578 research outputs found
Principles of Small-Molecule Transport through Synthetic Nanopores
Synthetic nanopores made from DNA replicate the key biological processes of transporting molecular cargo across lipid bilayers. Understanding transport across the confined lumen of the nanopores is of fundamental interest and of relevance to their rational design for biotechnological applications. Here we reveal the transport principles of organic molecules through DNA nanopores by synergistically combining experiments and computer simulations. Using a highly parallel nanostructured platform, we synchronously measure the kinetic flux across hundreds of individual pores to obtain rate constants. The single-channel transport kinetics are close to the theoretical maximum, while selectivity is determined by the interplay of cargo charge and size, the pores' sterics and electrostatics, and the composition of the surrounding lipid bilayer. The narrow distribution of transport rates implies a high structural homogeneity of DNA nanopores. The molecular passageway through the nanopore is elucidated via coarse-grained constant-velocity steered molecular dynamics simulations. The ensemble simulations pinpoint with high resolution and statistical validity the selectivity filter within the channel lumen and determine the energetic factors governing transport. Our findings on these synthetic pores' structure-function relationship will serve to guide their rational engineering to tailor transport selectivity for cell biological research, sensing, and drug delivery
Synthetic protein-conductive membrane nanopores built with DNA
Nanopores are key in portable sequencing and research given their ability to transport
elongated DNA or small bioactive molecules through narrow transmembrane channels.
Transport of folded proteins could lead to similar scientific and technological benefits. Yet
this has not been realised due to the shortage of wide and structurally defined natural pores.
Here we report that a synthetic nanopore designed via DNA nanotechnology can accommodate folded proteins. Transport of fluorescent proteins through single pores is kinetically
analysed using massively parallel optical readout with transparent silicon-on-insulator cavity
chips vs. electrical recordings to reveal an at least 20-fold higher speed for the electrically
driven movement. Pores nevertheless allow a high diffusive flux of more than 66 molecules
per second that can also be directed beyond equillibria. The pores may be exploited to sense
diagnostically relevant proteins with portable analysis technology, to create molecular gates
for drug delivery, or to build synthetic cells
Assessing Retinal Structure In Complete Congenital Stationary Night Blindness and Oguchi Disease
Purpose To examine retinal structure and changes in photoreceptor intensity after dark adaptation in patients with complete congenital stationary night blindness and Oguchi disease. Design Prospective, observational case series. Methods We recruited 3 patients with complete congenital stationary night blindness caused by mutations in GRM6, 2 brothers with Oguchi disease caused by mutations in GRK1, and 1 normal control. Retinal thickness was measured from optical coherence tomography images. Integrity of the rod and cone mosaic was assessed using adaptive optics scanning light ophthalmoscopy. We imaged 5 of the patients after a period of dark adaptation and examined layer reflectivity on optical coherence tomography in a patient with Oguchi disease under light- and dark-adapted conditions. Results Retinal thickness was reduced in the parafoveal region in patients with GRM6 mutations as a result of decreased thickness of the inner retinal layers. All patients had normal photoreceptor density at all locations analyzed. On removal from dark adaptation, the intensity of the rods (but not cones) in the patients with Oguchi disease gradually and significantly increased. In 1 Oguchi disease patient, the outer segment layer contrast on optical coherence tomography was 4-fold higher under dark-adapted versus light-adapted conditions. Conclusions The selective thinning of the inner retinal layers in patients with GRM6 mutations suggests either reduced bipolar or ganglion cell numbers or altered synaptic structure in the inner retina. Our finding that rods, but not cones, change intensity after dark adaptation suggests that fundus changes in Oguchi disease are the result of changes within the rods as opposed to changes at a different retinal locus
The IGF2 intronic miR-483 selectively enhances transcription from IGF2 fetal promoters and enhances tumorigenesis
Insulin-like growth factor 2 (IGF2), a developmentally regulated and maternally imprinted gene, is frequently overexpressed in pediatric cancers. Although loss of imprinting (LOI) at fetal promoters contributes to increased IGF2 in tumors, the magnitude of IGF2 expression suggests the involvement of additional regulatory mechanisms. A microRNA (miRNA) screen of primary Wilms' tumors identified specific overexpression of miR-483-5p, which is embedded within the IGF2 gene. Unexpectedly, the IGF2 mRNA itself is transcriptionally up-regulated by miR-483-5p. A nuclear pool of miR-483-5p binds directly to the 5′ untranslated region (UTR) of fetal IGF2 mRNA, enhancing the association of the RNA helicase DHX9 to the IGF2 transcript and promoting IGF2 transcription. Ectopic expression of miR-483-5p in IGF2-dependent sarcoma cells is correlated with increased tumorigenesis in vivo. Together, these observations suggest a functional positive feedback loop of an intronic miRNA on transcription of its host gene
Thoracic and Lumbar Vertebral Bone Mineral Density Changes in a Natural Occurring Dog Model of Diffuse Idiopathic Skeletal Hyperostosis
Ankylosing spinal disorders can be associated with alterations in vertebral bone mineral density (BMD). There is however controversy about vertebral BMD in patients wuse idiopathic skeletal hyperostosis (DISH). DISH in Boxer dogs has been considered a natural occurring disease model for DISH in people. The purpose of this study was to compare vertebral BMD between Boxers with and without DISH. Fifty-nine Boxers with (n=30) or without (n=29) DISH that underwent computed tomography were included. Vertebral BMD was calculated for each thoracic and lumbar vertebra by using an earlier reported and validated protocol. For each vertebral body, a region of interest was drawn on the axial computed tomographic images at three separate locations: immediately inferior to the superior end plate, in the middle of the vertebral body, and superior to the inferior end plate. Values from the three axial slices were averaged to give a mean Hounsfield Unit value for each vertebral body. Univariate statistical analysis was performed to identify factors to be included in a multivariate model. The multivariate model including all dogs demonstrated that vertebral DISH status (Coefficient 24.63; 95% CI 16.07 to 33.19; p <0.001), lumbar vertebrae (Coefficient -17.25; 95% CI -23.42 to -11.09; p < 0.01), and to a lesser extent higher age (Coefficient -0.56; 95% CI -1.07 to -0.05; p = 0.03) were significant predictors for vertebral BMD. When the multivariate model was repeated using only dogs with DISH, vertebral DISH status (Coefficient 20.67; 95% CI, 10.98 to 30.37; p < 0.001) and lumbar anatomical region (Coefficient -38.24; 95% CI, -47.75 to -28.73; p < 0.001) were again predictors for vertebral BMD but age was not. The results of this study indicate that DISH can be associated with decreased vertebral BMD. Further studies are necessary to evaluate the clinical importance and pathophysiology of this finding
Inhibition of Ubc13-mediated ubiquitination by GPS2 regulates multiple stages of B cell development
Non-proteolytic ubiquitin signaling mediated by Lys63 ubiquitin chains plays a critical role in multiple pathways that are key to the development and activation of immune cells. Our previous work indicates that GPS2 (G-protein Pathway Suppressor 2) is a multifunctional protein regulating TNF signaling and lipid metabolism in the adipose tissue through modulation of Lys63 ubiquitination events. However, the full extent of GPS2-mediated regulation of ubiquitination and the underlying molecular mechanisms are unknown. Here, we report that GPS2 is required for restricting the activation of TLR and BCR signaling pathways and the AKT/FOXO1 pathway in immune cells based on direct inhibition of Ubc13 enzymatic activity. Relevance of this regulatory strategy is confirmed in vivo by B cell-targeted deletion of GPS2, resulting in developmental defects at multiple stages of B cell differentiation. Together, these findings reveal that GPS2 genomic and non-genomic functions are critical for the development and cellular homeostasis of B cells
Superconductivity in Fullerides
Experimental studies of superconductivity properties of fullerides are
briefly reviewed. Theoretical calculations of the electron-phonon coupling, in
particular for the intramolecular phonons, are discussed extensively. The
calculations are compared with coupling constants deduced from a number of
different experimental techniques. It is discussed why the A_3 C_60 are not
Mott-Hubbard insulators, in spite of the large Coulomb interaction. Estimates
of the Coulomb pseudopotential , describing the effect of the Coulomb
repulsion on the superconductivity, as well as possible electronic mechanisms
for the superconductivity are reviewed. The calculation of various properties
within the Migdal-Eliashberg theory and attempts to go beyond this theory are
described.Comment: 33 pages, latex2e, revtex using rmp style, 15 figures, submitted to
Review of Modern Physics, more information at
http://radix2.mpi-stuttgart.mpg.de/fullerene/fullerene.htm
From Compact Plasma Particle Sources to Advanced Accelerators with Modeling at Exascale
Developing complex, reliable advanced accelerators requires a coordinated,
extensible, and comprehensive approach in modeling, from source to the end of
beam lifetime. We present highlights in Exascale Computing to scale accelerator
modeling software to the requirements set for contemporary science drivers. In
particular, we present the first laser-plasma modeling on an exaflop
supercomputer using the US DOE Exascale Computing Project WarpX. Leveraging
developments for Exascale, the new DOE SCIDAC-5 Consortium for Advanced
Modeling of Particle Accelerators (CAMPA) will advance numerical algorithms and
accelerate community modeling codes in a cohesive manner: from beam source,
over energy boost, transport, injection, storage, to application or
interaction. Such start-to-end modeling will enable the exploration of hybrid
accelerators, with conventional and advanced elements, as the next step for
advanced accelerator modeling. Following open community standards, we seed an
open ecosystem of codes that can be readily combined with each other and
machine learning frameworks. These will cover ultrafast to ultraprecise
modeling for future hybrid accelerator design, even enabling virtual test
stands and twins of accelerators that can be used in operations.Comment: 4 pages, 3 figures, submitted to the 20th Advanced Accelerator
Concepts Workshop (AAC22
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