Sciences
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    Publication Date: 2012-02-22
    Description: Therapies that target estrogen signaling have made a very considerable contribution to reducing mortality from breast cancer. However, resistance to tamoxifen remains a major clinical problem. Here we have used a genome-wide functional profiling approach to identify multiple genes that confer resistance or sensitivity to tamoxifen. Combining whole-genome shRNA screening with massively parallel sequencing, we have profiled the impact of more than 56,670 RNA interference reagents targeting 16,487 genes on the cellular response to tamoxifen. This screen, along with subsequent validation experiments, identifies a compendium of genes whose silencing causes tamoxifen resistance (including BAP1, CLPP, GPRC5D, NAE1, NF1, NIPBL, NSD1, RAD21, RARG, SMC3, and UBA3) and also a set of genes whose silencing causes sensitivity to this endocrine agent (C10orf72, C15orf55/NUT, EDF1, ING5, KRAS, NOC3L, PPP1R15B, RRAS2, TMPRSS2, and TPM4). Multiple individual genes, including NF1, a regulator of RAS signaling, also correlate with clinical outcome after tamoxifen treatment.
    Keywords: Breast Cancer Special Feature
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    Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia [Medical Sciences] (2012)
    National Academy of Sciences
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    Publication Date: 2012-02-22
    Description: Antiangiogenic therapy has been thought to hold significant potential for the treatment of cancer. However, the efficacy of such treatments, especially in breast cancer patients, has been called into question, as recent clinical trials reveal only limited effectiveness of antiangiogenic agents in prolonging patient survival. New research using preclinical models further suggests that antiangiogenic agents actually increase invasive and metastatic properties of breast cancer cells. We demonstrate that by generating intratumoral hypoxia in human breast cancer xenografts, the antiangiogenic agents sunitinib and bevacizumab increase the population of cancer stem cells. In vitro studies revealed that hypoxia-driven stem/progenitor cell enrichment is primarily mediated by hypoxia-inducible factor 1α. We further show that the Akt/β-catenin cancer stem cell regulatory pathway is activated in breast cancer cells under hypoxic conditions in vitro and in sunitinib-treated mouse xenografts. These studies demonstrate that hypoxia-driven cancer stem cell stimulation limits the effectiveness of antiangiogenic agents, and suggest that to improve patient outcome, these agents might have to be combined with cancer stem cell-targeting drugs.
    Keywords: Breast Cancer Special Feature
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    Defining the cellular precursors to human breast cancer [Medical Sciences] (2012)
    National Academy of Sciences
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    Publication Date: 2012-02-22
    Description: Human breast cancers are broadly classified based on their gene-expression profiles into luminal- and basal-type tumors. These two major tumor subtypes express markers corresponding to the major differentiation states of epithelial cells in the breast: luminal (EpCAM+) and basal/myoepithelial (CD10+). However, there are also rare types of breast cancers, such as metaplastic carcinomas, where tumor cells exhibit features of alternate cell types that no longer resemble breast epithelium. Until now, it has been difficult to identify the cell type(s) in the human breast that gives rise to these various forms of breast cancer. Here we report that transformation of EpCAM+ epithelial cells results in the formation of common forms of human breast cancer, including estrogen receptor-positive and estrogen receptor-negative tumors with luminal and basal-like characteristics, respectively, whereas transformation of CD10+ cells results in the development of rare metaplastic tumors reminiscent of the claudin-low subtype. We also demonstrate the existence of CD10+ breast cells with metaplastic traits that can give rise to skin and epidermal tissues. Furthermore, we show that the development of metaplastic breast cancer is attributable, in part, to the transformation of these metaplastic breast epithelial cells. These findings identify normal cellular precursors to human breast cancers and reveal the existence of a population of cells with epidermal progenitor activity within adult human breast tissues.
    Keywords: Breast Cancer Special Feature
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    Altered antisense-to-sense transcript ratios in breast cancer [Medical Sciences] (2012)
    National Academy of Sciences
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    Publication Date: 2012-02-22
    Description: Transcriptome profiling studies suggest that a large fraction of the genome is transcribed and many transcripts function independent of their protein coding potential. The relevance of noncoding RNAs (ncRNAs) in normal physiological processes and in tumorigenesis is increasingly recognized. Here, we describe consistent and significant differences in the distribution of sense and antisense transcripts between normal and neoplastic breast tissues. Many of the differentially expressed antisense transcripts likely represent long ncRNAs. A subset of genes that mainly generate antisense transcripts in normal but not cancer cells is involved in essential metabolic processes. These findings suggest fundamental differences in global RNA regulation between normal and cancer cells that might play a role in tumorigenesis.
    Keywords: Breast Cancer Special Feature
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    Synthetic biology--change, accelerated [Core Concepts] (2014)
    National Academy of Sciences
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    Publication Date: 2014-12-03
    Description: Dr. Jay Keasling has biologically done what no one has been able to do chemically: cheaply and quickly synthesize an effective malaria medication (1). As part of the 2013 International Genetically Engineered Machine Foundation synthetic biology competition, students were able to reclaim gold from electronic waste with the help of...
    Keywords: Core Concepts
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    Gravitational lensing [Core Concepts] (2013)
    National Academy of Sciences
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    Publication Date: 2013-07-17
    Description: An image from the CFHT Legacy Survey, containing a group of massive galaxies behaving as a gravitational lens. Courtesy of CFHTLS/Terapix/Space Warps. Since Galileo, the arrays of lenses in telescopes have revolutionized the way we see planets, moons, and the universe. Now gravitational lenses made of warped spacetime are helping...
    Keywords: Core Concepts
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    Nonpathogenic prions [Core Concepts] (2013)
    National Academy of Sciences
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    Publication Date: 2013-04-24
    Description: pnas;110/17/6612/UNFIG01F1unfig01The HET-s prion fibril. (The fibril axis is indicated by an arrow.) From ref. 2. Reprinted with permission from AAAS.pnas;110/17/6612/UNFIG02F2unfig02Genetically distinct strains (het-s and het-S) of P. anserina separated by abnormal contact zones called barrages. (Image courtesy of Sven Saupe.)During the early 1980s, the discovery of prions as self-replicating, infectious...
    Keywords: Core Concepts
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    Phylogeography [Core Concepts] (2013)
    National Academy of Sciences
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    Publication Date: 2013-03-13
    Description: pnas;110/11/4158/UNFIG01F1unfig01Kemp’s ridley sea turtle nesting. Image courtesy of the National Park Service.The Kemp’s ridley sea turtle, a small, crab-eating, day-nesting turtle, is currently listed as endangered throughout its range in the western Gulf of Mexico. Its sister species, the olive ridley, nests around the globe, from Brazil to Australia to...
    Keywords: Core Concepts
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    PM 2.5 [Core Concepts] (2013)
    National Academy of Sciences
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    Publication Date: 2013-05-29
    Description: High levels of air pollution in Beijing contain a large quantity of PM 2.5. © iStockPhoto.com/beijingstory. We know that air pollution is bad for your lungs, but some 20 years ago researchers made the surprising and consequential finding that fine-particle pollution can also affect your heart, causing heart attacks and...
    Keywords: Core Concepts
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    Metamaterials [Core Concepts] (2013)
    National Academy of Sciences
    Details
    Publication Date: 2013-05-22
    Description: These metamaterial cloaks can hide objects from bands of microwave radiation. Image courtesy of David Schurig. In the June 2006 issue of Science, two independent teams of physicists simultaneously presented blueprints for an invisibility cloak. One team included David Smith from Duke University and John Pendry from Imperial College London...
    Keywords: Core Concepts
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    Paleobiology [Core Concepts] (2013)
    National Academy of Sciences
    Details
    Publication Date: 2013-06-19
    Description: Childhood field trips to natural history museums were, for many of us, our first brush with the field of paleobiology. Paleobiologists still use many of the tools and methods we associate with the study of ancient animals: exploration, digging, fossil collecting, and microscope work. In recent years, however, the field...
    Keywords: Core Concepts
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    Mirror neurons [Core Concepts] (2014)
    National Academy of Sciences
    Details
    Publication Date: 2014-05-07
    Description: Just over 20 years ago, an Italian team reported findings on macaques showing the existence of a “surprising new class” of neurons in a particular region of the premotor cortex of the macaque brain (1). These neurons were active not only when the macaque performed an action—like grabbing an object—but...
    Keywords: Core Concepts
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    Silicene [Core Concepts] (2014)
    National Academy of Sciences
    Details
    Publication Date: 2014-07-30
    Description: In 2003, physicists from the University of Manchester isolated flakes of graphene, a single layer of carbon atoms arranged in a honeycomb. The researchers described their methods in 2004 (1), and in 2010 they were awarded the Nobel Prize in Physics for discovering the wonder substance. Since then, researchers have...
    Keywords: Core Concepts
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    Epigenetics [Core Concepts] (2013)
    National Academy of Sciences
    Details
    Publication Date: 2013-02-27
    Description: pnas;110/9/3209/UNFIG01F1unfig01This image shows a DNA molecule that is methylated on both strands on the center cytosine. DNA methylation plays an important role for epigenetic gene regulation in development and cancer. Image courtesy Christoph Bock, Max Planck Institute for Informatics.Despite the fact that every cell in a human body contains the...
    Keywords: Core Concepts
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    Brain-machine interface [Core Concepts] (2013)
    National Academy of Sciences
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    Publication Date: 2013-11-13
    Description: Woman with tetraplegia uses a robotic arm to drink coffee from a bottle. Image reprinted by permission from Macmillan Publishers Ltd: Nature (4), copyright 2012. In a world awash in technology, the line between humans and machines has begun to blur, our thoughts and actions increasingly shaped and substantiated by...
    Keywords: Core Concepts
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    Antibody-drug con{jnodot}ugates [Core Concepts] (2013)
    National Academy of Sciences
    Details
    Publication Date: 2013-08-21
    Description: Antibodies (yellow and blue) can be engineered to carry a cytotoxic drug and deposit it in the target cell. © iStockphoto.com/Eraxion. Ideally, targeted therapies attack diseased cells while leaving healthy ones alone. It’s a strategy that could result in more effective treatments for cancer (or other diseases) with fewer toxic...
    Keywords: Core Concepts
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    Connectome [Core Concepts] (2013)
    National Academy of Sciences
    Details
    Publication Date: 2013-04-10
    Description: pnas;110/15/5739/UNFIG01F1unfig01The mind’s tangled web: Electron microscope reconstruction of mouse brain cortex. Image courtesy of D. Berger, N. Kasthuri, H. S. Seung, and J. W. Lichtman (Harvard University and Massachusetts Institute of Technology).Ever since the 19th century Spanish pathologist Santiago Ramón y Cajal etched the first sepia-toned illustrations of stained brain...
    Keywords: Core Concepts
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    Giant magnetoresistance [Core Concepts] (2013)
    National Academy of Sciences
    Details
    Publication Date: 2013-03-06
    Description: pnas;110/10/3710/UNFIG01F1unfig01A read/write head sits above a computer hard disk, manipulating the stored information by the use of giant magnetoresistance.©iStockphoto.com/BrandonSeidelScientists have known for more than 150 years that a magnetic field can change electrical resistance in a material, ever since Scottish physicist William Thomson (Lord Kelvin) first measured the effect in...
    Keywords: Core Concepts
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    Circulating tumor cells [Core Concepts] (2013)
    National Academy of Sciences
    Details
    Publication Date: 2013-03-27
    Description: pnas;110/13/4861/UNFIG01F1unfig01A circulating tumor cell has sloughed off cancerous tissue and moves through the bloodstream to a new site. ©iStockPhoto.com/Eraxion.A typical cancerous tumor contains millions or even billions of cells harboring genetic mutations driving them to grow, divide, and invade the local tissue in which they’re embedded. However, as the cells...
    Keywords: Core Concepts
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    Gnotobiotics [Core Concepts] (2014)
    National Academy of Sciences
    Details
    Publication Date: 2014-02-05
    Description: The average mouse, like the average human, is home to trillions of bacteria and viruses. The average mouse in a gnotobiotic facility, however, hosts zero. No germs live on its skin, in its nostrils, or in its gut. Its food and water—even its bedding—is heated to more than 100 °C...
    Keywords: Core Concepts
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