The molecular basis for selective inhibition of unconventional mRNA splicing by an IRE1-binding small molecule

IRE1 couples endoplasmic reticulum unfolded protein load to RNA cleavage events that culminate in the sequence-specific splicing of the Xbp1 mRNA and in the regulated degradation of diverse membrane-bound mRNAs. We report on the identification of a small molecule inhibitor that attains its selectivity by forming an unusually stable Schiff base with lysine 907 in the IRE1 endonuclease domain, explained by solvent inaccessibility of the imine bond in the enzyme-inhibitor complex. The inhibitor (abbreviated 4μ8C) blocks substrate access to the active site of IRE1 and selectively inactivates both Xbp1 splicing and IRE1-mediated mRNA degradation. Surprisingly, inhibition of IRE1 endonuclease activity does not sensitize cells to the consequences of acute endoplasmic reticulum stress, but rather interferes with the expansion of secretory capacity. Thus, the chemical reactivity and sterics of a unique residue in the endonuclease active site of IRE1 can be exploited by selective inhibitors to interfere with protein secretion in pathological settings.

Field-effect transistors based on self-organized molecular nanostripes

Charge transport properties in organic semiconductors depend strongly on molecular order. Here we demonstrate field-effect transistors where drain current flows through a precisely defined array of nanostripes made of crystalline and highly ordered molecules. The molecular stripes are fabricated across the channel of the transistor by a stamp-assisted deposition of the molecular semiconductors from a solution. As the solvent evaporates, the capillary forces drive the solution to form menisci under the stamp protrusions. The solute precipitates only in the regions where the solution is confined by the menisci once the critical concentration is reached and self-organizes into molecularly ordered stripes 100-200 nm wide and a few monolayers high. The charge mobility measured along the stripes is 2 orders of magnitude larger than the values measured for spin-coated thin films.

Annealing-free high-mobility diketopyrrolopyrrole-quaterthiophene copolymer for solution-processed organic thin film transistors

A donor-acceptor polymer semiconductor, PDQT, comprising diketopyrrolopyrrole (DPP) and β-unsubstituted quaterthiophene (QT) for organic thin film transistors (OTFTs) is reported. This polymer forms ordered layer-by-layer lamellar packing with an edge-on orientation in thin films even without thermal annealing. The strong intermolecular interactions arising from the fused aromatic DPP moiety and the DPP-QT donor-acceptor interaction facilitate the spontaneous self-assembly of the polymer chains into close proximity and form a large π-π overlap, which are favorable for intermolecular charge hopping. The well-interconnected crystalline grains form efficient intergranular charge transport pathways. The desirable chemical, electronic, and morphological structures of PDQT bring about high hole mobility of up to 0.97 cm2/(V·s) in OTFTs with polymer thin films annealed at a mild temperature of 100 °C and similarly high mobility of 0.89 cm2/(V·s) for polymer thin films even without thermal annealing.

Simultaneous enhancement of brightness, efficiency, and switching in RGB organic light emitting transistors

An innovative design strategy for light emitting field effect transistors (LEFETs) to harvest higher luminance and switching is presented. The strategy uses a non-planar electrode geometry in tri-layer LEFETs for simultaneous enhancement of the key parameters of quantum efficiency, brightness, switching, and mobility across the RGB color gamut.

A high mobility P-type DPP-thieno[3,2-b]thiophene copolymer for organic thin-film transistors

A copolymer comprising 1,4-diketopyrrolo[3,4-c]pyrrole (DPP) and thieno[3,2-b]thiophene moieties, PDBT-co-TT, shows high hole mobility of up to 0.94 cm2 V-1 s-1 in organic thin-film transistors. The strong intermolecular interactions originated from π-π stacking and donor-acceptor interaction lead to the formation of interconnected polymer networks having an ordered lamellar structure, which have established highly efficient pathways for charge carrier transport.

Expression of mammalian glutathione S-transferase 5-5 in Salmonella typhimurium TA1535 leads to base-pair mutations upon exposure to dihalomethanes

Dihalomethanes can produce liver tumors in mice but not in rats, and concern exists about the risk of these compounds to humans. Glutathione (GSH) conjugation of dihalomethanes has been considered to be a critical event in the bioactivation process, and risk assessment is based upon this premise; however, there is little experimental support for this view or information about the basis of genotoxicity. A plasmid vector containing rat GSH S-transferase 5-5 was transfected into the Salmonella typhimurium tester strain TA1535, which then produced active enzyme. The transfected bacteria produced base-pair revertants in the presence of ethylene dihalides or dihalomethanes, in the order CH2Br2 > CH2BrCl > CH2Cl2. However, revertants were not seen when cells were exposed to GSH, CH2Br2, and an amount of purified GSH S-transferase 5-5 (20-fold excess in amount of that expressed within the cells). HCHO, which is an end product of the reaction of GSH with dihalomethanes, also did not produce mutations. S-(1-Acetoxymethyl)GSH was prepared as an analog of the putative S-(1-halomethyl)GSH reactive intermediates. This analog did not produce revertants, consistent with the view that activation of dihalomethanes must occur within the bacteria to cause genetic damage, presenting a model to be considered in studies with mammalian cells. S-(1-Acetoxymethyl)GSH reacted with 2′-deoxyguanosine to yield a major adduct, identified as S-[1-(N2-deoxyguanosinyl)methyl]GSH. Demonstration of the activation of dihalomethanes by this mammalian GSH S-transferase theta class enzyme should be of use in evaluating the risk of these chemicals, particularly in light of reports of the polymorphic expression of a similar activity in humans.

Regioregular poly(3-hexyl-thiophene) helical self-organization on carbon nanotubes

Mixtures of Regioregular Poly(3-hexyl-thiophene) (rrP3HT) and multi wall carbon nanotubes have been investigated by Scanning Tunneling Microscopy in Ultra High Vacuum. Carbon nanotubes covered by rrP3HT have been imaged and analyzed, providing a clear evidence that this polymer self assembles on the nanotube surface following geometrical constraints and adapting its equilibrium chain-to-chain distance. Largely spaced covered nanotubes have been analyzed to investigate the role played by nanotube chirality in the polymer wrapping, evidencing strong rrP3HT interactions along well defined directions.

Primary students’ spatial visualization and spatial orientation : an evidence base for instruction

This paper reports on the performance of 58 11 to 12-year-olds on a spatial visualization task and a spatial orientation task. The students completed these tasks and explained their thinking during individual interviews. The qualitative data were analysed to inform pedagogical content knowledge for spatial activities. The study revealed that “matching” or “matching and eliminating” were the typical strategies that students employed on these spatial tasks. However, errors in making associations between parts of the same or different shapes were noted. Students also experienced general difficulties with visual memory and language use to explain their thinking. The students’ specific difficulties in spatial visualization related to obscured items, the perspective used, and the placement and orientation of shapes.

From resource base to dynamic capabilities : an investigation of new firms

Despite the numerous observations that dynamic capabilities lie at the source of competitive advantage, we still have limited knowledge as to how access to firm-based resources and changes to these affect the development of dynamic capabilities. In this paper, we examine founder human capital, access to employee human capital, access to technological expertise, access to other specific expertise, and access to two types of tangible resources in a sample of new firms in Sweden. We empirically measure four dynamic capabilities and find that the nature and effect of resources employed in the development of these capabilities vary greatly. For the most part, there are positive effects stemming from access to particular resources. However, for some resources, such as access to employee human capital and access to financial capital, unexpected negative effects also appear. This study therefore provides statistical evidence as to the varying role of resources in capability development. Importantly, we also find that changes in resource bases have more influential roles in the development of dynamic capabilities than the resource stock variables that were measured at an earlier stage of firm development. This provides empirical support for the notion of treating the firm as a dynamic flow of resources as opposed to a static stock. This finding also highlights the importance of longitudinal designs in studies of dynamic capability development. Further recommendations for future empirical studies of dynamic capabilities are presented.

PhD forum : multiple camera management using wide base-line matching

Manual calibration of large and dynamic networks of cameras is labour intensive and time consuming. This is a strong motivator for the development of automatic calibration methods. Automatic calibration relies on the ability to find correspondences between multiple views of the same scene. If the cameras are sparsely placed, this can be a very difficult task. This PhD project focuses on the further development of uncalibrated wide baseline matching techniques.

Poly(3-hexyl-thiophene) coil-wrapped single wall carbon nanotube investigated by scanning tunneling spectroscopy

Scanning Tunneling Spectroscopy was performed on a (15,0) single wall carbon nanotube partially wrapped by Poly(3-hexyl-thiophene). On the bare nanotube section, the local density of states is in good agreement with the theoretical model based on local density approximation and remarkably is not perturbed by the polymer wrapping. On the coiled section, a rectifying current-voltage characteristic has been observed along with the charge transfer from the polymer to the nanotube. The electron transfer from Poly(3-hexyl-thiophene) to metallic nanotube was previously theoretically proposed and contributes to the presence of the Schottky barrier at the interface responsible for the rectifying behavior.