Magnetic resonance imaging (MRI) is a non-invasive imaging modality used in longitudinal cell tracking. Previous studies suggest that MagA, a putative iron transport protein from magnetotactic ...bacteria, is a useful gene-based magnetic resonance contrast agent. Hemagglutinin-tagged MagA was stably expressed in undifferentiated embryonic mouse teratocarcinoma, multipotent P19 cells to provide a suitable model for tracking these cells during differentiation. Western blot and immunocytochemistry confirmed the expression and membrane localization of MagA in P19 cells. Surprisingly, elemental iron analysis using inductively-coupled plasma mass spectrometry revealed significant iron uptake in both parental and MagA-expressing P19 cells, cultured in the presence of iron-supplemented medium. Withdrawal of this extracellular iron supplement revealed unexpected iron export activity in P19 cells, which MagA expression attenuated. The influence of iron supplementation on parental and MagA-expressing cells was not reflected by longitudinal relaxation rates. Measurement of transverse relaxation rates (R2* and R2) reflected changes in total cellular iron content but did not clearly distinguish MagA-expressing cells from the parental cell type, despite significant differences in the uptake and retention of total cellular iron. Unlike other cell types, the reversible component R2' (R2* ‒ R2) provided only a moderately strong correlation to amount of cellular iron, normalized to amount of protein. This is the first report to characterize MagA expression in a previously unrecognized iron exporting cell type. The interplay between contrast gene expression and systemic iron metabolism substantiates the potential for diverting cellular iron toward the formation of a novel iron compartment, however rudimentary when using a single magnetotactic bacterial gene expression system like magA. Since relatively few mammalian cells export iron, the P19 cell line provides a tractable model of ferroportin activity, suitable for magnetic resonance analysis of key iron-handling activities and their influence on gene-based MRI contrast.
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We previously showed that
mice exhibit a lean phenotype and slower metabolic ageing. Their characteristics include lower plasma glucose and cholesterol, greater glucose tolerance and insulin ...sensitivity, and a reduction in age-related weight gain and whole-body fat deposition. In this paper, nuclear magnetic resonance (NMR) spectroscopy-based metabolite analyses of the urine of
and wild-type mice identified two isomers of 2,3-butanediol as discriminating urinary biomarkers of
mice. Antibiotic-treatment of
mice increased plasma cholesterol concentration and substantially reduced urinary excretion of 2,3-butanediol isomers, indicating that the gut microbiome contributed to the lower plasma cholesterol of
mice, and that 2,3-butanediol is microbially derived. Short- and long-term treatment of wild-type mice with a 2,3-butanediol isomer mix decreased plasma cholesterol and epididymal fat deposition but had no effect on plasma concentrations of glucose or insulin, or on body weight. In the case of long-term treatment, the effects were maintained after withdrawal of 2,3-butanediol. Short-, but not long-term treatment, also decreased plasma concentrations of triglycerides and non-esterified fatty acids. Fecal transplant from
to wild-type mice had no effect on plasma cholesterol, and 2,3-butanediol was not detected in the urine of recipient mice, suggesting that the microbiota of the large intestine was not the source of 2,3-butanediol. However, 2,3-butanediol was detected in the stomach of
mice, which was enriched for
genera, known to produce 2,3-butanediol. Our results indicate a microbial contribution to the phenotypic characteristic of
mice of decreased plasma cholesterol and identify 2,3-butanediol as a potential agent for lowering plasma cholesterol.
Autosomal dominant polycystic kidney disease is the most common hereditary kidney disease. TKV is a promising imaging biomarker for tracking and predicting the natural history of autosomal dominant ...polycystic kidney disease. The prognostic value of TKV was evaluated, in combination with age and eGFR, for the outcomes of 30% decline in eGFR and progression to ESRD. Observational data including 2355 patients with TKV measurements were available.
Multivariable Cox models were developed to assess the prognostic value of age, TKV, height-adjusted TKV, eGFR, sex, race, and genotype for the probability of a 30% decline in eGFR or ESRD.
TKV was the most important prognostic term for 30% decline in eGFR in autosomal dominant polycystic kidney disease patients with and without preserved baseline eGFR. For a 40-year-old subject with preserved eGFR (70 ml/min per 1.73 m
), the adjusted hazard ratios for a 30% decline in eGFR were 1.86 (95% CI, 1.65-2.10) for a 2-fold larger TKV (600 vs. 1200 ml) and 2.68 (95% CI, 2.22-3.24) for a 3-fold larger TKV (600 vs. 1800 ml), respectively. Hazard ratios for progression to ESRD for 2- and 3-fold larger TKV were 1.72 (95% CI, 1.49-1.99) and 2.36 (95% CI, 1.88-2.97), respectively.
The capability to predict 30% decline in eGFR is a novel aspect of this study. TKV was formally qualified, both by FDA and EMA, as a prognostic enrichment biomarker for selecting patients at high risk for a progressive decline in renal function for inclusion in interventional clinical trials.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The fibrillar structure of aqueous methylcellulose (MC) gels was probed using a combination of small-angle neutron scattering (SANS), ultra-small-angle neutron scattering (USANS), and cryogenic ...transmission electron microscopy (cryo-TEM). The effect of molecular weight (M w) and concentration on the gel structure was explored. The fibrillar morphology was consistently observed at elevated temperatures (≥70 °C), independent of concentration and M w. Moreover, the fibril dimensions extracted from SANS by fitting to a scattering function for semiflexible cylinders with disperse radii revealed that the fibril diameter of ca. 14 ± 1 nm is constant for a mass fraction range of 0.01%–3.79% and for all M w investigated (49–530 kg/mol). Comparison of the measured SANS curves with predicted scattering traces revealed that at 70 °C the fibrils contain an average volume fraction of 40% polymer. Taking linear combinations of low temperature (solution state) and high temperature (gel state) SANS traces, the progression of fibril growth with temperature for aqueous MC materials was determined. At low temperatures (≤30 °C) no fibrils are present, whereas in the vicinity of 40–50 °C a small fraction begins to form. For temperatures ≥70 °C, virtually all of the chains are incorporated into the fibrillar structure. The persistence of the fibril structure during cooling was probed by SANS and cryo-TEM. The well-established rheological hysteresis upon cooling is directly correlated to the persistence of the fibril structures. Furthermore, cryo-TEM images taken upon heating to 50 °C showed no fibrils, whereas images for samples that were first heated to 70 °C and then cooled to 50 °C clearly display the fibrillar structure. USANS measurements revealed that heterogeneities in the gels persist beyond the largest length scale accessed in scattering experiments (∼20 μm), consistent with the observed optical turbidity.
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A series of symmetric poly(oligo(ethylene glycol) methyl ether methacrylate-co-oligo(ethylene glycol) propyl sodium sulfonate methacrylate)-block-polystyrene (PsOEGMA-PS) diblock copolymers were ...synthesized as a model system to probe the effect of charge fraction on the phase behavior of charged-neutral single-ion conducting diblock copolymers. Small-angle X-ray scattering (SAXS) experiments showed that increasing the charge fraction does not alter the ordered phase morphology (lamellar) but increases the order–disorder transition temperature (T ODT) significantly. Additionally, the effective Flory–Huggins interaction parameter (χeff) was found to increase linearly with the charge fraction, similar to the case of conventional salt-doped diblock copolymers. This indicates that the effect of counterion solvation, attributed to the significant mismatch between the dielectric constant of each block, provides the dominant effect in tuning the phase behavior of this charged diblock copolymer. We therefore infer that electrostatic cohesion (local charge ordering induced by Coulombic interactions), which is predicted to suppress microphase separation and lead to asymmetric phase diagrams, only plays a minor role in this model system.
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498.
Nanoparticle delivery in infant lungs Semmler-Behnke, Manuela; Kreyling, Wolfgang G; Schulz, Holger ...
Proceedings of the National Academy of Sciences - PNAS,
03/2012, Volume:
109, Issue:
13
Journal Article
Peer reviewed
Open access
The lung surface is an ideal pathway to the bloodstream for nanoparticle-based drug delivery. Thus far, research has focused on the lungs of adults, and little is known about nanoparticle behavior in ...the immature lungs of infants. Here, using nonlinear dynamical systems analysis and in vivo experimentation in developing animals, we show that nanoparticle deposition in postnatally developing lungs peaks at the end of bulk alveolation. This finding suggests a unique paradigm, consistent with the emerging theory that as alveoli form through secondary septation, alveolar flow becomes chaotic and chaotic mixing kicks in, significantly enhancing particle deposition. This finding has significant implications for the application of nanoparticle-based inhalation therapeutics in young children with immature lungs from birth to 2 y of age.
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A Staudinger/aza‐Wittig reaction sequence is described that is catalytic in phosphorus. Towards this end, the phosphane oxide is reduced in situ by diphenylsilane, which allows for substoichiometric ...amounts of the catalyst 5‐phenyldibenzophosphole to be used. The substrate scope is investigated and benzoxazoles, benzodiazepine imidates and a 2‐methoxypyrrole were successfully synthesized. These investigations show that a fast aza‐Wittig reaction is required to obtain high yields.
A catalytic Staudinger/aza‐Wittig reaction sequence, involving in situ phosphane oxide reduction, was successfully developed. Benzoxazoles, benzodiazepine imidates and 2‐methoxypyrrole were synthesized without phosphane oxide waste products.
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In this paper we present a customized finite-difference-time-domain (FDTD) Maxwell solver for the particle-in-cell (PIC) algorithm. The solver is customized to effectively eliminate the numerical ...Cerenkov instability (NCI) which arises when a plasma (neutral or non-neutral) relativistically drifts on a grid when using the PIC algorithm. We control the EM dispersion curve in the direction of the plasma drift of a FDTD Maxwell solver by using a customized higher order finite difference operator for the spatial derivative along the direction of the drift (1ˆ direction). We show that this eliminates the main NCI modes with moderate |k1|, while keeps additional main NCI modes well outside the range of physical interest with higher |k1|. These main NCI modes can be easily filtered out along with first spatial aliasing NCI modes which are also at the edge of the fundamental Brillouin zone. The customized solver has the possible advantage of improved parallel scalability because it can be easily partitioned along 1ˆ which typically has many more cells than other directions for the problems of interest. We show that FFTs can be performed locally to current on each partition to filter out the main and first spatial aliasing NCI modes, and to correct the current so that it satisfies the continuity equation for the customized spatial derivative. This ensures that Gauss’ Law is satisfied. We present simulation examples of one relativistically drifting plasma, of two colliding relativistically drifting plasmas, and of nonlinear laser wakefield acceleration (LWFA) in a Lorentz boosted frame that show no evidence of the NCI can be observed when using this customized Maxwell solver together with its NCI elimination scheme.
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