Composites of titanium dioxide (TiO2) and reduced graphene oxide (RGO) have proven to be much more effective photocatalysts than TiO2 alone. However, little attention has been paid so far to the ...chemical structure of TiO2/RGO interfaces and to the role that the unavoidable residual oxygen functional groups of RGO play in the photocatalytic mechanism. In this work, we develop models of TiO2 rutile (110)/RGO interfaces by including a variety of oxygen functional groups known to be present in RGO. Using hybrid density functional theory calculations, we demonstrate that the presence of oxygen functional groups and the formation of interfacial cross-links (Ti–O–C covalent bonds and strong hydrogen bonds between TiO2 and RGO) have a major effect on the electronic properties of RGO and RGO-based composites. The electronic structure changes from semimetallic to semiconducting with an indirect band gap, with the lowest unoccupied band positioned below the TiO2 conduction band and largely localized on RGO oxygen and carbon orbitals, with some contributions of RGO-bonded Ti atoms. We suggest that this RGO-based lowest unoccupied band acts as a photoelectron trap and the indirect nature of the band gap hinders electron–hole recombination. These results can explain the experimentally observed extended lifetimes of photoexcited charge carriers in TiO2/RGO composites and the enhancement of photocatalytic efficiency of these composites.
The hair bundle--the sensory organelle of inner-ear hair cells of vertebrates--exemplifies the ability of a cell to assemble complex, elegant structures. Proper construction of the bundle is required ...for proper mechanotransduction in response to external forces and to transmit information about sound and movement. Bundles contain tightly controlled numbers of actin-filled stereocilia, which are arranged in defined rows of precise heights. Indeed, many deafness mutations that disable hair-cell cytoskeletal proteins also disrupt bundles. Bundle assembly is a tractable problem in molecular and cellular systems biology; the sequence of structural changes in stereocilia is known, and a modest number of proteins may be involved.
Mechanotransduction, the transformation of mechanical force into an electrical signal, allows living organisms to hear, register movement and gravity, detect touch, and sense changes in cell volume ...and shape. Hair cells in the inner ear are specialized mechanoreceptor cells that detect sound and head movement. The mechanotransduction machinery of hair cells is extraordinarily sensitive and responds to minute physical displacements on a submillisecond timescale. The recent discovery of several molecular constituents of the mechanotransduction machinery of hair cells provides a new framework for the interpretation of biophysical data and necessitates revision of prevailing models of mechanotransduction.
Composite systems of TiO2 with nanocarbon materials, such as graphene, graphene oxide, and carbon nanotubes, have proven to be efficient photocatalyst materials. However, a detailed understanding of ...their electronic structure and the mechanisms of the charge transfer processes is still lacking. Here, we use hybrid density functional theory calculations to analyze the electronic properties of the ideal rutile (110)–graphene interface, in order to understand experimentally observed trends in photoinduced charge transfer. We show that the potential energy surface of pristine graphene physisorbed above rutile (110) is relatively flat, enabling many possible positions of graphene above the rutile (110) surface. We verify that tensile and compressive strain has a negligible effect on the electronic properties of graphene at low levels of strain. By analyzing the band structure of this composite material and the composition of the valence and conduction band edges, we show that both the highest occupied states and the lowest unoccupied states of this composite are dominated by graphene, and that there is also a significant contribution of Ti orbitals to the two lowest unoccupied bands. We suggest that a transition from graphene-dominated occupied bands to mixed graphene and TiO2-based unoccupied bands is responsible for the experimentally observed photoinduced charge transfer from graphene to TiO2 under visible light irradiation; however, the most stable state for an excess (e.g., photoexcited) electron is localized on the carbon orbitals, which make up the lowest-energy conduction band. This separation of photogenerated electrons and holes makes TiO2–graphene an efficient photocatalyst material.
The linkage between duplicated chromosomes (sister chromatids) is established during S phase by the action of cohesin, a multisubunit complex conserved from yeast to humans. Most cohesin dissociates ...from chromosome arms when the cell enters mitotic prophase, leading to the formation of metaphase chromosomes with two cytologically discernible chromatids. This process is known as sister-chromatid resolution. Although two mitotic kinases have been implicated in this process, it remains unknown exactly how the cohesin-mediated linkage is destabilized at a mechanistic level.
The wings apart-like (Wapl) protein was originally identified as a gene product that potentially regulates heterochromatin organization in Drosophila melanogaster. We show that the human ortholog of Wapl is a cohesin-binding protein that facilitates cohesin's timely release from chromosome arms during prophase. Depletion of Wapl from HeLa cells causes transient accumulation of prometaphase-like cells with chromosomes that display poorly resolved sister chromatids with a high level of cohesin. Reduction of cohesin relieves the Wapl-depletion phenotype, and depletion of Wapl rescues premature sister separation observed in Sgo1-depleted or Esco2-depleted cells. Conversely, overexpression of Wapl causes premature separation of sister chromatids. Wapl physically associates with cohesin in HeLa-cell nuclear extracts. Remarkably, in vitro reconstitution experiments demonstrate that Wapl forms a stoichiometric, ternary complex with two regulatory subunits of cohesin, implicating its noncatalytic function in inactivating cohesin's ability to interact with chromatin.
Wapl is a new regulator of sister chromatid resolution and promotes release of cohesin from chromosomes by directly interacting with its regulatory subunits.
New treatment options for hearing loss Muller, Ulrich; Barr-Gillespie, Peter G
Nature reviews. Drug discovery,
05/2015, Letnik:
14, Številka:
5
Journal Article
Recenzirano
Hearing loss is the most common form of sensory impairment in humans and affects more than 40 million people in the United States alone. No drug-based therapy has been approved by the Food and Drug ...Administration, and treatment mostly relies on devices such as hearing aids and cochlear implants. Over recent years, more than 100 genetic loci have been linked to hearing loss and many of the affected genes have been identified. This understanding of the genetic pathways that regulate auditory function has revealed new targets for pharmacological treatment of the disease. Moreover, approaches that are based on stem cells and gene therapy, which may have the potential to restore or maintain auditory function, are beginning to emerge.
Key points
Mechanoelectrical transduction at auditory hair cells requires highly specialized stereociliary bundles that project from their apical surface, forming a characteristic graded ‘staircase’ ...structure.
The morphogenesis and maintenance of these stereociliary bundles is a tightly regulated process requiring the involvement of several actin‐binding proteins, many of which are still unidentified.
We identify a new stereociliary protein, the I‐BAR protein BAIAP2L2, which localizes to the tips of the shorter transducing stereocilia in both inner and outer hair cells (IHCs and OHCs).
We find that Baiap2l2 deficient mice lose their second and third rows of stereocilia, their mechanoelectrical transducer current, and develop progressive hearing loss, becoming deaf by 8 months of age.
We demonstrate that BAIAP2L2 localization to stereocilia tips is dependent on the motor protein MYO15A and its cargo EPS8.
We propose that BAIAP2L2 is a new key protein required for the maintenance of the transducing stereocilia in mature cochlear hair cells.
The transduction of sound waves into electrical signals depends upon mechanosensitive stereociliary bundles that project from the apical surface of hair cells within the cochlea. The height and width of these actin‐based stereocilia is tightly regulated throughout life to establish and maintain their characteristic staircase‐like structure, which is essential for normal mechanoelectrical transduction. Here, we show that BAIAP2L2, a member of the I‐BAR protein family, is a newly identified hair bundle protein that is localized to the tips of the shorter rows of transducing stereocilia in mouse cochlear hair cells. BAIAP2L2 was detected by immunohistochemistry from postnatal day 2.5 (P2.5) throughout adulthood. In Baiap2l2 deficient mice, outer hair cells (OHCs), but not inner hair cells (IHCs), began to lose their third row of stereocilia and showed a reduction in the size of the mechanoelectrical transducer current from just after P9. Over the following post‐hearing weeks, the ordered staircase structure of the bundle progressively deteriorates, such that, by 8 months of age, both OHCs and IHCs of Baiap2l2 deficient mice have lost most of the second and third rows of stereocilia and become deaf. We also found that BAIAP2L2 interacts with other key stereociliary proteins involved in normal hair bundle morphogenesis, such as CDC42, RAC1, EPS8 and ESPNL. Furthermore, we show that BAIAP2L2 localization to the stereocilia tips depends on the motor protein MYO15A and its cargo EPS8. We propose that BAIAP2L2 is key to maintenance of the normal actin structure of the transducing stereocilia in mature mouse cochlear hair cells.
Key points
Mechanoelectrical transduction at auditory hair cells requires highly specialized stereociliary bundles that project from their apical surface, forming a characteristic graded ‘staircase’ structure.
The morphogenesis and maintenance of these stereociliary bundles is a tightly regulated process requiring the involvement of several actin‐binding proteins, many of which are still unidentified.
We identify a new stereociliary protein, the I‐BAR protein BAIAP2L2, which localizes to the tips of the shorter transducing stereocilia in both inner and outer hair cells (IHCs and OHCs).
We find that Baiap2l2 deficient mice lose their second and third rows of stereocilia, their mechanoelectrical transducer current, and develop progressive hearing loss, becoming deaf by 8 months of age.
We demonstrate that BAIAP2L2 localization to stereocilia tips is dependent on the motor protein MYO15A and its cargo EPS8.
We propose that BAIAP2L2 is a new key protein required for the maintenance of the transducing stereocilia in mature cochlear hair cells.
Assembly of the hair bundle, the sensory organelle of the inner ear, depends on differential growth of actin-based stereocilia. Separate rows of stereocilia, labeled 1 through 3 from tallest to ...shortest, lengthen or shorten during discrete time intervals during development. We used lattice structured illumination microscopy and surface rendering to measure dimensions of stereocilia from mouse apical inner hair cells during early postnatal development; these measurements revealed a sharp transition at postnatal day 8 between stage III (row 1 and 2 widening; row 2 shortening) and stage IV (final row 1 lengthening and widening). Tip proteins that determine row 1 lengthening did not accumulate simultaneously during stages III and IV; while the actin-bundling protein EPS8 peaked at the end of stage III, GNAI3 peaked several days later-in early stage IV-and GPSM2 peaked near the end of stage IV. To establish the contributions of key macromolecular assemblies to bundle structure, we examined mouse mutants that eliminated tip links (Cdh23v2J or Pcdh15av3J), transduction channels (TmieKO), or the row 1 tip complex (Myo15ash2). Cdh23v2J/v2J and Pcdh15av3J/av3J bundles had adjacent stereocilia in the same row that were not matched in length, revealing that a major role of these cadherins is to synchronize lengths of side-by-side stereocilia. Use of the tip-link mutants also allowed us to distinguish the role of transduction from effects of transduction proteins themselves. While levels of GNAI3 and GPSM2, which stimulate stereocilia elongation, were greatly attenuated at the tips of TmieKO/KO row 1 stereocilia, they accumulated normally in Cdh23v2J/v2J and Pcdh15av3J/av3J stereocilia. These results reinforced the suggestion that the transduction proteins themselves facilitate localization of proteins in the row 1 complex. By contrast, EPS8 concentrates at tips of all TmieKO/KO, Cdh23v2J/v2J, and Pcdh15av3J/av3J stereocilia, correlating with the less polarized distribution of stereocilia lengths in these bundles. These latter results indicated that in wild-type hair cells, the transduction complex prevents accumulation of EPS8 at the tips of shorter stereocilia, causing them to shrink (rows 2 and 3) or disappear (row 4 and microvilli). Reduced rhodamine-actin labeling at row 2 stereocilia tips of tip-link and transduction mutants suggests that transduction's role is to destabilize actin filaments there. These results suggest that regulation of stereocilia length occurs through EPS8 and that CDH23 and PCDH15 regulate stereocilia lengthening beyond their role in gating mechanotransduction channels.
Correct regulation of the replication licensing system ensures that chromosomal DNA is precisely duplicated in each cell division cycle. Licensing proteins are inappropriately expressed at an early ...stage of tumorigenesis in a wide variety of cancers. Here we discuss evidence that misregulation of replication licensing is a consequence of oncogene-induced cell proliferation. This misregulation can cause either under- or over-replication of chromosomal DNA, and could explain the genetic instability commonly seen in cancer cells.
Sound detection by inner ear hair cells requires tip links that interconnect mechanosensory stereocilia and convey force to yet unidentified transduction channels. Current models postulate a static ...composition of the tip link, with protocadherin 15 (PCDH15) at the lower and cadherin 23 (CDH23) at the upper end of the link. In terminally differentiated mammalian auditory hair cells, tip links are subjected to sound-induced forces throughout an organism's life. Although hair cells can regenerate disrupted tip links and restore hearing, the molecular details of this process are unknown. We developed a novel implementation of backscatter electron scanning microscopy to visualize simultaneously immuno-gold particles and stereocilia links, both of only a few nanometers in diameter. We show that functional, mechanotransduction-mediating tip links have at least two molecular compositions, containing either PCDH15/CDH23 or PCDH15/PCDH15. During regeneration, shorter tip links containing nearly equal amounts of PCDH15 at both ends appear first. Whole-cell patch-clamp recordings demonstrate that these transient PCDH15/PCDH15 links mediate mechanotransduction currents of normal amplitude but abnormal Ca(2+)-dependent decay (adaptation). The mature PCDH15/CDH23 tip link composition is re-established later, concomitant with complete recovery of adaptation. Thus, our findings provide a molecular mechanism for regeneration and maintenance of mechanosensory function in postmitotic auditory hair cells and could help identify elusive components of the mechanotransduction machinery.
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