316 research outputs found
Localization of dexamethasone within dendritic core-multishell (CMS) nanoparticles and skin penetration properties studied by multi-frequency electron paramagnetic resonance (EPR) spectroscopy
The skin and especially the stratum corneum (SC) act as a barrier and protect epidermal cells and thus the whole body against xenobiotica of the external environment. Topical skin treatment requires an efficient drug delivery system (DDS). Polymer-based nanocarriers represent novel transport vehicles for dermal application of drugs. In this study dendritic core-multishell (CMS) nanoparticles were investigated as promising candidates. CMS nanoparticles were loaded with a drug (analogue) and were applied to penetration studies of skin. We determined by dual-frequency electron paramagnetic resonance (EPR) how dexamethasone (Dx) labelled with 3-carboxy-2,2,5,5-tetramethyl-1-pyrrolidinyloxy (PCA) is associated with the CMS. The micro-environment of the drug loaded to CMS nanoparticles was investigated by pulsed high-field EPR at cryogenic temperature, making use of the fact that magnetic parameters (g-, A-matrices, and spin-lattice relaxation time) represent specific probes for the micro-environment. Additionally, the rotational correlation time of spin-labelled Dx was probed by continuous wave EPR at ambient temperature, which provides independent information on the drug environment. Furthermore, the penetration depth of Dx into the stratum corneum of porcine skin after different topical applications was investigated. The location of Dx in the CMS nanoparticles is revealed and the function of CMS as penetration enhancers for topical application is shown
A blue light receptor that mediates RNA binding and translational regulation
Sensory photoreceptor proteins underpin light-dependent adaptations in nature and enable the optogenetic control of organismal behavior and physiology. We identified the bacterial light-oxygen-voltage (LOV) photoreceptor PAL that sequence-specifically binds short RNA stem loops with around 20 nM affinity in blue light and weaker than 1 µM in darkness. A crystal structure rationalizes the unusual receptor architecture of PAL with C-terminal LOV photosensor and N-terminal effector units. The light-activated PAL–RNA interaction can be harnessed to regulate gene expression at the RNA level as a function of light in both bacteria and mammalian cells. The present results elucidate a new signal-transduction paradigm in LOV receptors and conjoin RNA biology with optogenetic regulation, thereby paving the way toward hitherto inaccessible optoribogenetic modalities
a FD-FT THz-EPR study
A combined X-band and frequency-domain Fourier-transform THz electron
paramagnetic resonance (FD-FT THz-EPR) approach has been employed to determine
heme Fe(III) S = 5/2 zero-field splitting (ZFS) parameters of frozen metHb and
metMb solutions, both with fluoro and aquo ligands. Frequency-domain EPR
measurements have been carried out by an improved synchrotron-based FD-FT THz-
EPR spectrometer. ZFS has been determined by field dependence of spin
transitions within the mS = ±1/2 manifold, for all four protein systems, and
by zero-field spin transitions between mS = ±1/2 and mS = ±3/2 levels, for
metHb and metMb flouro-states. FD-FT THz-EPR data were simulated with a novel
numerical routine based on Easyspin, which allows now for direct comparison of
EPR spectra in field and frequency domain. We found purely axial ZFSs of D =
5.0(1) cm−1 (flouro-metMb), D = 9.2(4) cm−1 (aquo-metMb), D = 5.1(1) cm−1
(flouro-metHB) and D = 10.4(2) cm−1 (aquo-metHb)
Site-selective measurement of coupled spin pairs in an organic semiconductor
From organic electronics to biological systems, understanding the role of
intermolecular interactions between spin pairs is a key challenge. Here we show
how such pairs can be selectively addressed with combined spin and optical
sensitivity. We demonstrate this for bound pairs of spin-triplet excitations
formed by singlet fission, with direct applicability across a wide range of
synthetic and biological systems. We show that the site-sensitivity of exchange
coupling allows distinct triplet pairs to be resonantly addressed at different
magnetic fields, tuning them between optically bright singlet (S=0) and dark
triplet, quintet (S=1,2) configurations: this induces narrow holes in a broad
optical emission spectrum, uncovering exchange-specific luminescence. Using
fields up to 60 T, we identify three distinct triplet-pair sites, with exchange
couplings varying over an order of magnitude (0.3-5 meV), each with its own
luminescence spectrum, coexisting in a single material. Our results reveal how
site-selectivity can be achieved for organic spin pairs in a broad range of
systems.Comment: 8 pages, article, 7 pages, supporting informatio
Contemporary percutaneous treatment of unprotected left main coronary stenoses: initial results from a multicenter registry analysis 1994-1996.
BACKGROUND: Coronary artery bypass surgery (CABG) has been considered the therapy of choice for patients with unprotected left main (ULMT) coronary stenoses. Selected single-center reports suggest that the results of percutaneous intervention may now approach those of CABG. METHODS AND RESULTS: To assess the results of percutaneous ULMT treatment from a wide variety of experienced interventional centers, we requested data on consecutive patients treated after January 1, 1994, from 25 centers. One hundred seven patients were identified who were treated either electively (n=91) or for acute myocardial infarction (n=16). Of patients treated electively, 25% were considered inoperable, and 27% were considered high risk for bypass surgery. Primary treatment included stents (50%), directional atherectomy (24%), and balloon angioplasty (20%). Follow-up was 98.8% complete at 15+/-8 months. Results varied considerably, depending on presentation and treatment. For patient
crystal and solution structures of the multidomain cochaperone DnaJ
Hsp70 chaperones assist in a large variety of protein-folding processes in the
cell. Crucial for these activities is the regulation of Hsp70 by Hsp40
cochaperones. DnaJ, the bacterial homologue of Hsp40, stimulates ATP
hydrolysis by DnaK (Hsp70) and thus mediates capture of substrate protein, but
is also known to possess chaperone activity of its own. The first structure of
a complete functional dimeric DnaJ was determined and the mobility of its
individual domains in solution was investigated. Crystal structures of the
complete molecular cochaperone DnaJ from Thermus thermophilus comprising the
J, GF and C-terminal domains and of the J and GF domains alone showed an
ordered GF domain interacting with the J domain. Structure-based EPR spin-
labelling studies as well as cross-linking results showed the existence of
multiple states of DnaJ in solution with different arrangements of the various
domains, which has implications for the function of DnaJ.1\. Auflag
2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery: Executive Summary A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the American Association for Thoracic Surgery, Society of Cardiovascular Anesthesiologists, and Society of Thoracic Surgeons
Strongly exchange-coupled triplet pairs in an organic semiconductor
From biological complexes to devices based on organic semiconductors, spin interactions play a key role in the function of molecular systems. For instance, triplet-pair reactions impact operation of organic light-emitting diodes as well as photovoltaic devices. Conventional models for triplet pairs assume they interact only weakly. Here, using electron spin resonance, we observe long-lived, strongly-interacting triplet pairs in an organic semiconductor, generated via singlet fission. Using coherent spin-manipulation of these two-triplet states, we identify exchange-coupled (spin-2) quintet complexes co-existing with weakly coupled (spin-1) triplets. We measure strongly coupled pairs with a lifetime approaching 3 µs and a spin coherence time approaching 1 µs, at 10 K. Our results pave the way for the utilization of high-spin systems in organic semiconductors.Gates-Cambridge Trust, Winton Programme for the Physics of Sustainability, Freie Universität Berlin within the Excellence Initiative of the German Research Foundation, Engineering and Physical Sciences Research Council (Grant ID: EP/G060738/1)This is the author accepted manuscript. The final version is available from Nature Publishing Group at http://dx.doi.org/10.1038/nphys3908
Drug-eluting stents appear superior to bare metal stents for vein-graft PCI in vessels up to a stent diameter of 4 mm.
BACKGROUND: Research trials have shown improved short-term outcome with drug-eluting stents (DES) over bare metal stents (BMS) in saphenous vein graft (SVG) percutaneous coronary intervention (PCI), primarily by reducing target vessel revascularization (TVR) for in-stent restenosis. We compared the outcomes in patients undergoing SVG stent implantation treated with DES or BMS. In exploratory analyses we investigated the influence of stent generation and diameter. METHODS: Data were obtained from a prospective database of 657 patients who underwent PCI for SVG lesions between 2003 and 2011. A total of 344 patients had PCI with BMS and 313 with DES. Propensity scores were developed based on 15 observed baseline covariates in a logistic regression model with stent type as the dependent variable. The nearest-neighbour-matching algorithm with Greedy 5-1 Digit Matching was used to produce two patient cohorts of 313 patients each. We assessed major adverse cardiac events (MACE) out to a median of 3.3 years (interquartile range: 2.1-4.1). MACE was defined as all-cause mortality, myocardial infarction (MI), TVR and stroke. RESULTS: There was a significant difference in MACE between the two groups in favour of DES (17.9% DES vs. 31.2% BMS group; p = 0.0017) over the 5-year follow-up period. MACE was driven by increased TVR in the BMS group. There was no difference in death, MI or stroke. Adjusted Cox analysis confirmed a decreased risk of MACE for DES compared with BMS 0.75 (95% confidence interval (CI) 0.52-0.94), with no difference in the hazard of all-cause mortality (hazard ratio: 1.08; 95% CI: 0.77-1.68). However, when looking at stent diameters greater than 4 mm, no difference was seen in MACE rates between BMS and DES. CONCLUSIONS: Overall in our cohort of patients who had PCI for SVG disease, DES use resulted in lower MACE rates compared with BMS over a 5-year follow-up period; however, for stent diameters over 4 mm no difference in MACE rates was seen
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