The digital dissector--a study of design issues in educational multimedia

Thesis (M. Eng.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 1994.Includes bibliographical references (leaves 129-130).by Christopher A. Horton.M.Eng

Targeting Toll-Like Receptors for Treatment of SLE

Toll-like receptors (TLRs) are important innate immune receptors for the identification and clearance of invading pathogens. Twelve TLRs that recognize various conserved components of microorganisms are currently known. Among these, the endosomal TLRs 3, 7/8, and 9 recognize dsRNA, ssRNA, and CpG DNA, respectively. Nucleic acid-sensing TLRs, TLR 7 in particular, have been implicated in systemic lupus erythematosus (SLE) and are thought to exacerbate disease pathology. Activation of these TLRs results in the production of inflammatory cytokines and type I interferon. Genome-wide association studies, single nucleotide polymorphism analyses as well as experimental mouse models have provided evidence of TLR signaling involvement in SLE and other autoimmune diseases. Since activation of these receptor pathways promotes autoimmune phenotypes, inhibitory drugs that target these pathways constitute important new therapeutic strategies for the treatment of systemic autoimmunity

Single live-cell imaging for systems biology

Understanding how mammalian cells function requires a dynamic perspective. However, due to the complexity of signalling networks these non-linear systems can easily elude human intuition. The central aim of systems biology is to improve our understanding of the temporal complexity of cell signalling pathways, using a combination of experimental and computational approaches. Live cell imaging and computational modelling are compatible techniques which allow quantitative analysis of cell signalling pathway dynamics. Non-invasive imaging techniques, based on the use of various luciferases and fluorescent proteins, trace cellular events such as gene expression, protein-protein interactions and protein localisation in cells. By employing a number of markers in a single assay, multiple parameters can be measured simultaneously in the same cell. Following acquisition using specialised microscopy, analysis of multi-parameter time-lapse images facilitates the identification of important qualitative and quantitative relationships – linking intracellular signalling, gene expression and cell fate. Improvements in reporter genes coupled with significant advances in detector technologies, are now allowing us to image gene expression non-invasively in individual living cells. These methods are providing remarkable insights into the dynamics of gene expression during complex processes, such as the cell cycle and the responses of cells to hormones, growth factors and nutrients. On a larger scale, dynamics of gene expression may also be monitored in living organisms. This new technology will greatly assist attempts to decipher the complex behaviours exhibited by biological signalling networks, for instance the ability to integrate multiple input signals over time, and generate specific outputs

Application of Transmetalation to the Synthesis of Planar Chiral and Chiral-at-Metal Iridacycles

Diastereoselective lithiation of (S)-2-ferrocenyl-4-(1-methylethyl)oxazoline followed by addition of HgCl2 resulted in the formation by transmetallation of an (S,Sp)-configured mercury substituted complex. Addition to this of [Cp*IrCl2]2 and tetrabutylammonium chloride resulted in a second transmetallation reaction and formation of an (S,Sp,RIr)-configured chloride-substituted half-sandwich iridacycle as exclusively a single diastereoisomer. By reversing the lithiation diastereoselectivity by use of a deuterium blocking group an alternative (S,Rp,SIr)-configured iridacycle was synthesised similarly. Use of (R)-Ugi’s amine as substrate in the lithiation/double transmetallation sequence gave a (R,Sp,SIr)-configured half-sandwich iridacycle, complexes of this type being previously unavailable by direct cycloiridation. Lithium to gold transmetallation was also demonstrated with the synthesis of an (S,Sp)-configured Au(I) ferrocenyloxazoline derivative. Use of the (S,Rp,SIr)-iridacycle as a catalyst for the formation of a chiral product by reductive amination with azeotropic HCO2H/NEt3 resulted in a racemate

Posture-Induced Changes in Distortion-Product Otoacoustic Emissions and the Potential for Noninvasive Monitoring of Changes in Intracranial Pressure

Introduction Intracranial pressure (ICP) monitoring is currently an invasive procedure that requires access to the intracranial space through an opening in the skull. Noninvasive monitoring of ICP via the auditory system is theoretically possible because changes in ICP transfer to the inner ear through connections between the cerebral spinal fluid and the cochlear fluids. In particular, low-frequency distortion-product otoacoustic emissions (DPOAEs), measured noninvasively in the external ear canal, have magnitudes that depend on ICP. Postural changes in healthy humans cause systematic changes in ICP. Here, we quantify the effects of postural changes, and presumably ICP changes, on DPOAE magnitudes. Methods DPOAE magnitudes were measured on seven normal-hearing, healthy subjects at four postural positions on a tilting table (angles 90°, 0°, −30°, and −45° to the horizontal). At these positions, it is expected that ICP varied from about 0 (90°) to 22 mm Hg (−45°). DPOAE magnitudes were measured for a set of frequencies 750\u3cf 2\u3c4000, with f 2/f 1=1.2. Results For the low-frequency range of 750≤f 2≤1500, the differences in DPOAE magnitude between upright and −45° were highly significant (all p\u3c0.01), and above 1500 Hz there were minimal differences between magnitudes at 90° versus −45°. There were no significant differences in the DPOAE magnitudes with subjects at 90° and 0° postures. Conclusions Changes in ICP can be detected using the auditory-based measurement of DPOAEs. In particular, changes are largest at low frequencies. Although this approach does not allow for absolute measurement of ICP, it appears that measurement of DPOAEs may be a useful means of noninvasively monitoring ICP

Posture Systematically Alters Ear-Canal Reflectance and DPOAE Properties

Several studies have demonstrated that the auditory system is sensitive to changes in posture, presumably through changes in intracranial pressure (ICP) that in turn alter the intracochlear pressure, which affects the stiffness of the middle-ear system. This observation has led to efforts to develop an ear-canal based noninvasive diagnostic measure for monitoring ICP, which is currently monitored invasively via access through the skull or spine. Here, we demonstrate the effects of postural changes, and presumably ICP changes, on distortion product otoacoustic emissions (DPOAE) magnitude, DPOAE angle, and power reflectance. Measurements were made on 12 normal-hearing subjects in two postural positions: upright at 90 degrees and tilted at −45 degrees to the horizontal. Measurements on each subject were repeated five times across five separate measurement sessions. All three measures showed significant changes (p \u3c 0.001) between upright and tilted for frequencies between 500 and 2000 Hz, and DPOAE angle changes were significant at all measured frequencies (500–4000 Hz). Intrasubject variability, assessed via standard deviations for each subject’s multiple measurements, were generally smaller in the upright position relative to the tilted position

Highly ordered N-heterocyclic carbene monolayers on Cu(111)

EA and FG acknowledge funding from EPSRC grants (EA: EP/R512199/1; FG: EP/S027270/1). We thank the EaStCHEM for computational support via the EaStCHEM Research Computing facility. CMC thanks the Natural Sciences and Engineering Research Council of Canada (NSERC) and the Canada Foundation for Innovation (CFI) for funding of the work from her lab described in this article. AJV acknowledges NSERC for a Vanier scholarship and the Walter C. Sumner foundation for additional financial support. IS acknowledges Queen’s University for the RT Mohan Scholarship and the Ontario government for an Ontario Graduate Scholarship.The benzannulated N-heterocyclic carbene, 1,3-dibenzylbenzimidazolylidene (NHCDBZ) forms large, highly ordered domains when adsorbed on Cu(111) under ultrahigh vacuum conditions. A combination of scanning tunnelling microscopy (STM), high resolution electron energy loss spectroscopy (HREELS) and density functional theory (DFT) calculations reveals that the overlayer consists of vertical benzannulated NHC moieties coordinating to Cu adatoms. Long range order results from the placement of the two benzyl substituents on opposite sides of the benzimidazole moiety, with their aromatic rings approximately parallel to the surface. The organization of three surface-bound benzyl substituents from three different NHCs into a triangular array controls the formation of a highly ordered Kagome-like surface lattice. By comparison with earlier studies of NHCs on Cu(111), we show that the binding geometry and self-assembly of NHCDBZ are influenced by intermolecular and adsorbate-substrate interactions and facilitated by the flexibility of the methylene linkage between the N-heterocycle and the aromatic wingtip substituents.Publisher PDFPeer reviewe

CD38-driven mitochondrial trafficking promotes bioenergetic plasticity in multiple myeloma

Metabolic adjustments are necessary for the initiation, proliferation, and spread of cancer cells. Although mitochondria have been shown to move to cancer cells from their microenvironment, the metabolic consequences of this phenomenon have yet to be fully elucidated. Here we report that multiple myeloma (MM) cells use mitochondrial-based metabolism as well as glycolysis when located within the bone marrow microenvironment (BMM). The reliance of MM cells on oxidative phosphorylation was caused by intercellular mitochondrial transfer to MM cells from neighboring non-malignant bone marrow stromal cells (BMSC). This mitochondrial transfer occurred through tumor-derived tunneling nanotubes (TNT). Moreover, shRNA mediated knockdown of CD38 inhibits mitochondrial transfer and TNT formation in-vitro and blocks mitochondrial transfer and improves animal survival in vivo. This study describes a potential treatment strategy to inhibit mitochondrial transfer for clinical benefit and scientifically expands the understanding of the functional effects of mitochondrial transfer on tumor metabolism

N-heterocyclic carbenes reduce and functionalize copper oxide surfaces in one pot

The Natural Sciences and Engineering Research Council of Canada (NSERC) and the Canada Foundation for Innovation (CFI) are thanked for financial support of this work in terms of operating and equipment grants to CMC and JHH. AJV and MRN thank the Ontario government for OGS fellowships. AJV thanks NSERC for a Vanier Scholarship and also the Walter C. Sumner foundation for additional scholarship support.Benzimidazolium hydrogen carbonate salts have been shown to act as N-heterocyclic carbene precursors which can remove oxide from copper oxide surfaces and functionalize the resulting metallic surfaces in a single step. Both the surfaces and the etching products are fully characterized by spectroscopic methods. Analysis of surfaces before and after NHC treatment by X-ray photoelectron spectroscopy demonstrates the complete removal of copper(II) oxide. Using 13C-labelling, we determine that the products of this transformation include a cyclic urea, a ring-opened formamide and a bis-carbene copper(I) complex. These results illustrate the potential of NHCs to functionalize a much broader class of metals, including those prone to oxide treatment, greatly facilitating the preparation of NHC-based films on metals other than gold.PostprintPeer reviewe

The Sydney-AAO Multi-object Integral field spectrograph (SAMI)

We demonstrate a novel technology that combines the power of the multi-object spectrograph with the spatial multiplex advantage of an integral field spectrograph (IFS). The Sydney-AAO Multi-object IFS (SAMI) is a prototype wide-field system at the Anglo-Australian Telescope (AAT) that allows 13 imaging fibre bundles ("hexabundles") to be deployed over a 1-degree diameter field of view. Each hexabundle comprises 61 lightly-fused multimode fibres with reduced cladding and yields a 75 percent filling factor. Each fibre core diameter subtends 1.6 arcseconds on the sky and each hexabundle has a field of view of 15 arcseconds diameter. The fibres are fed to the flexible AAOmega double-beam spectrograph, which can be used at a range of spectral resolutions (R=lambda/delta(lambda) ~ 1700-13000) over the optical spectrum (3700-9500A). We present the first spectroscopic results obtained with SAMI for a sample of galaxies at z~0.05. We discuss the prospects of implementing hexabundles at a much higher multiplex over wider fields of view in order to carry out spatially--resolved spectroscopic surveys of 10^4 to 10^5 galaxies.Comment: 24 pages, 16 figures. Accepted by MNRA