12 research outputs found

    A Regression-based Approach to Robust Estimation and Inference for Genetic Covariance

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    Genome-wide association studies (GWAS) have identified thousands of genetic variants associated with complex traits, and some variants are shown to be associated with multiple complex traits. Genetic covariance between two traits is defined as the underlying covariance of genetic effects and can be used to measure the shared genetic architecture. The data used to estimate such a genetic covariance can be from the same group or different groups of individuals, and the traits can be of different types or collected based on different study designs. This paper proposes a unified regression-based approach to robust estimation and inference for genetic covariance of general traits that may be associated with genetic variants nonlinearly. The asymptotic properties of the proposed estimator are provided and are shown to be robust under certain model mis-specification. Our method under linear working models provides a robust inference for the narrow-sense genetic covariance, even when both linear models are mis-specified. Numerical experiments are performed to support the theoretical results. Our method is applied to an outbred mice GWAS data set to study the overlapping genetic effects between the behavioral and physiological phenotypes. The real data results reveal interesting genetic covariance among different mice developmental traits.</p

    Orally Administrated Olsalazine-Loaded Multilayer Pectin/Chitosan/Alginate Composite Microspheres for Ulcerative Colitis Treatment

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    The pathogenesis of inflammatory bowel diseases (IBDs) including ulcerative colitis (UC) and Crohn’s disease is extremely cloudy. Maintaining the level of remission lesions in colitis is the default treatment attitude at present. Epithelial barrier restoration is considered as the same important strategy as colonic targeted drug delivery in UC treatment. In this paper, we developed a multilayer natural polysaccharide microsphere (pectin/chitosan/alginate) with pH and enzyme dual sensitivity to reduce the loss of medication in the upper digestive tract and preferentially adhere to exposed epithelial cells in colonic tissues by electrostatic forces for efficiently targeted UC treatment. Olsalazine as an inflammatory drug was efficiently loaded in the chitosan layer and realized a colonic pH-responsive drug release. Furthermore, the multilayer microspheres exhibited excellent capability in suppressing harmful flora and a bio-adhesion effect to extend the duration of local medicine. In the in vivo anti-colitis study, the downregulated levels of pro-inflammatory factors and the increase of tight junction protein indicated the excellent anti-inflammation effect of the olsalazine-loaded microspheres. In summary, these results showed that the multilayer natural polysaccharide microspheres could be a powerful candidate in the targeted drug delivery system for UC therapy

    Additional file 3: of Inducement and identification of chromosome introgression and translocation of Gossypium australe on Gossypium hirsutum

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    The set of SSR markers and their locations on the genome that were used for the identification of G. australe chromatins. Note: One hundred and forty pairs of SSR markers in bold (screened by Chen et al. [5]) and One hundred and five pairs of markers in red (screened in this study) were used while twenty pairs of underlined markers (screened by Chen et al. [5]) were not used due to their low reproducibility. The locations of SSRs on the genome are based on the backbone map of the Dt subgenome of tetraploid cotton constructed using the BC1 population of (G. hirsutum × G. barbadense) × G. hirsutum (Guo et al. 2007). (TIFF 10040 kb

    Improved Charge Transfer in a Mn<sub>2</sub>O<sub>3</sub>@Co<sub>1.2</sub>Ni<sub>1.8</sub>O<sub>4</sub> Hybrid for Highly Stable Alkaline Direct Methanol Fuel Cells with Good Methanol Tolerance

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    A three-dimensional Mn<sub>2</sub>O<sub>3</sub>@Co<sub>1.2</sub>Ni<sub>1.8</sub>O<sub>4</sub> hybrid was synthesized via facile two-step processes and employed as a cathode catalyst in direct methanol fuel cells (DMFCs) for the first time. Because of the unique architecture with ultrathin and porous nanosheets of the Co<sub>1.2</sub>Ni<sub>1.8</sub>O<sub>4</sub> shell, this composite exhibits better electrochemical performance than the pristine Mn<sub>2</sub>O<sub>3</sub>. Remarkably, it shows excellent methanol tolerance, even in a high concentration solution. The DMFC was assembled with Mn<sub>2</sub>O<sub>3</sub>@Co<sub>1.2</sub>Ni<sub>1.8</sub>O<sub>4</sub>, polymer fiber membranes, and PtRu/C as the cathode, membrane, and anode, respectively. The power densities of 57.5 and 70.5 mW cm<sup>–2</sup> were recorded at 18 and 28 °C, respectively, especially the former is the best result reported in the literature at such a low temperature. The stability of the Mn<sub>2</sub>O<sub>3</sub>@Co<sub>1.2</sub>Ni<sub>1.8</sub>O<sub>4</sub> catalyzed cathode was evaluated, and the results show that this compound possesses excellent stability in a high methanol concentration. The improved electrochemical activity could be attributed to the narrow band gap of the hybrid, which accelerates the electrons jumping from the valence band to the conduction band. Therefore, Mn<sup>III</sup> could be oxidized into Mn<sup>IV</sup> more easily, simultaneously providing an electron to the absorbed oxygen

    Experimental setups to measure the cell response in vertical direction. A)

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    <p>AFM: The cantilever is moved up and down with the z-piezo. When the AFM tip touches and indents the cell, the cantilever will bend. The amount of bending is measured via a laser beam that is reflected onto a split photodiode. Its electrical signal is linear proportional with the applied force on the cell. <b>B)</b> Optical trap: A laser beam, emitted from a single mode fibre, is coupled into the optical path of a standard upright microscope via a dichroic mirror and focused into the sample by the objective. The vertical position of the trap is controlled by a z-piezo that moves the objective up and down. The inset figure shows a bead that is trapped in the focus, and pushed into a cell. To monitor the displacement of the bead from the centre of the trap, the laser light is collected by the condenser, coupled out of the optical path via a second dichroic mirror and cast onto a photodiode. Both scale bars are 10 µm.</p

    Cell stretching experiments. A)

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    <p>Beads that got stuck during cell indentation were used as a handle to stretch the cell. The stretching curve (orange) is steeper than the indentation curve. <b>B)</b> The Young’s modulus that is estimated from the stretching experiments is about twice as high (239 Pa) as the modulus we calculated from the indentation experiments (100 Pa).</p

    Sub-micron cell indentation with the optical trap and AFM.

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    <p><b>A)</b> Cell indentation measured with AFM. The force was limited to 140 pN. The indentation (black) and retraction (grey) curves are not identical, but show a considerable amount of hysteresis. <b>B)</b> When the indentation force is limited to 75 pN the difference between the curves is reduced. <b>C)</b> At a force of 25 pN, close to the intrinsic noise of the AFM cantilever, hysteresis between the indentation and retraction curves cannot be clearly distinguished. <b>D)</b> Cell indentation measured with the optical trap. The high force resolution allows the controlled application of forces of less than 10 pN. The indentation (red) and retraction (orange) curves look identical with no obvious hysteresis. <b>E)</b> The relative amount of energy lost between indentation and retraction curves (mean ± s.e.m) was obtained by numerically calculating the area that is enclosed by the indentation and retraction curve, and dividing this by the area under the indentation curve. Only those measurements were analyzed that showed no sticking of the bead to the cell (which is clearly visible as a negative force during retraction). Each point represents measurements on 7 to 15 different cells. Both optical trap (red) and AFM (black) measurements that were performed at forces of up to 30 pN show that less than 15% of the indentation energy is lost. At higher forces this increased to almost 50%. <b>F)</b> The cell indentation was estimated for all indentation curves that were used for E). Data is shown as mean ± s.e.m. Measurements performed at the lowest forces (<30 pN) resulted at indentations of 0.2 µm, which increases to 0.8 µm at 150 pN. The contact point was defined as the position in the indentation curve where the force reaches a value below 0 pN (starting from the maximum force). The error in this method depends on the noise during the force measurement and will lead to an underestimation of the real indentation. Since the force noise in the AFM measurements is larger as compared to optical trapping also the error in the estimated indentation is larger.</p

    Multistep Targeted Nano Drug Delivery System Aiming at Leukemic Stem Cells and Minimal Residual Disease

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    Refractory leukemia remains the most common therapeutic problem in clinical treatment of leukemia. The key therapy of refractory leukemia is to kill, thoroughly, the minimal residual disease and leukemia stem cells in the highly vascularized red marrow areas. In this study, two new conjugates, alendronate-polyethylene glycol (100) monostearate and folate-polyethylene glycol (100) monostearate, were synthesized to develop a multistep targeting nanostructured lipid carriers by enhancing drug transport to the high bone turnover areas adjacent to the red marrow and targeting the minimal residual disease and leukemia stem cells. This dual targeting system demonstrated a great binding affinity to hydroxyapatite, a model component of bone minerals, and higher cell uptake (in the form of carriers but not drug) and cytotoxicity in the K562 cell line, a leukemia cell line with overexpressed folate receptors, were observed <i>in vitro</i> compared to unmodified carriers, especially when the cells were pretreated and the receptors were up-regulated by all-<i>trans</i> retinoic acid. The comodel test of K562 cells and HA showed that this dual targeting system could desorb from bone surface and be taken up by leukemia cells. For the <i>in vivo</i> study, this dual targeting system exhibited a significant increase in plasma half-life and could specifically accumulate in the bone tissue of rats or mice after intravenous injection. <i>Ex vivo</i> imaging of mice femurs and confocal laser scanning microscope imaging of mice femur slices further confirmed that this dual targeting system could favorably deposit to the osteoblast-enriched areas of high bone turnover in regions of trabecular bone surrounded by red marrow. <i>In vivo</i> antitumor activity in K562/BALB/c-nu leukemia mice showed that the treatment of this dual targeting system significantly reduced the white blood cell (WBC) number in peripheral blood and bone marrow to the normal level. In conclusion, this dual targeting system could precisely target to the regions where the minimal residual disease and leukemia stem cells are located and then be specifically uptaken in large amounts, which is a valuable target for refractory leukemia therapy

    Structural transitions and LAMP1 binding of the LASV GP spikes upon acidification.

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    <p>(A) GP structures at different pHs are shown from side (top row) and top (bottom row). All volumes were filtered to 17-Ã… resolution, rendered at molecular threshold corresponding to the expected molecular mass, and colored as in <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1005418#ppat.1005418.g001" target="_blank">Fig 1</a>. Residual density corresponding to LAMP1 is colored in green. Inserts in the lower left corners show a close-up of the interface between two spike monomers. Insets in the top right corners show Western blot analysis of GP1 and GP2 subunits. The arrowheads indicate the missing density in the central top part and side of the pH 3 structure.</p
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