Hyaluronic acid enhances the effect of the PAMPS/PDMAAm double-network hydrogel on chondrogenic differentiation of ATDC5 cells

PubMed Central

2014-01-01

Background A double-network (DN) gel, which was composed of poly-(2-Acrylamido-2-methylpropanesulfonic acid) and poly-(N,N’-dimethyl acrylamide) (PAMPS/PDMAAm), has the potential to induce chondrogenesis both in vitro and in vivo. The present study investigated whether DN gel induced chondrogenic differentiation of ATDC5 cells in a maintenance medium without insulin, and whether supplementation of hyaluronic acid enhanced the chondrogenic differentiation effect of DN gel. Methods ATDC5 cells were cultured on the DN gel and the polystyrene (PS) dish in maintenance media without insulin for 21 days. Hyaluronic acid having a molecular weight of approximately 800 kDa was supplemented into the medium so that the concentration became 0.01, 0.1, or 1.0 mg/mL. The cultured cells were evaluated using immunocytochemistry for type-2 collagen and real time PCR for gene expression of type-2 collagen, aggrecan, and Sox9 at 7 and 21 days of culture. Results The cells cultured on the DN gel formed nodules and were stained with an anti-type-2 collagen antibody, and expression of type-2 collagen and aggrecan mRNA was significantly greater on the DN gel than on the PS dish surface (p < 0.05) in the hyaluronic acid-free maintenance medium. Hyaluronic acid supplementation of a high concentration (1.0 mg/mL) significantly enhanced expression of type-2 collagen and aggrecan mRNA in comparison with culture without hyaluronic acid at 21 days (p < 0.05). Conclusions The DN gel induced chondrogenic differentiation of ATDC5 cells without insulin. This effect was significantly affected by hyaluronic acid, depending on the level of concentration. There is a high possibility that hyaluronic acid plays an important role in the in vivo hyaline cartilage regeneration phenomenon induced by the DN gel. PMID:24997593

Hyaluronic acid enhances the effect of the PAMPS/PDMAAm double-network hydrogel on chondrogenic differentiation of ATDC5 cells.

PubMed

Kitamura, Nobuto; Kurokawa, Takayuki; Fukui, Takaaki; Gong, Jian P; Yasuda, Kazunori

2014-07-06

A double-network (DN) gel, which was composed of poly-(2-Acrylamido-2-methylpropanesulfonic acid) and poly-(N,N'-dimethyl acrylamide) (PAMPS/PDMAAm), has the potential to induce chondrogenesis both in vitro and in vivo. The present study investigated whether DN gel induced chondrogenic differentiation of ATDC5 cells in a maintenance medium without insulin, and whether supplementation of hyaluronic acid enhanced the chondrogenic differentiation effect of DN gel. ATDC5 cells were cultured on the DN gel and the polystyrene (PS) dish in maintenance media without insulin for 21 days. Hyaluronic acid having a molecular weight of approximately 800 kDa was supplemented into the medium so that the concentration became 0.01, 0.1, or 1.0 mg/mL. The cultured cells were evaluated using immunocytochemistry for type-2 collagen and real time PCR for gene expression of type-2 collagen, aggrecan, and Sox9 at 7 and 21 days of culture. The cells cultured on the DN gel formed nodules and were stained with an anti-type-2 collagen antibody, and expression of type-2 collagen and aggrecan mRNA was significantly greater on the DN gel than on the PS dish surface (p < 0.05) in the hyaluronic acid-free maintenance medium. Hyaluronic acid supplementation of a high concentration (1.0 mg/mL) significantly enhanced expression of type-2 collagen and aggrecan mRNA in comparison with culture without hyaluronic acid at 21 days (p < 0.05). The DN gel induced chondrogenic differentiation of ATDC5 cells without insulin. This effect was significantly affected by hyaluronic acid, depending on the level of concentration. There is a high possibility that hyaluronic acid plays an important role in the in vivo hyaline cartilage regeneration phenomenon induced by the DN gel.

Depletion of pro-inflammatory CD161(+) double negative (CD3(+)CD4(-)CD8(-)) T cells in AIDS patients is ameliorated by expansion of the γδ T cell population.

PubMed

Singleterry, Will L; Henderson, Harold; Cruse, Julius M

2012-02-01

In this present investigation, flow cytometry was utilized to evaluate 13 healthy controls and 31 HIV-1 infected patients who had advanced to the AIDS stage of infection (CD4 count below 200 cells/mm(3)), for the expression of CD161 on CD3(+) double negative (DN) (CD3(+)CD4(-)CD8(-)) T cells, CD4(+) T cells, CD8(+) T cells and γδ T cells. The observed depletion of CD161(+) T cells from peripheral circulation was due primarily to the loss of CD4(+)CD161(+) T cells; as these cells represented 8.67±0.74% of the total healthy control peripheral T cell population, while the CD4(+)CD161(+) T cells of the AIDS group represented only 3.35±0.41% (p=<0.0001) of the total peripheral T cell population. We have also shown here that the DN T cell population was more than doubled in the AIDS group, with the DN T cell population expanding from 3.29±0.45% of the healthy control peripheral T cell population to 8.64±1.16% (p=0.0001) of the AIDS group peripheral T cell population. By evaluating the expression of CD161 on the surface of the DN T cells we showed that within the healthy control group, 47.4±4.99% of the DN T cells were positive for the expression of CD161, while only 26.4±3.54% (p=0.002) of the AIDS group's DN T cells expressed CD161. Despite CD161 expression being halved on the DN T cells of the AIDS group, when we compared the total peripheral T cell percentage of CD161(+) DN T cells between the healthy control group and the AIDS group, there was no statistical difference. Even though only 26.4% DN T cells within the AIDS group were positive for CD161(+), the overall DN T cell population had expanded to such an extent that there was no statistical difference between the groups with regard to CD161(+) DN T cells as a percentage of the total peripheral T cell population. Furthermore, we showed that within the DN T cell population, there was an approximate 2:1 ratio of γδ to αβ T cells, and this ratio was maintained in both the healthy control group and the AIDS group. While evaluating γδ T cells we also discovered that CD8(+) γδ T cells were expanded from 0.62±.09% of the healthy control peripheral T cell population to 5.01±.88% (p=<0.0001) of the peripheral T cell population of the AIDS group; and that this population of CD8(+) γδ T cells underwent the same reduction in percentage of cells expressing CD161(+), further demonstrated that the phenomenon of CD161(+) percentage reduction and compensatory increase in total cell population was affecting the entire circulating γδ T cell population. Copyright © 2011 Elsevier Inc. All rights reserved.

Internal structure analysis of particle-double network gels used in a gel organ replica

NASA Astrophysics Data System (ADS)

Abe, Mei; Arai, Masanori; Saito, Azusa; Sakai, Kazuyuki; Kawakami, Masaru; Furukawa, Hidemitsu

2016-04-01

In recent years, the fabrication of patient organ replicas using 3D printers has been attracting a great deal of attention in medical fields. However, the cost of these organ replicas is very high as it is necessary to employ very expensive 3D printers and printing materials. Here we present a new gel organ replica, of human kidney, fabricated with a conventional molding technique, using a particle-double network hydrogel (P-DN gel). The replica is transparent and has the feel of a real kidney. It is expected that gel organ replicas produced this way will be a useful tool for the education of trainee surgeons and clinical ultrasonography technologists. In addition to developing a gel organ replica, the internal structure of the P-DN gel used is also discussed. Because the P-DN gel has a complex structure comprised of two different types of network, it has not been possible to investigate them internally in detail. Gels have an inhomogeneous network structure. If it is able to get a more uniform structure, it is considered that this would lead to higher strength in the gel. In the present study we investigate the structure of P-DN gel, using the gel organ replica. We investigated the internal structure of P-DN gel using Scanning Microscopic Light Scattering (SMILS), a non-contacting and non-destructive.

Mechanical and transport properties of the poly(ethylene oxide)-poly(acrylic acid) double network hydrogel from molecular dynamic simulations.

PubMed

Jang, Seung Soon; Goddard, William A; Kalani, M Yashar S

2007-02-22

We used atomistic molecular dynamics (MD) simulations to investigate the mechanical and transport properties of the PEO-PAA double network (DN) hydrogel with 76 wt % water content. By analyzing the pair correlation functions for polymer-water pairs and for ion-water pairs and the solvent accessible surface area, we found that the solvation of polymer and ion in the DN hydrogel is enhanced in comparison with both PEO and PAA single network (SN) hydrogels. The effective mesh size of this DN hydrogel is smaller than that of the SN hydrogels with the same water content and the same molecular weight between the cross-linking points (Mc). Applying uniaxial extensions, we obtained the stress-strain curves for the hydrogels. This shows that the DN hydrogel has a sudden increase of stress above approximately 100% strain, much higher than the sum of the stresses of the two SN hydrogels at the same strain. This arises because PEO has a smaller Mc value than PAA, so that the PEO in the DN reaches fully stretched out at 100% strain that corresponds to 260% strain in the PEO SN (beyond this point, the bond stretching and the angle bending increase dramatically). We also calculated the diffusion coefficients of solutes such as D-glucose and ascorbic acid in the hydrogels, where we find that the diffusion coefficients of those solutes in the DN hydrogel are 60% of that in the PEO SN and 40% of that in the PAA SN due to its smaller effective mesh size.

MTOR ACTIVATION TRIGGERS IL-4 PRODUCTION AND NECROTIC DEATH OF DOUBLE-NEGATIVE T CELLS IN PATIENTS WITH SYSTEMIC LUPUS ERYHTHEMATOSUS

PubMed Central

Lai, Zhi-Wei; Borsuk, Rebecca; Shadakshari, Ashwini; Yu, Jianghong; Dawood, Maha; Garcia, Ricardo; Francis, Lisa; Tily, Hajra; Bartos, Adam; Faraone, Stephen V.; Phillips, Paul; Perl, Andras

2013-01-01

The mechanistic target of rapamycin (mTOR) is recognized as a sensor of mitochondrial dysfunction and effector of T-cell lineage development, however, its role in autoimmunity, including systemic lupus erythematosus, remains unclear. Here, we prospectively evaluated mitochondrial dysfunction and mTOR activation in PBL relative to SLE disease activity index (SLEDAI) during 274 visits of 59 patients and 54 matched healthy subjects. Partial least square-discriminant analysis identified 15 of 212 parameters that accounted for 70.2% of the total variance and discriminated lupus and control samples (p<0.0005); increased mitochondrial mass of CD3+/CD4−/CD8− double-negative (DN) T cells (p=1.1×10−22) and FoxP3 depletion in CD4+/CD25+ T cells were top contributors (p=6.7×10−7). Prominent necrosis and mTOR activation were noted in DN T cells during 15 visits characterized by flares (SLEDAI increase ≥4) relative to 61 visits of remission (SLEDAI decrease ≥4). mTOR activation in DN T cells was also noted at pre-flare visits of SLE patients relative to those of stable disease or healthy controls. DN lupus T cells showed increased production of IL-4, which correlated with depletion of CD25+/CD19+B cells. Rapamycin treatment in vivo blocked the IL-4 production and necrosis of DN T cells, increased the expression of FoxP3 in CD25+/CD4+T cells, and expanded CD25+/CD19+ B cells. These results identify mTOR activation to be a trigger of IL-4 production and necrotic death of DN T cells in patients with SLE. PMID:23913957

Defective thymic progenitor development and mature T-cell responses in a mouse model for Down syndrome

PubMed Central

Lorenzo, Laureanne P E; Shatynski, Kristen E; Clark, Sarah; Yarowsky, Paul J; Williams, Mark S

2013-01-01

In addition to archetypal cognitive defects, Down syndrome (DS) is characterized by altered lymphocyte development and function, including premature thymic involution and increased incidence of infections. However, the potential mechanisms for these changes have not been fully elucidated. The current study used the Ts65Dn mouse model of DS to assess deficiencies in T-cell development and possible molecular alterations. Ts65Dn mice exhibited premature thymic involution and a threefold to fourfold decrease in the number and proportion of immature, double-negative thymocyte progenitors. In addition, there were twofold fewer double-positive and CD4 single-positive thymocytes in Ts65Dn thymuses. Reflecting this deficient thymic function, there were fewer naive T cells in the spleen and polyclonal stimulation of peripheral T cells exhibited a marked reduction in proliferation, suggesting a senescent phenotype. In contrast, B-cell progenitors were unchanged in the bone marrow of Ts65Dn mice, but in the spleen, there were decreased transitional and follicular B cells and these cells proliferated less upon antigen receptor stimulus but not in response to lipopolysaccharide. As a potential mechanism for diminished thymic function, immature thymocyte populations expressed diminished levels of the cytokine receptor interleukin-7Rα, which was associated with decreased proliferation and increased apoptosis. Increased oxidative stress and inhibition of the Notch pathway were identified as possible mediators of decreased interleukin-7Rα expression in Ts65Dn mice. The data suggest that immature thymocyte defects underlie immune dysfunction in DS and that increased oxidative stress and reduced cytokine signalling may alter lymphocyte development in Ts65Dn mice. PMID:23432468

Perturbed thymopoiesis in vitro in the absence of Suppressor of Cytokine Signalling 1 and 3

PubMed Central

Croom, Hayley A.; Izon, David J.; Chong, Mark M.; Curtis, David J.; Roberts, Andrew W.; Kay, Thomas W.H.; Hilton, Douglas J.; Alexander, Warren S.; Starr, Robyn

2014-01-01

Cytokine signals are central to the differentiation of thymocytes and their stepwise progression through defined developmental stages. The intensity and duration of cytokine signals are regulated by the suppressor of cytokine signalling (SOCS) proteins. A clear role for SOCS1 during the later stages of thymopoiesis has been established, but little is known about its role during early thymopoiesis, nor the function of its closest relative, SOCS3. Here, we find that both SOCS1 and SOCS3 are expressed during early thymopoiesis, with expression coincident during the double negative (DN)2 and DN3 stages. We examined thymocyte differentiation in vitro by co-culture of SOCS-deficient bone marrow cells with OP9 cells expressing the Notch ligand Delta-like1 (OP9-DL1). Cells lacking SOCS1 were retarded at the DN3:DN4 transition and appeared unable to differentiate into double positive (DP) thymocytes. Cells lacking both SOCS1 and SOCS3 were more severely affected, and displayed an earlier block in T cell differentiation at DN2, the stage at which expression of SOCS1 and SOCS3 coincides. This indicates that, in addition to their specific roles, SOCS1 and SOCS3 share overlapping roles during thymopoiesis. This is the first demonstration of functional redundancy within the SOCS family, and has uncovered a vital role for SOCS1 and SOCS3 during two important checkpoints in early T cell development. PMID:18321577

A highly stretchable double-network composite.

PubMed

Feng, Xiangchao; Ma, Zhuo; MacArthur, Jonathan V; Giuffre, Christopher J; Bastawros, Ashraf F; Hong, Wei

2016-11-09

Inspired by the toughening mechanism of double-network (DN) hydrogels, a soft composite consisting of a fabric mesh and VHB tape layers was fabricated. The composite was as stiff as the fabric mesh, and as stretchable as the VHB tape. At certain compositions, the composite was significantly stronger and tougher than the base materials. The extensibility and toughness of the composite can be attributed to a damage delocalization mechanism similar to that of the DN gels. In the partially damaged regions, the fabric mesh fragmented into small islands, surrounded by the highly stretched VHB tapes. Accommodated by the finite sliding at the interface, the large deformation of the composite is highly non-affine. Just as the DN gels, the coexistence of the partially damaged and intact regions resulted in a stable necking in the composite when subjected to uniaxial tension. The propagation of the necking zone corresponded to a plateau on the stress-stretch curve. During cyclic loading, the composite also exhibited stress hysteresis with almost recoverable strain, similar to that in a DN gel. To rationalize these observations and to better understand the underlying physical mechanism, a simple 1D model has been developed for the damage evolution process in the composite. The predictions of the model have achieved good agreement with the measured properties of the composite of various compositions. Furthermore, the composite itself may also be regarded as a macroscopic model when studying the properties and toughening mechanism of the DN gels.

Impurity screening behavior of the high-field side scrape-off layer in near-double-null configurations: prospect for mitigating plasma-material interactions on RF actuators and first-wall components

NASA Astrophysics Data System (ADS)

LaBombard, B.; Kuang, A. Q.; Brunner, D.; Faust, I.; Mumgaard, R.; Reinke, M. L.; Terry, J. L.; Howard, N.; Hughes, J. W.; Chilenski, M.; Lin, Y.; Marmar, E.; Rice, J. E.; Rodriguez-Fernandez, P.; Wallace, G.; Whyte, D. G.; Wolfe, S.; Wukitch, S.

2017-07-01

The impurity screening response of the high-field side (HFS) scrape-off layer (SOL) to localized nitrogen injection is investigated on Alcator C-Mod for magnetic equilibria spanning lower-single-null, double-null and upper-single-null configurations under otherwise identical plasma conditions. L-mode, EDA H-mode and I-mode discharges are investigated. HFS impurity screening is found to depend on magnetic flux balance and the direction of B  ×  \

The dependence of divertor power sharing on magnetic flux balance in near double-null configurations on Alcator C-Mod

NASA Astrophysics Data System (ADS)

Brunner, D.; Kuang, A. Q.; LaBombard, B.; Terry, J. L.

2018-07-01

Management of power exhaust will be a crucial task for tokamak fusion reactors. Reactor concepts are often proposed with double-null divertors, i.e. having two magnetic separatrices in an up-down symmetric configuration. This arrangement is potentially advantageous since the majority of the tokamak exhaust power tends to flow to the outer pair of divertor legs at large major radius, where the geometry is favorable for spreading the heat over a large surface area and there is more room for advanced divertor configurations. Despite the importance, there have been relatively few studies of divertor power sharing in near double null configurations and no studies at the poloidal magnetic fields and scrape-off layer power widths anticipated for a reactor. Motivated by this need we have undertaken a systematic study on Alcator C-Mod, examining the effect of magnetic flux balance on the power sharing among the four divertor legs in near double-null plasmas. Ohmic L-modes at three values of plasma current and ICRF-heated enhanced D-alpha (EDA) H-modes and I-modes at a single value of plasma current are explored, producing poloidal magnetic fields of 0.42, 0.62 and 0.85 Tesla. For Ohmic L-modes and ICRF-heated EDA H-modes, we find that the point of equal power sharing between upper and lower divertors occurs remarkably close to a balanced double null. Power sharing amongst the outer (upper versus lower) and inner (upper versus lower) pairs of divertors can be described in terms of a logistic function of magnetic flux balance, consistent with heat flux mapping along magnetic field lines to the outer midplane. Power sharing between inner and outer legs is found to follow a Gaussian-like function of magnetic flux balance with non-zero power to the inner divertors at double null. The overall behavior of H-modes operated near double null and for I-modes operating to within one heat flux e-folding of double null are found similar to Ohmic L-modes, with a significant reduction of power on the inner divertor legs. The results are encapsulated in terms of empirically-informed analytic functions of magnetic flux balance. When combined with magnetic equilibrium control system specifications, these relationships can be used to specify the power flux handling requirements for each of the four divertor target plates.

Lubrication of 35-millimeter-bore ball bearings of several designs to 2.5 million DN

NASA Technical Reports Server (NTRS)

Schuller, F. T.

1983-01-01

Parametric tests were conducted with 35mm bore, angular contact ball bearings with either a single or double outer and guided cage. The bearings were either lubricated by oil jets or employed inner ring lubrication. Outer ring cooling was added in selected tests. Lubricant flow to the bearing ranged from 300 to 1900 cc/min. All bearings were successfully run at speeds to 2.5 million DN. Increasing the lubricant flow decreased bearing ring temperatures but increased bearing power lines. The power loss and race temperatures of a jet lubricated with double outer land guided cage were always higher than those of the single land guided design at similar test conditions. The lowest bearing operating temperatures were achieved when inner ring lubrication and outer ring cooling were combined. It is found that cage slip of a double outer land guided cage is approximately twice that of a single outer land guided cage.

Production of $${\\Sigma (1385)^{\\pm }}$$ and $${\\Xi (1530)^{0}}$$ in p–Pb collisions at $${\\sqrt{s_{\\mathrm{NN}}}= 5.02}$$ TeV

DOE PAGES

Adamová, D.; Aggarwal, M. M.; Aglieri Rinella, G.; ...

2017-06-13

The transverse momentum distributions of the strange and double-strange hyperon resonances (Σ(1385) ±, Ξ(1530) 0) produced in p–Pb collisions at √ sNN = 5.02 TeV were measured in the rapidity range –0.5 < y CMS < 0 for event classes corresponding to different charged-particle multiplicity densities, < dN ch/dη lab >. The mean transverse momentum values are presented as a function of < dN ch/dη lab >, as well as a function of the particle masses and compared with previous results on hyperon production. The integrated yield ratios of excited to ground-state hyperons are constant as a function of . The equivalent ratios to pions exhibit an increase with < dN ch/dη lab >, depending on their strangeness content.« less

Production of $${\\Sigma (1385)^{\\pm }}$$ and $${\\Xi (1530)^{0}}$$ in p–Pb collisions at $${\\sqrt{s_{\\mathrm{NN}}}= 5.02}$$ TeV

DOE Office of Scientific and Technical Information (OSTI.GOV)

Adamová, D.; Aggarwal, M. M.; Aglieri Rinella, G.

The transverse momentum distributions of the strange and double-strange hyperon resonances (Σ(1385) ±, Ξ(1530) 0) produced in p–Pb collisions at √ sNN = 5.02 TeV were measured in the rapidity range –0.5 < y CMS < 0 for event classes corresponding to different charged-particle multiplicity densities, < dN ch/dη lab >. The mean transverse momentum values are presented as a function of < dN ch/dη lab >, as well as a function of the particle masses and compared with previous results on hyperon production. The integrated yield ratios of excited to ground-state hyperons are constant as a function of . The equivalent ratios to pions exhibit an increase with < dN ch/dη lab >, depending on their strangeness content.« less

Protein Tyrosine Phosphatase PRL2 Mediates Notch and Kit Signals in Early T Cell Progenitors.

PubMed

Kobayashi, Michihiro; Nabinger, Sarah C; Bai, Yunpeng; Yoshimoto, Momoko; Gao, Rui; Chen, Sisi; Yao, Chonghua; Dong, Yuanshu; Zhang, Lujuan; Rodriguez, Sonia; Yashiro-Ohtani, Yumi; Pear, Warren S; Carlesso, Nadia; Yoder, Mervin C; Kapur, Reuben; Kaplan, Mark H; Daniel Lacorazza, Hugo; Zhang, Zhong-Yin; Liu, Yan

2017-04-01

The molecular pathways regulating lymphoid priming, fate, and development of multipotent bone marrow hematopoietic stem and progenitor cells (HSPCs) that continuously feed thymic progenitors remain largely unknown. While Notch signal is indispensable for T cell specification and differentiation, the downstream effectors are not well understood. PRL2, a protein tyrosine phosphatase that regulates hematopoietic stem cell proliferation and self-renewal, is highly expressed in murine thymocyte progenitors. Here we demonstrate that protein tyrosine phosphatase PRL2 and receptor tyrosine kinase c-Kit are critical downstream targets and effectors of the canonical Notch/RBPJ pathway in early T cell progenitors. While PRL2 deficiency resulted in moderate defects of thymopoiesis in the steady state, de novo generation of T cells from Prl2 null hematopoietic stem cells was significantly reduced following transplantation. Prl2 null HSPCs also showed impaired T cell differentiation in vitro. We found that Notch/RBPJ signaling upregulated PRL2 as well as c-Kit expression in T cell progenitors. Further, PRL2 sustains Notch-mediated c-Kit expression and enhances stem cell factor/c-Kit signaling in T cell progenitors, promoting effective DN1-DN2 transition. Thus, we have identified a critical role for PRL2 phosphatase in mediating Notch and c-Kit signals in early T cell progenitors. Stem Cells 2017;35:1053-1064. © 2016 AlphaMed Press.

Genetic interaction between two insulin-dependent diabetes susceptibility loci, Idd2 and Idd13, in determining immunoregulatory DN T cell proportion.

PubMed

Collin, Roxanne; Doyon, Kathy; Mullins-Dansereau, Victor; Karam, Martin; Chabot-Roy, Geneviève; Hillhouse, Erin E; Orthwein, Alexandre; Lesage, Sylvie

2018-04-25

Several immune regulatory cell types participate in the protection against autoimmune diseases such as autoimmune diabetes. Of these immunoregulatory cells, we and others have shown that peripheral CD4 - CD8 - double negative (DN) T cells can induce antigen-specific immune tolerance. Particularly, we have described that diabetes-prone mice exhibit a lower number of peripheral DN T cells compared to diabetes-resistant mice. Identifying the molecular pathways that influence the size of the DN T cell pool in peripheral lymphoid organs may thus be of interest for maintaining antigen-specific immune tolerance. Hence, through immunogenetic approaches, we found that two genetic loci linked to autoimmune diabetes susceptibility, namely Idd2 and Idd13, independently contribute to the partial restoration of DN T cell proportion in secondary lymphoid organs. We now extend these findings to show an interaction between the Idd2 and Idd13 loci in determining the number of DN T cells in secondary lymphoid organs. Using bioinformatics tools, we link potential biological pathways arising from interactions of genes encoded within the two loci. By focusing on cell cycle, we validate that both the Idd2 and Idd13 loci influence RAD51 expression as well as DN T cell progression through the cell cycle. Altogether, we find that genetic interactions between Idd2 and Idd13 loci modulate cell cycle progression, which contributes, at least in part, to defining the proportion of DN T cells in secondary lymphoid organs.

Effects of osteochondral defect size on cartilage regeneration using a double-network hydrogel.

PubMed

Higa, Kotaro; Kitamura, Nobuto; Goto, Keiko; Kurokawa, Takayuki; Gong, Jian Ping; Kanaya, Fuminori; Yasuda, Kazunori

2017-05-22

There has been increased interest in one-step cell-free procedures to avoid the problems related to cell manipulation and its inherent disadvantages. We have studied the chondrogenic induction ability of a PAMPS/PDMAAm double-network (DN) gel and found it to induce chondrogenesis in animal osteochondral defect models. The purpose of this study was to investigate whether the healing process and the degree of cartilage regeneration induced by the cell-free method using DN gel are influenced by the size of osteochondral defects. A total of 63 mature female Japanese white rabbits were used in this study, randomly divided into 3 groups of 21 rabbits each. A 2.5-mm diameter osteochondral defect was created in the femoral trochlea of the patellofemoral joint of bilateral knees in Group I, a 4.3-mm osteochondral defect in Group II, and a 5.8-mm osteochondral defect in Group III. In the right knee of each animal, a DN gel plug was implanted so that a vacant space of 2-mm depth was left above the plug. In the left knee, we did not conduct any treatment to obtain control data. Animals were sacrificed at 2, 4, and 12 weeks after surgery, and gross and histological evaluations were made. The present study demonstrated that all sizes of the DN gel implanted defects as well as the 2.5mm untreated defects showed cartilage regeneration at 4 and 12 weeks. The 4.3-mm and 5.8-mm untreated defects did not show cartilage regeneration during the 12-week period. The quantitative score reported by O'Driscoll et al. was significantly higher in the 4.3-mm and 5.8-mm DN gel-implanted defects than the untreated defects at 4 and 12 weeks (p < 0.05). The 2.5-mm and 4.3-mm DN gel implanted defects maintained relatively high macroscopic and histological scores for the 12-week implantation period, while the histological score of the 5.8-mm DN gel implanted defect had decreased somewhat but statistically significantly at 12 weeks (p = 0.0057). The DN gel induced cartilage regeneration in defects between 2.5 and 5.8 mm, offering a promising device to establish a cell-free cartilage regeneration therapy and applicable to various sizes of osteochondral defects.

Differential regulation of proximal and distal Vbeta segments upstream of a functional VDJbeta1 rearrangement upon beta-selection.

PubMed

Brady, Brenna L; Bassing, Craig H

2011-09-15

Developmental stage-specific regulation of transcriptional accessibility helps control V(D)J recombination. Vβ segments on unrearranged TCRβ alleles are accessible in CD4(-)/CD8(-) (double-negative [DN]) thymocytes, when they recombine, and inaccessible in CD4(+)/CD8(+) (double-positive [DP]) thymocytes, when they do not rearrange. Downregulation of Vβ accessibility on unrearranged alleles is linked with Lat-dependent β-selection signals that inhibit Vβ rearrangement, stimulate Ccnd3-driven proliferation, and promote DN-to-DP differentiation. Transcription and recombination of Vβs on VDJβ-rearranged alleles in DN cells has not been studied; Vβs upstream of functional VDJβ rearrangements have been found to remain accessible, yet not recombine, in DP cells. To elucidate contributions of β-selection signals in regulating Vβ transcription and recombination on VDJβ-rearranged alleles, we analyzed wild-type, Ccnd3(-/-), and Lat(-/-) mice containing a preassembled functional Vβ1DJCβ1 (Vβ1(NT)) gene. Vβ10 segments located just upstream of this VDJCβ1 gene were the predominant germline Vβs that rearranged in Vβ1(NT/NT) and Vβ1(NT/NT)Ccnd3(-/-) thymocytes, whereas Vβ4 and Vβ16 segments located further upstream rearranged at similar levels as Vβ10 in Vβ1(NT/NT)Lat(-/-) DN cells. We previously showed that Vβ4 and Vβ16, but not Vβ10, are transcribed on Vβ1(NT) alleles in DP thymocytes; we now demonstrate that Vβ4, Vβ16, and Vβ10 are transcribed at similar levels in Vβ1(NT/NT)Lat(-/-) DN cells. These observations indicate that suppression of Vβ rearrangements is not dependent on Ccnd3-driven proliferation, and DN residence can influence the repertoire of Vβs that recombine on alleles containing an assembled VDJCβ1 gene. Our findings also reveal that β-selection can differentially silence rearrangement of germline Vβ segments located proximal and distal to functional VDJβ genes.

Absence of Wip1 partially rescues Atm deficiency phenotypes in mice

PubMed Central

Darlington, Yolanda; Nguyen, Thuy-Ai; Moon, Sung-Hwan; Herron, Alan; Rao, Pulivarthi; Zhu, Chengming; Lu, Xiongbin; Donehower, Lawrence A.

2011-01-01

Wildtype p53-Induced Phosphatase 1 (WIP1) is a serine/threonine phosphatase that dephosphorylates proteins in the ataxia telangiectasia mutated (ATM)-initiated DNA damage response pathway. WIP1 may play a homeostatic role in ATM signaling by returning the cell to a normal pre-stress state following completion of DNA repair. To better understand the effects of WIP1 on ATM signaling, we crossed Atm-deficient mice to Wip1-deficient mice and characterized phenotypes of the double knockout progeny. We hypothesized that the absence of Wip1 might rescue Atm deficiency phenotypes. Atm null mice, like ATM-deficient humans with the inherited syndrome ataxia telangiectasia, exhibit radiation sensitivity, fertility defects, and are T-cell lymphoma prone. Most double knockout mice were largely protected from lymphoma development and had a greatly extended lifespan compared to Atm null mice. Double knockout mice had increased p53 and H2AX phosphorylation and p21 expression compared to their Atm null counterparts, indicating enhanced p53 and DNA damage responses. Additionally, double knockout splenocytes displayed reduced chromosomal instability compared to Atm null mice. Finally, doubly null mice were partially rescued from infertility defects observed in Atm null mice. These results indicate that inhibition of WIP1 may represent a useful strategy for cancer treatment in general and A-T patients in particular. PMID:21765465

Significant role of Fas ligand-binding but defective Fas receptor (CD95) in lymph node hyperplasia composed of abnormal double-negative T cells

PubMed Central

Matsuzawa, Akio; Shimizu, Motomu; Takeda, Yasutaka; Nagase, Hisashi; Sayama, Kazutoshi; Kimura, Mikio

2002-01-01

The functional differences between two mutations of the Fas (CD95) locus, Faslpr (lpr) and Faslprcg (lprcg), were investigated using bone marrow (BM) transplantation on the C3H mouse background. Both lpr/lpr and lprcg/lprcg BM transferred caused lymph node (LN) hyperplasia in lpr/+ and lprcg/+ recipients, although it was clearly smaller than that in lpr/lpr and lprcg/lprcg recipients of lpr/lpr and lprcg/lprcg BM. In addition, both BM induced significantly larger LN hyperplasia in lprcg/+ than lpr/+ recipients. Appearance of CD4− CD8−[double negative (DN)] T cells in the periphery is the most consistent phenotype of Fas mutations. Importantly, the proportion of DN T cells was higher in larger LN hyperplasia in the order of lpr/+, lprcg/+ and lpr/lpr or lprcg/lprcg recipients. On the other hand, both lpr/lpr and lprcg/lprcg BM transferred into wild-type (+/+) mice caused marked LN atrophy. The former, but not the latter, induced wasting syndrome. Faslg1d (gld)-homozygous lpr/lpr BM transferred into +/+ mice elicited LN hyperplasia of the same extent as that in lpr/lpr mice transferred with lpr/lpr BM, but not wasting syndrome. Taken together with the fact that DN T cells massively express Fas ligand (FasL), this study implied that FasL overexpressed on DN cells may be involved in the accumulation of DN T cells in LN, LN atrophy and wasting syndrome, and that lprcg Fas, which can bind to Fas ligand but not transduce apoptosis signal into cells, may modulate these pathological conditions by interfering with the binding of FasL to Fas. PMID:12153509

Notch ligands Delta1 and Jagged1 transmit distinct signals to T-cell precursors

PubMed Central

Lehar, Sophie M.; Dooley, James; Farr, Andrew G.; Bevan, Michael J.

2009-01-01

Signaling through the Notch pathway plays an essential role in inducing T-lineage commitment and promoting the maturation of immature thymocytes. Using an in vitro culture system, we show that 2 different classes of Notch ligands, Jagged1 or Delta1, transmit distinct signals to T-cell progenitors. OP9 stromal cells expressing either Jagged1 or Delta1 inhibit the differentiation of DN1 thymocytes into the B-cell lineage, but only the Delta1-expressing stromal cells promote the proliferation and maturation of T-cell progenitors through the early double-negative (DN) stages of thymocyte development. Whereas the majority of bone marrow-derived stem cells do not respond to Jagged1 signals, T-cell progenitors respond to Jagged1 signals during a brief window of their development between the DN1 and DN3 stages of thymic development. During these stages, Jagged1 signals can influence the differentiation of immature thymocytes along the natural killer (NK) and γδ T-cell lineages. PMID:15486060

Blocking of CD1d Decreases Trypanosoma cruzi-Induced Activation of CD4-CD8- T Cells and Modulates the Inflammatory Response in Patients With Chagas Heart Disease.

PubMed

Passos, Lívia Silva Araújo; Villani, Fernanda Nobre Amaral; Magalhães, Luísa Mourão Dias; Gollob, Kenneth J; Antonelli, Lis Ribeiro do Vale; Nunes, Maria Carmo Pereira; Dutra, Walderez Ornelas

2016-09-15

The control of inflammatory responses to prevent the deadly cardiac pathology in human Chagas disease is a desirable and currently unattained goal. Double-negative (DN) T cells are important sources of inflammatory and antiinflammatory cytokines in patients with Chagas heart disease and those with the indeterminate clinical form of Chagas disease, respectively. Given the importance of DN T cells in immunoregulatory processes and their potential as targets for controlling inflammation-induced pathology, we studied the involvement of CD1 molecules in the activation and functional profile of Trypanosoma cruzi-specific DN T cells. We observed that parasite stimulation significantly increased the expression of CD1a, CD1b, CD1c, and CD1d by CD14(+) cells from patients with Chagas disease. Importantly, among the analyzed molecules, only CD1d expression showed an association with the activation of DN T cells, as well as with worse ventricular function in patients with Chagas disease. Blocking of CD1d-mediated antigen presentation led to a clear reduction of DN T-cell activation and a decrease in the expression of interferon γ (IFN-γ) by DN T cells. Thus, our results showed that antigen presentation via CD1d is associated with activation of DN T cells in Chagas disease and that CD1d blocking leads to downregulation of IFN-γ by DN T cells from patients with Chagas heart disease, which may be a potential target for preventing progression of inflammation-mediated dilated cardiomyopathy. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

The expression of dominant negative TCF7L2 in pancreatic beta cells during the embryonic stage causes impaired glucose homeostasis.

PubMed

Shao, Weijuan; Xiong, Xiaoquan; Ip, Wilfred; Xu, Fenghao; Song, Zhuolun; Zeng, Kejing; Hernandez, Marcela; Liang, Tao; Weng, Jianping; Gaisano, Herbert; Nostro, M Cristina; Jin, Tianru

2015-04-01

Disruption of TCF7L2 in mouse pancreatic β-cells has generated different outcomes in several investigations. Here we aim to clarify role of β-cell TCF7L2 and Wnt signaling using a functional-knockdown approach. Adenovirus-mediated dominant negative TCF7L2 (TCF7L2DN) expression was conducted in Ins-1 cells. The fusion gene in which TCF7L2DN expression is driven by P TRE3G was utilized to generate the transgenic mouse line TCF7L2DN Tet . The double transgenic line was created by mating TCF7L2DN Tet with Ins2-rtTA, designated as βTCFDN. β-cell specific TCF7L2DN expression was induced in βTCFDN by doxycycline feeding. TCF7L2DN expression in Ins-1 cells reduced GSIS, cell proliferation and expression of a battery of genes including incretin receptors and β-cell transcription factors. Inducing TCF7L2DN expression in βTCFDN during adulthood or immediately after weaning generated no or very modest metabolic defect, while its expression during embryonic development by doxycycline feeding in pregnant mothers resulted in significant glucose intolerance associated with altered β-cell gene expression and reduced β-cell mass. Our observations support a cell autonomous role for TCF7L2 in pancreatic β-cells suggested by most, though not all, investigations. βTCFDN is a novel model for further exploring the role of TCF7L2 in β-cell genesis and metabolic homeostasis.

Renal calcinosis and stone formation in mice lacking osteopontin, Tamm-Horsfall protein, or both.

PubMed

Mo, Lan; Liaw, Lucy; Evan, Andrew P; Sommer, Andre J; Lieske, John C; Wu, Xue-Ru

2007-12-01

Although often supersaturated with mineral salts such as calcium phosphate and calcium oxalate, normal urine possesses an innate ability to keep them from forming harmful crystals. This inhibitory activity has been attributed to the presence of urinary macromolecules, although controversies abound regarding their role, or lack thereof, in preventing renal mineralization. Here, we show that 10% of the mice lacking osteopontin (OPN) and 14.3% of the mice lacking Tamm-Horsfall protein (THP) spontaneously form interstitial deposits of calcium phosphate within the renal papillae, events never seen in wild-type mice. Lack of both proteins causes renal crystallization in 39.3% of the double-null mice. Urinalysis revealed elevated concentrations of urine phosphorus and brushite (calcium phosphate) supersaturation in THP-null and OPN/THP-double null mice, suggesting that impaired phosphorus handling may be linked to interstitial papillary calcinosis in THP- but not in OPN-null mice. In contrast, experimentally induced hyperoxaluria provokes widespread intratubular calcium oxalate crystallization and stone formation in OPN/THP-double null mice, while completely sparing the wild-type controls. Whole urine from OPN-, THP-, or double-null mice all possessed a dramatically reduced ability to inhibit the adhesion of calcium oxalate monohydrate crystals to renal epithelial cells. These data establish OPN and THP as powerful and functionally synergistic inhibitors of calcium phosphate and calcium oxalate crystallization in vivo and suggest that defects in either molecule may contribute to renal calcinosis and stone formation, an exceedingly common condition that afflicts up to 12% males and 5% females.

From GLC to double-null coordinates and illustration with static black holes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nugier, Fabien, E-mail: fnugier@ntu.edu.tw

We present a system of coordinates deriving directly from the so-called Geodesic Light-Cone (GLC) coordinates and made of two null scalars intersecting on a 2-dimensional sphere parameterized by two constant angles along geodesics. These coordinates are shown to be equivalent to the well-known double-null coordinates. As GLC, they present interesting properties for cosmology and astrophysics. We discuss this latter topic for static black holes, showing simple descriptions for the metric or particles and photons trajectories. We also briefly comment on the time of flight of ultra-relativistic particles.

Highly Stretchable and Transparent Thermistor Based on Self-Healing Double Network Hydrogel.

PubMed

Wu, Jin; Han, Songjia; Yang, Tengzhou; Li, Zhong; Wu, Zixuan; Gui, Xuchun; Tao, Kai; Miao, Jianmin; Norford, Leslie K; Liu, Chuan; Huo, Fengwei

2018-06-06

An ultrastretchable thermistor that combines intrinsic stretchability, thermal sensitivity, transparency, and self-healing capability is fabricated. It is found the polyacrylamide/carrageenan double network (DN) hydrogel is highly sensitive to temperature and therefore can be exploited as a novel channel material for a thermistor. This thermistor can be stretched from 0 to 330% strain with the sensitivity as high as 2.6%/°C at extreme 200% strain. Noticeably, the mechanical, electrical, and thermal sensing properties of the DN hydrogel can be self-healed, analogous to the self-healing capability of human skin. The large mechanical deformations, such as flexion and twist with large angles, do not affect the thermal sensitivity. Good flexibility enables the thermistor to be attached on nonplanar curvilinear surfaces for practical temperature detection. Remarkably, the thermal sensitivity can be improved by introducing mechanical strain, making the sensitivity programmable. This thermistor with tunable sensitivity is advantageous over traditional rigid thermistors that lack flexibility in adjusting their sensitivity. In addition to superior sensitivity and stretchability compared with traditional thermistors, this DN hydrogel-based thermistor provides additional advantages of good transparency and self-healing ability, enabling it to be potentially integrated in soft robots to grasp real world information for guiding their actions.

The Arabidopsis Rho of Plants GTPase AtROP6 Functions in Developmental and Pathogen Response Pathways1[C][W][OA

PubMed Central

Poraty-Gavra, Limor; Zimmermann, Philip; Haigis, Sabine; Bednarek, Paweł; Hazak, Ora; Stelmakh, Oksana Rogovoy; Sadot, Einat; Schulze-Lefert, Paul; Gruissem, Wilhelm; Yalovsky, Shaul

2013-01-01

How plants coordinate developmental processes and environmental stress responses is a pressing question. Here, we show that Arabidopsis (Arabidopsis thaliana) Rho of Plants6 (AtROP6) integrates developmental and pathogen response signaling. AtROP6 expression is induced by auxin and detected in the root meristem, lateral root initials, and leaf hydathodes. Plants expressing a dominant negative AtROP6 (rop6DN) under the regulation of its endogenous promoter are small and have multiple inflorescence stems, twisted leaves, deformed leaf epidermis pavement cells, and differentially organized cytoskeleton. Microarray analyses of rop6DN plants revealed that major changes in gene expression are associated with constitutive salicylic acid (SA)-mediated defense responses. In agreement, their free and total SA levels resembled those of wild-type plants inoculated with a virulent powdery mildew pathogen. The constitutive SA-associated response in rop6DN was suppressed in mutant backgrounds defective in SA signaling (nonexpresser of PR genes1 [npr1]) or biosynthesis (salicylic acid induction deficient2 [sid2]). However, the rop6DN npr1 and rop6DN sid2 double mutants retained the aberrant developmental phenotypes, indicating that the constitutive SA response can be uncoupled from ROP function(s) in development. rop6DN plants exhibited enhanced preinvasive defense responses to a host-adapted virulent powdery mildew fungus but were impaired in preinvasive defenses upon inoculation with a nonadapted powdery mildew. The host-adapted powdery mildew had a reduced reproductive fitness on rop6DN plants, which was retained in mutant backgrounds defective in SA biosynthesis or signaling. Our findings indicate that both the morphological aberrations and altered sensitivity to powdery mildews of rop6DN plants result from perturbations that are independent from the SA-associated response. These perturbations uncouple SA-dependent defense signaling from disease resistance execution. PMID:23319551

Redundant roles of Sox17 and Sox18 in early cardiovascular development of mouse embryos

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sakamoto, Youhei; Hara, Kenshiro; Kanai-Azuma, Masami

Sox7, -17 and -18 constitute the Sox subgroup F (SoxF) of HMG box transcription factor genes, which all are co-expressed in developing vascular endothelial cells in mice. Here we characterized cardiovascular phenotypes of Sox17/Sox18-double and Sox17-single null embryos during early-somite stages. Whole-mount PECAM staining demonstrated the aberrant heart looping, enlarged cardinal vein and mild defects in anterior dorsal aorta formation in Sox17 single-null embryos. The Sox17/Sox18 double-null embryos showed more severe defects in formation of anterior dorsal aorta and head/cervical microvasculature, and in some cases, aberrant differentiation of endocardial cells and defective fusion of the endocardial tube. However, the posteriormore » dorsal aorta and allantoic microvasculature was properly formed in all of the Sox17/Sox18 double-null embryos. The anomalies in both anterior dorsal aorta and head/cervical vasculature corresponded with the weak Sox7 expression sites. This suggests the region-specific redundant activities of three SoxF members along the anteroposterior axis of embryonic vascular network.« less

Fc gamma RII/III and CD2 expression mark distinct subpopulations of immature CD4-CD8- murine thymocytes: in vivo developmental kinetics and T cell receptor beta chain rearrangement status.

PubMed

Rodewald, H R; Awad, K; Moingeon, P; D'Adamio, L; Rabinowitz, D; Shinkai, Y; Alt, F W; Reinherz, E L

1993-04-01

We have recently identified a dominant wave of CD4-CD8- (double-negative [DN]) thymocytes in early murine fetal development that express low affinity Fc gamma receptors (Fc gamma RII/III) and contain precursors for Ti alpha/beta lineage T cells. Here we show that Fc gamma RII/III is expressed in very immature CD4low single-positive (SP) thymocytes and that Fc gamma RII/III expression is downregulated within the DN subpopulation and before the CD3-CD8low SP stage in T cell receptor (TCR)-alpha/beta lineage-committed thymocytes. DN Fc gamma RII/III+ thymocytes also contain a small fraction of TCR-gamma/delta lineage cells in addition to TCR-alpha/beta progenitors. Fetal day 15.5 DN TCR-alpha/beta lineage progenitors can be subdivided into three major subpopulations as characterized by cell surface expression of Fc gamma RII/III vs. CD2 (Fc gamma RII/III+CD2-, Fc gamma RII/III+CD2+, Fc gamma RII/III-CD2+). Phenotypic analysis during fetal development as well as adoptive transfer of isolated fetal thymocyte subpopulations derived from C57B1/6 (Ly5.1) mice into normal, nonirradiated Ly5.2 congenic recipient mice identifies one early differentiation sequence (Fc gamma RII/III+CD2(-)-->Fc gamma RII/III+CD2(+)-->Fc gamma RII/III-CD2+) that precedes the entry of DN thymocytes into the CD4+CD8+ double-positive (DP) TCRlow/- stage. Unseparated day 15.5 fetal thymocytes develop into DP thymocytes within 2.5 d and remain at the DP stage for > 48 h before being selected into either CD4+ or CD8+ SP thymocytes. In contrast, Fc gamma RII/III+CD2- DN thymocytes follow this same developmental pathway but are delayed by approximately 24 h before entering the DP compartment, while Fc gamma RII/III-CD2+ display accelerated development by approximately 24 h compared with total day 15.5 thymocytes. Fc gamma RII/III-CD2+ are also more developmentally advanced than Fc gamma RII/III+CD2- fetal thymocytes with respect to their TCR beta chain V(D)J rearrangement. At day 15.5 in gestation, beta chain V(D)J rearrangement is mostly, if not entirely, restricted to the Fc gamma RII/III-CD2+ subset of DN fetal thymocytes. Consistent with this analysis in fetal thymocytes, > 90% of adult thymocytes derived from mice carrying a disrupting mutation at the recombination-activating gene 2 locus (RAG-2-/-) on both alleles are developmentally arrested at the DN CD2- stage. In addition, there is a fivefold increase in the relative percentage of thymocytes expressing Fc gamma RII/III in TCR and immunoglobulin gene rearrangement-incompetent homozygous RAG-2-/- mice (15% Fc gamma RII/III+) versus rearrangement-competent heterozygous RAG-2+/- mice (< 3% Fc gamma RII/III+). Thus, Fc gamma RII/III expression defines an early DN stage preceding V beta(D beta)I beta rearrangement, which in turn is followed by surface expression of CD2. Loss of Fc gamma RII/III and acquisition of CD2 expression characterize a late DN stage immediately before the conversion into DP thymocytes.

Use of a fermented dairy probiotic drink containing Lactobacillus casei (DN-114 001) to decrease the rate of illness in kids: the DRINK study. A patient-oriented, double-blind, cluster-randomized, placebo-controlled, clinical trial.

PubMed

Merenstein, D; Murphy, M; Fokar, A; Hernandez, R K; Park, H; Nsouli, H; Sanders, M E; Davis, B A; Niborski, V; Tondu, F; Shara, N M

2010-07-01

To evaluate whether a fermented dairy drink containing the probiotic strain Lactobacillus casei DN-114 001 could reduce the incidence of common infectious diseases (CIDs) and the change of behavior because of illness in children. We conducted a double-blinded, randomized, placebo-controlled allocation concealment clinical trial in the Washington, DC metropolitan area. Participants were 638 children 3-6 years old in daycare/schools. The intervention was a fermented dairy drink containing a specific probiotic strain or matching placebo with no live cultures for 90 consecutive days. Two primary outcomes were assessed: incidence of CIDs and change of behavior because of illness (both assessed by parental report). The rate of change of behavior because of illness was similar among active and control groups. However, the incidence rate for CIDs in the active group (0.0782) is 19% lower than that of the control group (0.0986) (incidence rate ratio=0.81, 95% CI: 0.65, 099) P=0.046. Daily intake of a fermented dairy drink containing the probiotic strain L. casei DN-114 001 showed some promise in reducing overall incidence of illness, but was primarily driven by gastrointestinal infections and there were no differences in change of behavior.

Disregulated expression of the transcription factor ThPOK during T-cell development leads to high incidence of T-cell lymphomas.

PubMed

Lee, Hyung-Ok; He, Xiao; Mookerjee-Basu, Jayati; Zhongping, Dai; Hua, Xiang; Nicolas, Emmanuelle; Sulis, Maria Luisa; Ferrando, Adolfo A; Testa, Joseph R; Kappes, Dietmar J

2015-06-23

The transcription factor T-helper-inducing POZ/Krueppel-like factor (ThPOK, encoded by the Zbtb7b gene) plays widespread and critical roles in T-cell development, particularly as the master regulator of CD4 commitment. Here we show that mice expressing a constitutive T-cell-specific ThPOK transgene (ThPOK(const) mice) develop thymic lymphomas. These tumors resemble human T-cell acute lymphoblastic leukemia (T-ALL), in that they predominantly exhibit activating Notch1 mutations. Lymphomagenesis is prevented if thymocyte development is arrested at the DN3 stage by recombination-activating gene (RAG) deficiency, but restored by introduction of a T-cell receptor (TCR) transgene or by a single injection of anti-αβTCR antibody into ThPOK(const) RAG-deficient mice, which promotes development to the CD4(+)8(+) (DP) stage. Hence, TCR signals and/or traversal of the DN (double negative) > DP (double positive) checkpoint are required for ThPOK-mediated lymphomagenesis. These results demonstrate a novel link between ThPOK, TCR signaling, and lymphomagenesis. Finally, we present evidence that ectopic ThPOK expression gives rise to a preleukemic and self-perpetuating DN4 lymphoma precursor population. Our results collectively define a novel role for ThPOK as an oncogene and precisely map the stage in thymopoiesis susceptible to ThPOK-dependent tumor initiation.

Different Doses of Tripterygium Glycosides in the Treatment of Diabetic Nephropathy: Effects on Blood Lipids.

PubMed

Wang, Wei

2018-06-07

The aim of this study was to investigate the therapeutic effect of different doses of tripterygium glycosides (TG) in the treatment of diabetic nephropathy (DN). The effect of TG on blood lipids and safety were also evaluated. Sixty patients with type 2 DN were randomly divided into three groups (n=20 per group): low-dose (30 mg/day TG), double-dose (60 mg/day TG) and control (placebo) groups, all three times daily for 6 months. The levels of triglycerides, total cholesterol, urinary protein, plasma albumin and serum tumour necrosis factor (TNF)-α were compared between the three groups. After treatment, urinary protein and TNF-α level significantly decreased in patients in the treatment groups, compared with the control group. This decrease was significantly larger in the double-dose group than in the low-dose group. However, there was no significant decrease in triglycerides and total cholesterol in the two treatment groups. Furthermore, plasma albumin was lower in the treatment groups than in the control group. The double dose of TG has improved clinical efficacy, compared with the low dose, and the same safety profile. © 2018 The Author(s). Published by S. Karger AG, Basel.

Influence of the gel thickness on in vivo hyaline cartilage regeneration induced by double-network gel implanted at the bottom of a large osteochondral defect: short-term results.

PubMed

Matsuda, Hidetoshi; Kitamura, Nobuto; Kurokawa, Takayuki; Arakaki, Kazunobu; Gong, Jian Ping; Kanaya, Fuminori; Yasuda, Kazunori

2013-01-31

A double-network (DN) gel, which is composed of poly(2-acrylamido-2-methylpropanesulfonic acid) and poly(N,N'-dimethyl acrylamide), can induce hyaline cartilage regeneration in vivo in a large osteochondral defect. The purpose of this study was to clarify the influence of the thickness of the implanted DN gel on the induction ability of hyaline cartilage regeneration. Thirty-eight mature rabbits were used in this study. We created an osteochondral defect having a diameter of 4.3-mm in the patellofemoral joint. The knees were randomly divided into 4 groups (Group I: 0.5-mm thick gel, Group II: 1.0-mm thick gel, Group III: 5.0-mm thick gel, and Group IV: untreated control). Animals in each group were further divided into 3 sub-groups depending on the gel implant position (2.0-, 3.0-, or 4.0-mm depth from the articular surface) in the defect. The regenerated tissues were evaluated with the Wayne's gross and histological grading scales and real time PCR analysis of the cartilage marker genes at 4 weeks. According to the total Wayne's score, when the depth of the final vacant space was set at 2.0 mm, the scores in Groups I, II, and III were significantly greater than that Group IV (p<0.05), although there were no significant differences between Groups I and IV at a 3.0-mm deep vacant space. The expression levels of type-2 collagen in Groups II and III were significantly higher (p<0.05) than that in Group IV. The 1.0-mm thick DN gel sheet had the same ability to induce hyaline cartilage regeneration as the 5.0-mm thick DN gel plug. However, the induction ability of the 0.5-mm thick sheet was significantly lower when compared with the 1.0-mm thick gel sheet. The 1.0-mm DN gel sheet is a promising device to establish a cell-free cartilage regeneration strategy that minimizes bone loss from the gel implantation.

Joint immobilization inhibits spontaneous hyaline cartilage regeneration induced by a novel double-network gel implantation.

PubMed

Arakaki, Kazunobu; Kitamura, Nobuto; Kurokawa, Takayuki; Onodera, Shin; Kanaya, Fuminori; Gong, Jian-Ping; Yasuda, Kazunori

2011-02-01

We have recently discovered that spontaneous hyaline cartilage regeneration can be induced in an osteochondral defect in the rabbit, when we implant a novel double-network (DN) gel plug at the bottom of the defect. To clarify whether joint immobilization inhibits the spontaneous hyaline cartilage regeneration, we conducted this study with 20 rabbits. At 4 or 12 weeks after surgery, the defect in the mobile knees was filled with a sufficient volume of the hyaline cartilage tissue rich in proteoglycan and type-2 collagen, while no cartilage tissues were observed in the defect in the immobilized knees. Type-2 collagen, Aggrecan, and SOX9 mRNAs were expressed only in the mobile knees at each period. This study demonstrated that joint immobilization significantly inhibits the spontaneous hyaline cartilage regeneration induced by the DN gel implantation. This fact suggested that the mechanical environment is one of the significant factors to induce this phenomenon.

CD4-veCD8-ve CD30+ve T cells are detectable in human lung transplant patients and their proportion of the lymphocyte population after in vitro stimulation with donor spleen cells correlates with preservation of lung physiology.

PubMed

Polster, K; Walker, A; Fildes, J; Entwistle, G; Yonan, N; Hutchinson, I V; Leonard, C T

2005-06-01

Survival following lung transplantation is less than 50% at 5 years, mainly due to immune-mediated chronic rejection. Recently a novel subset of T cells, CD4-veCD8-ve CD30+ve, so-called double negative (DN) CD30+ve T cells, has been described and shown to be responsible for tolerance in an animal model of skin transplantation. We investigated 18 lung transplant recipients for the presence of DN CD30+ve T cells in resting peripheral blood and also following in vitro stimulation of recipient peripheral blood mononuclear cells (PBMCs) with donor spleen cells. Small percentages (0.2% to 6%) of DN T cells are detectable in resting PBMCs of human transplant patients (n = 18), but these did not correlate with allograft function, acute rejection episodes, HLA mismatch, or CMV status. On repeated stimulation of recipient PBMCs (two exposures) in vitro by donor spleen cells (2:1 ratio stimulators to responders) the percentage of DN CD30+ve T cells within the lymphocyte pool correlated with preservation of allograft lung function (both for FEV(1), P = .009, and FEF(25-75), P = .036) and was inversely correlated with grade of chronic rejection. On repeated exposure of recipient PBMCs to donor spleen cells with a 1:1 ratio the percentage of DN CD30+ve T cells correlated with the number of acute rejection episodes of grade 2 or greater. The total number of HLA mismatches correlated with the percentage DN CD30+ve T cells present after primary stimulation of recipient PBMCs with donor spleen cells (1:1 ratio). The number of mismatches at the B locus inversely correlated with the percentage of DN CD30+ve T cells after primary stimulation of recipient PBMCs with donor spleen cells (1:1 ratio; P = .031, n = 18). Percentages of DN CD30+ve T cells present following repeated stimulation of recipient PBMCs by donor spleen cells correlated with preservation of graft function following lung transplantation.

BMP suppresses PTEN expression via RAS/ERK signaling.

PubMed

Beck, Stayce E; Carethers, John M

2007-08-01

Bone morphogenetic protein (BMP), a member of the transforming growth factor beta family, classically utilizes the SMAD signaling pathway for its growth suppressive effects,and loss of this signaling cascade may accelerate cell growth. In the colon cancer predisposition syndrome Juvenile Polyposis, as well as in the late progression stages of nonsyndromic colorectal cancers, SMAD4 function is typically abrogated. Here, we utilized the SMAD4-null SW480 colon cancer cell line to examine BMPs effect on a potential target gene, PTEN, and how its expression might be regulated. Initial treatment of the SMAD4-null cells with BMP resulted in mild growth suppression, but with prolonged exposure to BMP, the cells become growth stimulatory, which coincided with observed decreases in transcription and translation of PTEN, and with corresponding increases in phospho-AKT protein levels. BMP-induced PTEN suppression was mediated via the RAS/ERK pathway, as pharmacologic inhibition of RAS/ERK, or interference with protein function in the cytosol by DN-RAS prevented BMP-induced growth promotion and changes in PTEN levels, as did treatment with noggin, a BMP ligand inhibitor. Thus, BMP downregulates PTEN via RAS/ERK in a SMAD4-null environment that contributes to cell growth, and constitutes a SMAD4-independent but BMP-responsive signaling pathway.

Relativistic all-order many-body calculation of energies, wavelengths, and M 1 and E 2 transition rates for the 3 dn configurations in tungsten ions

NASA Astrophysics Data System (ADS)

Safronova, M. S.; Safronova, U. I.; Porsev, S. G.; Kozlov, M. G.; Ralchenko, Yu.

2018-01-01

Energy levels, wavelengths, magnetic-dipole and electric-quadrupole transition rates between the low-lying states are evaluated for W51 + to W54 + ions with 3 dn (n =2 to 5) electronic configurations by using an approach combining configuration interaction with the linearized coupled-cluster single-double method. The QED corrections are directly incorporated into the calculations and their effect is studied in detail. Uncertainties of the calculations are discussed. This study of such highly charged ions with the present method opens the way for future applications allowing an accurate prediction of properties for a very wide range of highly charged ions aimed at providing precision benchmarks for various applications.

Precision Measurement of the Neutron Twist-3 Matrix Element dn2: Probing Color Forces

DOE Office of Scientific and Technical Information (OSTI.GOV)

Posik, Matthew; Flay, David; Parno, Diana

2014-07-01

Double-spin asymmetries and absolute cross sections were measured at large Bjorken x (0.25 lte x lte 0.90), in both the deep-inelastic and resonance regions, by scattering longitudinally polarized electrons at beam energies of 4.7 and 5.9 GeV from a transversely and longitudinally polarized 3He target. In this dedicated experiment, the spin structure function g2 on 3He was determined with precision at large x, and the neutron twist-three matrix element dn2 was measured at ?Q2? of 3.21 and 4.32 GeV2/c2, with an absolute precision of about 10?5. Our results are found to be in agreement with lattice QCD calculations and resolvemore » the disagreement found with previous data at ?Q2?= 5 GeV2/c2. Combining dn2 and a newly extracted twist-four matrix element, fn2, the average neutron color electric and magnetic forces were extracted and found to be of opposite sign and about 60 MeV/fm in magnitude.« less

Design and Construction of Versatile Experiment Spherical Torus (VEST) at Seoul National University

NASA Astrophysics Data System (ADS)

An, Younghwa; Chung, Kyoung-Jae; Jung, Bongki; Lee, Hyunyeong; Sung, Choongki; Kim, Hyun-Seok; Na, Yong-Su; Hwang, Yong-Seok

2011-10-01

A new spherical torus, named as VEST (Versatile Experiment Spherical Torus), has been built at Seoul National University to investigate versatile research topics such as double null merging start-up, divertor engineering and non-inductive current drive. VEST is characterized by two partial solenoid coils installed at both vertical ends of a center stack, which will be used for double null merging start-up schemes. A poloidal field (PF) coil system including the partial solenoids for break-down and a long solenoid for the sustainment of merged plasma has been designed by solving circuit equations for the PF coils and vacuum vessel elements in consideration of required volt-second, null configuration and eddy current. To supply required currents to the PF coils and solenoids, power supplies based on double-swing circuit have been designed and fabricated with capacitor banks and thyristor switch assemblies. Also a power supply utilizing cost-effective commercial batteries has been developed for toroidal field(TF) coils. Detailed descriptions on the design of VEST and some initial test results will be presented.

The Impact of Pediatric Palliative Care Education on Medical Students' Knowledge and Attitudes

PubMed Central

Przysło, Łukasz; Kędzierska, Bogna; Stolarska, Małgorzata; Młynarski, Wojciech

2013-01-01

Purpose. Most undergraduate palliative care curricula omit pediatric palliative care (PPC) issues. Aim of the study was to evaluate the pilot education programme. Methods. All 391 students of Faculty of Medicine (FM) and 59 students of Division of Nursing (DN) were included in anonymous questionnaire study. Respondents were tested on their knowledge and attitude towards PPC issues before and at the end of the programme and were expected to evaluate the programme at the end. Results. For final analysis, authors qualified 375 double forms filled in correctly (320 FM and 55 DN). Before the programme, students' knowledge assessed on 0–100-point scale was low (FM: median: 43.35 points; 25%–75%: (40p–53.3p); DN: 26.7p; 13.3p–46.7p), and, in addition, there were differences (P < 0.001) between both faculties. Upon completion of the programme, significant increase of the level of knowledge in both faculties was noted (FM: 80p; 73.3–100; DN: 80p; 66.7p–80p). Participation in the programme changed declared attitudes towards some aspects of withholding of special procedures, euthanasia, and abortion. Both groups of students positively evaluated the programme. Conclusions. This study identifies medical students' limited knowledge of PPC. Educational intervention changes students' attitudes to the specific end-of-life issues. There is a need for palliative care curricula evaluation. PMID:24501581

Dual Constant Domain-Fab: A novel strategy to improve half-life and potency of a Met therapeutic antibody.

PubMed

Cignetto, Simona; Modica, Chiara; Chiriaco, Cristina; Fontani, Lara; Milla, Paola; Michieli, Paolo; Comoglio, Paolo M; Vigna, Elisa

2016-06-01

The kinase receptor encoded by the Met oncogene is a sensible target for cancer therapy. The chimeric monovalent Fab fragment of the DN30 monoclonal antibody (MvDN30) has an odd mechanism of action, based on cell surface removal of Met via activation of specific plasma membrane proteases. However, the short half-life of the Fab, due to its low molecular weight, is a severe limitation for the deployment in therapy. This issue was addressed by increasing the Fab molecular weight above the glomerular filtration threshold through the duplication of the constant domains, in tandem (DCD-1) or reciprocally swapped (DCD-2). The two newly engineered molecules showed biochemical properties comparable to the original MvDN30 in vitro, acting as full Met antagonists, impairing Met phosphorylation and activation of downstream signaling pathways. As a consequence, Met-mediated biological responses were inhibited, including anchorage-dependent and -independent cell growth. In vivo DCD-1 and DCD-2 showed a pharmacokinetic profile significantly improved over the original MvDN30, doubling the circulating half-life and reducing the clearance. In pre-clinical models of cancer, generated by injection of tumor cells or implant of patient-derived samples, systemic administration of the engineered molecules inhibited the growth of Met-addicted tumors. Copyright © 2016 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

The Prevalence and Management of Diabetic Nephropathy in Asia

PubMed Central

Tomino, Yasuhiko; Gohda, Tomohito

2015-01-01

Background Diabetic nephropathy (DN), especially type 2 diabetes, is now increasing rapidly worldwide, also in Asian countries, and is one of the major long-term vascular complications. The pathogenesis of DN involves both genetic and environmental factors. Around 30-40% of type 2 diabetic patients develop DN despite strict blood glucose and/or blood pressure control. Although it is considered that the genetic background may influence the initiation and progression of DN, the candidate genes are still obscure. Summary To search for genes that are involved in the susceptibility of DN, a candidate gene approach was taken in the beginning before the development of genome-wide association studies. Although a candidate gene approach can detect rare genetic variants, in advance we need known or presumed pathophysiological knowledge of the specific gene. Investigations using spontaneous animal models are important to determine the pathogenesis and treatment of DN patients. There are many spontaneous animal models, such as the NOD and Akita mice for type 1 diabetes and the Ob/Ob, db/db, Tsumura Suzuki Obese Diabetics, and KK-Ay mice for type 2 diabetes. Furthermore, the toxicity of persistent hyperglycemia, the activation of reactive oxygen species, systemic and/or glomerular hypertension, microinflammation, dyslipidemia, and other factors are considered to play important roles. Diabetic patients with normoalbuminuria and normal renal function showed typical histological patterns of DN. The discovery of a specific and reliable diagnostic and prognostic biomarker other than albuminuria is urgently needed and indispensable. Since large clinical trials of oral hypoglycemic drugs in renal failure are lacking, these recommendations will need to be regularly updated after results of larger randomized trials with longer follow-up durations are available. Key Message It is necessary to summarize the basic and clinical features of DN patients in Asia and to use these for the treatment of such patients. Facts from East and West The prevalence of DN is increasing in Asia and Western countries alike. The deletion (D) allele of the angiotensin-converting enzyme gene is associated with progression to end-stage renal disease in Asian patients with DN, but this association is uncertain in Europeans. An association between DN and polymorphism of the gene coding for acetyl coenzyme A carboxylase β has been reported in Asian and Western populations. Both in Japan and the US, criteria for diagnosis are a 5-year history of diabetes and persistent albuminuria. Renal biopsy should be done in patients with severe hematuria, cellular casts and - in the US - hepatitis and HIV to rule out other pathologies. Diabetic retinopathy is considered a key criterion in Japan, but the absence of it does not rule out DN in the US. Enlargement of the kidney is observed as a diagnostic criterion in Japan. The differential use of renal biopsy as diagnostic tool might account for a different prevalence between Asian countries. Some Japanese diabetic patients showed typical histological alterations for DN with a normal ACR and GFR. The clinical classification is similar between Japan and the US including five stages based on ACR and GFR. The Japanese guidelines do not include blood pressure values for the classification of DN. Guidelines for DN treatment are evolving quickly both in Asia and Western countries based on the numerous clinical trials performed worldwide. Targeting the angiotensin system for its hemodynamic and nonhemodynamic effects is a common approach. DPP-4 inhibitors are widely used in Japan and might have a higher glucose-lowering effect in Asian patients due to their specific diet. A randomized, double-blind placebo-controlled study has been launched to assess the efficacy of the Chinese herbal tea extract Shenyan Kangfu in DN. PMID:27536665

Temporal Expression of Bim Limits the Development of Agonist-Selected Thymocytes and Skews Their TCRβ Repertoire

PubMed Central

Li, Kun-Po; Fahnrich, Anke; Roy, Eron; Cuda, Carla M.; Grimes, H. Leighton; Perlman, Harris R.; Kalies, Kathrin; Hildeman, David A.

2017-01-01

CD8αα TCRαβ+ intestinal intraepithelial lymphocytes play a critical role in promoting intestinal homeostasis, although mechanisms controlling their development and peripheral homeostasis remain unclear. In this study, we examined the spatiotemporal role of Bim in the thymic selection of CD8αα precursors and the fate of these cells in the periphery. We found that T cell–specific expression of Bim during early/cortical, but not late/medullary, thymic development controls the agonist selection of CD8αα precursors and limits their private TCRβ repertoire. During this process, agonist-selected double-positive cells lose CD4/8 coreceptor expression and masquerade as double-negative (DN) TCRαβhi thymocytes. Although these DN thymocytes fail to re-express coreceptors after OP9-DL1 culture, they eventually mature and accumulate in the spleen where TCR and IL-15/STAT5 signaling promotes their conversion to CD8αα cells and their expression of gut-homing receptors. Adoptive transfer of splenic DN cells gives rise to CD8αα cells in the gut, establishing their precursor relationship in vivo. Interestingly, Bim does not restrict the IL-15–driven maturation of CD8αα cells that is critical for intestinal homeostasis. Thus, we found a temporal and tissue-specific role for Bim in limiting thymic agonist selection of CD8αα precursors and their TCRβ repertoire, but not in the maintenance of CD8αα intraepithelial lymphocytes in the intestine. PMID:27852740

Aiolos Overexpression in Systemic Lupus Erythematosus B Cell Subtypes and BAFF-Induced Memory B Cell Differentiation Are Reduced by CC-220 Modulation of Cereblon Activity.

PubMed

Nakayama, Yumi; Kosek, Jolanta; Capone, Lori; Hur, Eun Mi; Schafer, Peter H; Ringheim, Garth E

2017-10-01

BAFF is a B cell survival and maturation factor implicated in the pathogenesis of systemic lupus erythematosus (SLE). In this in vitro study, we describe that soluble BAFF in combination with IL-2 and IL-21 is a T cell contact-independent inducer of human B cell proliferation, plasmablast differentiation, and IgG secretion from circulating CD27 + memory and memory-like CD27 - IgD - double-negative (DN) B cells, but not CD27 - IgD + naive B cells. In contrast, soluble CD40L in combination with IL-2 and IL-21 induces these activities in both memory and naive B cells. Blood from healthy donors and SLE patients have similar circulating levels of IL-2, whereas SLE patients exhibit elevated BAFF and DN B cells and reduced IL-21. B cell differentiation transcription factors in memory, DN, and naive B cells in SLE show elevated levels of Aiolos, whereas Ikaros levels are unchanged. Treatment with CC-220, a modulator of the cullin ring ligase 4-cereblon E3 ubiquitin ligase complex, reduces Aiolos and Ikaros protein levels and BAFF- and CD40L-induced proliferation, plasmablast differentiation, and IgG secretion. The observation that the soluble factors BAFF, IL-2, and IL-21 induce memory and DN B cell activation and differentiation has implications for extrafollicular plasmablast development within inflamed tissue. Inhibition of B cell plasmablast differentiation by reduction of Aiolos and Ikaros may have utility in the treatment of SLE, where elevated levels of BAFF and Aiolos may prime CD27 + memory and DN memory-like B cells to become Ab-producing plasmablasts in the presence of BAFF and proinflammatory cytokines. Copyright © 2017 by The American Association of Immunologists, Inc.

Enforcement of γδ-lineage commitment by the pre-T-cell receptor in precursors with weak γδ-TCR signals.

PubMed

Zarin, Payam; Wong, Gladys W; Mohtashami, Mahmood; Wiest, David L; Zúñiga-Pflücker, Juan Carlos

2014-04-15

Developing thymocytes bifurcate from a bipotent precursor into αβ- or γδ-lineage T cells. Considering this common origin and the fact that the T-cell receptor (TCR) β-, γ-, and δ-chains simultaneously rearrange at the double negative (DN) stage of development, the possibility exists that a given DN cell can express and transmit signals through both the pre-TCR and γδ-TCR. Here, we tested this scenario by defining the differentiation outcomes and criteria for lineage choice when both TCR-β and γδ-TCR are simultaneously expressed in Rag2(-/-) DN cells via retroviral transduction. Our results showed that Rag2(-/-) DN cells expressing both TCRs developed along the γδ-lineage, down-regulated CD24 expression, and up-regulated CD73 expression, showed a γδ-biased gene-expression profile, and produced IFN-γ in response to stimulation. However, in the absence of Inhibitor of DNA-binding 3 expression and strong γδ-TCR ligand, γδ-expressing cells showed a lower propensity to differentiate along the γδ-lineage. Importantly, differentiation along the γδ-lineage was restored by pre-TCR coexpression, which induced greater down-regulation of CD24, higher levels of CD73, Nr4a2, and Rgs1, and recovery of functional competence to produce IFN-γ. These results confirm a requirement for a strong γδ-TCR ligand engagement to promote maturation along the γδ T-cell lineage, whereas additional signals from the pre-TCR can serve to enforce a γδ-lineage choice in the case of weaker γδ-TCR signals. Taken together, these findings further cement the view that the cumulative signal strength sensed by developing DN cells serves to dictate its lineage choice.

Aiolos Overexpression in Systemic Lupus Erythematosus B Cell Subtypes and BAFF-Induced Memory B Cell Differentiation Are Reduced by CC-220 Modulation of Cereblon Activity

PubMed Central

Nakayama, Yumi; Kosek, Jolanta; Capone, Lori; Schafer, Peter H.

2017-01-01

BAFF is a B cell survival and maturation factor implicated in the pathogenesis of systemic lupus erythematosus (SLE). In this in vitro study, we describe that soluble BAFF in combination with IL-2 and IL-21 is a T cell contact-independent inducer of human B cell proliferation, plasmablast differentiation, and IgG secretion from circulating CD27+ memory and memory-like CD27−IgD− double-negative (DN) B cells, but not CD27−IgD+ naive B cells. In contrast, soluble CD40L in combination with IL-2 and IL-21 induces these activities in both memory and naive B cells. Blood from healthy donors and SLE patients have similar circulating levels of IL-2, whereas SLE patients exhibit elevated BAFF and DN B cells and reduced IL-21. B cell differentiation transcription factors in memory, DN, and naive B cells in SLE show elevated levels of Aiolos, whereas Ikaros levels are unchanged. Treatment with CC-220, a modulator of the cullin ring ligase 4-cereblon E3 ubiquitin ligase complex, reduces Aiolos and Ikaros protein levels and BAFF- and CD40L-induced proliferation, plasmablast differentiation, and IgG secretion. The observation that the soluble factors BAFF, IL-2, and IL-21 induce memory and DN B cell activation and differentiation has implications for extrafollicular plasmablast development within inflamed tissue. Inhibition of B cell plasmablast differentiation by reduction of Aiolos and Ikaros may have utility in the treatment of SLE, where elevated levels of BAFF and Aiolos may prime CD27+ memory and DN memory-like B cells to become Ab-producing plasmablasts in the presence of BAFF and proinflammatory cytokines. PMID:28848067

RAS/ERK modulates TGFbeta-regulated PTEN expression in human pancreatic adenocarcinoma cells.

PubMed

Chow, Jimmy Y C; Quach, Khai T; Cabrera, Betty L; Cabral, Jennifer A; Beck, Stayce E; Carethers, John M

2007-11-01

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is rarely mutated in pancreatic cancers, but its regulation by transforming growth factor (TGF)-beta might mediate growth suppression and other oncogenic actions. Here, we examined the role of TGFbeta and the effects of oncogenic K-RAS/ERK upon PTEN expression in the absence of SMAD4. We utilized two SMAD4-null pancreatic cell lines, CAPAN-1 (K-RAS mutant) and BxPc-3 (WT-K-RAS), both of which express TGFbeta surface receptors. Cells were treated with TGFbeta1 and separated into cytosolic/nuclear fractions for western blotting with phospho-SMAD2, SMAD 2, 4 phospho-ATP-dependent tyrosine kinases (Akt), Akt and PTEN antibodies. PTEN mRNA levels were assessed by reverse transcriptase-polymerase chain reaction. The MEK1 inhibitor, PD98059, was used to block the downstream action of oncogenic K-RAS/ERK, as was a dominant-negative (DN) K-RAS construct. TGFbeta increased phospho-SMAD2 in both cytosolic and nuclear fractions. PD98059 treatment further increased phospho-SMAD2 in the nucleus of both pancreatic cell lines, and DN-K-RAS further improved SMAD translocation in K-RAS mutant CAPAN cells. TGFbeta treatment significantly suppressed PTEN protein levels concomitant with activation of Akt by 48 h through transcriptional reduction of PTEN mRNA that was evident by 6 h. TGFbeta-induced PTEN suppression was reversed by PD98059 and DN-K-RAS compared with treatments without TGFbeta. TGFbeta-induced PTEN expression was inversely related to cellular proliferation. Thus, oncogenic K-RAS/ERK in pancreatic adenocarcinoma facilitates TGFbeta-induced transcriptional down-regulation of the tumor suppressor PTEN in a SMAD4-independent manner and could constitute a signaling switch mechanism from growth suppression to growth promotion in pancreatic cancers.

Effect of Selenium Supplementation on Glycemic Control and Lipid Profiles in Patients with Diabetic Nephropathy.

PubMed

Bahmani, Fereshteh; Kia, Mahsa; Soleimani, Alireza; Asemi, Zatollah; Esmaillzadeh, Ahmad

2016-08-01

To our knowledge, data on the effects of selenium supplementation on glycemic control and lipid concentrations in patients with diabetic nephropathy (DN) are scarce. The current study was done to determine the effects of selenium supplementation on glycemic control and lipid concentrations in patients with DN. This was a randomized double-blind placebo-controlled clinical trial in which 60 patients with DN were randomly allocated into two groups to receive either 200 μg of selenium supplements (n = 30) or placebo (n = 30) daily for 12 weeks. Blood sampling was performed for the quantification of glycemic indicators and lipid profiles at the onset of the study and after 12 weeks of intervention. Selenium supplementation for 12 weeks resulted in a significant decrease in serum insulin levels (P = 0.01), homeostasis model of assessment-estimated insulin resistance (HOMA-IR) (P = 0.02), homeostasis model of assessment-estimated B cell function (HOMA-B) (P = 0.009) and a significant rise in plasma glutathione peroxidase (GPx) (P = 0.001) compared with the placebo. Taking selenium supplements had no significant effects on fasting plasma glucose (FPG), quantitative insulin sensitivity check index (QUICKI) and lipid profiles compared with the placebo. Overall, our study demonstrated that selenium supplementation for 12 weeks among patients with DN had beneficial effects on plasma GPx, serum insulin levels, HOMA-IR, and HOMA-B, while it did not affect FPG, QUICKI, and lipid profiles.

Clinical study of double dose of valsartan combined with tacrolimus in treatment of diabetic nephropathy.

PubMed

Jin, H; Zhang, H-N; Hou, X-L; Zhang, B; Wu, J; Zhang, H-B

2016-01-01

To investigate the clinical effect of double dose of valsartan combined with tacrolimus in the treatment of diabetic nephropathy (DN). HA total of 86 cases diagnosed with DN were selected from October 2013 to October 2014 in Zaozhuang Municipal Hospital, China. The study was approved by our hospital Ethics Committee and written consent was obtained from patients and their family members. Patients were randomly divided into three groups according to the sequence of admission, group A (conventional dose of valsartan group, n = 28 cases), group B (double dose of valsartan group, n = 29 cases) and group C (double dose of valsartan combined with tacrolimus group, n = 29). Clinical effects were compared by analyzing the renal function tests after 8 weeks. 24h urine protein, serum creatinine level of patients in group B and group C were significantly lower than that of group A. Those in group C was much lower. The glomerular filtration rates were significantly higher for group B and C than that of group A, and those in group C were much higher. The difference is statistically significant (p < 0.05). High-sensitivity C-reactive protein (hs CRP) and adiponectin levels of patients in group B and C of were significantly lower than that of group A and those in group C were much lower. The difference is statistically significant (p < 0.05). The high mobility group protein 1 (HMGB1) and renal tubular and interstitial damage index (TDI) of patients in B and C groups were significantly lower than those in the A group, and those in C group were significantly lower. The difference was statistically significant p < 0.05). The clinical effective rates of patients in group B and C were significantly higher than that in group A, and those of group C were much higher. The difference is statistically significant (p < 0.05). The recurrence rates of patients in group B and group C were significantly lower than those of group A and those in group C were much lower. The difference is statistically significant (p < 0.05). Patients in three groups showed no obvious drug complications. Double dose of valsartan combined with tacrolimus treatment of DN patients can improve clinical symptoms, reducing inflammation, inhibiting or even reversing the interstitial fibrosis, which will improve the curative effect and reduce the recurrence, as to provide a new theoretical basis for the clinical treatment of the disease.

Can levothyroxine treatment reduce urinary albumin excretion rate in patients with early type 2 diabetic nephropathy and subclinical hypothyroidism? A randomized double-blind and placebo-controlled study.

PubMed

Liu, Peng; Liu, Ruidong; Chen, Xia; Chen, Yingying; Wang, Debao; Zhang, Fengmei; Wang, Yangang

2015-12-01

To investigate the effect of levothyroxine (LT4) therapy on urinary albumin excretion rate (UAER) in early type 2 diabetic nephropathy (DN) and subclinical hypothyroidism (SCH) patients with mildly increased thyroid stimulating hormone (TSH) levels and serum thyroid peroxidase antibody (TPO-Ab) positivity. Application of randomized double-blind and placebo-controlled methods. A total of 136 normotensive patients with early type 2 DN and SCH (TSH 4.0-7.0 mIU/L and TPO-Ab positive) were selected, and were randomly divided into two groups for LT4 or placebo treatments, respectively. Changes in UAER, serum creatinine, glomerular filtration rate (GFR), blood pressure, serum uric acid and lipids in patients before and after 48 weeks of treatment were examined and compared between groups. There were no statistically significant differences in the baseline characteristics of study participants between two treatment groups (p > 0.05 for all). After 48 weeks of treatment, compared to the placebo treatment, the LT4 treatment was more effective in reducing total cholesterol (p < 0.05). Further comparison of therapy-related differences between groups showed that the LT4 treatment was better in reducing UAER, low-density lipoprotein cholesterol and uric acid than the placebo group (p < 0.01 for all). The LT4 treatment may decrease UAER and exert kidney protection effects in early type 2 DN and SCH patients with mildly increased TSH levels and serum TPO-Ab positivity. However, due to the short duration of follow-up and small number of cases, the results of this study need future trials with larger numbers of patients and longer follow-up periods to verify whether such a strategy can provide durable benefits.

Effect of Bifidobacterium bifidum containing yoghurt on dental plaque bacteria in children.

PubMed

Caglar, Esber

2014-01-01

The aim of the present study is to determine the possible effect of Bifidobacterium bifidum DN-173 010 on dental plaque of children. 52 children (25 F and 27 M), between the ages of 8-10, participated in the present study. The study had a double blind, randomized crossover design and the experimental period consisted of four consecutive time periods. During periods 2 and 4 (2 weeks each), children consumed 110 g probiotic fruit yogurt (Bifidobacterium DN-173 010 (1 x 10(10) cfu/g)), or a placebo fruit yogurt per day. Available supragingival plaque (24 h later) was collected from teeth 16, 11, 36 and 31 at baseline and at the end of periods 2 and 4. The counts of dental plaque mutans streptococci (MS) were evaluated using Dentocult SM (Strep Mutans). Changes of pre- and post-treatment levels of dental plaque MS were recorded for four consecutive sampling sites. There were no statistically differences between transition scores of test and placebo groups regarding different dental plaque sampling sites (p > 0.05) (unpaired t-test). Within the limitations of the present study, Bifidobacterium bifidum DN-173 010 has no effect on dental plaque MS levels in children.

Differences in CH4 and N2O emissions between rice nurseries in Chinese major rice cropping areas

NASA Astrophysics Data System (ADS)

Zhang, Yi; Li, Zhijie; Feng, Jinfei; Zhang, Xin; Jiang, Yu; Chen, Jin; Zhang, Mingqian; Deng, Aixing; Zhang, Weijian

2014-10-01

Studies on greenhouse gas (GHG) emissions from paddy field have primarily focused on the post-transplanting period, however, recent researches raise new concerns about GHGs emission from rice nursery. In this study, CH4 and N2O fluxes were determined from different nurseries under major rice cropping systems in China. The tested nurseries included flooded nursery (FN), moist nursery (MN) and dry nursery (DN). Methane emissions from FN were significantly higher than those from MN and DN under all the rice cropping systems. When comparing with FN, MN decreased total CH4 emissions by 74.2%, 72.1% and 49.6% under the rice-upland rotation cropping system (RUR), and the double rice cropping system for the early rice (EDR) and the late rice (LDR), respectively. DN decreased CH4 emissions by 99.2%, 92.0%, 99.0% and 78.6% compared to FN under the single rice cropping system (SR), RUR, EDR and LDR, respectively. When comparing with FN, MN and DN increased N2O emissions by 58.1-134.1% and 28.2-332.7%, respectively. Ultimately, compared with FN across the cropping systems, MN and DN decreased net global warming potentials (GWPs) of CH4 and N2O by 33-68% and 43-86%, respectively. The mitigating effect of MN and DN on total GWPs varied greatly across the systems, ranging from 30.8% in the LDR to 86.5% in the SR. Chinese actual emission from rice nurseries was reduced to 956.66 × 103 t CO2 eq from the theoretical estimate of 2242.59 × 103 t CO2 eq if under the flooded nursery scenario in 2012. Taking into account the large rice nursery area (2032.52 × 103 ha) in China, the results of this study clearly indicate the importance to estimate and mitigate GHGs emission from flooded rice nursery. Being effective to reduce GHG emissions and increase rice yield, dry nursery technique is a promising candidate for climate smart rice cropping.

Protein and quality characterization of complete and partial near isogenic lines of waxy wheat

USDA-ARS?s Scientific Manuscript database

The objective of this study was to evaluate protein composition and its effects on flour quality and physical dough test parameters using waxy wheat near-isogenic lines. Partial waxy (single and double nulls) and waxy (null at all three waxy loci, Wx-A1, Wx-B1, and Wx-D1) lines of N11 set (bread whe...

Gadolinium deposition in the brain: association with various GBCAs using a generalized additive model.

PubMed

Bae, Sohi; Lee, Ho-Joon; Han, Kyunghwa; Park, Yae-Won; Choi, Yoon Seong; Ahn, Sung Soo; Kim, Jinna; Lee, Seung-Koo

2017-08-01

To determine the relationship between the number of administrations of various gadolinium-based contrast agents (GBCAs) and increased T1 signal intensity in the globus pallidus (GP) and dentate nucleus (DN). This retrospective study included 122 patients who underwent double-dose GBCA-enhanced magnetic resonance imaging. Two radiologists calculated GP-to-thalamus (TH) signal intensity ratio, DN-to-pons signal intensity ratio and relative change (R change ) between the baseline and final examinations. Interobserver agreement was evaluated. The relationships between R change and several factors, including number of each GBCA administrations, were analysed using a generalized additive model. Six patients (4.9%) received linear GBCAs (mean 20.8 number of administration; range 15-30), 44 patients (36.1%) received macrocyclic GBCAs (mean 26.1; range 14-51) and 72 patients (59.0%) received both types of GBCAs (mean 31.5; range 12-65). Interobserver agreement was almost perfect (0.99; 95% CI: 0.99-0.99). R change (DN:pons) was associated with gadodiamide (p = 0.006) and gadopentetate dimeglumine (p < 0.001), but not with other GBCAs. R change (GP:TH) was not associated with GBCA administration. Previous administration of linear agents gadoiamide and gadopentetate dimeglumine is associated with increased T1 signal intensity in the DN, whereas macrocyclic GBCAs do not show an association. • Certain linear GBCAs are associated with T1 signal change in the dentate nucleus. • The signal change is related to the administration number of certain linear GBCAs. • Difference in signal change may reflect differences in stability of agents.

Complete stable remission and autoantibody specificity in myasthenia gravis.

PubMed

Baggi, Fulvio; Andreetta, Francesca; Maggi, Lorenzo; Confalonieri, Paolo; Morandi, Lucia; Salerno, Franco; Bernasconi, Pia; Montomoli, Cristina; Barberis, Massimo; Mantegazza, Renato; Antozzi, Carlo

2013-01-08

Patients with myasthenia gravis (MG) are subgrouped as acetylcholine receptor (AChR)-positive, muscle-specific kinase (MuSK)-positive, and AChR/MuSK-negative MG (or double negative [DN]) on the basis of autoantibody assay. We investigated the relationships between autoantibody specificity, main clinical features, and outcome of the disease, in particular the occurrence of complete stable remission (CSR), by means of a retrospective study on a cohort of 677 Italian patients with MG. A total of 517 (76%) patients with AChR-positive MG, 55 (8%) patients with MuSK-positive MG, and 105 (16%) patients with DN MG were included in the study. Kaplan-Meier and Cox proportional hazard regression analyses were used to evaluate associations between baseline characteristics, antibody specificity, and CSR. Clinical stage at onset and at maximal worsening was more severe for MuSK-positive patients: bulbar impairment at maximal worsening was found in 83.6% of MuSK-positive patients compared with 58.6% of AChR-positive patients and 43.8% of DN patients (p < 0.001). Baseline characteristics of AChR-positive and DN patients were similar. CSR was observed in 3.6% of MuSK-positive patients compared with 22.2% of AChR-positive and 21.9% of DN patients. In the whole MG cohort, onset before age 40 (hazard ratio [HR] = 1.96, 95% confidence interval [CI] 1.27-3.02, p = 0.002) and ocular and generalized clinical stages at maximal worsening were associated with CSR (ocular, HR = 8.05, 95% CI 1.88-34.53, p = 0.005; generalized, HR = 3.71, 95% CI 1.16-11.90, p = 0.023; bulbar, HR = 3.16, 95% CI 1.00-10.05, p = 0.051). MuSK antibodies identify a clinically distinguishable, more severe form of MG since the disease onset, with a lower occurrence of CSR. These features should be considered by the clinician in the management of this particular form of MG.

Metabotropic glutamate receptor-mediated use-dependent down-regulation of synaptic excitability involves the fragile X mental retardation protein.

PubMed

Repicky, Sarah; Broadie, Kendal

2009-02-01

Loss of the mRNA-binding protein FMRP results in the most common inherited form of both mental retardation and autism spectrum disorders: fragile X syndrome (FXS). The leading FXS hypothesis proposes that metabotropic glutamate receptor (mGluR) signaling at the synapse controls FMRP function in the regulation of local protein translation to modulate synaptic transmission strength. In this study, we use the Drosophila FXS disease model to test the relationship between Drosophila FMRP (dFMRP) and the sole Drosophila mGluR (dmGluRA) in regulation of synaptic function, using two-electrode voltage-clamp recording at the glutamatergic neuromuscular junction (NMJ). Null dmGluRA mutants show minimal changes in basal synapse properties but pronounced defects during sustained high-frequency stimulation (HFS). The double null dfmr1;dmGluRA mutant shows repression of enhanced augmentation and delayed onset of premature long-term facilitation (LTF) and strongly reduces grossly elevated post-tetanic potentiation (PTP) phenotypes present in dmGluRA-null animals. Null dfmr1 mutants show features of synaptic hyperexcitability, including multiple transmission events in response to a single stimulus and cyclic modulation of transmission amplitude during prolonged HFS. The double null dfmr1;dmGluRA mutant shows amelioration of these defects but does not fully restore wildtype properties in dfmr1-null animals. These data suggest that dmGluRA functions in a negative feedback loop in which excess glutamate released during high-frequency transmission binds the glutamate receptor to dampen synaptic excitability, and dFMRP functions to suppress the translation of proteins regulating this synaptic excitability. Removal of the translational regulator partially compensates for loss of the receptor and, similarly, loss of the receptor weakly compensates for loss of the translational regulator.

Properties of SnO2 thin films deposited by chemical spray pyrolysis using different precursor solutions

NASA Astrophysics Data System (ADS)

Abdul-Hamead, Alaa A.

2018-05-01

In this article single and double nozzle (SN, DN) chemical spray pyrolysis techniques(CSP) proved that tin dioxide SnO2 thin film can be fabricated with different structures. SnO2 prepared from three different salts of tin with a concentration of 0.05 M, with thicknesses were about 0.2 ±0.02 µm. Microstructures inspections were achieved on films, beside optical transparency addition to the contact angle CA. The results show that films have tetragonal crystalline with different micro-structures, from sheet to rod and flower-like aggregates, by the variation of the used salts by DN more than SN, also the value of the CA of the prepared films varies with different structures, reaching its highest value for flower-like aggregates of about 130°. Finally, the optical transparency was different corresponding to the disparity in surfaces roughness and topography.

Effect of two inner-ring oil-flow distribution schemes on the operating characteristics of a 35 millimeter bore ball bearing to 2.5 million DN

NASA Technical Reports Server (NTRS)

Schuller, F. T.; Pinel, S. I.; Signer, H. R.

1985-01-01

Parametric tests were conducted with a 35-mm-bore, split-inner-ring ball bearing with a double-inner-land-guided cage. Provisions were made for through-the-inner-ring lubrication. Test condictions were either a thrust load of 667 N (150 lb) or a combined load of 667 N (150 lb) thrust and 222 N (50 lb) radial, shaft speeds from 32000 to 72000 rpm, and an oil-inlet temperature of 394 K (250 deg F). Outer ring cooling was used in some tests. Tests were run with either 50 or 75 percent of the total oil flow distributed to the inner-ring raceway. Successful operation was experienced with both 50% and 75% flow patterns to 2.5 million DN. Cooling the outer ring had little effect on inner-ring temperature; however, the outer-ring temperature decreased as much as 7% at 2.5 million DN. Maximum recorded power loss was 3.1 kW (4.2 hp), and maximum cage slip was 8.7 percent. Both occurred at a shaft speed of 72000 rpm, a lubricant flow rate of 1900 cu/min (0.50 gal/min), a combined load, and no outer-ring cooling.

A randomized controlled study of finerenone versus placebo in Japanese patients with type 2 diabetes mellitus and diabetic nephropathy.

PubMed

Katayama, Shigehiro; Yamada, Daishiro; Nakayama, Mikihiro; Yamada, Takashi; Myoishi, Masafumi; Kato, Masaharu; Nowack, Christina; Kolkhof, Peter; Yamasaki, Yoshimitsu

2017-04-01

Finerenone (BAY 94-8862) is a novel non-steroidal mineralocorticoid receptor antagonist. The aim of this study was to compare the efficacy and safety of seven once-daily oral doses of finerenone (1.25-20mg) and placebo in 96 patients with type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN) receiving a RAS blocker. ARTS-DN Japan was a multicenter, randomized, double-blind, placebo-controlled, phase 2b study. Analysis of the urinary albumin-to-creatinine ratio (UACR) at day 90 relative to baseline indicated a nominally significant effect of finerenone. The UACR at day 90 relative to baseline for each finerenone treatment group was numerically reduced compared with placebo. No serious adverse events (AEs) or deaths were reported and no patients experienced treatment-emergent AEs resulting in discontinuation of study drug. Small mean increases in serum potassium level were observed in the finerenone treatment groups (0.025-0.167mmol/L) compared with the placebo group (-0.075mmol/L); no patients developed hyperkalemia. When given in addition to a RAS inhibitor, finerenone reduced albuminuria without adverse effects on serum potassium levels or renal function in Japanese patients with T2DM and DN. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Effects of starch synthase IIa gene dosage on grain, protein and starch in endosperm of wheat.

PubMed

Konik-Rose, Christine; Thistleton, Jenny; Chanvrier, Helene; Tan, Ihwa; Halley, Peter; Gidley, Michael; Kosar-Hashemi, Behjat; Wang, Hong; Larroque, Oscar; Ikea, Joseph; McMaugh, Steve; Regina, Ahmed; Rahman, Sadequr; Morell, Matthew; Li, Zhongyi

2007-11-01

Starch synthases (SS) are responsible for elongating the alpha-1,4 glucan chains of starch. A doubled haploid population was generated by crossing a line of wheat, which lacks functional ssIIa genes on each genome (abd), and an Australian wheat cultivar, Sunco, with wild type ssIIa alleles on each genome (ABD). Evidence has been presented previously indicating that the SGP-1 (starch granule protein-1) proteins present in the starch granule in wheat are products of the ssIIa genes. Analysis of 100 progeny lines demonstrated co-segregation of the ssIIa alleles from the three genomes with the SGP-1 proteins, providing further evidence that the SGP-1 proteins are the products of the ssIIa genes. From the progeny lines, 40 doubled haploid lines representing the eight possible genotypes for SSIIa (ABD, aBD, AbD, ABd, abD, aBd, Abd, abd) were characterized for their grain weight, protein content, total starch content and starch properties. For some properties (chain length distribution, pasting properties, swelling power, and gelatinization properties), a progressive change was observed across the four classes of genotypes (wild type, single nulls, double nulls and triple nulls). However, for other grain properties (seed weight and protein content) and starch properties (total starch content, granule morphology and crystallinity, granule size distribution, amylose content, amylose-lipid dissociation properties), a statistically significant change only occurred for the triple nulls, indicating that all three genes had to be missing or inactive for a change to occur. These results illustrate the importance of SSIIa in controlling grain and starch properties and the importance of amylopectin fine structure in controlling starch granule properties in wheat.

The effects of dual and triple combinations of trandolapril, telmisartan, and verapamil on overt proteinuria in the patients with diabetic nephropathy.

PubMed

Albayrak, Bülent; Cankaya, Erdem; Cetinkaya, Ramazan; Cerrah, Serkan; Bilen, Yusuf

2016-05-01

Diabetic nephropathy (DN) is one of the most important causes of the end-stage renal failure and its prevalence is found to be increasing. The presence of hypertension and progressive proteinuria is among the important findings. In this study, the effects of double and triple combinations of trandolapril, telmisartan, and verapamil on proteinuria were investigated in diabetic patients with nephropathy. Seventy-eight patients (mean age: 56.11 ± 11.26 years; 47 females and 31 males) with overt proteinuria and DN were included in this study. The patients were divided into four groups: Group I (n: 18, trandolapril + telmisartan), Group II (n: 20, trandolapril + verapamil), Group III (n: 20, trandolapril +telmisartan + verapamil), and Group IV (n: 20, telmisartan + verapamil). At the end of a three-month therapy, within and between group comparisons were done about the effects of the use of double or triple drug combinations on proteinuria, glomerular filtration rate (GFR), electrolytes, serum albumin, low-density lipoprotein (LDL)- cholesterol, and HbA1C. There was no significant difference among groups in terms of age, gender, diabetes duration, body mass index, and retinopathy frequency. The decreases in proteinuria and mean arterial blood pressure (MABP) were significant in all groups. The decrease in proteinuria was independent of the decrease in MABP [the reduction rate in proteinuria was 39% (P <0.001) in Group I, 37% (P <0.001) in Group II, 42% (P <0.001) in Group III, and 43% (P <0.001) in Group IV; the reduction rate in MABP was 10.6% (P <0.001) in Group I, 13.7% (P <0.001) in Group II, 17.5% (P <0.001) in Group III, and 15.4% (P <0.001) in Group IV]. Decrease in HbA1C (before and after treatment) was significant in Groups III and IV when com- pared to Groups I and II. Any adverse event, like hyperkalemia, was not observed. There was no significant difference among the groups in terms of GFR, LDL-cholesterol, albumin, and potassium. All the patients tolerated the drugs well. In conclusion, in patients with DN, both double or triple combinations of trandolapril, telmisartan and verapamil resulted in significant decreases in proteinuria and MABP. Triple combinations did not have any superiority over double combinations. Therefore, the suitable drug combinations may be chosen according to the clinical status of a patient.

Circulating CD4+CD28null and extra-thymic CD4+CD8+ double positive T cells are independently associated with disease damage in systemic lupus erythematosus patients.

PubMed

Ugarte-Gil, M F; Sánchez-Zúñiga, C; Gamboa-Cárdenas, R V; Aliaga-Zamudio, M; Zevallos, F; Tineo-Pozo, G; Cucho-Venegas, J M; Mosqueira-Riveros, A; Medina, M; Perich-Campos, R A; Alfaro-Lozano, J L; Rodriguez-Bellido, Z; Alarcón, G S; Pastor-Asurza, C A

2016-03-01

To determine whether circulating CD4+CD28null and extra-thymic CD4+CD8+ double positive (DP) T cells are independently associated with damage accrual in systemic lupus erythematosus (SLE) patients. This cross-sectional study was conducted between September 2013 and April 2014 in consecutive SLE patients from our Rheumatology Department. CD4+CD28null and CD4+CD8+ DP T-cell frequencies were analyzed by flow-cytometry. The association of damage (SLICC/ACR Damage Index, SDI) and CD4+CD28null and CD4+CD8+ DP T cells was examined by univariable and multivariable Poisson regression models, adjusting for possible confounders. All analyses were performed using SPSS 21.0. Patients' (n = 133) mean (SD) age at diagnosis was 35.5 (16.8) years, 124 (93.2%) were female; all were mestizo (mixed Caucasian and Amerindian ancestry). Disease duration was 7.4 (6.8) years. The SLE Disease Activity Index was 5.5 (4.2), and the SDI 0.9 (1.2). The percentages of CD4+CD28null and CD4+CD8+ DP T cells were 17.1 (14.4) and 0.4 (1.4), respectively. The percentage of CD4+CD28null and CD4+CD8+ DP T cells were positively associated with a higher SDI in both univariable (rate ratio (RR) 1.02, 95% confidence interval (CI): 1.01-1.03 and 1.17, 95% CI: 1.07-1.27, respectively; p < 0.001 for both) and multivariable analyses RR 1.02, 95% CI: 1.01-1.03, p = 0.001 for CD4+CD28null T cells and 1.28, 95% CI: 1.13-1.44, p < 0.001 for CD4+CD8+ DP T cells). Only the renal domain remained associated with CD4+CD28null in multivariable analyses (RR 1.023 (1.002-1.045); p = 0.034). In SLE patients, CD4+CD28null and CD4+CD8+ DP T cells are independently associated with disease damage. Longitudinal studies are warranted to determine the predictive value of these associations. © The Author(s) 2015.

Superoxide dismutases and glutaredoxins have a distinct role in the response of Candida albicans to oxidative stress generated by the chemical compounds menadione and diamide.

PubMed

Chaves, Guilherme Maranhão; da Silva, Walicyranison Plinio

2012-12-01

To cope with oxidative stress, Candida albicans possesses several enzymes involved in a number of biological processes, including superoxide dismutases (Sods) and glutaredoxins (Grxs). The resistance of C. albicans to reactive oxygen species is thought to act as a virulence factor. Genes such as SOD1 and GRX2, which encode for a Sod and Grx, respectively, in C. albicans are widely recognised to be important for pathogenesis. We generated a double mutant, Δgrx2/sod1, for both genes. This strain is very defective in hyphae formation and is susceptible to killing by neutrophils. When exposed to two compounds that generate reactive oxygen species, the double null mutant was susceptible to menadione and resistant to diamide. The reintegration of the SOD1 gene in the null mutant led to recovery in resistance to menadione, whereas reintegration of the GRX2 gene made the null mutant sensitive to diamide. Despite having two different roles in the responses to oxidative stress generated by chemical compounds, GRX2 and SOD1 are important for C. albicans pathogenesis because the double mutant Δgrx2/sod1 was very susceptible to neutrophil killing and was defective in hyphae formation in addition to having a lower virulence in an animal model of systemic infection.

Combinatorial Statistics on Trees and Networks

DTIC Science & Technology

2010-09-29

interaction graph is drawn from the Erdos- Renyi , G(n,p), where each edge is present independently with probability p. For this model we establish a double...special interest is the behavior of Gibbs sampling on the Erdos- Renyi random graph G{n, d/n), where each edge is chosen independently with...which have no counterparts in the coloring setting. Our proof presented here exploits in novel ways the local treelike structure of Erdos- Renyi

Magnetic coherent population trapping in a single ion

NASA Astrophysics Data System (ADS)

Das, S.; Liu, P.; Grémaud, B.; Mukherjee, M.

2018-03-01

Magnetically induced coherent population trapping has been studied in a single trapped laser cooled ion. The magnetic-field-dependent narrow spectral feature is found to be a useful tool in determining the null point of magnetic field at the ion position. In particular, we use a double Λ scheme that allows us to measure the null magnetic-field point limited by the detector shot noise. We analyzed the system theoretically and found certain long-lived bright states as the dark state is generated under steady-state condition.

Ionic liquid based multifunctional double network gel

NASA Astrophysics Data System (ADS)

Ahmed, Kumkum; Higashihara, Tomoya; Arafune, Hiroyuki; Kamijo, Toshio; Morinaga, Takashi; Sato, Takaya; Furukawa, Hidemitsu

2015-04-01

Gels are a promising class of soft and wet materials with diverse application in tissue engineering and bio-medical purpose. In order to accelerate the development of gels, it is required to synthesize multi-functional gels of high mechanical strength, ultra low surface friction and suitable elastic modulus with a variety of methods and new materials. Among many types of gel ionic gel made from ionic liquids (ILs) could be used for diverse applications in electrochemical devices and in the field of tribology. IL, a promising materials for lubrication, is a salt with a melting point lower than 100 °C. As a lubricant, ILs are characterized by an extremely low vapor pressure, high thermal stability and high ion conductivity. In this work a novel approach of making double network DN ionic gel using IL has been made utilizing photo polymerization process. A hydrophobic monomer Methyl methacrylate (MMA) has been used as a first network and a hydrophobic IL monomer, N,N-diethyl-N-(2-mthacryloylethyl)-N-methylammonium bistrifluoromethylsulfonyl)imide (DEMM-TFSI) has been used as a second network using photo initiator benzophenon and crosslinker triethylene glycol dimethacrylate (TEGDMA). The resulting DN ionic gel shows transparency, flexibility, high thermal stability, good mechanical toughness and low friction coefficient value which can be a potential candidate as a gel slider in different mechanical devices and can open a new area in the field of gel tribology.

Onecut1 and Onecut2 redundantly regulate early retinal cell fates during development

PubMed Central

Sapkota, Darshan; Chintala, Hemabindu; Wu, Fuguo; Fliesler, Steven J.; Hu, Zihua; Mu, Xiuqian

2014-01-01

Previously, we have shown that Onecut1 (Oc1) and Onecut2 (Oc2) are expressed in retinal progenitor cells, developing retinal ganglion cells (RGCs), and horizontal cells (HCs). However, in Oc1-null mice, we only observed an 80% reduction in HCs, but no defects in other cell types. We postulated that the lack of defects in other cell types in Oc1-null retinas was a result of redundancy with Oc2. To test this theory, we have generated Oc2-null mice and now show that their retinas also only have defects in HCs, with a 50% reduction in their numbers. However, when both Oc1 and Oc2 are knocked out, the retinas exhibit more profound defects in the development of all early retinal cell types, including completely failed genesis of HCs, compromised generation of cones, reduced production (by 30%) of RGCs, and absence of starburst amacrine cells. Cone subtype diversification and RGC subtype composition also were affected in the double-null retina. Using RNA-Seq expression profiling, we have identified downstream genes of Oc1 and Oc2, which not only confirms the redundancy between the two factors and renders a molecular explanation for the defects in the double-null retinas, but also shows that the onecut factors suppress the production of the late cell type, rods, indicating that the two factors contribute to the competence of retinal progenitor cells for the early retinal cell fates. Our results provide insight into how onecut factors regulate the creation of cellular diversity in the retina and, by extension, in the central nervous system in general. PMID:25228773

Metformin ameliorates IL-6-induced hepatic insulin resistance via induction of orphan nuclear receptor small heterodimer partner (SHP) in mouse models.

PubMed

Kim, Y D; Kim, Y H; Cho, Y M; Kim, D K; Ahn, S W; Lee, J M; Chanda, D; Shong, M; Lee, C H; Choi, H S

2012-05-01

IL-6 is a proinflammatory cytokine associated with the pathogenesis of hepatic diseases. Metformin is an anti-diabetic drug used for the treatment of type 2 diabetes, and orphan nuclear receptor small heterodimer partner (SHP, also known as NR0B2), a transcriptional co-repressor, plays an important role in maintaining metabolic homeostasis. Here, we demonstrate that metformin-mediated activation of AMP-activated protein kinase (AMPK) increases SHP protein production and regulates IL-6-induced hepatic insulin resistance. We investigated metformin-mediated SHP production improved insulin resistance through the regulation of an IL-6-dependent pathway (involving signal transducer and activator of transcription 3 [STAT3] and suppressor of cytokine signalling 3 [SOCS3]) in both Shp knockdown and Shp null mice. IL-6-induced STAT3 transactivation and SOCS3 production were significantly repressed by metformin, adenoviral constitutively active AMPK (Ad-CA-AMPK), and adenoviral SHP (Ad-SHP), but not in Shp knockdown, or with the adenoviral dominant negative form of AMPK (Ad-DN-AMPK). Chromatin immunoprecipitation (ChIP), co-immunoprecipitation (Co-IP) and protein localisation studies showed that SHP inhibits DNA binding of STAT3 on the Socs3 gene promoter via interaction and colocalisation within the nucleus. Upregulation of inflammatory genes and downregulation of hepatic insulin signalling by acute IL-6 treatment were observed in wild-type mice but not in Shp null mice. Finally, chronic IL-6 exposure caused hepatic insulin resistance, leading to impaired insulin tolerance and elevated gluconeogenesis, and these phenomena were aggravated in Shp null mice. Our results demonstrate that SHP upregulation by metformin may prevent hepatic disorders by regulating the IL-6-dependent pathway, and that this pathway can help to ameliorate the pathogenesis of cytokine-mediated metabolic dysfunction.

A symplectic map for trajectories of magnetic field lines in double-null divertor tokamaks

NASA Astrophysics Data System (ADS)

Crank, Willie; Ali, Halima; Punjabi, Alkesh

2009-11-01

The coordinates of the area-preserving map equations for integration of magnetic field line trajectories in tokamaks can be any coordinates for which a transformation to (ψ,θ,φ) coordinates exists [A. Punjabi, H. Ali, T. Evans, and A. Boozer, Phys. Lett. A 364, 140 (2007)]. ψ is toroidal magnetic flux, θ is poloidal angle, and φ is toroidal angle. This freedom is exploited to construct a map that represents the magnetic topology of double-null divertor tokamaks. For this purpose, the generating function of the simple map [A. Punjabi, A. Verma, and A. Boozer, Phys. Rev. Lett. 69, 3322 (1992)] is slightly modified. The resulting map equations for the double-null divertor tokamaks are: x1=x0-ky0(1-y0^2 ), y1=y0+kx1. k is the map parameter. It represents the generic topological effects of toroidal asymmetries. The O-point is at (0.0). The X-points are at (0,±1). The equilibrium magnetic surfaces are calculated. These surfaces are symmetric about the x- and y- axes. The widths of stochastic layer near the X-points in the principal plane, and the fractal dimensions of the magnetic footprints on the inboard and outboard side of upper and lower X-points are calculated from the map. This work is supported by US Department of Energy grants DE-FG02-07ER54937, DE-FG02-01ER54624 and DE-FG02-04ER54793.

Isolation and Characterization of Novel Polymorphic Microsatellite Markers for Cimex hemipterus F. (Hemiptera: Cimicidae).

PubMed

Seri Masran, Siti Nor Ain; Ab Majid, Abdul Hafiz

2018-05-04

Due to the growing public health and tourism awareness, Cimex hemipterus Fabricius (Hemiptera: Cimicidae) has gained a great interest in increasing reported infestation cases in tropical regions of the world, including Malaysia. Since the information on the molecular ecology and population biology of this species are tremendously lacking, the isolation and development of molecular markers can be used to determine its genetic structure. In this study, novel microsatellite primers isolated from enriched genomic libraries of C. hemipterus were developed using 454 Roche shotgun sequencing. Seven validated polymorphic microsatellite primers were consistently amplified and characterized from 70 tropical bed bugs collected from seven locations throughout Malaysia. The number of alleles per locus identified ranged from 6 to 14. Comparison of loci for overall and between population were done with mean observed and expected heterozygosity were determined at 0.320 and 0.814, 0.320 and 0.727, respectively. Polymorphic information criteria (PIC) valued the markers as highly informative as PIC >0.5. Overall population, they are possibly in Hardy-Weinberg equilibrium with loci Ch_09ttn, Ch_01dn, and Ch_13dn showing signs of a null allele. There were no scoring errors caused by stutter peaks, no large allele dropout was detected for all loci and showed no evidence of linkage disequilibrium. In conclusion, all seven molecular microsatellite markers identified can be beneficially used to gain more information on the population genetic structure and breeding patterns of C. hemipterus as well as the relationship of dispersal and infestation.

Fabrication tolerant chalcogenide mid-infrared multimode interference coupler design with applications for Bracewell nulling interferometry.

PubMed

Goldsmith, Harry-Dean Kenchington; Cvetojevic, Nick; Ireland, Michael; Madden, Stephen

2017-02-20

Understanding exoplanet formation and finding potentially habitable exoplanets is vital to an enhanced understanding of the universe. The use of nulling interferometry to strongly attenuate the central star's light provides the opportunity to see objects closer to the star than ever before. Given that exoplanets are usually warm, the 4 µm Mid-Infrared region is advantageous for such observations. The key performance parameters for a nulling interferometer are the extinction ratio it can attain and how well that is maintained across the operational bandwidth. Both parameters depend on the design and fabrication accuracy of the subcomponents and their wavelength dependence. Via detailed simulation it is shown in this paper that a planar chalcogenide photonic chip, consisting of three highly fabrication tolerant multimode interference couplers, can exceed an extinction ratio of 60 dB in double nulling operation and up to 40 dB for a single nulling operation across a wavelength window of 3.9 to 4.2 µm. This provides a beam combiner with sufficient performance, in theory, to image exoplanets.

Double gene deletion reveals the lack of cooperation between PPAR{alpha} and PPAR{beta} in skeletal muscle

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bedu, E.; Desplanches, D.; Pequignot, J.

2007-06-15

The peroxisome proliferator-activated receptors (PPARs) are involved in the regulation of most of the pathways linked to lipid metabolism. PPAR{alpha} and PPAR{beta} isotypes are known to regulate muscle fatty acid oxidation and a reciprocal compensation of their function has been proposed. Herein, we investigated muscle contractile and metabolic phenotypes in PPAR{alpha}-/-, PPAR{beta}-/-, and double PPAR{alpha}-/- {beta}-/- mice. Heart and soleus muscle analyses show that the deletion of PPAR{alpha} induces a decrease of the HAD activity ({beta}-oxidation) while soleus contractile phenotype remains unchanged. A PPAR{beta} deletion alone has no effect. However, these mild phenotypes are not due to a reciprocal compensationmore » of PPAR{beta} and PPAR{alpha} functions since double gene deletion PPAR{alpha}-PPAR{beta} mostly reproduces the null PPAR{alpha}-mediated reduced {beta}-oxidation, in addition to a shift from fast to slow fibers. In conclusion, PPAR{beta} is not required for maintaining skeletal muscle metabolic activity and does not compensate the lack of PPAR{alpha} in PPAR{alpha} null mice.« less

Identification and Expression Profiling of the Auxin Response Factors in Dendrobium officinale under Abiotic Stresses

PubMed Central

Chen, Zhehao; Yuan, Ye; Fu, Di; Shen, Chenjia; Yang, Yanjun

2017-01-01

Auxin response factor (ARF) proteins play roles in plant responses to diverse environmental stresses by binding specifically to the auxin response element in the promoters of target genes. Using our latest public Dendrobium transcriptomes, a comprehensive characterization and analysis of 14 DnARF genes were performed. Three selected DnARFs, including DnARF1, DnARF4, and DnARF6, were confirmed to be nuclear proteins according to their transient expression in epidermal cells of Nicotiana benthamiana leaves. Furthermore, the transcription activation abilities of DnARF1, DnARF4, and DnARF6 were tested in a yeast system. Our data showed that DnARF6 is a transcriptional activator in Dendrobium officinale. To uncover the basic information of DnARF gene responses to abiotic stresses, we analyzed their expression patterns under various hormones and abiotic treatments. Based on our data, several hormones and significant stress responsive DnARF genes have been identified. Since auxin and ARF genes have been identified in many plant species, our data is imperative to reveal the function of ARF mediated auxin signaling in the adaptation to the challenging Dendrobium environment. PMID:28471373

Identification and Expression Profiling of the Auxin Response Factors in Dendrobium officinale under Abiotic Stresses.

PubMed

Chen, Zhehao; Yuan, Ye; Fu, Di; Shen, Chenjia; Yang, Yanjun

2017-05-04

Auxin response factor (ARF) proteins play roles in plant responses to diverse environmental stresses by binding specifically to the auxin response element in the promoters of target genes. Using our latest public Dendrobium transcriptomes, a comprehensive characterization and analysis of 14 DnARF genes were performed. Three selected DnARFs , including DnARF1 , DnARF4 , and DnARF6 , were confirmed to be nuclear proteins according to their transient expression in epidermal cells of Nicotiana benthamiana leaves. Furthermore, the transcription activation abilities of DnARF1 , DnARF4 , and DnARF6 were tested in a yeast system. Our data showed that DnARF6 is a transcriptional activator in Dendrobium officinale . To uncover the basic information of DnARF gene responses to abiotic stresses, we analyzed their expression patterns under various hormones and abiotic treatments. Based on our data, several hormones and significant stress responsive DnARF genes have been identified. Since auxin and ARF genes have been identified in many plant species, our data is imperative to reveal the function of ARF mediated auxin signaling in the adaptation to the challenging Dendrobium environment.

De Novo DQ Donor-Specific Antibodies Are Associated with Chronic Lung Allograft Dysfunction after Lung Transplantation.

PubMed

Tikkanen, Jussi M; Singer, Lianne G; Kim, S Joseph; Li, Yanhong; Binnie, Matthew; Chaparro, Cecilia; Chow, Chung-Wai; Martinu, Tereza; Azad, Sassan; Keshavjee, Shaf; Tinckam, Kathryn

2016-09-01

Despite increasing evidence about the role of donor-specific human leukocyte antigen (HLA) antibodies in transplant outcomes, the incidence and impact of de novo donor-specific antibodies (dnDSA) after lung transplantation remains unclear. To describe the incidence, characteristics, and impact of dnDSA after lung transplantation. We investigated a single-center cohort of 340 lung transplant recipients undergoing transplant during 2008 to 2011. All patients underwent HLA-antibody testing quarterly pretransplant and at regular intervals over the first 24 months after transplant. The patients received modified immunosuppression depending on their pretransplant sensitization status. Risk factors for dnDSA development, as well as the associations of dnDSA with patient survival and chronic lung allograft dysfunction (CLAD), were determined using multivariable analysis. The cumulative incidence of dnDSA was 47% at a median of 86 days (range, 44-185 d) after lung transplantation. Seventy-six percent of recipients with dnDSA had DQ-DSA. Male sex and the use of ex vivo lung perfusion were associated with an increased risk of dnDSA, whereas increased HLA-DQB1 matching was protective. DQ-dnDSA preceded or coincided with the diagnosis of CLAD in all cases. Developing dnDSA (vs. no dnDSA) was associated with a twofold increased risk of CLAD (hazard ratio, 2.04; 95% confidence interval, 1.13-3.69). This association appeared to be driven by the development of DQ-dnDSA. dnDSA are common after lung transplantation, with the majority being DQ DSA. DQ-dnDSA are associated with an increased risk of CLAD. Strategies to prevent or treat DQ-dnDSA may improve outcomes for lung transplant recipients.

Note of the methodological flaws in the paper entitled "GSTT1 and GSTM1 polymorphisms predict treatment outcome for breast cancer: a systematic review and meta-analysis".

PubMed

Qiu, Mali; Wu, Xu; Qu, Xiaobing

2016-09-01

With great interest, we read the paper "GSTT1 and GSTM1 polymorphisms predict treatment outcome for breast cancer: a systematic review and meta-analysis" (by Hu XY et al.), which has reached important conclusions that GSTM1 null and GSTT1/GSTM1 double null polymorphisms might be significantly associated with an increased tumor response in breast cancer. The result is encouraging. Nevertheless, several methodological flaws in this meta-analysis are worth noticing.

Review of Herbal Traditional Chinese Medicine for the Treatment of Diabetic Nephropathy

PubMed Central

Sun, Guang-dong; Li, Chao-yuan; Cui, Wen-peng; Guo, Qiao-yan; Dong, Chang-qing; Zou, Hong-bin; Liu, Shu-jun; Dong, Wen-peng; Miao, Li-ning

2016-01-01

Diabetic nephropathy (DN) is the most serious chronic complications of diabetes; 20–40% of diabetic patients develop into end stage renal disease (ESRD). However, exact pathogenesis of DN is not fully clear and we have great difficulties in curing DN; poor treatment of DN led to high chances of mortality worldwide. A lot of western medicines such as ACEI and ARB have been demonstrated to protect renal function of DN but are not enough to delay or retard the progression of DN; therefore, exploring exact and feasible drug is current research hotspot in medicine. Traditional Chinese medicine (TCM) has been widely used to treat and control diabetes and its complications such as DN in a lot of scientific researches, which will give insights into the mechanism of DN, but they are not enough to reveal all the details. In this paper, we summarize the applications of herbal TCM preparations, single herbal TCM, and/or monomers from herbal TCM in the treatment of DN in the recent 10 years, depicting the renal protective effects and the corresponding mechanism, through which we shed light on the renal protective roles of TCM in DN with a particular focus on the molecular basis of the effect and provide a beneficial supplement to the drug therapy for DN. PMID:26649322

Soft shell clams Mya arenaria with disseminated neoplasia demonstrate reverse transcriptase activity

USGS Publications Warehouse

House, M.L.; Kim, C.H.; Reno, P.W.

1998-01-01

Disseminated neoplasia (DN), a proliferative cell disorder of the circulatory system of bivalves, was first reported in oysters in 1969. Since that time, the disease has been determined to be transmissible through water-borne exposure, but the etiological agent has not been unequivocally identified. In order to determine if a viral agent, possibly a retrovirus, could be the causative agent of DN, transmission experiments were performed, using both a cell-free filtrate and a sucrose gradient-purified preparation of a cell-free filtrate of DN positive materials. Additionally, a PCR-enhanced reverse transcriptase assay was used to determine if reverse transcriptase was present in tissues or hemolymph from DN positive soft shell clams Mya arenaria. DN was transmitted to healthy clams by injection with whole DN cells, but not with cell-free flitrates prepared from either tissues from DN positive clams, or DN cells. The cell-free preparations from DN-positive tissues and hemolymph having high levels of DN cells in circulation exhibited positive reactions in the PCR-enhanced reverse transcriptase assay. Cell-free preparations of hemolymph from clams having low levels of DN (<0.1% of cells abnormal), hemocytes from normal soft shell clams, and normal soft shell clam tissues did not produce a positive reaction in the PCR enhanced reverse transcriptase assay.

Review of Herbal Traditional Chinese Medicine for the Treatment of Diabetic Nephropathy.

PubMed

Sun, Guang-dong; Li, Chao-yuan; Cui, Wen-peng; Guo, Qiao-yan; Dong, Chang-qing; Zou, Hong-bin; Liu, Shu-jun; Dong, Wen-peng; Miao, Li-ning

2016-01-01

Diabetic nephropathy (DN) is the most serious chronic complications of diabetes; 20-40% of diabetic patients develop into end stage renal disease (ESRD). However, exact pathogenesis of DN is not fully clear and we have great difficulties in curing DN; poor treatment of DN led to high chances of mortality worldwide. A lot of western medicines such as ACEI and ARB have been demonstrated to protect renal function of DN but are not enough to delay or retard the progression of DN; therefore, exploring exact and feasible drug is current research hotspot in medicine. Traditional Chinese medicine (TCM) has been widely used to treat and control diabetes and its complications such as DN in a lot of scientific researches, which will give insights into the mechanism of DN, but they are not enough to reveal all the details. In this paper, we summarize the applications of herbal TCM preparations, single herbal TCM, and/or monomers from herbal TCM in the treatment of DN in the recent 10 years, depicting the renal protective effects and the corresponding mechanism, through which we shed light on the renal protective roles of TCM in DN with a particular focus on the molecular basis of the effect and provide a beneficial supplement to the drug therapy for DN.

[Financing Regional Dementia Networks in Germany: Determinants of Sustainable Healthcare Networks].

PubMed

Michalowsky, B; Wübbeler, M; Thyrian, J R; Holle, B; Gräske, J; Schäfer-Walkmann, S; Fleßa, S; Hoffmann, W

2017-12-01

Analysis of practice-based financing concepts in German dementia networks (DN); Provision of sustainable financing structures and their determinants in DN. Qualitative expert interviews with leaders of 13 DN were conducted. A semi-structured interview guide was used to analyse four main topics: Finance-related organization, cost, sources of funding and financial sustainability. DN were primarily financed by membership fees, earnings of services provided, public funds and payments by municipalities or health care providers. 63% of the DN reported a financial sustainability. Funds to support the interpersonal expanding, a mix of internal and external financing sources and investments of the municipality were determinants of a sustainable financing. Overall, DN in rural areas seemed to be disadvantaged due to a lack of potential linkable service providers. DN in urban regions are more likely able to gather sustainable funding resources. A minimum funding of 50.000 €/year for human resources coordinating the DN, seems to be a threshold for a sustainable DN. © Georg Thieme Verlag KG Stuttgart · New York.

Retracted: Association of ACE I/D gene polymorphism with T2DN susceptibility and the risk of T2DM developing into T2DN in a Caucasian population.

PubMed

Liu, Guohui; Zhou, Tian-Biao; Jiang, Zongpei; Zheng, Dongwen

2015-03-01

The association of the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism with type-2 diabetic nephropathy (T2DN) susceptibility and the risk of type-2 diabetes mellitus (T2DM) developing into T2DN in Caucasian populations is still controversial. A meta-analysis was performed to evaluate the association of ACE I/D gene polymorphism with T2DN susceptibility and the risk of T2DM developing into T2DN in Caucasian populations. A predefined literature search and selection of eligible relevant studies were performed to collect data from electronic databases. Sixteen articles were identified for the analysis of the association of ACE I/D gene polymorphism with T2DN susceptibility and the risk of T2DM developing into T2DN in Caucasian populations. ACE I/D gene polymorphism was not associated with T2DN susceptibility and the risk of patients with T2DM developing T2DN in Caucasian populations. Sensitivity analysis according to sample size of case (<100 vs. ≥100) was also performed, and the results were similar to the non-sensitivity analysis. ACE I/D gene polymorphism was not associated with T2DN susceptibility and the risk of patients with T2DM developing T2DN in Caucasian populations. However, more studies should be performed in the future. © The Author(s) 2014.

Effects of Probiotic Lactobacillus Casei DN-114 001 in Prevention of Radiation-Induced Diarrhea: Results From Multicenter, Randomized, Placebo-Controlled Nutritional Trial

DOE Office of Scientific and Technical Information (OSTI.GOV)

Giralt, Jordi; Regadera, Jose Perez; Verges, Ramona

Purpose: To determine whether a probiotic drink containing Lactobacillus casei DN-114 001 reduces the incidence of radiation-induced diarrhea in patients with gynecologic cancer. Methods and Materials: Patients who were undergoing pelvic radiotherapy (45-50 Gy, conventional fractionation) for either cervical carcinoma (radiotherapy and weekly cisplatin) or endometrial adenocarcinoma (postoperative radiotherapy) were randomly assigned to a probiotic drink or placebo, in a double-blind fashion. The probiotic drink consisted of liquid yogurt containing L. casei DN-114 001 at 10{sup 8} CFU/g. The patients recorded the daily the number of bowel movements and scored the stool consistency using the Bristol scale. Diarrhea was gradedmore » weekly according the Common Toxicity Criteria system. The primary endpoint was to reduce the incidence of diarrhea, defined by a Common Toxicity Criteria Grade of 2 or greater or the need for loperamide. Results: A total of 85 patients were enrolled. Grade 2 or greater diarrhea and/or the use of loperamide was observed in 24 of 41 patients in the placebo group and 30 of 44 in the probiotic group (p = 0.568). No differences were found in the median time to the presentation of the primary endpoint. Probiotic intervention had a significant effect on stool consistency (p = 0.04). The median time for patients to present with Bristol scale stools of Type 6 or greater was 14 days for patients receiving the probiotic drink vs. 10 days for those receiving placebo. Conclusion: Nutritional intervention with the probiotic drink containing L. casei DN-114 001 does not reduce the incidence of radiation-induced diarrhea as defined by a Common Toxicity Criteria Grade 2 or greater. However, it had a significant effect on stool consistency as measured by the Bristol scale.« less

Soft and wet actuator developed with responsible high-strength gels

NASA Astrophysics Data System (ADS)

Harada, S.; Hidema, R.; Furukawa, H.

2012-04-01

Novel high-strength gels, named double network gels (DN gels), show a smart response to altering external electric field. It was reported that a plate shape of the DN gel bends toward a positive electrode direction when a static (DC) electric field is applied. Based on this previous result, it has been tried to develop a novel soft and wet actuator, which will be used as an automatically bulging button for cellar phones, or similar small devices. First, a bending experiment of a hung plate-shape DN gel was done, and its electric field response was confirmed. Second, the response of a lying plate-shape DN gels was confirmed in order to check the bulging phenomena. The edge of three plate-shape gels that was arranged radially on a plane surface was lifted 2mm by applying DC 8V. This system is a first step to make a gels button. However the critical problem is that electrolysis occurs simultaneously under electric field. Then, the water sweep out from gels, and gels is shrinking; They cause the separation between aluminum foil working as electrode and gels. That is why, a flexible electrode should be made by gels completely attached to the gels. As a third step, a push button is tried to make by a shape memory gels (SMG). The Young's modulus of the SMG is dramatically changed by temperature. This change in the modulus is applied to control the input-acceptable state and input-not-acceptable states of the button. A novel push button is proposed as a trial, and its user-friendliness is checked by changing the size of the button. The button is deformed by pushing and is back to original shape due to the property of shape memory. We believe the mechanism of this button will be applied to develop new devices especially for visually impaired persons.

A murine model of neurofibromatosis type 1 tibial pseudarthrosis featuring proliferative fibrous tissue and osteoclast-like cells.

PubMed

El-Hoss, Jad; Sullivan, Kate; Cheng, Tegan; Yu, Nicole Y C; Bobyn, Justin D; Peacock, Lauren; Mikulec, Kathy; Baldock, Paul; Alexander, Ian E; Schindeler, Aaron; Little, David G

2012-01-01

Neurofibromatosis type 1 (NF1) is a common genetic condition caused by mutations in the NF1 gene. Patients often suffer from tissue-specific lesions associated with local double-inactivation of NF1. In this study, we generated a novel fracture model to investigate the mechanism underlying congenital pseudarthrosis of the tibia (CPT) associated with NF1. We used a Cre-expressing adenovirus (AdCre) to inactivate Nf1 in vitro in cultured osteoprogenitors and osteoblasts, and in vivo in the fracture callus of Nf1(flox/flox) and Nf1(flox/-) mice. The effects of the presence of Nf1(null) cells were extensively examined. Cultured Nf1(null)-committed osteoprogenitors from neonatal calvaria failed to differentiate and express mature osteoblastic markers, even with recombinant bone morphogenetic protein-2 (rhBMP-2) treatment. Similarly, Nf1(null)-inducible osteoprogenitors obtained from Nf1 MyoDnull mouse muscle were also unresponsive to rhBMP-2. In both closed and open fracture models in Nf1(flox/flox) and Nf1(flox/-) mice, local AdCre injection significantly impaired bone healing, with fracture union being <50% that of wild type controls. No significant difference was seen between Nf1(flox/flox) and Nf1(flox/-) mice. Histological analyses showed invasion of the Nf1(null) fractures by fibrous and highly proliferative tissue. Mean amounts of fibrous tissue were increased upward of 10-fold in Nf1(null) fractures and bromodeoxyuridine (BrdU) staining in closed fractures showed increased numbers of proliferating cells. In Nf1(null) fractures, tartrate-resistant acid phosphatase-positive (TRAP+) cells were frequently observed within the fibrous tissue, not lining a bone surface. In summary, we report that local Nf1 deletion in a fracture callus is sufficient to impair bony union and recapitulate histological features of clinical CPT. Cell culture findings support the concept that Nf1 double inactivation impairs early osteoblastic differentiation. This model provides valuable insight into the pathobiology of the disease, and will be helpful for trialing therapeutic compounds. Copyright © 2012 American Society for Bone and Mineral Research.

Shadoo/PrP (Sprn0/0/Prnp0/0) double knockout mice

PubMed Central

Daude, Nathalie; Westaway, David

2012-01-01

Shadoo (Sho) is a brain glycoprotein with similarities to the unstructured region of PrPC. Frameshift alleles of the Sho gene, Sprn, are reported in variant Creutzfeldt-Jakob disease (vCJD) patients while Sprn mRNA knockdown in PrP-null (Prnp0/0) embryos produces lethality, advancing Sho as the hypothetical PrP-like “pi” protein. Also, Sho levels are reduced as misfolded PrP accumulates during prion infections. To penetrate these issues we created Sprn null alleles (Daude et al., Proc. Natl. Acad. Sci USA 2012; 109(23): 9035–40). Results from the challenge of Sprn null and TgSprn transgenic mice with rodent-adapted prions coalesce to define downregulation of Sho as a “tracer” for the formation of misfolded PrP. However, classical BSE and rodent-adapted BSE isolates may behave differently, as they do for other facets of the pathogenic process, and this intriguing variation warrants closer scrutiny. With regards to physiological function, double knockout mice (Sprn0/0/Prnp0/0) mice survived to over 600 d of age. This suggests that Sho is not pi, or, given the accumulating data for many activities for PrPC, that the pi hypothesis invoking a discrete signaling pathway to maintain neuronal viability is no longer tenable. PMID:22929230

Spontaneous hyaline cartilage regeneration can be induced in an osteochondral defect created in the femoral condyle using a novel double-network hydrogel.

PubMed

Yokota, Masashi; Yasuda, Kazunori; Kitamura, Nobuto; Arakaki, Kazunobu; Onodera, Shin; Kurokawa, Takayuki; Gong, Jian-Ping

2011-02-22

Functional repair of articular osteochondral defects remains a major challenge not only in the field of knee surgery but also in tissue regeneration medicine. The purpose is to clarify whether the spontaneous hyaline cartilage regeneration can be induced in a large osteochondral defect created in the femoral condyle by means of implanting a novel double-network (DN) gel at the bottom of the defect. Twenty-five mature rabbits were used in this study. In the bilateral knees of each animal, we created an osteochondral defect having a diameter of 2.4-mm in the medial condyle. Then, in 21 rabbits, we implanted a DN gel plug into a right knee defect so that a vacant space of 1.5-mm depth (in Group I), 2.5-mm depth (in Group II), or 3.5-mm depth (in Group III) was left. In the left knee, we did not apply any treatment to the defect to obtain the control data. All the rabbits were sacrificed at 4 weeks, and the gross and histological evaluations were performed. The remaining 4 rabbits underwent the same treatment as used in Group II, and real-time PCR analysis was performed at 4 weeks. The defect in Group II was filled with a sufficient volume of the hyaline cartilage tissue rich in proteoglycan and type-2 collagen. The Wayne's gross appearance and histology scores showed that Group II was significantly greater than Group I, III, and Control (p < 0.012). The relative expression level of type-2 collagen, aggrecan, and SOX9 mRNAs was significantly greater in Group II than in the control group (p < 0.023). This study demonstrated that spontaneous hyaline cartilage regeneration can be induced in vivo in an osteochondral defect created in the femoral condyle by means of implanting the DN gel plug at the bottom of the defect so that an approximately 2-mm deep vacant space was intentionally left in the defect. This fact has prompted us to propose an innovative strategy without cell culture to repair osteochondral lesions in the femoral condyle.

Growth, yield, and disease resistance of 7- to 12-year-old poplar clones in the north central United States.

Treesearch

D.A. Netzer; D.N. Tolsted; M. E. Ostry; J. G. Isebrands; D.E. Riemenschneider; K.T. Ward

2002-01-01

Summarizes growth, yield, and disease resistance of 95 poplar clones at or near rotation age (culmination of mean annual increment). Plantations were established from 1986 to 1992 in Wisconsin, Minnesota, North and South Dakota. Clones DN164, DN177, DN154, NM2, NE264, DN170, and DN21 are recommended for further testing.

New Experimental Models of Diabetic Nephropathy in Mice Models of Type 2 Diabetes: Efforts to Replicate Human Nephropathy

PubMed Central

Soler, María José; Riera, Marta; Batlle, Daniel

2012-01-01

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. The use of experimental models of DN has provided valuable information regarding many aspects of DN, including pathophysiology, progression, implicated genes, and new therapeutic strategies. A large number of mouse models of diabetes have been identified and their kidney disease was characterized to various degrees. Most experimental models of type 2 DN are helpful in studying early stages of DN, but these models have not been able to reproduce the characteristic features of more advanced DN in humans such as nodules in the glomerular tuft or glomerulosclerosis. The generation of new experimental models of DN created by crossing, knockdown, or knockin of genes continues to provide improved tools for studying DN. These models provide an opportunity to search for new mechanisms involving the development of DN, but their shortcomings should be recognized as well. Moreover, it is important to recognize that the genetic background has a substantial effect on the susceptibility to diabetes and kidney disease development in the various models of diabetes. PMID:22461787

Effect of cage design on characteristics of high-speed-jet-lubricated 35-millimeter-bore ball bearing. [turbojet engines

NASA Technical Reports Server (NTRS)

Schuller, F. T.; Pinel, S. I.; Signer, H. R.

1980-01-01

Parametric tests were conducted with a 35 mm bore angular contact ball bearing with a double outer land guided cage. Provisions were made for jet lubrication and outer-ring cooling of the bearing. Test conditions included a combined thrust and radial load at nominal shaft speeds of 48,000 rpm, and an oil-in temperature of 394 K (250 F). Successful operation of the test bearing was accomplished up to 2.5 million DN. Test results were compared with those obtained with similar bearing having a single outer land guided cage. Higher temperatures were generated with the double outer land guided cage bearing, and bearing power loss and cage slip were greater. Cooling the outer ring resulted in a decrease in overall bearing operating temperature.

Motion perception during variable-radius swing motion in darkness.

PubMed

Rader, A A; Oman, C M; Merfeld, D M

2009-10-01

Using a variable-radius roll swing motion paradigm, we examined the influence of interaural (y-axis) and dorsoventral (z-axis) force modulation on perceived tilt and translation by measuring perception of horizontal translation, roll tilt, and distance from center of rotation (radius) at 0.45 and 0.8 Hz using standard magnitude estimation techniques (primarily verbal reports) in darkness. Results show that motion perception was significantly influenced by both y- and z-axis forces. During constant radius trials, subjects' perceptions of tilt and translation were generally almost veridical. By selectively pairing radius (1.22 and 0.38 m) and frequency (0.45 and 0.8 Hz, respectively), the y-axis acceleration could be tailored in opposition to gravity so that the combined y-axis gravitoinertial force (GIF) variation at the subject's ears was reduced to approximately 0.035 m/s(2) - in effect, the y-axis GIF was "nulled" below putative perceptual threshold levels. With y-axis force nulling, subjects overestimated their tilt angle and underestimated their horizontal translation and radius. For some y-axis nulling trials, a radial linear acceleration at twice the tilt frequency (0.25 m/s(2) at 0.9 Hz, 0.13 m/s(2) at 1.6 Hz) was simultaneously applied to reduce the z-axis force variations caused by centripetal acceleration and by changes in the z-axis component of gravity during tilt. For other trials, the phase of this radial linear acceleration was altered to double the magnitude of the z-axis force variations. z-axis force nulling further increased the perceived tilt angle and further decreased perceived horizontal translation and radius relative to the y-axis nulling trials, while z-axis force doubling had the opposite effect. Subject reports were remarkably geometrically consistent; an observer model-based analysis suggests that perception was influenced by knowledge of swing geometry.

Improved Neuroimaging Atlas of the Dentate Nucleus.

PubMed

He, Naying; Langley, Jason; Huddleston, Daniel E; Ling, Huawei; Xu, Hongmin; Liu, Chunlei; Yan, Fuhua; Hu, Xiaoping P

2017-12-01

The dentate nucleus (DN) of the cerebellum is the major output nucleus of the cerebellum and is rich in iron. Quantitative susceptibility mapping (QSM) provides better iron-sensitive MRI contrast to delineate the boundary of the DN than either T 2 -weighted images or susceptibility-weighted images. Prior DN atlases used T 2 -weighted or susceptibility-weighted images to create DN atlases. Here, we employ QSM images to develop an improved dentate nucleus atlas for use in imaging studies. The DN was segmented in QSM images from 38 healthy volunteers. The resulting DN masks were transformed to a common space and averaged to generate the DN atlas. The center of mass of the left and right sides of the QSM-based DN atlas in the Montreal Neurological Institute space was -13.8, -55.8, and -36.4 mm, and 13.8, -55.7, and -36.4 mm, respectively. The maximal probability and mean probability of the DN atlas with the individually segmented DNs in this cohort were 100 and 39.3%, respectively, in contrast to the maximum probability of approximately 75% and the mean probability of 23.4 to 33.7% with earlier DN atlases. Using QSM, which provides superior iron-sensitive MRI contrast for delineating iron-rich structures, an improved atlas for the dentate nucleus has been generated. The atlas can be applied to investigate the role of the DN in both normal cortico-cerebellar physiology and the variety of disease states in which it is implicated.

Quantification of cellular autofluorescence of human skin using multiphoton tomography and fluorescence lifetime imaging in two spectral detection channels

PubMed Central

Patalay, Rakesh; Talbot, Clifford; Alexandrov, Yuriy; Munro, Ian; Neil, Mark A. A.; König, Karsten; French, Paul M. W.; Chu, Anthony; Stamp, Gordon W.; Dunsby, Chris

2011-01-01

We explore the diagnostic potential of imaging endogenous fluorophores using two photon microscopy and fluorescence lifetime imaging (FLIM) in human skin with two spectral detection channels. Freshly excised benign dysplastic nevi (DN) and malignant nodular Basal Cell Carcinomas (nBCCs) were excited at 760 nm. The resulting fluorescence signal was binned manually on a cell by cell basis. This improved the reliability of fitting using a double exponential decay model and allowed the fluorescence signatures from different cell populations within the tissue to be identified and studied. We also performed a direct comparison between different diagnostic groups. A statistically significant difference between the median mean fluorescence lifetime of 2.79 ns versus 2.52 ns (blue channel, 300-500 nm) and 2.08 ns versus 1.33 ns (green channel, 500-640 nm) was found between nBCCs and DN respectively, using the Mann-Whitney U test (p < 0.01). Further differences in the distribution of fluorescence lifetime parameters and inter-patient variability are also discussed. PMID:22162820

Regulation of CCN2/CTGF Expression in the Nucleus Pulposus of the Intervertebral Disc: Role of Smad and AP1 Signaling

PubMed Central

Tran, Cassie M.; Markova, Dessislava; Smith, Harvey E.; Susarla, Bala; Ponnappan, Ravi Kumar; Anderson, D Greg; Symes, Aviva; Shapiro, Irving M.; Risbud, Makarand V.

2011-01-01

Objective To investigate TGFβ regulation of CTGF expression in cells of the nucleus pulposus. Methods Real Time RT-PCR and Western blot analysis was used to measure CTGF expression in the nucleus pulposus. Transfections were used to measure the effect of Smad2/3/7 and AP1on TGFβ mediated CTGF promoter activity. Results CTGF expression was lower in the neonatal disc compared with the skeletally mature rat disc. An increase in CTGF expression and promoter activity was observed in nucleus pulposus cells after TGFβ treatment. Deletion analysis indicated that promoter constructs lacking smad and AP1 motifs were unresponsive to treatment. Analysis showed that full-length Smad3 and the Smad3-MH2 domain alone increased CTGF activity. Further evidence of Smad3 and AP1 involvement was seen when DN-Smad3, SiRNA-Smad3, smad7 and DN-AP1 suppressed TGFβ mediated activation of the CTGF promoter. When either Smad3 or AP1 sites were mutated, CTGF promoter induction by TGFβ was suppressed. We also observed a decrease in expression of CTGF in discs of Smad3 null mice compared to the wild type. Analysis of human nucleus pulposus indicated a trend of increasing CTGF and TGFβ expression in the degenerate state. Conclusion TGFβ, through Smad3 and AP1, serves as a positive regulator of CTGF expression in the nucleus pulposus. We propose that CTGF is a part of the limited reparative response of the degenerate disc. PMID:20222112

Development of a face-to-face injunctive norms brief motivational intervention for college drinkers and preliminary outcomes

PubMed Central

Prince, Mark A.; Maisto, Stephen A.; Rice, Samara L.; Carey, Kate B.

2015-01-01

Findings are presented from the first randomized clinical trial that compared changes in alcohol consumption and alcohol-related consequences among college student drinkers from baseline to follow-up across four conditions: (a) a new single component injunctive norms brief motivational intervention (IN-BMI) condition, (b) a single component descriptive norms brief motivational intervention (DN-BMI), (c) a Combined IN and DN brief motivational intervention (Combined-BMI), and (d) assessment-only control. DN-BMI focused on the juxtaposition of personal, perceived, and actual alcohol use by typical same-sex students at your university. INBMI focused on the juxtaposition of personal, perceived, and actual attitudes about alcohol related consequences by the typical same-sex student at your university. Exploratory analyses assessed the effect of IN-BMI and DN-BMI on matched (e.g., the effect of DN-BMI on perceived DN) and mismatched norms (e.g., the effect of DN-BMI on perceived IN). IN-BMI resulted in greater decreases in alcohol use and consequences when delivered alone and in conjunction with DN-BMI compared to the control condition. Further, the Combined-BMI condition reported greater reductions in alcohol use but not consequences compared to the DN condition. Receiving IN-BMI either alone or in combination with DN-BMI produced greater changes in IN perceptions than were produced in the control group. Grounded in norms theory, this study examined how college student problem drinking is affected by both IN-BMI and DN-BMI alone and in combination. We conclude that IN-BMI alone or in combination with DN-BMI is able to modify alcohol use and reduce alcohol related consequences. PMID:26478943

Incidence and Factors Associated with De Novo DSA After BK Viremia in Renal Transplant Recipients.

PubMed

Patel, Samir J; Kuten, Samantha A; Knight, Richard J; Graviss, Edward A; Nguyen, Duc; Gaber, A Osama

2016-01-01

BK polyomavirus infection and de novo donor-human leukocyte antigen (HLA) specific antibodies (dnDSA) are two well-known and distinct complications occurring after kidney transplantation. Recent literature suggests an association between the two events. This study aims to examine the relationship between BK viremia (BKV) and dnDSA and to identify potential risk factors for dnDSA following BKV in kidney transplant recipients. A retrospective review of 1019 recipients from Houston Methodist Hospital was conducted. All patients underwent routine screening for BKV and dnDSA. Median follow-up was 44 months. BKV was detected in 186 (18%) patients at a median of 107 (82-205) days post-transplant. dnDSA occurred in 283 (28%) patients at a median of 272 (62-575) days post-transplant. Of the 69 dnDSA-positive/BKV-positive patients, dnDSA detection occurred after BKV onset in 46 patients. Thus, 46 (28%) previously DSA-negative patients later became dnDSA-positive following BKV, not significantly different from the rate seen in BKV-negative patients (26%; p=0.5). Median time to DSA detection following BKV onset was 232 days (interquartile range, 119-460) post-BKV detection. Multivariate analysis revealed a greater number of HLA mismatches and viral clearance as risk factors for development of dnDSA following BKV, whereas delayed graft function was associated with a lower risk of dnDSA. In conclusion, despite being considered a result of over-immunosuppression, BKV can still be followed by dnDSA in a substantial proportion of patients. Monitoring for dnDSA in patients being managed for BKV may be warranted. Copyright© 2017 by the Terasaki Research Institute.

Interactions between the default network and dorsal attention network vary across default subsystems, time, and cognitive states.

PubMed

Dixon, Matthew L; Andrews-Hanna, Jessica R; Spreng, R Nathan; Irving, Zachary C; Mills, Caitlin; Girn, Manesh; Christoff, Kalina

2017-02-15

Anticorrelation between the default network (DN) and dorsal attention network (DAN) is thought to be an intrinsic aspect of functional brain organization reflecting competing functions. However, the effect size of functional connectivity (FC) between the DN and DAN has yet to be established. Furthermore, the stability of anticorrelations across distinct DN subsystems, different contexts, and time, remains unexplored. In study 1 we summarize effect sizes of DN-DAN FC from 20 studies, and in study 2 we probe the variability of DN-DAN interactions across six different cognitive states in a new data set. We show that: (i) the DN and DAN have an independent rather than anticorrelated relationship when global signal regression is not used (median effect size across studies: r=-.06; 95% CI: -.15 to .08); (ii) the DAN exhibits weak negative FC with the DN Core subsystem but is uncorrelated with the dorsomedial prefrontal and medial temporal lobe subsystems; (iii) DN-DAN interactions vary significantly across different cognitive states; (iv) DN-DAN FC fluctuates across time between periods of anticorrelation and periods of positive correlation; and (v) changes across time in the strength of DN-DAN coupling are coordinated with interactions involving the frontoparietal control network (FPCN). Overall, the observed weak effect sizes related to DN-DAN anticorrelation suggest the need to re-conceptualize the nature of interactions between these networks. Furthermore, our findings demonstrate that DN-DAN interactions are not stable, but rather, exhibit substantial variability across time and context, and are coordinated with broader network dynamics involving the FPCN. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

A study of the association of glutathione S-transferase M1/T1 polymorphisms with susceptibility to vitiligo in Egyptian patients.

PubMed

Aly, Dalia Gamal; Salem, Samar Abdallah; Amr, Khalda Sayed; El-Hamid, Mahmoud Fawzy Abd

2018-01-01

The association of glutathione S-transferases M1/T1 (GSTM1/T1) null polymorphisms with vitiligo was proposed in several studies including two Egyptian studies with contradictory results. The aim here was to assess the association between GSTM1/T1 null polymorphisms and the susceptibility to vitiligo in a larger sample of Egyptian patients with generalized vitiligo. This study included 122 vitiligo patients and 200 healthy controls that were age, and gender matched. Assessment of GSTM1/T1 gene polymorphisms was done using a multiplex polymerase chain reaction (PCR). Increased odds of generalized vitiligo was observed with the null genotypes of GSTM1 and GSTT1 polymorphisms (P<0.05). Controls with GSTM1 null/GSTT1+ heterozygosis presented with a 2.97 odds protection from having generalized vitiligo (OR=2.97, 95%CI=1.1-7.7) (P=0.02) compared with patients. Small sample size of patients. This study showed a significant trend towards an association with the combination of the GSTM1/GSTT1 double null polymorphism and generalized vitiligo. Individuals with GSTM1 null/GSTT1+ heterozygosis have a 2.97 odds protection from having generalized vitiligo compared with patients. It was is the first time, to our knowledge, that such an association has been reported.

Double Negative (CD3+4-8-) TCRalphaBeta Splenic Cells from Young NOD Mice Provide Long-Lasting Protection against Type 1 Diabetes

DTIC Science & Technology

2010-07-02

indicated. Panel B, pancreatic infiltrating lymphocytes from 4 month-old NOD females ( left histogram) and males ( right histogram) (n = 8 mice/group...assay was used to measure the IL-2 secretion in the culture medium. Panel A, DN splenic cell cultures stimulated under Th1 ( left panel) and Th2 ( right ...variance test. The significance (p#0.005) of individual differences in frequency of DNCD3 thymocytes and splenocytes from female and male NOD littermates

Renin Angiotensin Aldosterone System (RAAS): its biology and drug targets for treating diabetic nephropathy.

PubMed

Zain, Maryam; Awan, Fazli Rabbi

2014-09-01

Diabetes mellitus is a multifactorial disorder of hyperglycemia caused by a combination of biochemical, molecular and genetic factors, which leads to the dysfunction of various organs including kidneys. Diabetic nephropathy (DN) is one of the microvascular complications of diabetes that results due to poor glycemic control. Several molecular and biochemical pathways have been implicated in the pathogenesis of DN. Of these, the Renin Angiotensin Aldosterone System (RAAS) is considered as a key pathway. RAAS involves various subsystems which contribute to the development of DN. Mutations in several genes of the RAAS pathway have been associated with the development of DN. These genes or their products present them as therapeutic targets for potent drugs to control or prevent DN, and development of new drugs for targeting the RAAS. Drugs in use for DN are mainly the Angiotensin Converting Enzyme (ACE) inhibitors, Angiotensin Receptors Blockers (ARB) and renin inhibitors which play important roles in reducing DN. Hence, the present review is focused on the pathophysiology and genetic factors for DN by exploring the RAAS pathway and emphasizing the benefits of blocking this pathway to control and prevent DN.

A case-control study of apoA5 -1131T-->C polymorphism that examines the role of triglyceride levels in diabetic nephropathy.

PubMed

Baum, Larry; Ng, Maggie C Y; So, Wing-Yee; Poon, Emily; Wang, Ying; Lam, Vincent K L; Tomlinson, Brian; Chan, Juliana C N

2007-01-01

Patients with diabetic nephropathy (DN) have increased plasma fasting triglyceride (TG) levels, and most prospective studies report that elevated TG precedes DN. TG-rich lipoprotein particles might promote progression of DN. To test the hypothesis that elevated TG levels contribute to the development of DN, one may examine whether a polymorphism strongly associated with TG levels affects DN risk. The apolipoprotein A5 (apoA5) -1131T-->C polymorphism has a large effect on the TG level, and all three genotypes are relatively common in East Asians. Therefore, we sought to examine the association of this polymorphism with DN. We genotyped the apoA5 -1131T-->C polymorphism in a case-control study involving 367 Chinese Type 2 diabetes patients with DN and 382 without DN, as well as 198 subjects without diabetes. Mean fasting TG levels were higher in CC than in TT carriers by 41%, 54%, and 62% in each of the three subject groups, respectively. However, the genotype distributions did not differ between patients with and without nephropathy (P=.69). Therefore, these results weigh against the hypothesis that high fasting TG per se causes DN. The strong association between TG level and DN may be due to a factor that is usually closely linked to TG level but that is not affected by the apoA5 polymorphism.

Evidence for complete epistasis of null mutations in murine Fanconi anemia genes Fanca and Fancg.

PubMed

van de Vrugt, Henri J; Koomen, Mireille; Bakker, Sietske; Berns, Mariska A D; Cheng, Ngan Ching; van der Valk, Martin A; de Vries, Yne; Rooimans, Martin A; Oostra, Anneke B; Hoatlin, Maureen E; Te Riele, Hein; Joenje, Hans; Arwert, Fré

2011-12-10

Fanconi anemia (FA) is a heritable disease characterized by bone marrow failure, congenital abnormalities, and cancer predisposition. The 15 identified FA genes operate in a molecular pathway to preserve genomic integrity. Within this pathway the FA core complex operates as an ubiquitin ligase that activates the complex of FANCD2 and FANCI to coordinate DNA repair. The FA core complex is formed by at least 12 proteins. However, only the FANCL subunit displays ubiquitin ligase activity. FANCA and FANCG are members of the FA core complex for which no other functions have been described than to participate in protein interactions. In this study we generated mice with combined null alleles for Fanca and Fancg to identify extended functions for these genes by characterizing the double mutant mice and cells. Double mutant a(-/-)/g(-/-) mice were born at near Mendelian frequencies without apparent developmental abnormalities. Histological analysis of a(-/-)/g(-/-) mice revealed a Leydig cell hyperplasia and frequent vacuolization of Sertoli cells in testes, while ovaries were depleted from developing follicles and displayed an interstitial cell hyperplasia. These gonadal aberrations were associated with a compromised fertility of a(-/-)/g(-/-) males and females. During the first year of life a(-/-)/g(-/-) did not develop malignancies or bone marrow failure. At the cellular level a(-/-)/g(-/-), Fanca(-/-), and Fancg(-/-) cells proved equally compromised in DNA crosslink and homology-directed repair. Overall the phenotype of a(-/-)/g(-/-) double knockout mice and cells appeared highly similar to the phenotype of Fanca or Fancg single knockouts. The lack of an augmented phenotype suggest that null mutations in Fanca or Fancg are fully epistatic, making additional important functions outside of the FA core complex highly unlikely. 2011 Elsevier B.V. All rights reserved.

Cis and trans RET signaling control the survival and central projection growth of rapidly adapting mechanoreceptors

PubMed Central

Fleming, Michael S; Vysochan, Anna; Paixão, Sόnia; Niu, Jingwen; Klein, Rüdiger; Savitt, Joseph M; Luo, Wenqin

2015-01-01

RET can be activated in cis or trans by its co-receptors and ligands in vitro, but the physiological roles of trans signaling are unclear. Rapidly adapting (RA) mechanoreceptors in dorsal root ganglia (DRGs) express Ret and the co-receptor Gfrα2 and depend on Ret for survival and central projection growth. Here, we show that Ret and Gfrα2 null mice display comparable early central projection deficits, but Gfrα2 null RA mechanoreceptors recover later. Loss of Gfrα1, the co-receptor implicated in activating RET in trans, causes no significant central projection or cell survival deficit, but Gfrα1;Gfrα2 double nulls phenocopy Ret nulls. Finally, we demonstrate that GFRα1 produced by neighboring DRG neurons activates RET in RA mechanoreceptors. Taken together, our results suggest that trans and cis RET signaling could function in the same developmental process and that the availability of both forms of activation likely enhances but not diversifies outcomes of RET signaling. DOI: http://dx.doi.org/10.7554/eLife.06828.001 PMID:25838128

Orexin Regulates Bone Remodeling via a Dominant Positive Central Action and a Subordinate Negative Peripheral Action

PubMed Central

Wei, Wei; Motoike, Toshiyuki; Krzeszinski, Jing Y.; Jin, Zixue; Xie, Xian-Jin; Dechow, Paul C.; Yanagisawa, Masashi; Wan, Yihong

2014-01-01

SUMMARY Orexin neuropeptides promote arousal, appetite, reward, and energy expenditure. However, whether orexin affects bone mass accrual is unknown. Here we show that orexin functions centrally through orexin receptor 2 (OX2R) in the brain to enhance bone formation. OX2R-null mice exhibit low-bone-mass owing to elevated circulating leptin; whereas central administration of an OX2R-selective agonist augments bone mass. Conversely, orexin also functions peripherally through orexin receptor 1 (OX1R) in the bone to suppress bone formation. OX1R-null mice exhibit high-bone-mass owing to a mesenchymal stem cell differentiation shift from adipocyte to osteoblast that results from higher osseous ghrelin expression. The central action is dominant over the peripheral action because bone mass is reduced in orexin-null and OX1R2R-double-null mice but enhanced in orexin over-expressing transgenic mice. These findings reveal orexin as a critical rheostat of skeletal homeostasis that exerts a yin-yang dual regulation, and highlight orexin as a therapeutic target for osteoporosis. PMID:24794976

Validity of the histopathological criteria used for diagnosing dysplastic naevi. An interobserver study by the pathology subgroup of the EORTC Malignant Melanoma Cooperative Group.

PubMed

de Wit, P E; van't Hof-Grootenboer, B; Ruiter, D J; Bondi, R; Bröcker, E B; Cesarini, J P; Hastrup, N; Hou-Jensen, K; MacKie, R M; Scheffer, E

1993-01-01

Ten (dermato)pathologists studied 50 cutaneous melanocytic lesions including common naevocellular naevi, dysplastic naevi (DN), melanomas in situ and invasive primary melanomas, with emphasis on the histological criteria of DN. Using a standardised form, 20 defined histopathological features were scored (semi)quantitatively. Concordance of diagnosis, efficacy and reproducibility of features were investigated. DN were distinguished well from the other entities (mean Po 0.87). Agreement on the degree of atypia of DN was low. The reproducibility of the scoring was best for the following features: irregular nests, lymphohistiocytic infiltrate, marked junctional proliferation and large nuclei. The overall values of these features to discriminate between DN and non-DN were better than for the other features studied. Using the presence of at least three of the four features as a condition for the diagnosis of DN, values for sensitivity, specificity and positive and negative predictive values were 0.86, 0.91, 0.96 and 0.73, respectively. On the basis of the results these features seem best suited as histological criteria for the diagnosis of DN.

Redundant role of protein kinase C delta and epsilon during mouse embryonic development.

PubMed

Carracedo, Sergio; Sacher, Frank; Brandes, Gudrun; Braun, Ursula; Leitges, Michael

2014-01-01

Protein Kinase C delta and epsilon are mediators of important cellular events, such as cell proliferation, migration or apoptosis. The formation of blood vessels, i.e., vasculo- and angiogenesis, is a process where these isoforms have also been shown to participate. However, mice deficient in either Protein Kinase C delta or epsilon are viable and therefore their individual contribution to the formation of the vasculature appeared so far dispensable. In this study, we show that double null mutation of Protein Kinase C delta and epsilon causes embryonic lethality at approximately E9.5. At this stage, whole mount staining of the endothelial marker CD31 in double null embryos revealed defective blood vessel formation. Moreover, culture of double deficient mouse allantois showed impaired endothelial cell organization, and analyses of double deficient embryo sections showed dilated vessels, decreased endothelial-specific adherent junctions, and decreased contact of endothelial cells with mural cells. Protein kinase C delta and epsilon also appeared essential for vascular smooth muscle cell differentiation, since α-smooth muscle actin, a classical marker for vascular smooth muscle cells, was almost undetectable in double deficient embryonic aorta at E9.5. Subsequent qPCR analyses showed decreased VE-cadherin, Vegfr2, Cd31, Cdh2, Ets1, and Fli-1, among other angiogenesis related transcripts in double deficient embryos. Taken together, these data suggest for the first time an in vivo redundant role between members of the novel Protein Kinase C subfamily that allows for mutual compensation during mouse embryonic development, with vasculogenesis/angiogenesis as an obvious common function of these two Protein Kinase Cs. Protein Kinase C delta and epsilon might therefore be useful targets for inhibiting vasculo- and/or angiogenesis.

A single group, pretest-posttest clinical trial for the effects of dry needling on wrist flexors spasticity after stroke.

PubMed

Fakhari, Zahra; Ansari, Noureddin Nakhostin; Naghdi, Soofia; Mansouri, Korosh; Radinmehr, Hojjat

2017-01-01

Spasticity is a common complication after stroke. Dry needling (DN) is suggested as a novel method for treatment of muscle spasticity. To explore the effects of DN on wrist flexors spasticity poststroke. A single group, pretest-posttest clinical trial was used. Twenty nine patients with stroke (16 male; mean age 54.3 years) were tested at baseline (T0), immediately after DN (T1), and one hour after DN (T2). DN was applied for flexor carpi radialis (FCR) and flexor carpi ulnaris on the affected arm for single session, one minute per muscle. The Modified Modified Ashworth Scale (MMAS), passive resistance force, wrist active and passive range of motion, Box and Block Test, and FCR H-reflex were outcome measures. Significant reductions in MMAS scores were seen both immediately after DN and at 1-hour follow-up (median 2 at T0 to 1 at T1 and T2). There were significant improvements in other measures between the baseline values at T0 and those recorded immediately after the DN at T1 or one hour later at T2. This study suggests that DN reduced wrist flexors spasticity and alpha motor neuron excitability in patients with stroke, and improvements persisted for one hour after DN.

Double-null divertor configuration discharge and disruptive heat flux simulation using TSC on EAST

NASA Astrophysics Data System (ADS)

Bo, SHI; Jinhong, YANG; Cheng, YANG; Desheng, CHENG; Hui, WANG; Hui, ZHANG; Haifei, DENG; Junli, QI; Xianzu, GONG; Weihua, WANG

2018-07-01

The tokamak simulation code (TSC) is employed to simulate the complete evolution of a disruptive discharge in the experimental advanced superconducting tokamak. The multiplication factor of the anomalous transport coefficient was adjusted to model the major disruptive discharge with double-null divertor configuration based on shot 61 916. The real-time feed-back control system for the plasma displacement was employed. Modeling results of the evolution of the poloidal field coil currents, the plasma current, the major radius, the plasma configuration all show agreement with experimental measurements. Results from the simulation show that during disruption, heat flux about 8 MW m‑2 flows to the upper divertor target plate and about 6 MW m‑2 flows to the lower divertor target plate. Computations predict that different amounts of heat fluxes on the divertor target plate could result by adjusting the multiplication factor of the anomalous transport coefficient. This shows that TSC has high flexibility and predictability.

Addressing the knowledge gap in clinical recommendations for management and complete excision of clinically atypical nevi/dysplastic nevi: Pigmented Lesion Subcommittee consensus statement.

PubMed

Kim, Caroline C; Swetter, Susan M; Curiel-Lewandrowski, Clara; Grichnik, James M; Grossman, Douglas; Halpern, Allan C; Kirkwood, John M; Leachman, Sancy A; Marghoob, Ashfaq A; Ming, Michael E; Nelson, Kelly C; Veledar, Emir; Venna, Suraj S; Chen, Suephy C

2015-02-01

The management of clinically atypical nevi/dysplastic nevi (CAN/DN) is controversial, with few data to guide the process. Management recommendations for DN with positive histologic margins were developed by the Delphi method to achieve consensus among members of the Pigmented Lesion Subcommittee (PLS) of the Melanoma Prevention Working Group (MPWG) after reviewing the current evidence. To outline key issues related to the management of CAN/DN: (1) biopsies of CAN and how positive margins arise, (2) whether incompletely excised DN evolve into melanoma, (3) current data on the outcomes of DN with positive histologic margins, (4) consensus recommendations, and (5) a proposal for future studies, including a large-scale study to help guide the management of DN with positive margins. The literature, including recent studies examining management and outcomes of DN with positive margins between 2009 to 2014, was reviewed. A consensus statement by the PLS of the MPWG following review of the literature, group discussions, and a structured Delphi method consensus. This consensus statement reviews the complexities of management of CAN/DN. A review of the literature and 2 rounds of a structured Delphi consensus resulted in the following recommendations: (1) mildly and moderately DN with clear margins do not need to be reexcised, (2) mildly DN biopsied with positive histologic margins without clinical residual pigmentation may be safely observed rather than reexcised, and (3) observation may be a reasonable option for management of moderately DN with positive histologic margins without clinically apparent residual pigmentation; however, more data are needed to make definitive recommendations in this clinical scenario.

Effects of glutathione s-transferase (GST) M1 and T1 polymorphisms on antioxidant vitamins and oxidative stress-related parameters in Korean subclinical hypertensive subjects after kale juice (Brassica oleracea acephala) supplementation.

PubMed

Lee, Hye-Jin; Han, Jeong-Hwa; Park, Yoo Kyoung; Kang, Myung-Hee

2018-04-01

Glutathione s-transferase ( GST ) is involved in the formation of a multigene family comprising phase II detoxification enzymes, involved in the detoxification of reactive oxygen species. This study evaluated whether daily supplementation with kale juice could modulate levels of plasma antioxidant vitamins and oxidative stress-related parameters. We further examined whether this modulation was affected by combined GSTM1 and T1 polymorphisms. Totally, 84 subclinical hypertensive patients having systolic blood pressure (BP) over 130 mmHg or diastolic BP over 85 mmHg, received 300 mL of kale juice daily for 6 weeks. Blood samples were drawn before start of study and after completion of 6 weeks. After supplementation, we observed significant decrease in DNA damage and increase in erythrocyte catalase activity in all genotypes. Plasma level of vitamin C was significantly increased in the wild/null and double null genotypes. The plasma levels of β-carotene, erythrocyte glutathione peroxidase activity, and nitric oxide were increased only in the wild/null genotype after kale juice supplementation. The effect of kale juice was significantly greater in the GSTM1 null genotype and wild/null genotype groups, suggesting possibility of personalized nutritional prescriptions based on personal genetics.

Aerodynamic parameters of across-wind self-limiting vibration for square sections after lock-in in smooth flow

NASA Astrophysics Data System (ADS)

Wu, Jong-Cheng; Chang, Feng-Jung

2011-08-01

The paper aims to identify the across-wind aerodynamic parameters of two-dimensional square section structures after the lock-in stage from the response measurements of wind tunnel tests under smooth wind flow conditions. Firstly, a conceivable self-limiting model was selected from the existent literature and the revisit of the analytical solution shows that the aerodynamic parameters (linear and nonlinear aerodynamic dampings Y1 and ɛ, and aerodynamic stiffness Y2) are not only functions of the section shape and reduced wind velocity but also dependent on both the mass ratio ( mr) and structural damping ratio ( ξ) independently, rather than on the Scruton number as a whole. Secondly, the growth-to-resonance (GTR) method was adopted for identifying the aerodynamic parameters of four different square section models (DN1, DN2, DN3 and DN4) by varying the density ranging from 226 to 409 kg/m 3. To improve the accuracy of the results, numerical optimization of the curve-fitting for experimental and analytical response in time domain was performed to finalize the results. The experimental results of the across-wind self-limiting steady-state amplitudes after lock-in stage versus the reduced wind velocity show that, except the tail part of the DN1 case slightly decreases indicating a pure vortex-induced lock-in persists, the DN2, DN3 and DN4 cases have a trend of monotonically increasing with the reduced wind velocity, which shows an asymptotic combination with the galloping behavior. Due to such a combination effect, all three aerodynamic parameters decrease as the reduced wind velocity increases and asymptotically approaches to a constant at the high branch. In the DN1 case, the parameters Y1 and Y2 decrease as the reduced wind velocity increases while the parameter ɛ slightly reverses in the tail part. The 3-dimensional surface plot of the Y1, ɛ and Y2 curves further show that, excluding the DN1 case, the parameters in the DN2, DN3 and DN4 cases almost follow a symmetric concave-up distribution versus the density under the same reduced wind velocity. This indicates that the aerodynamic parameters in the DN3 case are the minima along the density distribution.

Role of Aquaporin-4 in Airspace-to-Capillary Water Permeability in Intact Mouse Lung Measured by a Novel Gravimetric Method

PubMed Central

Song, Yuanlin; Ma, Tonghui; Matthay, Michael A.; Verkman, A.S.

2000-01-01

The mammalian peripheral lung contains at least three aquaporin (AQP) water channels: AQP1 in microvascular endothelia, AQP4 in airway epithelia, and AQP5 in alveolar epithelia. In this study, we determined the role of AQP4 in airspace-to-capillary water transport by comparing water permeability in wild-type mice and transgenic null mice lacking AQP1, AQP4, or AQP1/AQP4 together. An apparatus was constructed to measure lung weight continuously during pulmonary artery perfusion of isolated mouse lungs. Osmotically induced water flux (Jv) between the airspace and capillary compartments was measured from the kinetics of lung weight change in saline-filled lungs in response to changes in perfusate osmolality. Jv in wild-type mice varied linearly with osmotic gradient size (4.4 × 10−5 cm3 s−1 mOsm−1) and was symmetric, independent of perfusate osmolyte size, weakly temperature dependent, and decreased 11-fold by AQP1 deletion. Transcapillary osmotic water permeability was greatly reduced by AQP1 deletion, as measured by the same method except that the airspace saline was replaced by an inert perfluorocarbon. Hydrostatically induced lung edema was characterized by lung weight changes in response to changes in pulmonary arterial inflow or pulmonary venous outflow pressure. At 5 cm H2O outflow pressure, the filtration coefficient was 4.7 cm3 s−1 mOsm−1 and reduced 1.4-fold by AQP1 deletion. To study the role of AQP4 in lung water transport, AQP1/AQP4 double knockout mice were generated by crossbreeding of AQP1 and AQP4 null mice. Jv were (cm3 s−1 mOsm−1 × 10−5, SEM, n = 7–12 mice): 3.8 ± 0.4 (wild type), 0.35 ± 0.02 (AQP1 null), 3.7 ± 0.4 (AQP4 null), and 0.25 ± 0.01 (AQP1/AQP4 null). The significant reduction in P f in AQP1 vs. AQP1/AQP4 null mice was confirmed by an independent pleural surface fluorescence method showing a 1.6 ± 0.2-fold (SEM, five mice) reduced P f in the AQP1/AQP4 double knockout mice vs. AQP1 null mice. These results establish a simple gravimetric method to quantify osmosis and filtration in intact mouse lung and provide direct evidence for a contribution of the distal airways to airspace-to-capillary water transport. PMID:10613915

Initial development of the DIII–D snowflake divertor control

NASA Astrophysics Data System (ADS)

Kolemen, E.; Vail, P. J.; Makowski, M. A.; Allen, S. L.; Bray, B. D.; Fenstermacher, M. E.; Humphreys, D. A.; Hyatt, A. W.; Lasnier, C. J.; Leonard, A. W.; McLean, A. G.; Maingi, R.; Nazikian, R.; Petrie, T. W.; Soukhanovskii, V. A.; Unterberg, E. A.

2018-06-01

Simultaneous control of two proximate magnetic field nulls in the divertor region is demonstrated on DIII–D to enable plasma operations in an advanced magnetic configuration known as the snowflake divertor (SFD). The SFD is characterized by a second-order poloidal field null, created by merging two first-order nulls of the standard divertor configuration. The snowflake configuration has many magnetic properties, such as high poloidal flux expansion, large plasma-wetted area, and additional strike points, that are advantageous for divertor heat flux management in future fusion reactors. However, the magnetic configuration of the SFD is highly-sensitive to changes in currents within the plasma and external coils and therefore requires complex magnetic control. The first real-time snowflake detection and control system on DIII–D has been implemented in order to stabilize the configuration. The control algorithm calculates the position of the two nulls in real-time by locally-expanding the Grad–Shafranov equation in the divertor region. A linear relation between variations in the poloidal field coil currents and changes in the null locations is then analytically derived. This formulation allows for simultaneous control of multiple coils to achieve a desired SFD configuration. It is shown that the control enabled various snowflake configurations on DIII–D in scenarios such as the double-null advanced tokamak. The SFD resulted in a 2.5×  reduction in the peak heat flux for many energy confinement times (2–3 s) without any adverse effects on core plasma performance.

Can one ever prove that neutrinos are Dirac particles?

NASA Astrophysics Data System (ADS)

Hirsch, Martin; Srivastava, Rahul; Valle, José W. F.

2018-06-01

According to the "Black Box" theorem the experimental confirmation of neutrinoless double beta decay (0 ν 2 β) would imply that at least one of the neutrinos is a Majorana particle. However, a null 0 ν 2 β signal cannot decide the nature of neutrinos, as it can be suppressed even for Majorana neutrinos. In this letter we argue that if the null 0 ν 2 β decay signal is accompanied by a 0 ν 4 β quadruple beta decay signal, then at least one neutrino should be a Dirac particle. This argument holds irrespective of the underlying processes leading to such decays.

Distribution and diversity of Russian wheat aphid (Hemiptera: Aphididae) biotypes in South Africa and Lesotho.

PubMed

Jankielsohn, Astrid

2011-10-01

Russian wheat aphid, Diuraphis noxia (Kurdjumov) (Hemiptera: Aphididae) was recorded for the first time in South Africa in 1978. In 2005, a second biotype, RWASA2, emerged, and here we report on the emergence of yet another biotype, found for the first time in 2009. The discovery of new Russian wheat aphid biotypes is a significant challenge to the wheat, Triticum aestivum L., industry in South Africa. Russian wheat aphid resistance in wheat, that offered wheat producers a long-term solution to Russian wheat aphid control, may no longer be effective in areas where the new biotypes occur. It is therefore critical to determine the diversity and extent of distribution of biotypes in South Africa to successfully deploy Russian wheat aphid resistance in wheat. Screening of 96 Russian wheat aphid clones resulted in identification of three Russian wheat aphid biotypes. Infestations of RWASA1 caused susceptible damage symptoms only in wheat entries containing the Dn3 gene. Infestations of RWASA2 caused susceptible damage symptoms in wheat entries containing Dn1, Dn2, Dn3, and Dn9 resistant genes. Based on the damage-rating scores for the seven resistance sources, a new biotype, which caused damage rating scores different from those for RWASA1 and RWASA2, was evident among the Russian wheat aphid populations tested. This new biotype is virulent to the same resistance sources as RWASA2 (Dn1, Dn2, Dn3, and Dn9), but it also has added virulence to Dn4, whereas RWASA2 is avirulent to this resistance source.

The application of neuropathic pain questionnaires in burning mouth syndrome patients.

PubMed

Heo, Jun-Young; Ok, Soo-Min; Ahn, Yong-Woo; Ko, Myung-Yun; Jeong, Sung-Hee

2015-01-01

To evaluate and compare the validity of the PainDETECT, DN4, and abbreviated DN4 (DN4i) neuropathic pain questionnaires for primary burning mouth syndrome (BMS), which is a burning sensation in the oral mucosa in the absence of any identifiable organic etiology. Eighty-one patients (42 with primary BMS and 39 with nociceptive pain) complaining of a burning sensation and pain in their oral mucosa were enrolled in this study. All of the patients completed the neuropathic pain questionnaires. The sensitivity, specificity, positive predictive value, negative predictive value, and the area under the receiver operating characteristic (ROC) curve were estimated. Then the relationship between pain intensity and total neuropathic pain score was investigated. Data were analyzed with the chi-square test and independent t test for subjects' baseline characteristic differences, and with Pearson correlation coefficients for the relationship of variables. The mean area under the ROC curves (AUCs) for PainDETECT, DN4, and DN4i were 0.81, 0.79, and 0.81, respectively. There was no statistically significant difference in the AUCs among the questionnaires. PainDETECT, DN4, and DN4i had a lower sensitivity and specificity for BMS compared to previous validation studies. The total scores for PainDETECT, DN4, and DN4i in the primary BMS group were significantly associated with pain intensity. Although the results of this study suggest that neuropathic pain questionnaires, such as PainDETECT and DN4, are not ideal principal screening tools for BMS patients, a substantial proportion of neuropathic symptoms in primary BMS patients were identified.

The Role of Endoplasmic Reticulum Stress in Diabetic Nephropathy.

PubMed

Fan, Ying; Lee, Kyung; Wang, Niansong; He, John Cijiang

2017-03-01

Diabetic nephropathy (DN) has become the leading cause of end-stage renal disease (ESRD) worldwide. Accumulating evidence suggests that endoplasmic reticulum (ER) stress plays a major role in the development and progression of DN. Recent findings suggested that many attributes of DN, such as hyperglycemia, proteinuria, and increased advanced glycation end products and free fatty acids, can all trigger unfolded protein response (UPR) in kidney cells. Herein, we review the current knowledge on the role of ER stress in the setting of kidney injury with a specific emphasis on DN. As maladaptive ER stress response caused by excessively prolonged UPR will eventually cause cell death and increase kidney injury, several ER stress inhibitors have been shown to improve DN in animal models, albeit blocking both adaptive and maladaptive UPR. More recently, reticulon-1A (RTN1A), an ER-associated protein, was shown to be increased in both human and mouse diabetic kidneys. Its expression correlates with the progression of DN, and its polymorphisms are associated with kidney disease in people with diabetes. Increased RTN1A expression heightened the ER stress response and renal cell apoptosis, and conversely reduced RTN1A in renal cells decreased apoptosis and ameliorated kidney injury and DN progression, suggesting that RTN1A may be a novel target to specifically restrain the maladaptive UPR. These findings suggest that ER stress response in renal cells is a key driver of progression of DN and that the inhibition of the unchecked ER stress response in DN, such as by inhibition of RTN1A function, may be a promising therapeutic approach against DN.

Metabonomics revealed xanthine oxidase-induced oxidative stress and inflammation in the pathogenesis of diabetic nephropathy.

PubMed

Liu, Jingping; Wang, Chengshi; Liu, Fang; Lu, Yanrong; Cheng, Jingqiu

2015-03-01

Diabetic nephropathy (DN) is a serious complication of diabetes mellitus (DM), which is a major public health problem in the world. To reveal the metabolic changes associated with DN, we analyzed the serum, urine, and renal extracts obtained from control and streptozotocin (STZ)-induced DN rats by (1)H NMR-based metabonomics and multivariate data analysis. A significant difference between control and DN rats was revealed in metabolic profiles, and we identified several important DN-related metabolites including increased levels of allantoin and uric acid (UA) in the DN rats, suggesting that disturbed purine metabolism may be involved in the DN. Combined with conventional histological and biological methods, we further demonstrated that xanthine oxidase (XO), a key enzyme for purine catabolism, was abnormally activated in the kidney of diabetic rats by hyperglycemia. The highly activated XO increased the level of intracellular ROS, which caused renal injury by direct oxidative damage to renal cells, and indirect inducing inflammatory responses via activating NF-κB signaling pathway. Our study highlighted that metabonomics is a promising tool to reveal the metabolic changes and the underlying mechanism involved in the pathogenesis of DN.

Role of altered insulin signaling pathways in the pathogenesis of podocyte malfunction and microalbuminuria

PubMed Central

Jauregui, Alexandra; Mintz, Daniel H; Mundel, Peter; Fornoni, Alessia

2010-01-01

Purpose of review In diabetic nephropathy (DN), insulin resistance and hyperinsulinemia correlate with the development of albuminuria. The possibility that altered insulin signaling in glomerular cells and particularly podocytes contributes to the development of DN will be discussed. Recent findings While normal podocytes uptake glucose in response to insulin, diabetic podocytes become insulin resistant in experimental DN prior to the development of significant albuminuria. Both clinical and experimental data suggest that insulin sensitizers may be renoprotective independently of their systemic effects on the metabolic control of diabetes. Summary We will review the clinical and experimental evidence that altered insulin signaling correlates with the development of DN in both type 1 and type 2 diabetes, and that insulin sensitizers may be superior to other hypoglycemic agents in the prevention of DN. We will then review potential mechanisms by which altered podocyte insulin signaling may contribute to the development of DN. Understanding the role of podocyte in glucose metabolism is important because it may lead to the discovery of novel pathogenetic mechanisms of DN, it may affect current strategies for prevention and treatment of DN, and it may allow for the identification of novel therapeutic targets. PMID:19724224

Dysfunctional hippocampal inhibition in the Ts65Dn mouse model of Down syndrome

PubMed Central

Best, Tyler K.; Cramer, Nathan P.; Chakrabarti, Lina; Haydar, Tarik F.; Galdzicki, Zygmunt

2013-01-01

GABAergic dysfunction is implicated in hippocampal deficits of the Ts65Dn mouse model of Down syndrome (DS). Since Ts65Dn mice overexpress G-protein coupled inward-rectifying potassium (GIRK2) containing channels, we sought to evaluate whether increased GABAergic function disrupts the functioning of hippocampal circuitry. After confirming that GABAB/GIRK current density is significantly elevated in Ts65Dn CA1 pyramidal neurons, we compared monosynaptic inhibitory inputs in CA1 pyramidal neurons in response to proximal (stratum radiatum; SR) and distal (stratum lacunosum moleculare; SLM) stimulation of diploid and Ts65Dn acute hippocampal slices. Synaptic GABAB and GABAA mediated currents evoked by SR stimulation were generally unaffected in Ts65Dn CA1 neurons. However, the GABAB/GABAA ratios evoked by stimulation within the SLM of Ts65Dn hippocampus were significantly larger in magnitude, consistent with increased GABAB/GIRK currents after SLM stimulation. These results indicate that GIRK overexpression in Ts65Dn has functional consequences which affect the balance between GABAB and GABAA inhibition of CA1 pyramidal neurons, most likely in a pathway specific manner, and may contribute to cognitive deficits reported in these mice. PMID:22178330

Neurophysiological and clinical effects of dry needling in patients with upper trapezius myofascial trigger points.

PubMed

Abbaszadeh-Amirdehi, Maryam; Ansari, Noureddin Nakhostin; Naghdi, Soofia; Olyaei, Gholamreza; Nourbakhsh, Mohammad Reza

2017-01-01

Dry needling (DN) is a widely used in treatment of myofascial trigger points (MTrPs). The purpose of this pretest-posttest clinical trial was to investigate the neurophysiological and clinical effects of DN in patients with MTrPs. A sample of 20 patients (3 man, 17 women; mean age 31.7 ± 10.8) with upper trapezius MTrPs received one session of deep DN. The outcomes of neuromuscular junction response (NMJR), sympathetic skin response (SSR), pain intensity (PI) and pressure pain threshold (PPT) were measured at baseline and immediately after DN. There were significant improvements in SSR latency and amplitude, pain, and PPT after DN. The NMJR decreased and returned to normal after DN. A single session of DN to the active upper trapezius MTrP was effective in improving pain, PPT, NMJR, and SSR in patients with myofascial trigger points. Further studies are needed. Copyright © 2016 Elsevier Ltd. All rights reserved.

Hypothalamic-pituitary cytokine network.

PubMed

Kariagina, Anastasia; Romanenko, Dmitry; Ren, Song-Guang; Chesnokova, Vera

2004-01-01

Cytokines expressed in the brain and involved in regulating the hypothalamus-pituitary-adrenal (HPA) axis contribute to the neuroendocrine interface. Leukemia inhibitory factor (LIF) and LIF receptors are expressed in human pituitary cells and murine hypothalamus and pituitary. LIF potently induces pituitary proopiomelanocortin (POMC) gene transcription and ACTH secretion and potentiates CRH induction of POMC. In vivo, LIF, along with CRH, enhances POMC expression and ACTH secretion in response to emotional and inflammatory stress. To further elucidate specific roles for both CRH and LIF in activating the inflammatory HPA response, double-knockout mice (CRH/LIFKO) were generated by breeding the null mutants for each respective single gene. Inflammation produced by ip injection of lipopolysaccharide (1 microg/mouse) to double CRH and LIF-deficient mice elicited pituitary POMC induction similar to wild type and markedly higher than in single null animals (P<0.0.01). Double-knockout mice also demonstrated robust corticosterone response to inflammation. High pituitary POMC mRNA levels may reflect abundant TNFalpha, IL-1beta, and IL-6 activation observed in the hypothalamus and pituitary of these animals. Our results suggest that increased central proinflammatory cytokine expression can compensate for the impaired HPA axis function and activates inflammatory ACTH and corticosterone responses in mice-deficient in both CRH and LIF.

Induction of Unconventional T Cells by a Mutant Mycobacterium bovis BCG Strain Formulated in Cationic Liposomes Correlates with Protection against Mycobacterium tuberculosis Infections of Immunocompromised Mice

PubMed Central

Yabe, Idalia; Morris, Sheldon; Cowley, Siobhan

2016-01-01

Earlier studies aimed at defining protective immunity induced by Mycobacterium bovis BCG immunization have largely focused on the induction of antituberculosis CD4+ and CD8+ T cell responses. Here we describe a vaccine consisting of a BCGΔmmaA4 deletion mutant formulated in dimethyl dioctadecyl-ammonium bromide (DDA) with d-(+)-trehalose 6,6′-dibehenate (TDB) (DDA/TDB) adjuvant (A4/Adj) that protected TCRδ−/− mice depleted of CD4+, CD8+, and NK1.1+ T cells against an aerosol challenge with M. tuberculosis. These mice were significantly protected relative to mice immunized with a nonadjuvanted BCGΔmmaA4 (BCG-A4) mutant and nonvaccinated controls at 2 months and 9 months postvaccination. In the absence of all T cells following treatment with anti-Thy1.2 antibody, the immunized mice lost the ability to control the infection. These results indicate that an unconventional T cell population was mediating protection in the absence of CD4+, CD8+, NK1.1+, and TCRγδ T cells and could exhibit memory. Focusing on CD4− CD8− double-negative (DN) T cells, we found that these cells accumulated in the lungs postchallenge significantly more in A4/Adj-immunized mice and induced significantly greater frequencies of pulmonary gamma interferon (IFN-γ)-producing cells than were seen in the nonvaccinated or nonadjuvanted BCG control groups. Moreover, pulmonary DN T cells from the A4/Adj group exhibited significantly higher IFN-γ integrated median fluorescence intensity (iMFI) values than were seen in the control groups. We also showed that enriched DN T cells from mice immunized with A4/Adj could control mycobacterial growth in vitro significantly better than naive whole-spleen cells. These results suggest that formulating BCG in DDA/TDB adjuvant confers superior protection in immunocompromised mice and likely involves the induction of long-lived memory DN T cells. PMID:27226281

Potential role of alpha-synuclein and metallothionein in lead-induced inclusion body formation.

PubMed

Zuo, Peijun; Qu, Wei; Cooper, Ryan N; Goyer, Robert A; Diwan, Bhalchandra A; Waalkes, Michael P

2009-09-01

Lead (Pb) produces aggresome-like inclusion bodies (IBs) in target cells as a toxic response. Our prior work shows metallothionein (MT) is required for this process. We used MT-I/II double knockout (MT-null) and parental wild-type (WT) cell lines to further explore the formation process of Pb-induced IBs. Unlike WT cells, MT-null cells did not form IBs after Pb exposure. Western blot of cytosol showed soluble MT protein in WT cells was lost during Pb exposure as IBs formed. Transfection of MT-I into MT-null cells allowed IBs formation after Pb exposure. Considering Pb-induced IBs may be like disease-related aggresomes, which often contain alpha-synuclein (Scna), we investigated Scna expression in cells capable (WT) and incapable (MT-null) of producing IBs after Pb exposure. Scna protein showed poor basal expression in MT-null cells. Pb exposure increased Scna expression only in WT cells. MT transfection increased Scna transcript to WT levels. In WT or MT-transfected MT-null cells, Pb-induced Scna expression rapidly increased and then decreased over 48 h as Pb-induced IBs were formed. A direct interaction between Scna and MT was confirmed ex vivo by antibody pulldown assay where the proteins coprecipitated with an antibody to MT. Pb exposure caused increased colocalization of MT and Scna proteins with time only in WT cells. In WT mice after chronic Pb exposure Scna was localized in renal cells containing forming IBs, whereas MT-null mice did not form IBs. Thus, Scna could be component of Pb-induced IBs and, with MT, may play a role in IBs formation.

Change in Biotypic Diversity of Russian Wheat Aphid (Hemiptera: Aphididae) Populations in the United States.

PubMed

Puterka, G J; Giles, K L; Brown, M J; Nicholson, S J; Hammon, R W; Peairs, F B; Randolph, T L; Michaels, G J; Bynum, E D; Springer, T L; Armstrong, J S; Mornhinweg, D W

2015-04-01

A key component of Russian wheat aphid, Diuraphis noxia (Kurdjumov), management has been through planting resistant wheat cultivars. A new biotype, RWA2, appeared in 2003 which caused widespread damage to wheat cultivars containing the Dn4 gene. Biotypic diversity in Russian wheat aphid populations has not been addressed since 2005 when RWA2 dominated the biotype complex. Our objectives were to determine the biotypic diversity in the Central Great Plains and Colorado Plateau at regional (2010, 2011, 2013) and local (2012) levels and detect the presence of new Russian wheat aphid biotypes. Regional and within-field aphid collections were screened against Russian wheat aphid-resistant wheat genotypes containing genes Dn3, Dn4, Dn6, Dn7, Dn9, CI2401; and resistant barley STARS 9301B. In 2010, all aphid collections from Texas were avirulent to the Dn4 resistance gene in wheat. Regional results revealed Dn4 avirulent RWA6 was widespread (55-84%) in populations infesting wheat in both regions. Biotypes RWA1, 2, and 3/7 were equally represented with percentages<20% each while RWA8 was rarely detected. Combining percentages of RWA1, 6, and 8 across regions to estimate avirulence to Dn4 gene revealed high percentages for both 2011 (64-80%) and 2013 (69-90%). In contrast, the biotype structure at the local level differed where biotype percentages varied up to ≥2-fold between fields. No new biotypes were detected; therefore, Dn7, CI2401, and STARS9301B remained resistant to all known Russian wheat aphid biotypes. This study documents a shift to Dn4 avirulent biotypes and serves as a valuable baseline for biotypic diversity in Russian wheat aphid populations prior to the deployment of new Russian wheat aphid-resistant wheat cultivars. Published by Oxford University Press on behalf of Entomological Society of America 2015. This work is written by US Government employees and is in the public domain in the US.

The relationship between hemoglobin level and the type 1 diabetic nephropathy in Anhui Han's patients.

PubMed

Jiang, Jun; Lei, Lan; Zhou, Xiaowan; Li, Peng; Wei, Ren

2018-02-20

Recent studies have shown that low hemoglobin (Hb) level promote the progression of chronic kidney disease. This study assessed the relationship between Hb level and type 1 diabetic nephropathy (DN) in Anhui Han's patients. There were a total of 236 patients diagnosed with type 1 diabetes mellitus and (T1DM) seen between January 2014 and December 2016 in our centre. Hemoglobin levels in patients with DN were compared with those without DN. The relationship between Hb level and the urinary albumin-creatinine ratio (ACR) was examined by Spearman's correlational analysis and multiple stepwise regression analysis. The binary logistic multivariate regression analysis was performed to analyze the correlated factors for type 1 DN, calculate the Odds Ratio (OR) and 95%confidence interval (CI). The predicting value of Hb level for DN was evaluated by area under receiver operation characteristic curve (AUROC) for discrimination and Hosmer-Lemeshow goodness-of-fit test for calibration. The average Hb levels in the DN group (116.1 ± 20.8 g/L) were significantly lower than the non-DN group (131.9 ± 14.4 g/L) , P < 0.001. Hb levels were independently correlated with the urinary ACR in multiple stepwise regression analysis. The logistic multivariate regression analysis showed that the Hb level (OR: 0.936, 95% CI: 0.910 to 0.963, P < 0.001) was inversely correlated with DN in patients with T1DM. In sub-analysis, low Hb level (Hb < 120g/L in female, Hb < 130g/L in male) was still negatively associated with DN in patients with T1DM. The AUROC was 0.721 (95% CI: 0.655 to 0.787) in assessing the discrimination of the Hb level for DN. The value of P was 0.593 in Hosmer-Lemeshow goodness-of-fit test. In Anhui Han's patients with T1DM, the Hb level is inversely correlated with urinary ACR and DN. This article is protected by copyright. All rights reserved.

The Leu72Met polymorphism of the GHRL gene prevents the development of diabetic nephropathy in Chinese patients with type 2 diabetes mellitus.

PubMed

Zhuang, Langen; Li, Ming; Yu, Changhua; Li, Can; Zhao, Mingming; Lu, Ming; Zheng, Taishan; Zhang, Rong; Zhao, Weijing; Bao, Yuqian; Xiang, Kunsan; Jia, Weiping; Wang, Niansong; Liu, Limei

2014-02-01

The preproghrelin (GHRL) Leu72Met polymorphism (rs 696217) is associated with obesity, reduced glucose-induced insulin secretion in healthy or diabetic subjects, and reduced serum creatinine (Scr) levels in type 2 diabetes. We evaluated the association of the Leu72Met polymorphism with measures of insulin sensitivity in non-diabetic control individuals and type 2 diabetics, and whether this variation contributes to the development of diabetic nephropathy (DN) in type 2 diabetes. A case-control study was performed of 291 non-diabetic control subjects and 466 patients with type 2 diabetes, of whom 238 had DN with overt albuminuria (DN group; albuminuric excretion rate [AER] ≥ 300 mg/24 h) and 228 did not have DN, but had diabetes for more than 10 years (non-DN group). Genotyping was performed using a TaqMan PCR assay. The Leu/Leu, Leu/Met, and Met/Met genotype frequencies were significantly different between the non-DN and DN groups (p = 0.011). The frequency of the variant genotypes (Leu/Met, Met/Met) was significantly lower in the DN group than the non-DN group (23.5 vs. 36.0 %, p = 0.003). Met/Met non-diabetic control subjects had lower BMI and Scr levels and higher eGFR level than Leu/Leu or Leu/Met individuals (p < 0.05). Leu/Met and Met/Met type 2 diabetics had significantly lower AER and Scr levels and higher eGFR level than Leu/Leu type 2 diabetics (all p < 0.001). The GHRL Leu72Met polymorphism may help to maintain normal renal function and may protect against the development of DN by reducing albuminuria and improving renal function in Chinese patients with type 2 diabetes.

Protein S Protects against Podocyte Injury in Diabetic Nephropathy.

PubMed

Zhong, Fang; Chen, Haibing; Xie, Yifan; Azeloglu, Evren U; Wei, Chengguo; Zhang, Weijia; Li, Zhengzhe; Chuang, Peter Y; Jim, Belinda; Li, Hong; Elmastour, Firas; Riyad, Jalish M; Weber, Thomas; Chen, Hongyu; Wang, Yongjun; Zhang, Aihua; Jia, Weiping; Lee, Kyung; He, John C

2018-05-01

Background Diabetic nephropathy (DN) is a leading cause of ESRD in the United States, but the molecular mechanisms mediating the early stages of DN are unclear. Methods To assess global changes that occur in early diabetic kidneys and to identify proteins potentially involved in pathogenic pathways in DN progression, we performed proteomic analysis of diabetic and nondiabetic rat glomeruli. Protein S (PS) among the highly upregulated proteins in the diabetic glomeruli. PS exerts multiple biologic effects through the Tyro3, Axl, and Mer (TAM) receptors. Because increased activation of Axl by the PS homolog Gas6 has been implicated in DN progression, we further examined the role of PS in DN. Results In human kidneys, glomerular PS expression was elevated in early DN but suppressed in advanced DN. However, plasma PS concentrations did not differ between patients with DN and healthy controls. A prominent increase of PS expression also colocalized with the expression of podocyte markers in early diabetic kidneys. In cultured podocytes, high-glucose treatment elevated PS expression, and PS knockdown further enhanced the high-glucose-induced apoptosis. Conversely, PS overexpression in cultured podocytes dampened the high-glucose- and TNF- α -induced expression of proinflammatory mediators. Tyro3 receptor was upregulated in response to high glucose and mediated the anti-inflammatory response of PS. Podocyte-specific PS loss resulted in accelerated DN in streptozotocin-induced diabetic mice, whereas the transient induction of PS expression in glomerular cells in vivo attenuated albuminuria and podocyte loss in diabetic OVE26 mice. Conclusions Our results support a protective role of PS against glomerular injury in DN progression. Copyright © 2018 by the American Society of Nephrology.

Single-Dose Pharmacokinetic Study of Tramadol Extended-Release Tablets in Children and Adolescents.

PubMed

Vandenbossche, Joris; Van Peer, Achiel; Richards, Henry

2016-09-01

Combined analyses from 2 open-label, phase-1 studies-the pharmacokinetic profile of tramadol and its metabolite (M1) following a single oral dose of tramadol extended release (ER) (25 to 100 mg) in children (7 to 11 years old; study 1: n = 37) and adolescents (12 to 17 years old; study 2: n = 38) with painful conditions-were historically compared with that of healthy adults following similar dosing. The dose-normalized area under the curve (DN AUC0-24h ) and maximum concentration (DN Cmax ) of tramadol and of M1 in children and in adolescents were lower than those in adults (children vs adults: tramadol, DN AUC0-24h 82.19%; DN Cmax 80.38%, P = .0031; M1, DN AUC0-24h 51.19%, DN Cmax 52.68%, P < .0001; adolescents vs adults: tramadol, DN AUC0-24h 89.56%, DN Cmax 84.01%; M1, DN AUC0-24h 85.28%, DN Cmax 83.03%, P = .0004). The arithmetic mean terminal elimination t1/2 of tramadol in children and adolescents was comparable to that in adults (children 8.4 hours; adolescents 8.5 hours; adults 7.9 hours). The most frequently reported (≥5% of participants) treatment-emergent adverse events in children included headache, upper abdominal pain and constipation, and in adolescents were headache, nausea, dizziness, and stomach discomfort. Multiple factors may have contributed to these observations, including a higher proportion of children (56%) who may have a lower activity of CYP2D6, resulting in reduced clearance of tramadol. © 2016, The American College of Clinical Pharmacology.

GATA-3 is required for early T lineage progenitor development

PubMed Central

Hosoya, Tomonori; Kuroha, Takashi; Moriguchi, Takashi; Cummings, Dustin; Maillard, Ivan; Lim, Kim-Chew

2009-01-01

Most T lymphocytes appear to arise from very rare early T lineage progenitors (ETPs) in the thymus, but the transcriptional programs that specify ETP generation are not completely known. The transcription factor GATA-3 is required for the development of T lymphocytes at multiple late differentiation steps as well as for the development of thymic natural killer cells. However, a role for GATA-3 before the double-negative (DN) 3 stage of T cell development has to date been obscured both by the developmental heterogeneity of DN1 thymocytes and the paucity of ETPs. We provide multiple lines of in vivo evidence through the analysis of T cell development in Gata3 hypomorphic mutant embryos, in irradiated mice reconstituted with Gata3 mutant hematopoietic cells, and in mice conditionally ablated for the Gata3 gene to show that GATA-3 is required for ETP generation. We further show that Gata3 loss does not affect hematopoietic stem cells or multipotent hematopoietic progenitors. Finally, we demonstrate that Gata3 mutant lymphoid progenitors exhibit neither increased apoptosis nor diminished cell-cycle progression. Thus, GATA-3 is required for the cell-autonomous development of the earliest characterized thymic T cell progenitors. PMID:19934022

Immediate and short-term effects of the combination of dry needling and percutaneous TENS on post-needling soreness in patients with chronic myofascial neck pain

PubMed Central

León-Hernández, Jose V.; Martín-Pintado-Zugasti, Aitor; Frutos, Laura G.; Alguacil-Diego, Isabel M.; de la Llave-Rincón, Ana I.; Fernandez-Carnero, Josue

2016-01-01

ABSTRACT Background Dry needling (DN) and percutaneous electrical nerve stimulation (PENS) are widely used techniques in the treatment of myofascial pain. Objective To investigate the immediate and short-term effects of the combination of DN and PENS compared to DN alone on the upper trapezius muscle. Method This is a 72-hour follow-up single-blinded randomized controlled trial. Sixty-two volunteer patients with chronic myofascial neck pain with active Myofascial Trigger Points (MTrPs) in the upper trapezius muscle were recruited. Randomization was performed, and 31 patients received DN treatment (DN group) and 31 received DN and PENS (DN+PENS group). The primary outcomes were neck disability index (NDI) and visual analog scale for pain for both post-needling soreness (PNS) and neck pain intensity (NPI). Pressure pain threshold (PPT) and cervical range of motion (CROM) were the secondary outcomes. Results We detected between-group differences in NPI and PNS in favor of the DN+PENS group immediately after treatment. No between-group differences in NDI were observed. Conclusion PENS application after dry needling treatment is more effective than dry needling alone for decreasing soreness in the short term and improving neck pain intensity immediately in patients with myofascial chronic neck pain. PMID:27410163

Characterization of circulating CD4+ CD8+ double positive and CD4- CD8- double negative T-lymphocyte in children with β-thalassemia major.

PubMed

Zahran, Asmaa M; Saad, Khaled; Elsayh, Khalid I; Alblihed, Mohamd A

2017-03-01

Infectious complications represent the second most common cause of mortality and a major cause of morbidity in β-thalassemia major (BTM), with a prevalence of 12-13%. The data on unconventional T-lymphocyte subsets in BTM children are limited. The aim of the present study was to investigate and evaluate phenotypic alterations in CD4 + CD8 + double positive (DP), CD4 - CD8 - double negative (DN), and natural killer T-lymphocytes (NKT) in BTM children in comparison to healthy controls. Our case control study included 80 children with BTM and 40 healthy children as controls. Assessment of unconventional T-lymphocyte populations was done using sensitive four-color flow cytometry (FACSCalibur). Our analysis of the data showed a significantly higher frequency CD4 + CD8 + (double-positive) T cells, CD4 - CD8 - (double negative) T cells, and natural killer T cells in the peripheral blood of both BTM groups (splenectomized and non-splenectomized) as compared to healthy controls, suggesting that these cells may play a role in the clinical course of BTM. The relationship of the unconventional T-lymphocytes to immune disorders in BTM children remains to be determined. Further longitudinal study with a larger sample size is warranted to elucidate the role these cells in BTM. TRIAL NUMBER: UMIN000018950.

Emerging therapeutics for the treatment of diabetic nephropathy.

PubMed

Brenneman, Jehrod; Hill, Jon; Pullen, Steve

2016-09-15

Diabetic nephropathy (DN) is the most common pathology contributing to the development of chronic kidney disease (CKD). DN caused by hypertension and unmitigated inflammation in diabetics, renders the kidneys unable to perform normally, and leads to renal fibrosis and organ failure. The increasing global prevalence of DN has been directly attributed to rising incidences of Type II diabetes, and is now the largest non-communicable cause of death worldwide. Despite the high morbidity, successful new treatments for DN are lacking. This review seeks to provide new insight on emerging clinical candidates under investigation for the treatment of DN. Copyright © 2016 Elsevier Ltd. All rights reserved.

Hidden targets of ubiquitin proteasome system: To prevent diabetic nephropathy.

PubMed

Goru, Santosh Kumar; Kadakol, Almesh; Gaikwad, Anil Bhanudas

2017-06-01

Diabetic nephropathy (DN) is the major cause of end stage renal failure. Although, several therapeutic targets have emerged to prevent the progression of DN, the number of people with DN still continues to rise worldwide, suggesting an urgent need of novel targets to prevent DN completely. Currently, the role of ubiquitin proteasome system (UPS) has been highlighted in the pathogenesis and progression of various diseases like obesity, insulin resistance, atherosclerosis, cancers, neurodegerative disorders and including secondary complications of diabetes. UPS mainly involves in protein homeostatis through ubiquitination (post translational modification) and proteasomal degradation of various proteins. Ubiquitination, not only involves in proteasomal degradation, but also directs the substrate proteins to participate in multitude of cell signalling pathways. However, very little is known about ubiquitination and UPS in the progression of DN. This review mainly focuses on UPS and its components including E2 conjugating enzymes, E3 ligases and deubiquitinases (DUBs) in the development of DN and thus may help us to find novel therapeutic targets with in UPS to prevent DN completely in future. Copyright © 2017 Elsevier Ltd. All rights reserved.

Anti-inflammatory effects of 4′-demethylnobiletin, a major metabolite of nobiletin

PubMed Central

Rakariyatham, Kanyasiri; Zheng, Jinkai; Guo, Shanshan; Tang, Zhonghai; Zhou, Shuangde; Xiao, Hang

2015-01-01

Nobiletin, a citrus flavonoid has been associated with various beneficial biological activities. 4′-Demethylnobiletin (4DN) is a major metabolite of nobiletin and its tissue level was found to be much higher than that of nobiletin after oral administration of nobiletin in mice. Anti-inflammatory effects of 4DN were studied in lipopolysaccharide (LPS)-treated RAW 264.7 macrophages. The results showed 4DN not only dose-dependently inhibited LPS-induced nitric oxide production, but also significantly reduced expression of pro-inflammatory mediators, namely PGE2, IL-1β and IL-6. 4DN potently suppressed the expression of iNOS and COX-2 at both protein and mRNA levels. 4DN also inhibited nuclear translocation of NF-κB and AP-1. Furthermore, we demonstrated that 4DN activated transcription factor Nrf2 and its dependent genes including HO-1 and NQO1 whose expression may contribute to anti-inflammatory effects. The results demonstrated anti-inflammatory effects of 4DN and provided a scientific basis for using nobiletin as a nutraceutical to inhibit inflammation–driven diseases. PMID:26770275

Consumption of a fermented dairy product containing the probiotic Lactobacillus casei DN-114001 reduces the duration of respiratory infections in the elderly in a randomised controlled trial.

PubMed

Guillemard, E; Tondu, F; Lacoin, F; Schrezenmeir, J

2010-01-01

Common infectious diseases (CID) of the airways and the gastrointestinal tract are still a considerable cause of morbidity and mortality in elderly. The present study examined the beneficial effect of a dairy product containing the probiotic strain Lactobacillus casei DN-114 001 (fermented product) on the resistance of free-living elderly to CID. The study was multicentric, double blind and controlled, involving 1072 volunteers (median age = 76.0 years) randomised for consumption of either 200 g/d of fermented (n 537) or control (non-fermented) dairy product (n 535) for 3 months, followed by an additional 1 month's follow-up. The results showed that, when considering all CID, the fermented product significantly reduced the average duration per episode of CID (6.5 v. 8 d in control group; P = 0.008) and the cumulative duration of CID (7 v. 8 d in control group; P = 0.009). Reduction in both episode and cumulative durations was also significant for all upper respiratory tract infections (URTI; P < 0.001) and for rhinopharyngitis (P < 0.001). This was accompanied with an increase of L. casei species in stools throughout the fermented product consumption (2-3.8 x 107 equivalents of colony-forming unit/g of stools, P < 0.001). The cumulative number of CID (primary outcome) was not different between groups nor was the CID severity, fever, pathogens' occurrence, medication, immune blood parameters and quality of life. The fermented product was safe and well tolerated. In conclusion, consumption of a fermented dairy product containing the probiotic strain L. casei DN-114 001 in elderly was associated with a decreased duration of CID in comparison with the control group, especially for URTI such as rhinopharyngitis.

Effect of losartan and spironolactone on triglyceride-rich lipoproteins in diabetic nephropathy

PubMed Central

Srivastava, Anand; Adams-Huet, Beverley; Vega, Gloria L; Toto, Robert D

2016-01-01

Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) can improve dyslipidemia in patients with diabetes and albuminuria. Whether combined ACEi+ARB or ACEi+mineralocorticoid receptor blockade improves dyslipidemia is not known. We hypothesized long-term administration of either losartan 100 mg or spironolactone 25 mg once daily added onto lisinopril 80 mg once daily would improve dyslipidemia in diabetic nephropathy (DN). We measured lipid levels, very-low-density (V), intermediate-density (I), low-density (LDL), high-density (HDL) lipoprotein, LDL particle size with their respective cholesterol (C) and apolipoprotein B levels (ApoB), and urine albumin/creatinine ratio (UACR) at 12-week interval during a 48-week randomized, double-blind placebo-controlled trial in 81 patients with DN. Plasma lipids and lipoprotein C were analyzed enzymatically and Apo B was determined chemically. Data were analyzed by mixed model repeated measures. ΔUACR differed among treatment arms (placebo −24.6%, los −38.2%, spiro −51.6%, p=0.02). No correlation existed between ΔUACR and ΔTG or any of the lipid or lipoprotein measurements. Compared with placebo losartan, but not spironolactone, decreased TG (−20.9% vs +34.3%, p<0.01), V+I C(−18.8% vs +21.3%, p<0.01), and V+I-ApoB (−13.2% vs +21%, p<0.01). There were no significant changes in body weight, HbA1c or other lipoprotein variables. We conclude losartan improves dyslipidemia in patients with DN. We speculate the mechanism improved clearance of VLDL and remnant lipoproteins. Trial registration number NCT00381134; Results. PMID:27388615

FGF-23 as a Predictor of Renal Outcome in Diabetic Nephropathy

PubMed Central

Zatz, Roberto; Graciolli, Fabiana G.; dos Reis, Luciene M.; Barros, Rui T.; Jorgetti, Vanda; Moysés, Rosa M.A.

2011-01-01

Summary Background and objectives Fibroblast growth factor 23 (FGF-23) has emerged as a new factor in mineral metabolism in chronic kidney disease (CKD). An important regulator of phosphorus homeostasis, FGF-23 has been shown to independently predict CKD progression in nondiabetic renal disease. We analyzed the relation between FGF-23 and renal outcome in diabetic nephropathy (DN). Design, setting, participants, & measurements DN patients participating in a clinical trial (enalapril+placebo versus enalapril+losartan) had baseline data collected and were followed until June 2009 or until the primary outcome was reached. Four patients were lost to follow-up. The composite primary outcome was defined as death, doubling of serum creatinine, and/or dialysis need. Results At baseline, serum FGF-23 showed a significant association with serum creatinine, intact parathyroid hormone, proteinuria, urinary fractional excretion of phosphate, male sex, and race. Interestingly, FGF-23 was not related to calcium, phosphorus, 25OH-vitamin D, or 24-hour urinary phosphorus. Mean follow-up time was 30.7 ± 10 months. Cox regression showed that FGF-23 was an independent predictor of the primary outcome, even after adjustment for creatinine clearance and intact parathyroid hormone (10 pg/ml FGF-23 increase = hazard ratio, 1.09; 95% CI, 1.01 to 1.16, P = 0.02). Finally, Kaplan-Meier analysis showed a significantly higher risk of the primary outcome in patients with FGF-23 values of >70 pg/ml. Conclusions FGF-23 is a significant independent predictor of renal outcome in patients with macroalbuminuric DN. Further studies should clarify whether this relation is causal and whether FGF-23 should be a new therapeutic target for CKD prevention. PMID:20966122

Effects of glutathione s-transferase (GST) M1 and T1 polymorphisms on antioxidant vitamins and oxidative stress-related parameters in Korean subclinical hypertensive subjects after kale juice (Brassica oleracea acephala) supplementation

PubMed Central

2018-01-01

BACKGROUND/OBJECTIVES Glutathione s-transferase (GST) is involved in the formation of a multigene family comprising phase II detoxification enzymes, involved in the detoxification of reactive oxygen species. This study evaluated whether daily supplementation with kale juice could modulate levels of plasma antioxidant vitamins and oxidative stress-related parameters. We further examined whether this modulation was affected by combined GSTM1 and T1 polymorphisms. SUBJECTS/METHODS Totally, 84 subclinical hypertensive patients having systolic blood pressure (BP) over 130 mmHg or diastolic BP over 85 mmHg, received 300 mL of kale juice daily for 6 weeks. Blood samples were drawn before start of study and after completion of 6 weeks. RESULTS After supplementation, we observed significant decrease in DNA damage and increase in erythrocyte catalase activity in all genotypes. Plasma level of vitamin C was significantly increased in the wild/null and double null genotypes. The plasma levels of β-carotene, erythrocyte glutathione peroxidase activity, and nitric oxide were increased only in the wild/null genotype after kale juice supplementation. CONCLUSIONS The effect of kale juice was significantly greater in the GSTM1 null genotype and wild/null genotype groups, suggesting possibility of personalized nutritional prescriptions based on personal genetics. PMID:29629028

Diabetic nephropathy and antioxidants.

PubMed

Tavafi, Majid

2013-01-01

Oxidative stress has crucial role in pathogenesis of diabetic nephropathy (DN). Despite satisfactory results from antioxidant therapy in rodent, antioxidant therapy showed conflicting results in combat with DN in diabetic patients. Directory of Open Access Journals (DOAJ), Google Scholar,Pubmed (NLM), LISTA (EBSCO) and Web of Science have been searched. Treatment of DN in human are insufficient with rennin angiotensin system (RAS) blockers, so additional agent ought to combine with this management. Meanwhile based on DN pathogenesis and evidences in experimental and human researches, the antioxidants are the best candidate. New multi-property antioxidants may be improved human DN that show high power antioxidant capacity, long half-life time, high permeability to mitochondrion, improve body antioxidants enzymes activity and anti-inflammatory effects. Based on this review and our studies on diabetic rats, rosmarinic acid a multi-property antioxidant may be useful in DN patients, but of course, needs to be proven in clinical trials studies.

Initial development of the DIII–D snowflake divertor control

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kolemen, Egemen; Vail, P. J.; Makowski, M. A.

Simultaneous control of two proximate magnetic field nulls in the divertor region is demonstrated on DIII–D to enable plasma operations in an advanced magnetic configuration known as the snowflake divertor (SFD). The SFD is characterized by a second-order poloidal field null, created by merging two first-order nulls of the standard divertor configuration. The snowflake configuration has many magnetic properties, such as high poloidal flux expansion, large plasma-wetted area, and additional strike points, that are advantageous for divertor heat flux management in future fusion reactors. However, the magnetic configuration of the SFD is highly-sensitive to changes in currents within the plasmamore » and external coils and therefore requires complex magnetic control. The first real-time snowflake detection and control system on DIII–D has been implemented in order to stabilize the configuration. The control algorithm calculates the position of the two nulls in real-time by locally-expanding the Grad–Shafranov equation in the divertor region. A linear relation between variations in the poloidal field coil currents and changes in the null locations is then analytically derived. This formulation allows for simultaneous control of multiple coils to achieve a desired SFD configuration. It is shown that the control enabled various snowflake configurations on DIII–D in scenarios such as the double-null advanced tokamak. In conclusion, the SFD resulted in a 2.5×reduction in the peak heat flux for many energy confinement times (2–3s) without any adverse effects on core plasma performance.« less

Initial development of the DIII–D snowflake divertor control

DOE PAGES

Kolemen, Egemen; Vail, P. J.; Makowski, M. A.; ...

2018-04-11

Simultaneous control of two proximate magnetic field nulls in the divertor region is demonstrated on DIII–D to enable plasma operations in an advanced magnetic configuration known as the snowflake divertor (SFD). The SFD is characterized by a second-order poloidal field null, created by merging two first-order nulls of the standard divertor configuration. The snowflake configuration has many magnetic properties, such as high poloidal flux expansion, large plasma-wetted area, and additional strike points, that are advantageous for divertor heat flux management in future fusion reactors. However, the magnetic configuration of the SFD is highly-sensitive to changes in currents within the plasmamore » and external coils and therefore requires complex magnetic control. The first real-time snowflake detection and control system on DIII–D has been implemented in order to stabilize the configuration. The control algorithm calculates the position of the two nulls in real-time by locally-expanding the Grad–Shafranov equation in the divertor region. A linear relation between variations in the poloidal field coil currents and changes in the null locations is then analytically derived. This formulation allows for simultaneous control of multiple coils to achieve a desired SFD configuration. It is shown that the control enabled various snowflake configurations on DIII–D in scenarios such as the double-null advanced tokamak. In conclusion, the SFD resulted in a 2.5×reduction in the peak heat flux for many energy confinement times (2–3s) without any adverse effects on core plasma performance.« less

Mutations associated with base excision repair deficiency and methylation-induced genotoxic stress

PubMed Central

Sobol, Robert W.; Watson, David E.; Nakamura, Jun; Yakes, F. Michael; Hou, Esther; Horton, Julie K.; Ladapo, Joseph; Van Houten, Bennett; Swenberg, James A.; Tindall, Kenneth R.; Samson, Leona D.; Wilson, Samuel H.

2002-01-01

The long-term effect of exposure to DNA alkylating agents is entwined with the cell's genetic capacity for DNA repair and appropriate DNA damage responses. A unique combination of environmental exposure and deficiency in these responses can lead to genomic instability; this “gene–environment interaction” paradigm is a theme for research on chronic disease etiology. In the present study, we used mouse embryonic fibroblasts with a gene deletion in the base excision repair (BER) enzymes DNA β-polymerase (β-pol) and alkyladenine DNA glycosylase (AAG), along with exposure to methyl methanesulfonate (MMS) to study mutagenesis as a function of a particular gene–environment interaction. The β-pol null cells, defective in BER, exhibit a modest increase in spontaneous mutagenesis compared with wild-type cells. MMS exposure increases mutant frequency in β-pol null cells, but not in isogenic wild-type cells; UV light exposure or N-methyl-N′-nitro-N-nitrosoguanidine exposure increases mutant frequency similarly in both cell lines. The MMS-induced increase in mutant frequency in β-pol null cells appears to be caused by DNA lesions that are AAG substrates, because overexpression of AAG in β-pol null cells eliminates the effect. In contrast, β-pol/AAG double null cells are slightly more mutable than the β-pol null cells after MMS exposure. These results illustrate that BER plays a role in protecting mouse embryonic fibroblast cells against methylation-induced mutations and characterize the effect of a particular combination of BER gene defect and environmental exposure. PMID:11983862

Fe65 is required for Tip60-directed histone H4 acetylation at DNA strand breaks

PubMed Central

Stante, Maria; Minopoli, Giuseppina; Passaro, Fabiana; Raia, Maddalena; Vecchio, Luigi Del; Russo, Tommaso

2009-01-01

Fe65 is a binding partner of the Alzheimer's β-amyloid precursor protein APP. The possible involvement of this protein in the cellular response to DNA damage was suggested by the observation that Fe65 null mice are more sensitive to genotoxic stress than WT counterpart. Fe65 associated with chromatin under basal conditions and its involvement in DNA damage repair requires this association. A known partner of Fe65 is the histone acetyltransferase Tip60. Considering the crucial role of Tip60 in DNA repair, we explored the hypothesis that the phenotype of Fe65 null cells depended on its interaction with Tip60. We demonstrated that Fe65 knockdown impaired recruitment of Tip60-TRRAP complex to DNA double strand breaks and decreased histone H4 acetylation. Accordingly, the efficiency of DNA repair was decreased upon Fe65 suppression. To explore whether APP has a role in this mechanism, we analyzed a Fe65 mutant unable to bind to APP. This mutant failed to rescue the phenotypes of Fe65 null cells; furthermore, APP/APLP2 suppression results in the impairment of recruitment of Tip60-TRRAP complex to DNA double strand breaks, decreased histone H4 acetylation and repair efficiency. On these bases, we propose that Fe65 and its interaction with APP play an important role in the response to DNA damage by assisting the recruitment of Tip60-TRRAP to DNA damage sites. PMID:19282473

Elevated urinary level of vitamin D-binding protein as a novel biomarker for diabetic nephropathy

PubMed Central

TIAN, XIAO-QIN; ZHAO, LI-MIN; GE, JIA-PU; ZHANG, YAN; XU, YAN-CHENG

2014-01-01

Improving the early prediction and detection of diabetic nephropathy (DN) remains a great challenge in disease management. The aim of this study was to evaluate the early detection power of urinary vitamin D-binding protein (VDBP) for the diagnosis of DN. Urine samples were obtained from 45 healthy volunteers and 105 diabetic patients with normoalbuminuria (DM group), microalbuminuria (DN1 group) and macroalbuminuria (DN2 group) (n=35 per group). The VDBP expression patterns in urine from patients and controls were quantified by western blot analysis. The excretion levels of urinary VDBP were quantified with enzyme-linked immunosorbent assay. The quantification results were obtained by correcting for creatinine expression and showed that urinary VDBP levels were significantly elevated in the patients of the DN1 and DN2 groups compared with those of the DM group and normal controls (1,011.33±325.30 and 1,406.34±239.66 compared with 466.54±213.63 and 125.48±98.27 ng/mg, respectively) (P<0.001). Receiver operating characteristic analysis of urinary VDBP levels for the diagnosis of DN rendered an optimum cut-off value of 552.243 ng/mg corresponding to 92.86% sensitivity and 85.00% specificity, which also showed an area under the ROC curve of 0.966. In conclusion, the findings of the present study suggest that urinary VDBP may be a potential biomarker for the early detection and prevention of DN. Further studies are required to examine the pathogenic mechanisms of elevated VDBP levels and their role in the diagnosis of DN. PMID:24396416

Meta-analysis: the efficacy and safety of combined treatment with ARB and ACEI on diabetic nephropathy.

PubMed

Ren, Feifeng; Tang, Lin; Cai, Yin; Yuan, Xin; Huang, Wenhan; Luo, Lei; Zhou, Jun; Zheng, Yaning

2015-05-01

Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) reduce proteinuria in diabetic nephropathy (DN). Some studies have suggested that dual blockade of the renin-angiotensin system provides additive benefits in DN but others showed increased adverse events. We performed a meta-analysis to evaluate the efficacy and safety of combination therapy for DN. Studies were identified by searching MEDLINE, EMBASE, PubMed, and CNKI. All trials involved ACEI + ARB (combination therapy), and ACEI or ARB alone (monotherapy) for DN. The outcomes measured were urinary total proteinuria (UTP), urinary albumin excretion rate (UAER), serum creatinine, glomerular filtration rate (GFR), end-stage renal disease (ESRD), hyperkalemia, hypotension, and acute kidney injury (AKI). In the 32 included trials, 2596 patients received combination therapy and 3947 received monotherapy. UTP and UAER were significantly reduced by combined treatment compared with monotherapy. It was notable that low doses of combination therapy reduced UTP more than high doses. Serum creatinine, GFR, and ESRD were not significantly different between the two groups. In severe DN, the occurrence of hyperkalemia and AKI were higher with combination therapy. However, in mild DN, the prevalence of hyperkalemia and AKI were the same in both the groups. In mild DN, the occurrence of hypotension was higher with combination therapy; however, in severe DN, it was not different between the two groups. Our meta-analysis suggests that combination therapy can be used on DN with proteinuria, but should be used with caution in those with decreased renal function, especially with severe renal failure.

Pharmacological Modulation of Three Modalities of CA1 Hippocampal Long-Term Potentiation in the Ts65Dn Mouse Model of Down Syndrome

PubMed Central

Scott-McKean, Jonah J.; Roque, Adriano L.; Surewicz, Krystyna; Johnson, Mark W.; Surewicz, Witold K.

2018-01-01

The Ts65Dn mouse is the most studied animal model of Down syndrome. Past research has shown a significant reduction in CA1 hippocampal long-term potentiation (LTP) induced by theta-burst stimulation (TBS), but not in LTP induced by high-frequency stimulation (HFS), in slices from Ts65Dn mice compared with euploid mouse-derived slices. Additionally, therapeutically relevant doses of the drug memantine were shown to rescue learning and memory deficits in Ts65Dn mice. Here, we observed that 1 μM memantine had no detectable effect on HFS-induced LTP in either Ts65Dn- or control-derived slices, but it rescued TBS-induced LTP in Ts65Dn-derived slices to control euploid levels. Then, we assessed LTP induced by four HFS (4xHFS) and found that this form of LTP was significantly depressed in Ts65Dn slices when compared with LTP in euploid control slices. Memantine, however, did not rescue this phenotype. Because 4xHFS-induced LTP had not yet been characterized in Ts65Dn mice, we also investigated the effects of picrotoxin, amyloid beta oligomers, and soluble recombinant human prion protein (rPrP) on this form of LTP. Whereas ≥10 μM picrotoxin increased LTP to control levels, it also caused seizure-like oscillations. Neither amyloid beta oligomers nor rPrP had any effect on 4xHFS-induced LTP in Ts65Dn-derived slices. PMID:29849573

Doubling down on naturalness with a supersymmetric twin Higgs

NASA Astrophysics Data System (ADS)

Craig, Nathaniel; Howe, Kiel

2014-03-01

We show that naturalness of the weak scale can be comfortably reconciled with both LHC null results and observed Higgs properties provided the double protection of supersymmetry and the twin Higgs mechanism. This double protection radically alters conventional signs of naturalness at the LHC while respecting gauge coupling unification and precision electroweak limits. We find the measured Higgs mass, couplings, and percent-level naturalness of the weak scale are compatible with stops at ~ 3.5 TeV and higgsinos at ~ 1 TeV. The primary signs of naturalness in this scenario include modifications of Higgs couplings, a modest invisible Higgs width, resonant Higgs pair production, and an invisibly-decaying heavy Higgs.

Modulation of gut microbiota and increase in fecal water content in mice induced by administration of Lactobacillus kefiranofaciens DN1.

PubMed

Jeong, Dana; Kim, Dong-Hyeon; Kang, Il-Byeong; Kim, Hyunsook; Song, Kwang-Young; Kim, Hong-Seok; Seo, Kun-Ho

2017-02-22

Lactobacillus kefiranofaciens is the key probiotic bacterium in kefir. In this study, we investigated the effects of oral consumption of L. kefiranofaciens on the fecal quality and intestinal microbiota of mice. Four-week-old Balb/c mice were divided into two groups (n = 8 each) and administered 0.2 mL of saline (control group) or saline containing 2 × 10 8 cfu L. kefiranofaciens DN1 (LKF_DN1 group) for two weeks. At the end of the experiment, their fecal samples were collected and the fecal quality and microbiota were assessed. The LKF_DN1 group exhibited higher total fecal weight and fecal weight per stool sample than the control group (p < 0.05). Interestingly, the fecal water content was significantly higher in the fecal samples of the LKF_DN1 group than in those of the control group (p < 0.05). The numbers of total bacteria, Firmicutes, Bacteroidetes, Lactobacillus, and Prevotella were significantly higher in the LKF_DN1 group than in the control group (p < 0.05). In contrast, the number of opportunistic pathogens, including Proteobacteria and Enterobacteriaceae, and the percentage of genus Clostridium among the total bacteria were significantly reduced in the LKF_DN1 group (p < 0.05). Our data suggest that regular L. kefiranofaciens DN1 administration could alleviate constipation and improve gut microbiota.

Beneficial effects of β-conglycinin on renal function and nephrin expression in early streptozotocin-induced diabetic nephropathy rats.

PubMed

Yang, Hsin-Yi; Wu, Lin-Yi; Yeh, Wan-Ju; Chen, Jiun-Rong

2014-01-14

The objective of the present study was to investigate the effects of β-conglycinin and soya isoflavones on diabetic nephropathy (DN). DN was induced by an intravenous injection of streptozotocin (25 mg/kg) in spontaneously hypertensive rats. DN rats were divided into a non-diabetic group (C, control group) and three DN groups (D, DN with control diet; B, DN+control diet with one-eighth of casein replaced by β-conglycinin as the protein source; and I, DN+control diet with 0·01 % soya isoflavones). After a 4-week experimental period, we found that fasting blood sugar and plasma and kidney advanced glycation end product levels and 24 h urinary protein excretion of the B group were significantly lower than those of the D group and insulin sensitivity and nephrin expression of the B group were significantly higher than those of the D group. In addition, systolic blood pressure, angiotensin-converting enzyme activity, angiotensin II level and plasma TAG level of the B group were significantly lower than those of the D group, whereas only the levels of plasma TAG and thiobarbituric acid-reactive substances of the I group were lower than those of the D group. In conclusion, β-conglycinin may be beneficial for retarding DN progression and this effect cannot be completely explained by its isoflavone content.

Influence of injection speed on the effectiveness of incisive/mental nerve block: a randomized, controlled, double-blind study in adult volunteers.

PubMed

Whitworth, John Martin; Kanaa, Mohammad Dib; Corbett, Ian Porter; Meechan, John Gerald

2007-10-01

This randomized, double-blind trial tested the null hypothesis that speed of deposition has no influence on the injection discomfort, efficacy, distribution, and duration of pulp anesthesia after incisive/mental nerve block in adult volunteers. Thirty-eight subjects received incisive/mental nerve blocks of 2.0 mL lidocaine with 1:80,000 epinephrine slowly over 60 seconds or rapidly over 15 seconds at least 1 week apart. Pulp anesthesia was assessed electronically to 45 minutes after injection. Injection discomfort was self-recorded on visual analogue scales. Overall, 48.7% of volunteers developed pulp anesthesia in first molars, 81.8% in bicuspids, and 38.5% in lateral incisors. The mean duration of pulp anesthesia was 19.1 minutes for first molars, 28.5 minutes for bicuspids, and 19.0 minutes for lateral incisors. Speed of injection had no significant influence on anesthetic success or duration of anesthesia for individual teeth. Slow injection was significantly more comfortable than rapid injection (P < .001). The null hypothesis was supported, although slow injection was more comfortable.

A novel Ras-interacting protein required for chemotaxis and cyclic adenosine monophosphate signal relay in Dictyostelium.

PubMed

Lee, S; Parent, C A; Insall, R; Firtel, R A

1999-09-01

We have identified a novel Ras-interacting protein from Dictyostelium, RIP3, whose function is required for both chemotaxis and the synthesis and relay of the cyclic AMP (cAMP) chemoattractant signal. rip3 null cells are unable to aggregate and lack receptor activation of adenylyl cyclase but are able, in response to cAMP, to induce aggregation-stage, postaggregative, and cell-type-specific gene expression in suspension culture. In addition, rip3 null cells are unable to properly polarize in a cAMP gradient and chemotaxis is highly impaired. We demonstrate that cAMP stimulation of guanylyl cyclase, which is required for chemotaxis, is reduced approximately 60% in rip3 null cells. This reduced activation of guanylyl cyclase may account, in part, for the defect in chemotaxis. When cells are pulsed with cAMP for 5 h to mimic the endogenous cAMP oscillations that occur in wild-type strains, the cells will form aggregates, most of which, however, arrest at the mound stage. Unlike the response seen in wild-type strains, the rip3 null cell aggregates that form under these experimental conditions are very small, which is probably due to the rip3 null cell chemotaxis defect. Many of the phenotypes of the rip3 null cell, including the inability to activate adenylyl cyclase in response to cAMP and defects in chemotaxis, are very similar to those of strains carrying a disruption of the gene encoding the putative Ras exchange factor AleA. We demonstrate that aleA null cells also exhibit a defect in cAMP-mediated activation of guanylyl cyclase similar to that of rip3 null cells. A double-knockout mutant (rip3/aleA null cells) exhibits a further reduction in receptor activation of guanylyl cyclase, and these cells display almost no cell polarization or movement in cAMP gradients. As RIP3 preferentially interacts with an activated form of the Dictyostelium Ras protein RasG, which itself is important for cell movement, we propose that RIP3 and AleA are components of a Ras-regulated pathway involved in integrating chemotaxis and signal relay pathways that are essential for aggregation.

Predictive value of interleukin-10 promoter genotypes and haplotypes in determining the susceptibility to nephropathy in type 2 diabetes patients.

PubMed

Mtiraoui, Nabil; Ezzidi, Intissar; Kacem, Maha; Ben Hadj Mohamed, Manel; Chaieb, Molka; Haj Jilani, Aoutef Bel; Mahjoub, Touhami; Almawi, Wassim Y

2009-01-01

The IL-10 promoter polymorphisms -1082G/A, -819C/T, and -592C/A have been consistently associated with type 2 diabetes (T2DM). We examined whether these polymorphisms variants are also associated with progression of diabetic nephropathy (DN). These promoter variants were genotyped in 917 T2DM patients comprising 515 DN patients and 402 control patients without nephropathy (DWN), together with 748 non-diabetic control subjects. Haplotype analysis and multivariate regression analysis were employed in assessing the contribution of IL-10 haplotypes to DN risk, using genotype, clinical and biochemical profile, and their interactions as predictors of DN. Carriers of mutant -592A and -819T alleles, and -819T/T, -592A/A, and -819C/T genotypes were more frequent in T2DM. However, the -819C/T genotype appeared to be protective of DN, since lower frequency -819T allele and -819C/T genotype were seen in DN patients. Regression analysis identified -1082G/-819T/-592A (GTA) and -1082G/-819T/-592C (GTC) haplotypes as DN-protective haplotypes. Relative to the -1082G/-819C/-592C haplotype, GTA [P = 0.044; odds ratio (OR) = 0.54, 95% confidence interval (CI): 0.30-0.98] and GTC (P = 0.045; OR = 0.56, 95% CI: 0.31-0.99) haplotypes were associated with decreased odds ratio (OR) for DN, after controlling for a number of covariates (age, sex, body mass index (BMI), hypertension, glucose, HbA(1c), DN duration, total cholesterol). Our results indicate that genetic variations at the IL-10 promoter influence the risk of nephropathy in T2DM patients and thus represent a potential DN genetic-susceptibility locus worthy of replication. Copyright 2009 John Wiley & Sons, Ltd.

Identification of specific angiotensin-converting enzyme variants and haplotypes that confer risk and protection against type 2 diabetic nephropathy.

PubMed

Ezzidi, Intissar; Mtiraoui, Nabil; Kacem, Maha; Chaieb, Molka; Mahjoub, Touhami; Almawi, Wassim Y

2009-11-01

Cross-sectional and family studies identified angiotensin-converting enzyme (ACE) gene as a risk factor for diabetic nephropathy (DN). The contribution of ACE gene variants to DN development and progression is controversial and varies among different ethnic/racial groups. We investigated the association of three ACE gene variants with DN, rs1799752 insertion/deletion (I/D), rs1800764T/C and rs12449782A/G in 917 Tunisian type 2 diabetic (T2DM) patients: 515 with (DN) and 402 without (DWN) nephropathy. ACE genotyping was done by PCR-based assays; haplotype estimation was performed using H-Plus software (chi(2)-test based). Genotype frequency distributions of the three studied variants were in Hardy-Weinberg equilibrium. Minor allele frequency of rs1800764 was higher in DN patients than DWN patients or healthy controls, and minor allele frequency of rs1799752 was higher in DN than DWN patients. Higher frequency of rs1799752 and rs1800764 homozygous mutant genotypes was seen in DN compared to DWN patients. Of the three variants, only rs1799752 deletion/deletion (D/D) genotype was associated with a significant increase in albumin to creatinine ratios levels, and D/D carriers had elevated low-density lipoprotein, total cholesterol and urea. Three locus haplotype [rs1799752(I/D)/rs1800764(T/C)/rs12449782(A/G)] analysis revealed that the frequency of DCG haplotype was higher, while that of ITG and ICA haplotypes were lower among unselected type 2 diabetic patients. Taking ITA haplotype as reference, multivariate regression analysis confirmed the negative (ITG), and positive (DCG, DTG, DCA and DTA) association of specific ACE haplotypes with DN, after adjusting for potential nephropathy-linked covariates. Our results support the involvement of specific ACE variants in DN pathogenesis and demonstrate the presence of DN-specific haplotypes at the ACE locus.

Quantitative PET imaging of Met-expressing human cancer xenografts with 89Zr-labelled monoclonal antibody DN30.

PubMed

Perk, Lars R; Stigter-van Walsum, Marijke; Visser, Gerard W M; Kloet, Reina W; Vosjan, Maria J W D; Leemans, C René; Giaccone, Giuseppe; Albano, Raffaella; Comoglio, Paolo M; van Dongen, Guus A M S

2008-10-01

Targeting the c-Met receptor with monoclonal antibodies (MAbs) is an appealing approach for cancer diagnosis and treatment because this receptor plays a prominent role in tumour invasion and metastasis. Positron emission tomography (PET) might be a powerful tool for guidance of therapy with anti-Met MAbs like the recently described MAb DN30 because it allows accurate quantitative imaging of tumour targeting (immuno-PET). We considered the potential of PET with either (89)Zr-labelled (residualising radionuclide) or (124)I-labelled (non-residualising radionuclide) DN30 for imaging of Met-expressing tumours. The biodistribution of co-injected (89)Zr-DN30 and iodine-labelled DN30 was compared in nude mice bearing either the human gastric cancer line GLT-16 (high Met expression) or the head-and-neck cancer line FaDu (low Met expression). PET images were acquired in both xenograft models up to 4 days post-injection (p.i.) and used for quantification of tumour uptake. Biodistribution studies in GTL-16-tumour-bearing mice revealed that (89)Zr-DN30 achieved much higher tumour uptake levels than iodine-labelled DN30 (e.g. 19.6%ID/g vs 5.3%ID/g, 5 days p.i.), while blood levels were similar, indicating internalisation of DN30. Therefore, (89)Zr-DN30 was selected for PET imaging of GLT-16-bearing mice. Tumours as small as 11 mg were readily visualised with immuno-PET. A distinctive lower (89)Zr uptake was observed in FaDu compared to GTL-16 xenografts (e.g. 7.8%ID/g vs 18.1%ID/g, 3 days p.i.). Nevertheless, FaDu xenografts were also clearly visualised with (89)Zr-DN30 immuno-PET. An excellent correlation was found between PET-image-derived (89)Zr tumour uptake and ex-vivo-assessed (89)Zr tumour uptake (R(2)=0.98). The long-lived positron emitter (89)Zr seems attractive for PET-guided development of therapeutic anti-c-Met MAbs.

Genetic, epigenetic and protein analyses of intercellular adhesion molecule 1 in Malaysian subjects with type 2 diabetes and diabetic nephropathy.

PubMed

Abu Seman, Norhashimah; Anderstam, Björn; Wan Mohamud, Wan Nazaimoon; Östenson, Claes-Göran; Brismar, Kerstin; Gu, Harvest F

2015-01-01

Recent research has implicated that the inflammation may be a key pathophysiological mechanism in diabetic nephropathy (DN). Intercellular adhesion molecule 1 (ICAM-1) is an acute phase marker of inflammation. In the present study, we carried out genetic, epigenetic and protein analyses of ICAM-1 in a Malaysian population, including normal glucose tolerance (NGT) subjects and type 2 diabetes (T2D) patients with or without DN in order to evaluate its role in DN. Analyses of DNA polymorphism and methylation in the ICAM1 gene were performed with TaqMan allelic discrimination and pyrosequencing, respectively. Plasma ICAM-1 levels were determined using an enzyme-linked immune-sorbent assay kit. We found that the ICAM1 K469E(A/G) polymorphism (rs5498) was significantly associated with DN. Particularly, 86.1% of T2D patients with DN carried heterozygous genotype compared to the patients without DN (68.6%). Furthermore, plasma ICAM-1 levels were increased from NGT subjects to T2D patients without and with DN (P<0.001). The NGT subjects carrying heterozygous genotype had significantly lower plasma ICAM-1 levels compared to the K469(A/A) genotype carriers (P=0.009). In the ICAM1 gene promoter, DNA methylation levels of CpG sites were low, and no association of the ICAM1 DNA methylation alteration with DN was detected. The present study provided evidence that the ICAM1 K469E(A/G) polymorphism with high heterozygous index and elevation of plasma ICAM-1 levels were associated with DN in a Malaysian population. Further prospective study of ICAM-1 protein according to the ICAM1 K469E(A/G) genotypes is necessary for predicting the susceptibility to T2D and DN. Copyright © 2015 Elsevier Inc. All rights reserved.

Diamond Nanoparticles Modify Curcumin Activity: In Vitro Studies on Cancer and Normal Cells and In Ovo Studies on Chicken Embryo Model

PubMed Central

Strojny, Barbara; Grodzik, Marta; Sawosz, Ewa; Winnicka, Anna; Kurantowicz, Natalia; Jaworski, Sławomir; Kutwin, Marta; Urbańska, Kaja; Hotowy, Anna; Wierzbicki, Mateusz; Chwalibog, André

2016-01-01

Curcumin has been studied broadly for its wide range of biological activities, including anticancer properties. The major problem with curcumin is its poor bioavailability, which can be improved by the addition of carriers, such as diamond nanoparticles (DN). They are carbon allotropes, and are therefore biocompatible and easily taken up by cells. DN are non-toxic and have antiangiogenic properties with potential applications in cancer therapy. Their large surface makes them promising compounds in a drug delivery system for bioactive agents, as DN create bio-complexes in a fast and simple process of self-organisation. We investigated the cytotoxicity of such bio-complexes against liver cancer cells and normal fibroblasts, revealing that conjugation of curcumin with DN significantly improves its activity. The experiment performed in a chicken embryo model demonstrated that neither curcumin nor DN nor bio-complexes affect embryo development, even though DN can form deposits in tissues. Preliminary results confirmed the applicability of DN as an efficient carrier of curcumin, which improves its performance against cancer cells in vitro, yet is not toxic to an organism, which makes the bio-complex a promising anticancer agent. PMID:27736939

Low dose EGCG treatment beginning in adolescence does not improve cognitive impairment in a Down syndrome mouse model.

PubMed

Stringer, Megan; Abeysekera, Irushi; Dria, Karl J; Roper, Randall J; Goodlett, Charles R

2015-11-01

Down syndrome (DS) or Trisomy 21 causes intellectual disabilities in humans and the Ts65Dn DS mouse model is deficient in learning and memory tasks. DYRK1A is triplicated in DS and Ts65Dn mice. Ts65Dn mice were given up to ~20mg/kg/day epigallocatechin-3-gallate (EGCG), a Dyrk1a inhibitor, or water beginning on postnatal day 24 and continuing for three or seven weeks, and were tested on a series of behavioral and learning tasks, including a novel balance beam test. Ts65Dn as compared to control mice exhibited higher locomotor activity, impaired novel object recognition, impaired balance beam and decreased spatial learning and memory. Neither EGCG treatment improved performance of the Ts65Dn mice on these tasks. Ts65Dn mice had a non-significant increase in Dyrk1a activity in the hippocampus and cerebellum. Given the translational value of the Ts65Dn mouse model, further studies will be needed to identify the EGCG doses (and mechanisms) that may improve cognitive function. Copyright © 2015 Elsevier Inc. All rights reserved.

Diamond Nanoparticles Modify Curcumin Activity: In Vitro Studies on Cancer and Normal Cells and In Ovo Studies on Chicken Embryo Model.

PubMed

Strojny, Barbara; Grodzik, Marta; Sawosz, Ewa; Winnicka, Anna; Kurantowicz, Natalia; Jaworski, Sławomir; Kutwin, Marta; Urbańska, Kaja; Hotowy, Anna; Wierzbicki, Mateusz; Chwalibog, André

2016-01-01

Curcumin has been studied broadly for its wide range of biological activities, including anticancer properties. The major problem with curcumin is its poor bioavailability, which can be improved by the addition of carriers, such as diamond nanoparticles (DN). They are carbon allotropes, and are therefore biocompatible and easily taken up by cells. DN are non-toxic and have antiangiogenic properties with potential applications in cancer therapy. Their large surface makes them promising compounds in a drug delivery system for bioactive agents, as DN create bio-complexes in a fast and simple process of self-organisation. We investigated the cytotoxicity of such bio-complexes against liver cancer cells and normal fibroblasts, revealing that conjugation of curcumin with DN significantly improves its activity. The experiment performed in a chicken embryo model demonstrated that neither curcumin nor DN nor bio-complexes affect embryo development, even though DN can form deposits in tissues. Preliminary results confirmed the applicability of DN as an efficient carrier of curcumin, which improves its performance against cancer cells in vitro, yet is not toxic to an organism, which makes the bio-complex a promising anticancer agent.

Improving Protein Fold Recognition by Deep Learning Networks.

PubMed

Jo, Taeho; Hou, Jie; Eickholt, Jesse; Cheng, Jianlin

2015-12-04

For accurate recognition of protein folds, a deep learning network method (DN-Fold) was developed to predict if a given query-template protein pair belongs to the same structural fold. The input used stemmed from the protein sequence and structural features extracted from the protein pair. We evaluated the performance of DN-Fold along with 18 different methods on Lindahl's benchmark dataset and on a large benchmark set extracted from SCOP 1.75 consisting of about one million protein pairs, at three different levels of fold recognition (i.e., protein family, superfamily, and fold) depending on the evolutionary distance between protein sequences. The correct recognition rate of ensembled DN-Fold for Top 1 predictions is 84.5%, 61.5%, and 33.6% and for Top 5 is 91.2%, 76.5%, and 60.7% at family, superfamily, and fold levels, respectively. We also evaluated the performance of single DN-Fold (DN-FoldS), which showed the comparable results at the level of family and superfamily, compared to ensemble DN-Fold. Finally, we extended the binary classification problem of fold recognition to real-value regression task, which also show a promising performance. DN-Fold is freely available through a web server at http://iris.rnet.missouri.edu/dnfold.

Effect of Tongxinluo on Podocyte Apoptosis via Inhibition of Oxidative Stress and P38 Pathway in Diabetic Rats

PubMed Central

Cui, Fangqiang; Zhao, Wenjing; Zou, Dawei; Wu, Xiaoming; Tian, Nianxiu; Wang, Xiaolei; Liu, Jing; Tong, Yu

2016-01-01

Diabetic nephropathy (DN) has been the leading cause of end-stage renal disease (ESRD). Podocyte apoptosis is a main mechanism of progression of DN. It has been demonstrated that activated P38 and caspase-3 induced by oxidative stress mainly account for increased podocyte apoptosis and proteinuria in DN. Meanwhile, Tongxinluo (TXL) can ameliorate renal structure disruption and dysfunction in DN patients in our clinical practice. However, the effect of TXL on podocyte apoptosis and P38 pathway remains unclear. To explore the effect of TXL on podocyte apoptosis and its molecular mechanism in DN, our in vivo and in vitro studies were performed. TXL attenuated oxidative stress in podocyte in DN in our in vivo and in vitro studies. Moreover, TXL inhibited the activation of P38 and caspase-3. Bcl-2 and Bax expression was partially restored by TXL treatment in our in vivo and in vitro studies. More importantly, TXL decreased podocyte apoptosis in diabetic rats and high glucose cultured podocyte. In conclusion, TXL protects podocyte from apoptosis in DN, partially through its antioxidant effect and inhibiting of the activation of P38 and caspase-3. PMID:27672400

Attentional function and basal forebrain cholinergic neuron morphology during aging in the Ts65Dn mouse model of Down syndrome

PubMed Central

Powers, Brian E.; Velazquez, Ramon; Kelley, Christy M.; Ash, Jessica A.; Strawderman, Myla S.; Alldred, Melissa J.; Ginsberg, Stephen D.; Mufson, Elliott J.

2016-01-01

Individuals with Down syndrome (DS) exhibit intellectual disability and develop Alzheimer's disease-like neuropathology during the third decade of life. The Ts65Dn mouse model of DS exhibits key features of both disorders, including impairments in learning, attention and memory, as well as atrophy of basal forebrain cholinergic neurons (BFCNs). The present study evaluated attentional function in relation to BFCN morphology in young (3 months) and middle-aged (12 months) Ts65Dn mice and disomic (2N) controls. Ts65Dn mice exhibited attentional dysfunction at both ages, with greater impairment in older trisomics. Density of BFCNs was significantly lower for Ts65Dn mice independent of age, which may contribute to attentional dysfunction since BFCN density was positively associated with performance on an attention task. BFCN volume decreased with age in 2N but not Ts65Dn mice. Paradoxically, BFCN volume was greater in older trisomic mice, suggestive of a compensatory response. In sum, attentional dysfunction occurred in both young and middle-aged Ts65Dn mice, which may in part reflect reduced density and/or phenotypic alterations in BFCNs. PMID:26719290

Attentional function and basal forebrain cholinergic neuron morphology during aging in the Ts65Dn mouse model of Down syndrome.

PubMed

Powers, Brian E; Velazquez, Ramon; Kelley, Christy M; Ash, Jessica A; Strawderman, Myla S; Alldred, Melissa J; Ginsberg, Stephen D; Mufson, Elliott J; Strupp, Barbara J

2016-12-01

Individuals with Down syndrome (DS) exhibit intellectual disability and develop Alzheimer's disease-like neuropathology during the third decade of life. The Ts65Dn mouse model of DS exhibits key features of both disorders, including impairments in learning, attention and memory, as well as atrophy of basal forebrain cholinergic neurons (BFCNs). The present study evaluated attentional function in relation to BFCN morphology in young (3 months) and middle-aged (12 months) Ts65Dn mice and disomic (2N) controls. Ts65Dn mice exhibited attentional dysfunction at both ages, with greater impairment in older trisomics. Density of BFCNs was significantly lower for Ts65Dn mice independent of age, which may contribute to attentional dysfunction since BFCN density was positively associated with performance on an attention task. BFCN volume decreased with age in 2N but not Ts65Dn mice. Paradoxically, BFCN volume was greater in older trisomic mice, suggestive of a compensatory response. In sum, attentional dysfunction occurred in both young and middle-aged Ts65Dn mice, which may in part reflect reduced density and/or phenotypic alterations in BFCNs.

Clinicopathological characteristics of non-diabetic renal disease in patients with type 2 diabetes mellitus in a northeastern Chinese medical center: a retrospective analysis of 273 cases.

PubMed

Liu, Shujun; Guo, Qiaoyan; Han, Hongbo; Cui, Peihe; Liu, Xiao; Miao, Lining; Zou, Hongbin; Sun, Guangdong

2016-10-01

To investigate the clinical and histopathological features of non-diabetic renal disease (NDRD) superimposed on diabetic nephropathy (DN) in northeastern Chinese patients with type 2 diabetes mellitus (T2D), and compare the changes with those of pure DN and isolated NDRD. Single-center retrospective analysis based on medical records of 273 patients (172 men, mean age: 51.1 ± 12.4 years) with T2D who underwent renal biopsy between February 2000 and October 2015. All patients were diagnosed as cases of pure DN, isolated NDRD or NDRD superimposed on DN. Out of the 273 T2D patients, 68 (24.9 %) had DN, 175 (64.1 %) had NDRD, and 30 (11.0 %) had NDRD superimposed on DN. Idiopathic membranous nephropathy (IMN, 29.7 %) was the most common NDRD followed by IgA nephropathy (IgAN, 22.9 %), and hypertensive renal arteriolar sclerosis was the most common lesion in patients diagnosed as NDRD superimposed on DN. Patients with NDRD had a shorter duration of diabetes and lower frequencies of diabetic retinopathy (DR, 6.9 %) and renal failure (28.0 %), which is consistent with higher estimated glomerular filtration rates (eGFR) and lower systolic blood pressure (SBP). No significant between-group differences were observed with respect to proteinuria and hematuria. Renal biopsy is strongly recommended for T2D patients to distinguish DN, NDRD and NDRD superimposed on DN, especially in patients with no signs of DR. This approach may help in early diagnosis and treatment of NDRD and improve renal outcomes in northeastern Chinese T2D patients.

SOCS2 overexpression alleviates diabetic nephropathy in rats by inhibiting the TLR4/NF-κB pathway

PubMed Central

Yang, Suxia; Zhang, Junwei; Wang, Shiying; Zhao, Xinxin; Shi, Jun

2017-01-01

Suppressor of cytokine signaling 2 (SOCS2) was reported to be involved in the development of Diabetic Nephropathy (DN). However, its underlying mechanism remains undefined. Western blot was carried out to determine the expressions of SOCS2, Toll-like receptors 4 (TLR4) and nuclear factor kappa B (NF-κB) pathway-related proteins in DN patients, streptozotocin (STZ)-induced DN rats and high glucose (HG)-stimulated podocytes. The effects of SOCS2 overexpression on renal injury, the inflammatory cytokines production, renal pathological changes, apoptosis and the TLR4/NF-κB pathway in DN rats or HG-stimulated podocytes were investigated. TLR4 antagonist TAK-242 and NF-κB inhibitor PDTC were used to confirm the functional mechanism of SOCS2 overexpression in HG-stimulated podocytes. SOCS2 was down-regulated, while TLR4 and NF-κB were up-regulated in renal tissues of DN patients and DN rats. Ad-SOCS2 infection alleviated STZ-induced renal injury and pathological changes and inhibited STZ-induced IL-6, IL-1β and MCP-1 generation and activation of the TLR4/NF-κB pathway in DN rats. SOCS2 overexpression attenuated apoptosis, suppressed the inflammatory cytokines expression, and inactivated the TLR4/NF-κB pathway in HG-stimulated podocytes. Suppression of the TLR4/NF-κB pathway enhanced the inhibitory effect of SOCS2 overexpression on apoptosis and inflammatory cytokines expressions in HG-stimulated podocytes. SOCS2 overexpression alleviated the development of DN by inhibiting the TLR4/NF-κB pathway, contributing to developing new therapeutic strategies against DN. PMID:29207635

Effects of Maternal Choline Supplementation on the Septohippocampal Cholinergic System in the Ts65Dn Mouse Model of Down Syndrome.

PubMed

Kelley, Christy M; Ash, Jessica A; Powers, Brian E; Velazquez, Ramon; Alldred, Melissa J; Ikonomovic, Milos D; Ginsberg, Stephen D; Strupp, Barbara J; Mufson, Elliott J

2016-01-01

Down syndrome (DS), caused by trisomy of chromosome 21, is marked by intellectual disability (ID) and early onset of Alzheimer's disease (AD) neuropathology including hippocampal cholinergic projection system degeneration. Here we determined the effects of age and maternal choline supplementation (MCS) on hippocampal cholinergic deficits in Ts65Dn mice compared to 2N mice sacrificed at 6-8 and 14-18 months of age. Ts65Dn mice and disomic (2N) littermates sacrificed at ages 6-8 and 14-18 mos were used for an aging study and Ts65Dn and 2N mice derived from Ts65Dn dams were maintained on either a choline-supplemented or a choline-controlled diet (conception to weaning) and examined at 14-18 mos for MCS studies. In the latter, mice were behaviorally tested on the radial arm Morris water maze (RAWM) and hippocampal tissue was examined for intensity of choline acetyltransferase (ChAT) immunoreactivity. Hippocampal ChAT activity was evaluated in a separate cohort. ChAT-positive fiber innervation was significantly higher in the hippocampus and dentate gyrus in Ts65Dn mice compared with 2N mice, independent of age or maternal diet. Similarly, hippocampal ChAT activity was significantly elevated in Ts65Dn mice compared to 2N mice, independent of maternal diet. A significant increase with age was seen in hippocampal cholinergic innervation of 2N mice, but not Ts65Dn mice. Degree of ChAT intensity correlated negatively with spatial memory ability in unsupplemented 2N and Ts65Dn mice, but positively in MCS 2N mice. The increased innervation produced by MCS appears to improve hippocampal function, making this a therapy that may be exploited for future translational approaches in human DS.

Therapeutic effects of dry needling in patients with upper trapezius myofascial trigger points

PubMed Central

Abbaszadeh-Amirdehi, Maryam; Ansari, Noureddin Nakhostin; Naghdi, Soofia; Olyaei, Gholamreza; Nourbakhsh, Mohammad Reza

2017-01-01

Background Active myofascial trigger points (MTrPs) are major pain generators in myofascial pain syndrome. Dry needling (DN) is an effective method for the treatment of MTrPs. Objective To assess the immediate neurophysiological and clinical effects of DN in patients with upper trapezius MTrPs. Methods This was a prospective, clinical trial study of 20 patients with upper trapezius MTrPs and 20 healthy volunteers (matched for height, weight, body mass index and age), all of whom received one session of DN. Primary outcome measures were neuromuscular junction response (NMJR) and sympathetic skin response (SSR). Secondary outcomes were pain intensity (PI) and pressure pain threshold (PPT). Data were collected at baseline and immediately post-intervention. Results At baseline, SSR amplitude was higher in patients versus healthy volunteers (p<0.003). With respect to NMJR, a clinically abnormal increment and normal reduction was observed in patients and healthy volunteers, respectively. Moreover, PPT of patients was less than healthy volunteers (p<0.0001). After DN, SSR amplitude decreased significantly in patients (p<0.01), but did not change in healthy volunteers. A clinically important reduction in the NMJR of patients and increment in healthy volunteers was demonstrated after DN. PPT increased after DN in patients, but decreased in healthy volunteers (p<0.0001). PI improved after DN in patients (p<0.001). Conclusions The results of this study showed that one session of DN targeting active MTrPs appears to reduce hyperactivity of the sympathetic nervous system and irritability of the motor endplate. DN seems effective at improving symptoms and deactivating active MTrPs, although further research is needed. Trial registration number IRCT20130316128. PMID:27697768

Therapeutic effects of dry needling in patients with upper trapezius myofascial trigger points.

PubMed

Abbaszadeh-Amirdehi, Maryam; Ansari, Noureddin Nakhostin; Naghdi, Soofia; Olyaei, Gholamreza; Nourbakhsh, Mohammad Reza

2017-04-01

Active myofascial trigger points (MTrPs) are major pain generators in myofascial pain syndrome. Dry needling (DN) is an effective method for the treatment of MTrPs. To assess the immediate neurophysiological and clinical effects of DN in patients with upper trapezius MTrPs. This was a prospective, clinical trial study of 20 patients with upper trapezius MTrPs and 20 healthy volunteers (matched for height, weight, body mass index and age), all of whom received one session of DN. Primary outcome measures were neuromuscular junction response (NMJR) and sympathetic skin response (SSR). Secondary outcomes were pain intensity (PI) and pressure pain threshold (PPT). Data were collected at baseline and immediately post-intervention. At baseline, SSR amplitude was higher in patients versus healthy volunteers (p<0.003). With respect to NMJR, a clinically abnormal increment and normal reduction was observed in patients and healthy volunteers, respectively. Moreover, PPT of patients was less than healthy volunteers (p<0.0001). After DN, SSR amplitude decreased significantly in patients (p<0.01), but did not change in healthy volunteers. A clinically important reduction in the NMJR of patients and increment in healthy volunteers was demonstrated after DN. PPT increased after DN in patients, but decreased in healthy volunteers (p<0.0001). PI improved after DN in patients (p<0.001). The results of this study showed that one session of DN targeting active MTrPs appears to reduce hyperactivity of the sympathetic nervous system and irritability of the motor endplate. DN seems effective at improving symptoms and deactivating active MTrPs, although further research is needed. IRCT20130316128. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Effects of Maternal Choline Supplementation on the Septohippocampal Cholinergic System in the Ts65Dn Mouse Model of Down Syndrome

PubMed Central

Kelley, Christy M.; Ash, Jessica A.; Powers, Brian E.; Velazquez, Ramon; Alldred, Melissa J.; Ikonomovic, Milos D.; Ginsberg, Stephen D.; Strupp, Barbara J.; Mufson, Elliott J.

2016-01-01

Down syndrome (DS), caused by trisomy of chromosome 21, is marked by intellectual disability (ID) and early onset of Alzheimer’s disease (AD) neuropathology including hippocampal cholinergic projection system degeneration. Here we determined the effects of age and maternal choline supplementation (MCS) on hippocampal cholinergic deficits in Ts65Dn mice. Ts65Dn mice and disomic (2N) littermates sacrificed at ages 6–8 and 14–18 mos were used for an aging study, and Ts65Dn and 2N mice derived from Ts65Dn dams were maintained on either a choline-supplemented or a choline-controlled diet (conception to weaning) and examined at 14–18 mos for MCS studies. In the latter, mice were behaviorally tested on the radial arm Morris water maze (RAWM) and hippocampal tissue was examined for intensity of choline acetyltransferase (ChAT) immunoreactivity. Hippocampal ChAT activity was evaluated in a separate cohort. ChAT-positive fiber innervation was significantly higher in the hippocampus and dentate gyrus in Ts65Dn mice compared with 2N mice, independent of age or maternal diet. Similarly, hippocampal ChAT activity was significantly elevated in TS65Dn mice compared to 2N mice, independent of maternal diet. A significant increase with age was seen in hippocampal cholinergic innervation of 2N mice, but not Ts65Dn mice. Degree of ChAT intensity correlated negatively with spatial memory ability in unsupplemented 2N and Ts65Dn mice, but positively in MCS 2N mice. The increased innervation produced by MCS appears to improve hippocampal function, making this a therapy that may be exploited for future translational approaches in human DS. PMID:26391045

Drosophila fragile X mental retardation protein and metabotropic glutamate receptor A convergently regulate the synaptic ratio of ionotropic glutamate receptor subclasses.

PubMed

Pan, Luyuan; Broadie, Kendal S

2007-11-07

A current hypothesis proposes that fragile X mental retardation protein (FMRP), an RNA-binding translational regulator, acts downstream of glutamatergic transmission, via metabotropic glutamate receptor (mGluR) G(q)-dependent signaling, to modulate protein synthesis critical for trafficking ionotropic glutamate receptors (iGluRs) at synapses. However, direct evidence linking FMRP and mGluR function with iGluR synaptic expression is limited. In this study, we use the Drosophila fragile X model to test this hypothesis at the well characterized glutamatergic neuromuscular junction (NMJ). Two iGluR classes reside at this synapse, each containing common GluRIIC (III), IID and IIE subunits, and variable GluRIIA (A-class) or GluRIIB (B-class) subunits. In Drosophila fragile X mental retardation 1 (dfmr1) null mutants, A-class GluRs accumulate and B-class GluRs are lost, whereas total GluR levels do not change, resulting in a striking change in GluR subclass ratio at individual synapses. The sole Drosophila mGluR, DmGluRA, is also expressed at the NMJ. In dmGluRA null mutants, both iGluR classes increase, resulting in an increase in total synaptic GluR content at individual synapses. Targeted postsynaptic dmGluRA overexpression causes the exact opposite GluR phenotype to the dfmr1 null, confirming postsynaptic GluR subtype-specific regulation. In dfmr1; dmGluRA double null mutants, there is an additive increase in A-class GluRs, and a similar additive impact on B-class GluRs, toward normal levels in the double mutants. These results show that both dFMRP and DmGluRA differentially regulate the abundance of different GluR subclasses in a convergent mechanism within individual postsynaptic domains.

Synergistic roles of bone morphogenetic protein 15 and growth differentiation factor 9 in ovarian function.

PubMed

Yan, C; Wang, P; DeMayo, J; DeMayo, F J; Elvin, J A; Carino, C; Prasad, S V; Skinner, S S; Dunbar, B S; Dube, J L; Celeste, A J; Matzuk, M M

2001-06-01

Knockout mouse technology has been used over the last decade to define the essential roles of ovarian-expressed genes and uncover genetic interactions. In particular, we have used this technology to study the function of multiple members of the transforming growth factor-beta superfamily including inhibins, activins, and growth differentiation factor 9 (GDF-9 or Gdf9). Knockout mice lacking GDF-9 are infertile due to a block in folliculogenesis at the primary follicle stage. In addition, recombinant GDF-9 regulates multiple cumulus granulosa cell functions in the periovulatory period including hyaluronic acid synthesis and cumulus expansion. We have also cloned an oocyte-specific homolog of GDF-9 from mice and humans, which is termed bone morphogenetic protein 15 (BMP-15 or Bmp15). To define the function of BMP-15 in mice, we generated embryonic stem cells and knockout mice, which have a null mutation in this X-linked gene. Male chimeric and Bmp15 null mice are normal and fertile. In contrast to Bmp15 null males and Gdf9 knockout females, Bmp15 null females (Bmp15(-/-)) are subfertile and usually have minimal ovarian histopathological defects, but demonstrate decreased ovulation and fertilization rates. To further decipher possible direct or indirect genetic interactions between GDF-9 and BMP-15, we have generated double mutant mice lacking one or both alleles of these related homologs. Double homozygote females (Bmp15(-/-)Gdf9(-/-)) display oocyte loss and cysts and resemble Gdf9(-/-) mutants. In contrast, Bmp15(-/-)Gdf9(+/-) female mice have more severe fertility defects than Bmp15(-/-) females, which appear to be due to abnormalities in ovarian folliculogenesis, cumulus cell physiology, and fertilization. Thus, the dosage of intact Bmp15 and Gdf9 alleles directly influences the destiny of the oocyte during folliculogenesis and in the periovulatory period. These studies have important implications for human fertility control and the maintenance of fertility and normal ovarian physiology.

Role of Nuclear Factor Erythroid 2-Related Factor 2 in Diabetic Nephropathy

PubMed Central

Min, Xu; Xu, Xiaohong

2017-01-01

Diabetic nephropathy (DN) is manifested as increased urinary protein level, decreased glomerular filtration rate, and final renal dysfunction. DN is the leading cause of end-stage renal disease worldwide and causes a huge societal healthcare burden. Since satisfied treatments are still limited, exploring new strategies for the treatment of this disease is urgently needed. Oxidative stress takes part in the initiation and development of DN. In addition, nuclear factor erythroid 2-related factor 2 (Nrf2) plays a key role in the cellular response to oxidative stress. Thus, activation of Nrf2 seems to be a new choice for the treatment of DN. In current review, we discussed and summarized the therapeutic effects of Nrf2 activation on DN from both basic and clinical studies. PMID:28512642

Personality and complex brain networks: The role of openness to experience in default network efficiency

PubMed Central

Kaufman, Scott Barry; Benedek, Mathias; Jung, Rex E.; Kenett, Yoed N.; Jauk, Emanuel; Neubauer, Aljoscha C.; Silvia, Paul J.

2015-01-01

Abstract The brain's default network (DN) has been a topic of considerable empirical interest. In fMRI research, DN activity is associated with spontaneous and self‐generated cognition, such as mind‐wandering, episodic memory retrieval, future thinking, mental simulation, theory of mind reasoning, and creative cognition. Despite large literatures on developmental and disease‐related influences on the DN, surprisingly little is known about the factors that impact normal variation in DN functioning. Using structural equation modeling and graph theoretical analysis of resting‐state fMRI data, we provide evidence that Openness to Experience—a normally distributed personality trait reflecting a tendency to engage in imaginative, creative, and abstract cognitive processes—underlies efficiency of information processing within the DN. Across two studies, Openness predicted the global efficiency of a functional network comprised of DN nodes and corresponding edges. In Study 2, Openness remained a robust predictor—even after controlling for intelligence, age, gender, and other personality variables—explaining 18% of the variance in DN functioning. These findings point to a biological basis of Openness to Experience, and suggest that normally distributed personality traits affect the intrinsic architecture of large‐scale brain systems. Hum Brain Mapp 37:773–779, 2016. © 2015 Wiley Periodicals, Inc. PMID:26610181

Surface Electromyographic Activity of the Upper Trapezius Before and After a Single Dry Needling Session in Female Office Workers With Trapezius Myalgia.

PubMed

De Meulemeester, Kayleigh; Calders, Patrick; Dewitte, Vincent; Barbe, Tom; Danneels, Lieven; Cagnie, Barbara

2017-12-01

Myofascial pain can be accompanied by a disturbed surface electromyographic (sEMG) activity. Nevertheless, the effect of myofascial treatment techniques, such as dry needling (DN), on the sEMG activity is poorly investigated. Several DN studies also emphasize the importance of eliciting local twitch responses (LTRs) during treatment. However, studies investigating the added value of LTRs are scarce. Therefore, the aims of this study were first to evaluate the effect of DN on the sEMG activity of myalgic muscle tissue, compared with no intervention (rest), and secondly to identify whether this effect is dependent of eliciting LTRs during DN. Twenty-four female office workers with work-related trapezius myalgia were included. After completion of a typing task, changes in sEMG activity were evaluated after a DN treatment of the upper trapezius, compared with rest. The sEMG activity increased after rest and after DN, but this increase was significantly smaller 10 minutes after DN, compared with rest. These differences were independent whether LTRs were elicited or not. Dry needling leads to a significantly lower increase in sEMG activity of the upper trapezius, compared with no intervention, after a typing task. This difference was independent of eliciting LTRs.

[Research on land use structure optimization based on nonpoint source dissolved nitrogen load estimation in Shuaishui watershed].

PubMed

Lu, Yu-Chao; Bi, Meng-Fei; Li, Ze-Li; Sha, Jian; Wang, Yu-Qiu; Qian, Li-Ping

2014-06-01

Regional Nutrient Management (ReNuMa) was applied to estimate dissolved nitrogen (DN) load and perform source apportionment in Shuaishui watershed during 2000-2010. Satisfactory performance of ReNuMa was revealed by the E(ns) and R2 of greater than 0.9 in calibrating and validating streamflow and DN. The average nonpoint DN load in this watershed was 1.11 x 10(3) t x a(-1), with the load intensity of (0.75 +/- 0.22) t x km(-2). Among all the land uses, paddy field had the largest DN load intensity [28.60 kg x (hm2 x a)(-1)], while forest had the least [2.71 kg x (hm2 x a)(-1)]. Agricultural land (including paddy, grain, cash crop, tea plant and orchard) contributed most to DN load in Shuaishui watershed, indicating that the human dominated agricultural activities was the major contributor of nonpoint source pollution. Land use structure optimization for Shuaishui watershed in 2015 was conducted under the rule of reducing pollutants loads and maximizing the agricultural output value. The results demonstrated that agricultural monetary growth was accompanied with the increasing DN load at the optimal level, although output increment was higher than that of DN load.

Improving Protein Fold Recognition by Deep Learning Networks

NASA Astrophysics Data System (ADS)

Jo, Taeho; Hou, Jie; Eickholt, Jesse; Cheng, Jianlin

2015-12-01

For accurate recognition of protein folds, a deep learning network method (DN-Fold) was developed to predict if a given query-template protein pair belongs to the same structural fold. The input used stemmed from the protein sequence and structural features extracted from the protein pair. We evaluated the performance of DN-Fold along with 18 different methods on Lindahl’s benchmark dataset and on a large benchmark set extracted from SCOP 1.75 consisting of about one million protein pairs, at three different levels of fold recognition (i.e., protein family, superfamily, and fold) depending on the evolutionary distance between protein sequences. The correct recognition rate of ensembled DN-Fold for Top 1 predictions is 84.5%, 61.5%, and 33.6% and for Top 5 is 91.2%, 76.5%, and 60.7% at family, superfamily, and fold levels, respectively. We also evaluated the performance of single DN-Fold (DN-FoldS), which showed the comparable results at the level of family and superfamily, compared to ensemble DN-Fold. Finally, we extended the binary classification problem of fold recognition to real-value regression task, which also show a promising performance. DN-Fold is freely available through a web server at http://iris.rnet.missouri.edu/dnfold.

Combined glutathione S transferase M1/T1 null genotypes is associated with type 2 diabetes mellitus

PubMed Central

POROJAN, MIHAI D.; BALA, CORNELIA; ILIES, ROXANA; CATANA, ANDREEA; POPP, RADU A.; DUMITRASCU, DAN L.

2015-01-01

Background Due to new genetic insights, a considerably large number of genes and polymorphic gene variants are screened and linked with the complex pathogenesis of type 2 diabetes (DM). Our study aimed to investigate the association between the two isoforms of the glutathione S-transferase genes (Glutathione S transferase isoemzyme type M1- GSTM1 and Glutathione S transferase isoemzyme type T1-GSTT1) and the prevalence of DM in the Northern Romanian population. Methods We conducted a cross-sectional, randomized, case-control study evaluating the frequency of GSTM1 and GSTT1 null alleles in patients diagnosed with DM. A total of 106 patients diagnosed with DM and 124 healthy controls were included in the study. GSTM1 and GSTT1 null alleles genotyping was carried out using Multiplex PCR amplification of relevant gene fragments, followed by gel electrophoresis analysis of the resulting amplicons. Results Molecular analysis did not reveal an increased frequency of the null GSTM1 and GSTT1 alleles (mutant genotypes) respectively in the DM group compared to controls (p=0.171, OR=1.444 CI=0.852–2.447; p=0.647, OR=0.854, CI=0.436–1.673). Nevertheless, the combined GSTM1/GSTT1 null genotypes were statistically significantly higher in DM patients compared to control subjects (p=0.0021, OR=0.313, CI=0.149–0.655) Conclusions The main finding of our study is that the combined, double GSTM1/GSTT1 null genotypes are to be considered among the polymorphic genetic risk factors for type 2 DM. PMID:26528065

Yeast Genes Controlling Responses to Topogenic Signals in a Model Transmembrane Protein

PubMed Central

Tipper, Donald J.; Harley, Carol A

2002-01-01

Yeast protein insertion orientation (PIO) mutants were isolated by selecting for growth on sucrose in cells in which the only source of invertase is a C-terminal fusion to a transmembrane protein. Only the fraction with an exocellular C terminus can be processed to secreted invertase and this fraction is constrained to 2–3% by a strong charge difference signal. Identified pio mutants increased this to 9–12%. PIO1 is SPF1, encoding a P-type ATPase located in the endoplasmic reticulum (ER) or Golgi. spf1-null mutants are modestly sensitive to EGTA. Sensitivity is considerably greater in an spf1 pmr1 double mutant, although PIO is not further disturbed. Pmr1p is the Golgi Ca2+ ATPase and Spf1p may be the equivalent ER pump. PIO2 is STE24, a metalloprotease anchored in the ER membrane. Like Spf1p, Ste24p is expressed in all yeast cell types and belongs to a highly conserved protein family. The effects of ste24- and spf1-null mutations on invertase secretion are additive, cell generation time is increased 60%, and cells become sensitive to cold and to heat shock. Ste24p and Rce1p cleave the C-AAX bond of farnesylated CAAX box proteins. The closest paralog of SPF1 is YOR291w. Neither rce1-null nor yor291w-null mutations affected PIO or the phenotype of spf1- or ste24-null mutants. Mutations in PIO3 (unidentified) cause a weaker Pio phenotype, enhanced by a null mutation in BMH1, one of two yeast 14-3-3 proteins. PMID:11950929

Genetic determinants in the metabolism of bladder carcinogens in relation to risk of bladder cancer

PubMed Central

Yuan, Jian-Min; Chan, Kenneth K.; Coetzee, Gerhard A.; Castelao, J.Esteban; Watson, Mary A.; Bell, Douglas A.; Wang, Renwei; Yu, Mimi C.

2008-01-01

Genetically determined factors that alter the metabolism of tobacco carcinogens can influence an individual’s susceptibility to bladder cancer. The associations between the genotypes of glutathione S-transferase (GST) M1, GSTP1, GSTT1 and N-acetyltransferase (NAT) 1 and the phenotypes of NAT2 and cytochrome P450 (CYP) 1A2 and bladder cancer risk were examined in a case–control study involving 731 bladder cancer patients and 740 control subjects in Los Angeles County, California. Individual null/low-activity genotypes of GSTM1, GSTT1 and GSTP1 were associated with a 19–48% increase in odds ratio (OR) of bladder cancer. The strongest association was noted for GSTM1 [OR for the null genotype = 1.48, 95% confidence interval (CI) = 1.19–1.83]. When the three GST genes were examined together, there was a monotonic, statistically significant association between increasing number of null/low-activity genotypes and risk (P for trend = 0.002). OR (95% CI) for one and two or more null/low-activity GST genotypes was 1.42 (1.12–1.81) and 1.71 (1.25–2.34), respectively, relative to the absence of null/low-activity GST genotype. NAT2 slow acetylation was associated with doubled risk of bladder cancer among individuals with known high exposures to carcinogenic arylamines (OR = 2.03, 95% CI = 1.12–3.69, P = 0.02). The effect of NAT2 slow acetylation was even stronger in the presence of two or more null/low-activity GST genotypes. There were no associations between bladder cancer risk and NAT1 genotype or CYP1A2 phenotype. PMID:18544563

Metallothionein blocks oxidative DNA damage induced by acute inorganic arsenic exposure

DOE Office of Scientific and Technical Information (OSTI.GOV)

Qu, Wei, E-mail: qu@niehs.nih.gov; Waalkes, Michael P.

We studied how protein metallothionein (MT) impacts arsenic-induced oxidative DNA damage (ODD) using cells that poorly express MT (MT-I/II double knockout embryonic cells; called MT-null cells) and wild-type (WT) MT competent cells. Arsenic (as NaAsO{sub 2}) was less cytolethal over 24 h in WT cells (LC{sub 50} = 11.0 ± 1.3 μM; mean ± SEM) than in MT-null cells (LC{sub 50} = 5.6 ± 1.2 μM). ODD was measured by the immuno-spin trapping method. Arsenic (1 or 5 μM; 24 h) induced much less ODD in WT cells (121% and 141% of control, respectively) than in MT-null cells (202% andmore » 260%). In WT cells arsenic caused concentration-dependent increases in MT expression (transcript and protein), and in the metal-responsive transcription factor-1 (MTF-1), which is required to induce the MT gene. In contrast, basal MT levels were not detectable in MT-null cells and unaltered by arsenic exposure. Transfection of MT-I gene into the MT-null cells markedly reduced arsenic-induced ODD levels. The transport genes, Abcc1 and Abcc2 were increased by arsenic in WT cells but either showed no or very limited increases in MT-null cells. Arsenic caused increases in oxidant stress defense genes HO-1 and GSTα2 in both WT and MT-null cells, but to much higher levels in WT cells. WT cells appear more adept at activating metal transport systems and oxidant response genes, although the role of MT in these responses is unclear. Overall, MT protects against arsenic-induced ODD in MT competent cells by potential sequestration of scavenging oxidant radicals and/or arsenic. - Highlights: • Metallothionein blocks arsenic toxicity. • Metallothionein reduces arsenic-induced DNA damage. • Metallothionein may bind arsenic or radicals produced by arsenic.« less

The App-Runx1 Region Is Critical for Birth Defects and Electrocardiographic Dysfunctions Observed in a Down Syndrome Mouse Model

PubMed Central

Raveau, Matthieu; Lignon, Jacques M.; Nalesso, Valérie; Duchon, Arnaud; Groner, Yoram; Sharp, Andrew J.; Dembele, Doulaye; Brault, Véronique; Hérault, Yann

2012-01-01

Down syndrome (DS) leads to complex phenotypes and is the main genetic cause of birth defects and heart diseases. The Ts65Dn DS mouse model is trisomic for the distal part of mouse chromosome 16 and displays similar features with post-natal lethality and cardiovascular defects. In order to better understand these defects, we defined electrocardiogram (ECG) with a precordial set-up, and we found conduction defects and modifications in wave shape, amplitudes, and durations in Ts65Dn mice. By using a genetic approach consisting of crossing Ts65Dn mice with Ms5Yah mice monosomic for the App-Runx1 genetic interval, we showed that the Ts65Dn viability and ECG were improved by this reduction of gene copy number. Whole-genome expression studies confirmed gene dosage effect in Ts65Dn, Ms5Yah, and Ts65Dn/Ms5Yah hearts and showed an overall perturbation of pathways connected to post-natal lethality (Coq7, Dyrk1a, F5, Gabpa, Hmgn1, Pde10a, Morc3, Slc5a3, and Vwf) and heart function (Tfb1m, Adam19, Slc8a1/Ncx1, and Rcan1). In addition cardiac connexins (Cx40, Cx43) and sodium channel sub-units (Scn5a, Scn1b, Scn10a) were found down-regulated in Ts65Dn atria with additional down-regulation of Cx40 in Ts65Dn ventricles and were likely contributing to conduction defects. All these data pinpoint new cardiac phenotypes in the Ts65Dn, mimicking aspects of human DS features and pathways altered in the mouse model. In addition they highlight the role of the App-Runx1 interval, including Sod1 and Tiam1, in the induction of post-natal lethality and of the cardiac conduction defects in Ts65Dn. These results might lead to new therapeutic strategies to improve the care of DS people. PMID:22693452

Niabella hibiscisoli sp. nov., isolated from soil of a Rose of Sharon garden.

PubMed

Ngo, Hien T T; Trinh, Huan; Yan, Zheng-Fei; Moya, Gabriela; Kook, MooChang; Yi, Tae-Hoo

2017-04-01

A Gram-stain-negative, strictly aerobic, non-motile, rod-shaped and yellow-pigmented bacterium, designated strain THG-DN5.5T, was isolated from soil of a Rose of Sharon garden in Daejeon, South Korea. According to 16S rRNA gene sequence comparisons, strain THG-DN5.5T was found to be most closely related to Niabella yanshanensis CCBAU 05354T (97.7 % sequence similarity), Niabella ginsengisoli GR10-1T (97.0 %), 'Niabella terrae' ICM 1-15 (96.0 %), Niabella soli DSM 19437T (95.7 %) and Niabella aquatica RP-2T (95.6 %). The DNA-DNA relatedness between strain THG-DN5.5T and its phylogenetically closest neighbours was below 50.0 %. The DNA G+C content was 43.1 mol%. The major polar lipid of strain THG-DN5.5T was found to be phosphatidylethanolamine. The major fatty acids were identified as C16 : 0, iso-C15 : 0, iso-C15 : 1 G, and iso-C17 : 0 3-OH. MK-7 was the only menaquinone present. These data supported the affiliation of strain THG-DN5.5T to the genus Niabella. Strain THG-DN5.5T was distinguished from related species of the genus Niabellaby physiological and biochemical tests. In conclusion, strain THG-DN5.5T represents a novel species of the genus Niabella, for which the name Niabella hibiscisolisp. nov. is proposed. The type strain is THG-DN5.5T (=KACC 18857T=CCTCC AB 2016086T).

OCTANOL/WATER PARTITION COEFFICIENTS AND WATER SOLUBILITIES OF PHTHALATE ESTERS

EPA Science Inventory

Measurements of the octanol/water partition coefficients (K-ow) and water solubilities of di-n-octyl phthalate (DnOP) and di-n-decyl phthalate (DnDP) by the slow-stirring method are reported. The water solubility was also measured for di-n-hexyl phthalate (DnHP). The log K-ow val...

Peripheral neuropathy in children with type 1 diabetes.

PubMed

Louraki, M; Karayianni, C; Kanaka-Gantenbein, C; Katsalouli, M; Karavanaki, K

2012-10-01

Diabetic neuropathy (DN) is a major complication of type 1 diabetes mellitus (T1DM) with significant morbidity and mortality in adulthood. Clinical neuropathy is rarely seen in paediatric populations, whereas subclinical neuropathy is commonly seen, especially in adolescents. Peripheral DN involves impairment of the large and/or small nerve fibres, and can be diagnosed by various methods. Nerve conduction studies (NCS) are the gold-standard method for the detection of subclinical DN; however, it is invasive, difficult to perform and selectively detects large-fibre abnormalities. Vibration sensation thresholds (VSTs) and thermal discrimination thresholds (TDTs) are quicker and easier and, therefore, more suitable as screening tools. Poor glycaemic control is the most important risk factor for the development of DN. Maintaining near-normoglycaemia is the only way to prevent or reverse neural impairment, as the currently available treatments can only relieve the symptoms of DN. Early detection of children and adolescents with nervous system abnormalities is crucial to allow all appropriate measures to be taken to prevent the development of DN. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Naringin ameliorates diabetic nephropathy by inhibiting NADPH oxidase 4.

PubMed

Zhang, Junwei; Yang, Suxia; Li, Huicong; Chen, Fang; Shi, Jun

2017-06-05

Naringin, a naturally flavanone glycoside, has been previously demonstrated to alleviate diabetic kidney disease by inhibiting oxidative stress and inflammatory reaction. However, the underlying mechanism of naringin in diabetic nephropathy (DN) has not been fully elucidated. Here, the beneficial effect of naringin on DN in streptozotocin (STZ)-induced DN rats and high glucose (HG)-induced podocytes and its underlying mechanism were elaborated. The result revealed that naringin alleviated STZ-induced renal dysfunction and injury in DN rats, relieved STZ-induced oxidative stress in vivo and inhibited HG-induced apoptosis and reactive oxygen species level i20n vitro. More importantly, naringin inhibited NOX4 expression at mRNA and protein levels in STZ-induced DN rats and HG-induced podocytes. Loss of function indicated that NADPH oxidases 4 (NOX4) down-regulation suppressed apoptosis and reactive oxygen species level in HG-treated podocytes. Take together, this study demonstrated that naringin ameliorates diabetic nephropathy by inhibiting NOX4, contributing to a better understanding of the progression of DN. Copyright © 2017 Elsevier B.V. All rights reserved.

MTORC1 EXPANDS TH17 AND IL-4+ DN T CELLS AND CONTRACTS TREGS IN SLE

PubMed Central

Kato, Hiroshi; Perl, Andras

2014-01-01

The mechanistic target of rapamycin (mTOR) is activated in CD4−CD8− double-negative (DN) T cells and its blockade is therapeutic in systemic lupus erythematosus (SLE) patients. Murine studies showed the involvement of mTOR complex 1 (mTORC1) and 2 (mTORC2) in the differentiation of Th1/Th17 cells and Th2 cells, respectively. Here, we investigated the roles of mTORC1 and mTORC2 in T-cell lineage development in SLE and matched healthy control (HC) subjects. mTORC1 activity was increased while mTORC2 was reduced as assessed by phosphorylation of their substrates pS6K or pS6RP and pAkt, respectively. Rapamycin inhibited mTORC1 and enhanced mTORC2. IL-4 expression was increased in freshly isolated CD8+ lupus T cells (SLE: 8.09±1.93%, HC: 3.61±0.49%; p=0.01). DN T cells had greater IL-4 expression than CD4+ or CD8+ T cells of SLE patients after 3 day in vitro stimulation, which was suppressed by rapamycin (control: 9.26±1.48%, rapamycin: 5.03±0.66%; p<0.001). GATA-3 expression was increased in CD8+ lupus T cells (p<0.01) and insensitive to rapamycin treatment. IFN-γ expression was reduced in all lupus T cell subsets (p=1.0×10−5) and also resisted rapamycin. IL-17 expression was increased in CD4+ lupus T cells (SLE: 3.62±0.66%, HC: 2.29±0.27%; p=0.019), which was suppressed by rapamycin (control: 3.91±0.79%, rapamycin: 2.22±0.60%; p<0.001). Frequency of Tregs was reduced in SLE (SLE: 1.83±0.25%, HC: 2.97±0.27%; p=0.0012). Rapamycin inhibited mTORC1 in Tregs and promoted their expansion. Neutralization of IL-17 but not IL-4 also expanded Tregs in SLE and HC subjects. These results indicate that mTORC1 expands IL-4+ DN T and Th17 cells and contracts Tregs in SLE. PMID:24683191

Cost-effectiveness Evaluation of the Inclusion of Dry Needling into an Exercise Program for Subacromial Pain Syndrome: Evidence from a Randomized Clinical Trial.

PubMed

Arias-Buría, José L; Martín-Saborido, Carlos; Cleland, Joshua; Koppenhaver, Shane L; Plaza-Manzano, Gustavo; Fernández-de-Las-Peñas, César

2018-02-22

To evaluate the cost-effectiveness of the inclusion of trigger point-dry needling (TrP-DN) into an exercise program for the management of subacromial pain syndrome. Fifty patients with unilateral subacromial pain syndrome were randomized with concealed allocation to exercise alone or exercise plus TrP-DN. Both groups were asked to perform an exercise program targeting the rotator cuff musculature twice daily for five weeks. Patients allocated to the exercise plus TrP-DN group also received dry needling during the second and fourth sessions. Societal costs and health-related quality of life (estimated by EuroQol-5D-5L) over a one-year follow-up were used to generate incremental cost per quality-adjusted life-year (QALY) ratios for each intervention.  Intention-to-treat analysis was possible for 48 (96%) of the participants. Those in the exercise group made more visits to medical doctors and received a greater number of other treatments (P < 0.001). The major contributor to societal costs (77%) was the absenteeism paid labor in favor of the exercise plus TrP-DN group (P = 0.03). The combination of exercise plus TrP-DN was less costly (mean difference cost/patient = €517.34, P = 0.003) than exercise alone. Incremental QALYs showed greater benefit for exercise plus TrP-DN (difference = 2.87, 95% confidence interval = 2.85-2.89). Therefore, the inclusion of TrP-DN into an exercise program was more likely to be cost-effective than an exercise program alone, with 99.5% of the iterations falling in the dominant area. The inclusion of TrP-DN into an exercise program was more cost-effective for individuals with subacromial pain syndrome than exercise alone. From a cost-benefit perspective, the inclusion of TrP-DN into multimodal management of patients with subacromial pain syndrome should be considered.

Identification, prevalence, and treatment of painful diabetic neuropathy in patients from a rural area in South Carolina.

PubMed

Pruitt, Jimmy; Moracho-Vilrriales, Carolina; Threatt, Tiffaney; Wagner, Sarah; Wu, Jun; Romero-Sandoval, E Alfonso

2017-01-01

Diabetic peripheral neuropathy (DPN) represents significant burdens to many patients and the public health-care system. Patients with diabetes in rural areas have higher risk of developing complications and having less access to proper treatment. We studied a rural population of patients with diabetes who attended a pharmacist-led free clinic for a diabetic education program. Our objectives were to 1) determine the prevalence of DPN and painful diabetic neuropathy (p-DN) in patients with type 2 diabetes; 2) assess the proportion of patients with DPN and p-DN left undocumented upon physician referral to a pharmacist-led free clinic; and 3) determine the appropriateness of pain medication regimen. We performed a retrospective analysis of clinical records of patients from the Presbyterian College School of Pharmacy (PCSP) Wellness Center located in Clinton, SC. Diagnoses of DPN and/or p-DN were obtained from referral notes in the clinical records and compared with results from foot examinations performed in the free clinic and clinical features. Medication regimens were also obtained and compared using American Academy of Neurology (AAN) treatment guidelines. Within our study population (n=111), the prevalence of DPN was 62.2% (national average of 28%-45%) and that of p-DN was 23.4% (national average of 11%-24%). In p-DN patients (n=26), 53.8% (n=14) had a documented diagnosis of p-DN by the referring physician, and 46.2% (n=12) were identified by the pharmacists. A total of 95% (19 of 20) of the patients treated for p-DN received adequate pharmacological agents, though suboptimal as per clinical guidelines. More than 50% of the patients used subtherapeutic doses of their medications. Gabapentin was the most frequently used medication in our population (65.4%). Patients in rural South Carolina had a higher prevalence of DPN and p-DN with >60% undocumented cases of p-DN. More than 95% of treated patients did not receive optimum therapy according to AAN guidelines.

Development and validation of Arabic version of the douleur neuropathique 4 questionnaire.

PubMed

Terkawi, Abdullah Sulieman; Abolkhair, Abdullah; Didier, Bouhassira; Alzhahrani, Tariq; Alsohaibani, Mazen; Terkawi, Yazzed Sulieman; Almoqbali, Yousuf; Tolba, Yasser Younis; Pangililan, Evelyn; Foula, Farida; Tsang, Siny

2017-05-01

The douleur neuropathique 4 (DN4) questionnaire is a widely used tool for diagnosis of neuropathic pain (NP). The aim was to translate, culturally adapt, and validate the DN4 questionnaire in Arabic. A systematic translation process was used to translate the original English DN4 into Arabic. After the pilot study, the Arabic version was validated among patients with chronic pain in two tertiary care centers. The reliability of the translated version was examined using internal consistency, test-retest reliability, and intraclass correlation coefficients. We examined the validity of the Arabic DN4 via construct validity, concurrent validity (associations with the numeric rating scale, brief pain inventory, and Self-Completed Leeds Assessment of Neuropathic Symptoms and Signs [S-LANSS]), face validity, and diagnostic validity. To investigate the responsiveness, the translated DN4 was administered twice among the same group of patients. A total of 142 subjects (68 men, 74 women) were included in the study. Cronbach's α was 0.67 (95% confidence interval [CI]: 0.59-0.75), and interclass correlation coefficients was 0.81 (95% CI: 0.76-0.87). The DN4 was moderately associated with the S-LANSS questionnaire. Results showed our Arabic DN4 to have good diagnostic accuracy, with area under the curve of 0.88 (95% CI: 0.82-0.94). As with the original version, a score of ≥4 was found to be the best cut-off for the diagnosis of NP, with a sensitivity of 88.31%, specificity of 74.47%, a positive predictive value of 85%, and a negative predictive value of 80%. Most patients found the DN4 questionnaire to be clear and easy to understand, and thought the questionnaire items covered all their problem areas regarding their pain. Our Arabic version of the DN4 is a reliable and valid screening tool that can be easily administered among patients to differentiate between NP and non-NP.

Tweezering the core of dendrimers: medium effect on the kinetic and thermodynamic properties.

PubMed

Giansante, Carlo; Mazzanti, Andrea; Baroncini, Massimo; Ceroni, Paola; Venturi, Margherita; Klärner, Frank-Gerrit; Vögtle, Fritz

2009-10-02

We have investigated the complex formation between dendritic guests and a molecular tweezer host by NMR, absorption, and emission spectroscopy as well as electrochemical techniques. The dendrimers are constituted by an electron-acceptor 4,4'-bipyridinium core appended with one (DnB(2+)) or two (Dn(2)B(2+)) polyaryl-ether dendrons. Tweezer T comprises a naphthalene and four benzene components bridged by four methylene groups. Medium effects on molecular recognition phenomena are discussed and provide insight into the conformation of dendrimers: change in solvent polarity from pure CH(2)Cl(2) to CH(2)Cl(2)/CH(3)CN mixtures and addition of tetrabutylammonium hexafluorophosphate (NBu(4)PF(6), up to 0.15 M), the supporting electrolyte used in the electrochemical measurements, have been investigated. The association constants measured in different media show the following trend: (i) they decrease upon increasing polarity of the solvent, as expected for host-guest complexes stabilized by electron donor-acceptor interactions; (ii) no effect of generation and number of dendrons (one for the DnB(2+) family and two for the Dn(2)B(2+) family) appended to the core is observed in higher polarity media; and (iii) in a low-polarity solvent, like CH(2)Cl(2), the stability of the inclusion complexes is higher for DnB(2+) dendrimers than for Dn(2)B(2+) ones, while within each dendrimer family it increases by decreasing dendron generation, and upon addition of NBu(4)PF(6). The last result has been ascribed to a partial dendron unfolding. Kinetic investigations performed in lower polarity media evidence that the rate constants of complex formation are slower for symmetric Dn(2)B(2+) dendrimers than for the nonsymmetric DnB(2+) ones, and that within the Dn(2)B(2+) family, they decrease by increasing dendron generation. The dependence of the rate constants for the formation and dissociation of the complexes upon addition of NBu(4)PF(6) has also been investigated and discussed.

Potential Role of Serum and Urinary Biomarkers in Diagnosis and Prognosis of Diabetic Nephropathy.

PubMed

Campion, Carole G; Sanchez-Ferras, Oraly; Batchu, Sri N

2017-01-01

Diabetic nephropathy (DN) is a progressive kidney disease caused by alterations in kidney architecture and function, and constitutes one of the leading causes of end-stage renal disease (ESRD). The purpose of this review is to summarize the state of the art of the DN-biomarker field with a focus on the new strategies that enhance the sensitivity of biomarkers to predict patients who will develop DN or are at risk of progressing to ESRD. In this review, we provide a description of the pathophysiology of DN and propose a panel of novel putative biomarkers associated with DN pathophysiology that have been increasingly investigated for diagnosis, to predict disease progression or to provide efficient personal treatment. We performed a review of the literature with PubMed and Google Scholar to collect baseline data about the pathophysiology of DN and biomarkers associated. We focused our research on new and emerging biomarkers of DN. In this review, we summarized the critical signaling pathways and biological processes involved in DN and highlighted the pathogenic mediators of this disease. We next proposed a large review of the major advances that have been made in identifying new biomarkers which are more sensitive and reliable compared with currently used biomarkers. This includes information about emergent biomarkers such as functional noncoding RNAs, microRNAs, long noncoding RNAs, exosomes, and microparticles. Despite intensive strategies and constant investigation, no current single treatment has been able to reverse or at least mitigate the progression of DN, or reduce the morbidity and mortality associated with this disease. Major difficulties probably come from the renal disease being heterogeneous among the patients. Expanding the proteomics screening, including oxidative stress and inflammatory markers, along with metabolomics approaches may further improve the prognostic value and help in identifying the patients with diabetes who are at high risk of developing kidney diseases.

Berberine ameliorates diabetic nephropathy by inhibiting TLR4/NF-κB pathway.

PubMed

Zhu, Liping; Han, Jiakai; Yuan, Rongrong; Xue, Lei; Pang, Wuyan

2018-03-31

Diabetic nephropathy (DN) is the leading cause of end-stage renal failure, contributing to severe morbidity and mortality in diabetic patients. Berberine (BBR) has been well characterized to exert renoprotective effects in DN progression. However, the action mechanism of BBR in DN remains to be fully understood. The DN rat model was generated by intraperitoneal injection of streptozotocin (STZ, 65 mg/kg body weight) while 30 mM high glucose (HG)-treated podocytes were used as an in vitro DN model. The fasting blood glucose level and ratio of kidney weight to body weight were measured after BBR treatment (50, 100, or 200 mg/kg) in STZ-induced DN rats. The renal injury parameters including 24-h urinary protein, blood urea nitrogen and serum creatinine were assessed. qRT-PCR was performed to detect the transcript amounts of inflammatory factors. The concentrations of inflammatory factors were evaluated by ELISA kits. Western blot analysis was conducted to measure the amounts of TLR4/NF-κB-related proteins. The apoptotic rate of podocytes was analyzed by flow cytometry using Annexin V/propidium iodide. Berberine reduced renal injury in STZ-induced DN rat model, as evidenced by the decrease in fasting blood glucose, ratio of kidney weight to body weight, 24-h urinary protein, serum creatinine, and blood urine nitrogen. BBR attenuated the systemic and renal cortex inflammatory response and inhibited TLR4/NF-κB pathway in STZ-induced DN rats and HG-induced podocytes. Also, HG-induced apoptosis of podocytes was lowered by BBR administration. Furthermore, blockade of TLR4/NF-κB pathway by resatorvid (TAK-242) or pyrrolidine dithiocarbamate aggravated the inhibitory effect of BBR on HG-induced inflammatory response and apoptosis in podocytes. Berberine ameliorated DN through relieving STZ-induced renal injury, inflammatory response, and podocyte HG-induced apoptosis via inactivating TLR4/NF-κB pathway.

mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice

PubMed Central

Inoki, Ken; Mori, Hiroyuki; Wang, Junying; Suzuki, Tsukasa; Hong, SungKi; Yoshida, Sei; Blattner, Simone M.; Ikenoue, Tsuneo; Rüegg, Markus A.; Hall, Michael N.; Kwiatkowski, David J.; Rastaldi, Maria P.; Huber, Tobias B.; Kretzler, Matthias; Holzman, Lawrence B.; Wiggins, Roger C.; Guan, Kun-Liang

2011-01-01

Diabetic nephropathy (DN) is among the most lethal complications that occur in type 1 and type 2 diabetics. Podocyte dysfunction is postulated to be a critical event associated with proteinuria and glomerulosclerosis in glomerular diseases including DN. However, molecular mechanisms of podocyte dysfunction in the development of DN are not well understood. Here we have shown that activity of mTOR complex 1 (mTORC1), a kinase that senses nutrient availability, was enhanced in the podocytes of diabetic animals. Further, podocyte-specific mTORC1 activation induced by ablation of an upstream negative regulator (PcKOTsc1) recapitulated many DN features, including podocyte loss, glomerular basement membrane thickening, mesangial expansion, and proteinuria in nondiabetic young and adult mice. Abnormal mTORC1 activation caused mislocalization of slit diaphragm proteins and induced an epithelial-mesenchymal transition–like phenotypic switch with enhanced ER stress in podocytes. Conversely, reduction of ER stress with a chemical chaperone significantly protected against both the podocyte phenotypic switch and podocyte loss in PcKOTsc1 mice. Finally, genetic reduction of podocyte-specific mTORC1 in diabetic animals suppressed the development of DN. These results indicate that mTORC1 activation in podocytes is a critical event in inducing DN and suggest that reduction of podocyte mTORC1 activity is a potential therapeutic strategy to prevent DN. PMID:21606597

The wnt/β-catenin signaling pathway participates in rhein ameliorating kidney injury in DN mice.

PubMed

Duan, Suyan; Wu, Yingyi; Zhao, Chuanyan; Chen, Mingyu; Yuan, Yanggang; Xing, Changying; Zhang, Bo

2016-01-01

The present study aimed to investigate the relationship between wnt/β-catenin signaling pathway and kidney impairment in diabetic nephropathy (DN) mice as well as the renoprotective effect of rhein (RH). Mice were randomly divided into four groups (n = 6): db/db mice treated with RH (DN + RH), db/db mice (DN), db/m mice treated with RH (NC + RH) and db/m mice (NC). RH-treated groups were administered orally at a daily dose 120 mg/kg. Mice were sacrificed after 12 weeks of treatments. In our study, increased albuminuria, together with weight gain and hyperglycemia was observed in the beginning of the study and continued to increase throughout the length of the study (12 weeks). Histopathologic changes were observed in the DN group. Expectedly, mice receiving the treatment with RH were protected from this injury. Meanwhile, the expression of nephrin, a podocyte-specific marker, was significantly reduced while wnt1, p-GSK-3β/tGSK-3β, p-β-catenin/tβ-catenin were higher in the DN group mice when analyzed by immunofluorescence and Western blotting. RH reversed these above changes. wnt/β-catenin signaling pathway participates in RH ameliorating kidney injury in DN mice. The manipulation of RH might act as a promising therapeutic intervention for DN.

A new model of diabetic nephropathy in C57BL/6 mice challenged with advanced oxidation protein products.

PubMed

Bai, Xiaoyan; Li, Xiao; Tian, Jianwei; Xu, Liting; Wan, Jiao; Liu, Youhua

2018-04-01

There remains a lack of robust mouse models with key features of advanced human diabetic nephropathy (DN). Few options of murine models of DN require mutations to be superimposed to obtain desired phenotypic characteristics. Most genetically modified mice are on the C57BL/6 background; however, they are notorious for resistance to develop DN. To overcome these conundrums, this study reports a novel DN model by challenging with advanced oxidation protein products (AOPPs) in streptozotocin-induced diabetic C57BL/6 mice. AOPPs-challenged diabetic C57BL/6 mice were more sensitive to develop progressive proteinuria, causing a 5.59-fold increase in urine albumin to creatinine ratio as compared to diabetic controls by 24 weeks. Typical lesions were present as demonstrated by significant diffuse mesangial expansion, diffuse podocyte foot process effacement, increased glomerular basement membrane thickness, focal arteriolar hyalinosis, mesangiolysis, and mild interstitial fibrosis. These changes were alleviated by losartan treatment. Collectively, these results suggest that AOPPs can accelerate the progression of DN in the resistant C57BL/6 mouse strain. Our studies offer a novel model for studying the pathogenesis of DN that resembles human diabetic kidney disease. It also makes it possible to interrogate the role of specific genetic modifications and to evaluate novel therapeutics to treat DN in preclinical setting. Copyright © 2018. Published by Elsevier Inc.

A Randomized, Prospective, Parallel Group Study of Laparoscopic vs. Laparoendoscopic Single Site Donor Nephrectomy for Kidney Donation

PubMed Central

Aull, Meredith J.; Afaneh, Cheguevara; Charlton, Marian; Serur, David; Douglas, Melissa; Christos, Paul J.; Kapur, Sandip; Del Pizzo, Joseph J.

2014-01-01

Few prospective, randomized studies have assessed benefits of laparoendoscopic single site donor nephrectomy (LESS-DN) over laparoscopic donor nephrectomy (LDN). Our center initiated such a trial in January 2011, following subjects randomized to LESS-DN vs. LDN from surgery through 5 years post-donation. Subjects complete recovery/satisfaction questionnaires at 2, 6, and 12 months post-donation; transplant recipient outcomes are also recorded. 100 subjects (49 LESS-DN, 51 LDN) underwent surgery; donor demographics were similar between groups, and included a predominance of female, living unrelated donors, mean age of 47 years who underwent left donor nephrectomy. Operative parameters (overall time, time to extraction, warm ischemia time, blood loss) were similar between groups. Conversion to hand-assist laparoscopy was required in 3 LESS-DN (6.1%) vs. 2 LDN (3.9%; P=0.67). Questionnaires revealed 97.2% of LESS-DN vs. 79.5% of LDN (P=0.03) were 100% recovered by two months after donation. No significant difference was seen in satisfaction scores between the groups. Recipient outcomes were similar between groups. Our randomized trial comparing LESS donor nephrectomy to LDN confirms that LESS-DN offers a safe alternative to conventional LDN in terms of intra- and post-operative complications. LDN and LESS-DN offer similar recovery and satisfaction after donation. PMID:24934732

Electrical Stimulation of Denervated Rat Skeletal Muscle Retards Capillary and Muscle Loss in Early Stages of Disuse Atrophy

PubMed Central

Nakagawa, Kouki; Hayao, Keishi; Yotani, Kengo; Ogita, Futoshi; Yamamoto, Noriaki; Onishi, Hideaki

2017-01-01

The purpose of the present study is to investigate the effects of low-frequency electrical muscle stimulation (ES) on the decrease in muscle mass, fiber size, capillary supply, and matrix metalloproteinase (MMP) immunoreactivity in the early stages of denervation-induced limb disuse. Direct ES was performed on the tibialis anterior muscle following denervation in seven-week-old male rats. The rats were divided into the following groups: control (CON), denervation (DN), and denervation with direct ES (DN + ES). Direct ES was performed at an intensity of 16 mA and a frequency of 10 Hz for 30 min per day, six days a week, for one week. We performed immunohistochemical staining to determine the expression of dystrophin, CD34, and MMP-2 in transverse sections of TA muscles. The weight, myofiber cross-sectional area (FCSA), and capillary-to-fiber (C/F) ratio of the tibialis anterior (TA) muscle were significantly reduced in the DN group compared to the control and DN + ES groups. The MMP-2 positive area was significantly greater in DN and DN + ES groups compared to the control group. These findings suggest beneficial effects of direct ES in reducing muscle atrophy and capillary regression without increasing MMP-2 immunoreactivity in the early stages of DN-induced muscle disuse in rat hind limbs. PMID:28497057

Association of lipoprotein lipase S447X, apolipoprotein E exon 4, and apoC3 -455T>C polymorphisms on the susceptibility to diabetic nephropathy.

PubMed

Ng, M C Y; Baum, L; So, W-Y; Lam, V K L; Wang, Y; Poon, E; Tomlinson, B; Cheng, S; Lindpaintner, K; Chan, J C N

2006-07-01

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. In DN patients, triglyceride (TG) level is elevated and lipoprotein lipase (LPL) activity, which hydrolyzes TG, is decreased. The LPL S447X and apolipoprotein E (APOE) exon 4 polymorphisms affect TG levels, and the APOC3 -455T>C polymorphism affects LPL activity. Our aim was to examine the association of these polymorphisms with nephropathy in type 2 diabetes. We examined these polymorphisms in a case-control study of type 2 diabetic patients including 374 with DN and 392 without DN. LPL 447X-containing genotypes (447X+) were significantly decreased in DN patients [18.6 vs 25.6%, odds ratio (OR) = 0.66, p = 0.02], as were APOE epsilon3/epsilon3 genotypes (64.8 vs 73.1%, OR = 0.68, p = 0.01). In addition, combinations of genotypes [APOE epsilon3/epsilon3 and LPL 447X+ (OR = 0.56), APOC3 CC and LPL 447X+ (OR = 0.31), APOE epsilon3/epsilon3 and APOC3 CC (OR = 0.61] were protective for DN compared with the most common combination of the respective polymorphisms. Our findings suggest the importance of interactions among lipid genes in modulating the risk of DN.

Management of diabetic nephropathy: Recent progress and future perspective.

PubMed

Ahmad, Jamal

2015-01-01

Diabetic nephropathy (DN), a leading cause of end-stage renal disease (ESRD) affecting ∼20-30% diabetics, is associated with increased cardiovascular mortality. The progression of kidney disease in patients with diabetes can take many years. It occurs as a result of interaction between both genetic and environmental factors in individuals with both type 1 and type 2 diabetes. Hyperglycaemia, hypertension, and genetic pre-disposition are the main risk factors besides elevated serum lipids, smoking habits, and the amount of dietary proteins. Interventions such as glycaemic control, blood pressure control and inhibition of the renin-angiotensin-aldosterone system have been shown to slow this progression. Despite the implementation of these strategies, the number of patients with diabetes that ultimately develop end-stage renal disease remains high. The treatment of DN, therefore, has posed a formidable challenge besides optimization of renin-angiotensin-aldosterone system blockade in patients with DN; additional investigation has focused on the potential of novel therapies that target various pathways upregulated by hyperglycaemia or other targets believed to promote the progression of DN such as oxidative stress, inflammation, endothelin system and vitamin D receptors. This review article addresses the pathogenesis and some of the well established principles regarding the progression and accepted management of DN, and also includes the perspectives of novel anti-DN agents and the future directions for the prevention of DN. Copyright © 2015 Diabetes India. Published by Elsevier Ltd. All rights reserved.

Designing mid-wave infrared (MWIR) thermo-optic coefficient (dn/dT) in chalcogenide glasses

NASA Astrophysics Data System (ADS)

Gleason, Benn; Sisken, Laura; Smith, Charmayne; Richardson, Kathleen

2016-05-01

Seventeen infrared-transmitting GeAsSe chalcogenide glasses were fabricated to determine the role of chemistry and structure on mid-wave infrared (MWIR) optical properties. The refractive index and thermoptic coefficients of samples were measured at λ = 4.515 μm using an IR-modified Metricon prism coupler, located at University of Central Florida. Thermo-optic coefficient (dn/dT) values were shown to range from approximately -40 ppm/°C to +65 ppm/°C, and refractive index was shown to vary between approximately 2.5000 and 2.8000. Trends in refractive index and dn/dT were found to be related to the atomic structures present within the glassy network, as opposed to the atomic percentage of any individual constituent. A linear correlation was found between the quantity (n-3•dn/dT) and the coefficient of thermal expansion (CTE) of the glass, suggesting the ability to compositionally design chalcogenide glass compositions with zero dn/dT, regardless of refractive index or dispersion performance. The tunability of these novel glasses offer increased thermal and mechanical stability as compared to the current commercial zero dn/dT options such as AMTIR-5 from Amorphous Materials Inc. For IR imaging systems designed to achieve passive athermalization, utilizing chalcogenide glasses with their tunable ranges of dn/dT (including zero) can be key to addressing system size, weight, and power (SWaP) limitations.

Maternal choline supplementation programs greater activity of the phosphatidylethanolamine N-methyltransferase (PEMT) pathway in adult Ts65Dn trisomic mice

PubMed Central

Yan, Jian; Ginsberg, Stephen D.; Powers, Brian; Alldred, Melissa J.; Saltzman, Arthur; Strupp, Barbara J.; Caudill, Marie A.

2014-01-01

Maternal choline supplementation (MCS) induces lifelong cognitive benefits in the Ts65Dn mouse, a trisomic mouse model of Down syndrome and Alzheimer's disease. To gain insight into the mechanisms underlying these beneficial effects, we conducted a study to test the hypothesis that MCS alters choline metabolism in adult Ts65Dn offspring. Deuterium-labeled methyl-d9-choline was administered to adult Ts65Dn and disomic (2N) female littermates born to choline-unsupplemented or choline-supplemented Ts65Dn dams. Enrichment of d9-choline metabolites (derived from intact choline) and d3 + d6-choline metabolites [produced when choline-derived methyl groups are used by phosphatidylethanolamine N-methyltransferase (PEMT)] was measured in harvested tissues. Adult offspring (both Ts65Dn and 2N) of choline-supplemented (vs. choline-unsupplemented) dams exhibited 60% greater (P≤0.007) activity of hepatic PEMT, which functions in de novo choline synthesis and produces phosphatidylcholine (PC) enriched in docosahexaenoic acid. Higher (P<0.001) enrichment of PEMT-derived d3 and d6 metabolites was detected in liver, plasma, and brain in both genotypes but to a greater extent in the Ts65Dn adult offspring. MCS also yielded higher (P<0.05) d9 metabolite enrichments in liver, plasma, and brain. These data demonstrate that MCS exerts lasting effects on offspring choline metabolism, including up-regulation of the hepatic PEMT pathway and enhanced provision of choline and PEMT-PC to the brain.—Yan, J., Ginsberg, S. D., Powers, B., Alldred, M. J., Saltzman, A., Strupp, B. J., Caudill, M. A. Maternal choline supplementation programs greater activity of the phosphatidylethanolamine N-methyltransferase (PEMT) pathway in adult Ts65Dn trisomic mice. PMID:24963152

Occurrence and risk assessment of phthalate esters (PAEs) in vegetables and soils of suburban plastic film greenhouses.

PubMed

Wang, Jun; Chen, Gangcai; Christie, Peter; Zhang, Manyun; Luo, Yongming; Teng, Ying

2015-08-01

Phthalate esters (PAEs) are suspected of having adverse effects on human health and have been frequently detected in soils and vegetables. The present study investigated their occurrence and composition in plastic film greenhouse soil-vegetable systems and assessed their potential health risks to farmers exposed to these widespread pollutants. Six priority control phthalates, namely dimethyl phthalate (DMP), diethyl phthalate (DEP), di-n-butyl phthalate (DnBP), butyl benzyl phthalate (BBP), di-(2-ethylhexyl) phthalate (DEHP) and di-n-octyl phthalate (DnOP), were determined in 44 plastic film greenhouse vegetables and corresponding soils. Total PAEs ranged from 0.51 to 7.16mgkg(-1) in vegetables and 0.40 to 6.20mgkg(-1) in soils with average concentrations of 2.56 and 2.23mgkg(-1), respectively. DnBP, DEHP and DnOP contributed more than 90% of the total PAEs in both vegetables and soils but the proportions of DnBP and DnOP in vegetables were significantly (p<0.05) higher than in soils. The average concentrations of PAEs in pot herb mustard, celery and lettuce were >3.00mgkg(-1) but were <2.50mgkg(-1) in the corresponding soils. Stem and leaf vegetables accumulated more PAEs. There were no clear relationships between vegetable and soil PAEs. Risk assessment indicates that DnBP, DEHP and DnOP exhibited elevated non-cancer risk with values of 0.039, 0.338 and 0.038, respectively. The carcinogenic risk of DEHP was about 3.94×10(-5) to farmers working in plastic film greenhouses. Health risks were mainly by exposure through vegetable consumption and soil ingestion. Copyright © 2015 Elsevier B.V. All rights reserved.

Functional characterization of DnSIZ1, a SIZ/PIAS-type SUMO E3 ligase from Dendrobium.

PubMed

Liu, Feng; Wang, Xiao; Su, Mengying; Yu, Mengyuan; Zhang, Shengchun; Lai, Jianbin; Yang, Chengwei; Wang, Yaqin

2015-09-17

SUMOylation is an important post-translational modification of eukaryotic proteins that involves the reversible conjugation of a small ubiquitin-related modifier (SUMO) polypeptide to its specific protein substrates, thereby regulating numerous complex cellular processes. The PIAS (protein inhibitor of activated signal transducers and activators of transcription [STAT]) and SIZ (scaffold attachment factor A/B/acinus/PIAS [SAP] and MIZ) proteins are SUMO E3 ligases that modulate SUMO conjugation. The characteristic features and SUMOylation mechanisms of SIZ1 protein in monocotyledon are poorly understood. Here, we examined the functions of a homolog of Arabidopsis SIZ1, a functional SIZ/PIAS-type SUMO E3 ligase from Dendrobium. In Dendrobium, the predicted DnSIZ1 protein has domains that are highly conserved among SIZ/PIAS-type proteins. DnSIZ1 is widely expressed in Dendrobium organs and has a up-regulated trend by treatment with cold, high temperature and wounding. The DnSIZ1 protein localizes to the nucleus and shows SUMO E3 ligase activity when expressed in an Escherichia coli reconstitution system. Moreover, ectopic expression of DnSIZ1 in the Arabidopsis siz1-2 mutant partially complements several phenotypes and results in enhanced levels of SUMO conjugates in plants exposed to heat shock conditions. We observed that DnSIZ1 acts as a negative regulator of flowering transition which may be via a vernalization-induced pathway. In addition, ABA-hypersensitivity of siz1-2 seed germination can be partially suppressed by DnSIZ1. Our results suggest that DnSIZ1 is a functional homolog of the Arabidopsis SIZ1 with SUMO E3 ligase activity and may play an important role in the regulation of Dendrobium stress responses, flowering and development.

Altered synaptic marker abundance in the hippocampal stratum oriens of Ts65Dn mice is associated with exuberant expression of versican

PubMed Central

Howell, Matthew D; Gottschall, Paul E

2012-01-01

DS (Down syndrome), resulting from trisomy of chromosome 21, is the most common cause of genetic mental retardation; however, the molecular mechanisms underlying the cognitive deficits are poorly understood. Growing data indicate that changes in abundance or type of CSPGs (chondroitin sulfate proteoglycans) in the ECM (extracellular matrix) can influence synaptic structure and plasticity. The purpose of this study was to identify changes in synaptic structure in the hippocampus in a model of DS, the Ts65Dn mouse, and to determine the relationship to proteoglycan abundance and/or cleavage and cognitive disability. We measured synaptic proteins by ELISA and changes in lectican expression and processing in the hippocampus of young and old Ts65Dn mice and LMCs (littermate controls). In young (5 months old) Ts65Dn hippocampal extracts, we found a significant increase in the postsynaptic protein PSD-95 (postsynaptic density 95) compared with LMCs. In aged (20 months old) Ts65Dn hippocampus, this increase was localized to hippocampal stratum oriens extracts compared with LMCs. Aged Ts65Dn mice exhibited impaired hippocampal-dependent spatial learning and memory in the RAWM (radial-arm water maze) and a marked increase in levels of the lectican versican V2 in stratum oriens that correlated with the number of errors made in the final RAWM block. Ts65Dn stratum oriens PNNs (perineuronal nets), an extension of the ECM enveloping mostly inhibitory interneurons, were dispersed over a larger area compared with LMC mice. Taken together, these data suggest a possible association with alterations in the ECM and inhibitory neurotransmission in the Ts65Dn hippocampus which could contribute to cognitive deficits. PMID:22225533

Examining Innovative Divertor and Main Chamber Options for a National Divertor Test Tokamak

NASA Astrophysics Data System (ADS)

Labombard, B.; Umansky, M.; Brunner, D.; Kuang, A. Q.; Marmar, E.; Wallace, G.; Whyte, D.; Wukitch, S.

2016-10-01

The US fusion community has identified a compelling need for a National Divertor Test Tokamak. The 2015 Community Planning Workshop on PMI called for a national working group to develop options. Important elements of a NDTT, adopted from the ADX concept, include the ability to explore long-leg divertor `solutions for power exhaust and particle control' (Priority Research Direction B) and to employ inside-launch RF actuators combined with double-null topologies as `plasma solution for main chamber wall components, including tools for controllable sustained operation' (PRD-C). Here we examine new information on these ideas. The projected performance of super-X and X-point target long-leg divertors is looking very promising; a stable fully-detached divertor condition handling an order-of-magnitude increase in power handling over conventional divertors may be possible. New experiments on Alcator C-Mod are addressing issues of high-field side versus low-field side heat flux sharing in double-null topologies and the screening of impurities that might originate from RF actuators placed in the high-field side - both with favorable results. Supported by USDoE Awards DE-FC02-99ER54512 and DE-AC52-07NA27344.

A Novel Ras-interacting Protein Required for Chemotaxis and Cyclic Adenosine Monophosphate Signal Relay in Dictyostelium

PubMed Central

Lee, Susan; Parent, Carole A.; Insall, Robert; Firtel, Richard A.

1999-01-01

We have identified a novel Ras-interacting protein from Dictyostelium, RIP3, whose function is required for both chemotaxis and the synthesis and relay of the cyclic AMP (cAMP) chemoattractant signal. rip3 null cells are unable to aggregate and lack receptor activation of adenylyl cyclase but are able, in response to cAMP, to induce aggregation-stage, postaggregative, and cell-type-specific gene expression in suspension culture. In addition, rip3 null cells are unable to properly polarize in a cAMP gradient and chemotaxis is highly impaired. We demonstrate that cAMP stimulation of guanylyl cyclase, which is required for chemotaxis, is reduced ∼60% in rip3 null cells. This reduced activation of guanylyl cyclase may account, in part, for the defect in chemotaxis. When cells are pulsed with cAMP for 5 h to mimic the endogenous cAMP oscillations that occur in wild-type strains, the cells will form aggregates, most of which, however, arrest at the mound stage. Unlike the response seen in wild-type strains, the rip3 null cell aggregates that form under these experimental conditions are very small, which is probably due to the rip3 null cell chemotaxis defect. Many of the phenotypes of the rip3 null cell, including the inability to activate adenylyl cyclase in response to cAMP and defects in chemotaxis, are very similar to those of strains carrying a disruption of the gene encoding the putative Ras exchange factor AleA. We demonstrate that aleA null cells also exhibit a defect in cAMP-mediated activation of guanylyl cyclase similar to that of rip3 null cells. A double-knockout mutant (rip3/aleA null cells) exhibits a further reduction in receptor activation of guanylyl cyclase, and these cells display almost no cell polarization or movement in cAMP gradients. As RIP3 preferentially interacts with an activated form of the Dictyostelium Ras protein RasG, which itself is important for cell movement, we propose that RIP3 and AleA are components of a Ras-regulated pathway involved in integrating chemotaxis and signal relay pathways that are essential for aggregation. PMID:10473630

Developmental abnormalities and age-related neurodegeneration in a mouse model of Down syndrome

PubMed Central

Holtzman, David M.; Santucci, Daniela; Kilbridge, Joshua; Chua-Couzens, Jane; Fontana, David J.; Daniels, Scott E.; Johnson, Randolph M.; Chen, Karen; Sun, Yuling; Carlson, Elaine; Alleva, Enrico; Epstein, Charles J.; Mobley, William C.

1996-01-01

To study the pathogenesis of central nervous system abnormalities in Down syndrome (DS), we have analyzed a new genetic model of DS, the partial trisomy 16 (Ts65Dn) mouse. Ts65Dn mice have an extra copy of the distal aspect of mouse chromosome 16, a segment homologous to human chromosome 21 that contains much of the genetic material responsible for the DS phenotype. Ts65Dn mice show developmental delay during the postnatal period as well as abnormal behaviors in both young and adult animals that may be analogous to mental retardation. Though the Ts65Dn brain is normal on gross examination, there is age-related degeneration of septohippocampal cholinergic neurons and astrocytic hypertrophy, markers of the Alzheimer disease pathology that is present in elderly DS individuals. These findings suggest that Ts65Dn mice may be used to study certain developmental and degenerative abnormalities in the DS brain. PMID:8917591

Effect of Refractive Index Variation on Two-Wavelength Interferometry for Fluid Measurements

NASA Technical Reports Server (NTRS)

Mercer, Carolyn R.

1998-01-01

Two wavelength interferometry can in principle be used to measure changes in both temperature and concentration in a fluid, but measurement errors may be large if the fluid dispersion is small. This paper quantifies the effects of uncertainties in dn/dT and dn/dC on the measured temperature and concentration when using the simple expression dn = (dn/dT)dT + (dn/dC)dC. For the data analyzed here, ammonium chloride in water from -5 to 10(exp infinity) C over a concentration range of 2-14% and for wavelengths 514.5 and 633 nm, it is shown that the gradients must be known to within 0.015% to produce a modest 10% uncertainty in the measured temperature and concentration. These results show that real care must be taken to ensure the accuracy of refractive index gradients when using two wavelength interferometry for the simultaneous measurement of temperature and concentration.

Inactivation of Mre11 does not affect VSG gene duplication mediated by homologous recombination in Trypanosoma brucei.

PubMed

Robinson, Nicholas P; McCulloch, Richard; Conway, Colin; Browitt, Alison; Barry, J David

2002-07-19

We demonstrate, by gene deletion analysis, that Mre11 has a critical role in maintaining genomic integrity in Trypanosoma brucei. mre11(-/-) null mutant strains exhibited retarded growth but no delay or disruption of cell cycle progression. They showed also a weak hyporecombination phenotype and the accumulation of gross chromosomal rearrangements, which did not involve sequence translocation, telomere loss, or formation of new telomeres. The trypanosome mre11(-/-) strains were hypersensitive to phleomycin, a mutagen causing DNA double strand breaks (DSBs) but, in contrast to mre11(-/-) null mutants in other organisms and T. brucei rad51(-/-) null mutants, displayed no hypersensitivity to methyl methanesulfonate, which causes point mutations and DSBs. Mre11 therefore is important for the repair of chromosomal damage and DSBs in trypanosomes, although in this organism the intersection of repair pathways appears to differ from that in other organisms. Mre11 inactivation appears not to affect VSG gene switching during antigenic variation of a laboratory strain, which is perhaps surprising given the importance of homologous recombination during this process.

Accelerated Activation of SOCE Current in Myotubes from Two Mouse Models of Anesthetic- and Heat-Induced Sudden Death

PubMed Central

Yarotskyy, Viktor; Protasi, Feliciano; Dirksen, Robert T.

2013-01-01

Store-operated calcium entry (SOCE) channels play an important role in Ca2+ signaling. Recently, excessive SOCE was proposed to play a central role in the pathogenesis of malignant hyperthermia (MH), a pharmacogenic disorder of skeletal muscle. We tested this hypothesis by characterizing SOCE current (ISkCRAC) magnitude, voltage dependence, and rate of activation in myotubes derived from two mouse models of anesthetic- and heat-induced sudden death: 1) type 1 ryanodine receptor (RyR1) knock-in mice (Y524S/+) and 2) calsequestrin 1 and 2 double knock-out (dCasq-null) mice. ISkCRAC voltage dependence and magnitude at -80 mV were not significantly different in myotubes derived from wild type (WT), Y524S/+ and dCasq-null mice. However, the rate of ISkCRAC activation upon repetitive depolarization was significantly faster at room temperature in myotubes from Y524S/+ and dCasq-null mice. In addition, the maximum rate of ISkCRAC activation in dCasq-null myotubes was also faster than WT at more physiological temperatures (35-37°C). Azumolene (50 µM), a more water-soluble analog of dantrolene that is used to reverse MH crises, failed to alter ISkCRAC density or rate of activation. Together, these results indicate that while an increased rate of ISkCRAC activation is a common characteristic of myotubes derived from Y524S/+ and dCasq-null mice and that the protective effects of azumolene are not due to a direct inhibition of SOCE channels. PMID:24143248

Mammalian Exo1 encodes both structural and catalytic functions that play distinct roles in essential biological processes

PubMed Central

Schaetzlein, Sonja; Chahwan, Richard; Avdievich, Elena; Roa, Sergio; Wei, Kaichun; Eoff, Robert L.; Sellers, Rani S.; Clark, Alan B.; Kunkel, Thomas A.; Scharff, Matthew D.; Edelmann, Winfried

2013-01-01

Mammalian Exonuclease 1 (EXO1) is an evolutionarily conserved, multifunctional exonuclease involved in DNA damage repair, replication, immunoglobulin diversity, meiosis, and telomere maintenance. It has been assumed that EXO1 participates in these processes primarily through its exonuclease activity, but recent studies also suggest that EXO1 has a structural function in the assembly of higher-order protein complexes. To dissect the enzymatic and nonenzymatic roles of EXO1 in the different biological processes in vivo, we generated an EXO1-E109K knockin (Exo1EK) mouse expressing a stable exonuclease-deficient protein and, for comparison, a fully EXO1-deficient (Exo1null) mouse. In contrast to Exo1null/null mice, Exo1EK/EK mice retained mismatch repair activity and displayed normal class switch recombination and meiosis. However, both Exo1-mutant lines showed defects in DNA damage response including DNA double-strand break repair (DSBR) through DNA end resection, chromosomal stability, and tumor suppression, indicating that the enzymatic function is required for those processes. On a transformation-related protein 53 (Trp53)-null background, the DSBR defect caused by the E109K mutation altered the tumor spectrum but did not affect the overall survival as compared with p53-Exo1null mice, whose defects in both DSBR and mismatch repair also compromised survival. The separation of these functions demonstrates the differential requirement for the structural function and nuclease activity of mammalian EXO1 in distinct DNA repair processes and tumorigenesis in vivo. PMID:23754438

Roles of FGFR3 during morphogenesis of Meckel's cartilage and mandibular bones

PubMed Central

Havens, Bruce A.; Velonis, Dimitris; Kronenberg, Mark S.; Lichtler, Alex C.; Oliver, Bonnie; Mina, Mina

2008-01-01

To address the functions of FGFR2 and FGFR3 signaling during mandibular skeletogenesis, we over-expressed in the developing chick mandible, replication-competent retroviruses carrying truncated FGFR2c or FGFR3c that function as dominant negative receptors (RCAS-dnFGFR2 and RCAS-dnFGFR3). Injection of RCAS-dnFGFR3 between HH15−20 led to reduced proliferation, increased apoptosis, and decreased differentiation of chondroblasts in Meckel's cartilage. These changes resulted in the formation of a hypoplastic mandibular process and truncated Meckel's cartilage. This treatment also affected the proliferation and survival of osteoprogenitor cells in osteogenic condensations, leading to the absence of five mandibular bones on the injected side. Injection of RCAS-dnFGFR2 between HH15−20 or RCAS-dnFGFR3 at HH26 did not affect the morphogenesis of Meckel's cartilage but resulted in truncations of the mandibular bones. RCAS-dnFGFR3 affected the proliferation and survival of the cells within the periosteum and osteoblasts. Together these results demonstrate that FGFR3 signaling is required for the elongation of Meckel's cartilage and FGFR2 and FGFR3 have roles during intramembranous ossification of mandibular bones. PMID:18339367

Inhibitory Effects of 4'-Demethylnobiletin, a Metabolite of Nobiletin, on 12-O-Tetradecanoylphorbol-13-acetate (TPA)-Induced Inflammation in Mouse Ears.

PubMed

Wu, Xian; Song, Mingyue; Rakariyatham, Kanyasiri; Zheng, Jinkai; Wang, Minqi; Xu, Fei; Gao, Zili; Xiao, Hang

2015-12-30

Nobiletin (NOB) is major citrus flavonoid with many health-promoting benefits. We reported previously that 4'-demethylnobiletin (4DN), a major metabolite of NOB, significantly inhibited lipopolysaccharide (LPS)-stimulated inflammation in RAW 264.7 macrophages. In this study, we further studied the anti-inflammatory effects of 4DN in TPA-induced skin inflammation in mice. We demonstrated that topical application of 4DN decreased TPA-induced ear edema by >88 ± 4.77% in mice. This inhibitory effect was associated with inhibition on TPA-induced up-regulation of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α. Immunoblotting results showed that 4DN resulted in profound effects on multiple proteins related with inflammation and carcinogenesis. 4DN significantly decreased the expression levels of iNOS, COX-2, and MMP-9, suppressed phosphorylation of PI3K/Akt and ERK, and increased the levels of HO-1 and NQO1 in TPA-treated mice. Overall, the results demonstrated that 4DN had strong anti-inflammatory effects in vivo, which provided a scientific basis for using NOB to inhibit inflammation-driven diseases.

Benefit of magnesium-25 carrying porphyrin-fullerene nanoparticles in experimental diabetic neuropathy

PubMed Central

Hosseini, Asieh; Sharifzadeh, Mohammad; Rezayat, Seyed Mahdi; Hassanzadeh, Gholamreza; Hassani, Shokoufeh; Baeeri, Maryam; Shetab-Bushehri, Vahid; Kuznetsov, Dmitry A; Abdollahi, Mohammad

2010-01-01

Diabetic neuropathy (DN) is a debilitating disorder occurring in most diabetic patients without a viable treatment yet. The present work examined the protective effect of 25Mg-PMC16 nanoparticle (porphyrin adducts of cyclohexil fullerene-C60) in a rat model of streptozotocin (STZ)-induced DN. 25Mg-PMC16 (0.5 lethal dose50 [LD50]) was administered intravenously in two consecutive days before intraperitoneal injection of STZ (45 mg/kg). 24Mg-PMC16 and MgCl2 were used as controls. Blood 2,3-diphosphoglycerate (2,3-DPG), oxidative stress biomarkers, adenosine triphosphate (ATP) level in dorsal root ganglion (DRG) neurons were determined as biomarkers of DN. Results indicated that 2,3-DPG and ATP decreased whereas oxidative stress increased by induction of DN which all were improved in 25Mg-PMC16-treated animals. No significant changes were observed by administration of 24Mg-PMC16 or MgCl2 in DN rats. It is concluded that in DN, oxidative stress initiates injuries to DRG neurons that finally results in death of neurons whereas administration of 25Mg-PMC16 by release of Mg and increasing ATP acts protectively. PMID:20957114

The Influence of Immunosuppressive Agents on the Risk of De Novo Donor-Specific HLA Antibody Production in Solid Organ Transplant Recipients

PubMed Central

O'Leary, Jacqueline G.; Samaniego, Millie; Barrio, Marta Crespo; Potena, Luciano; Zeevi, Adriana; Djamali, Arjang; Cozzi, Emanuele

2016-01-01

Production of de novo donor-specific antibodies (dnDSA) is a major risk factor for acute and chronic antibody-mediated rejection and graft loss after all solid organ transplantation. In this article, we review the data available on the risk of individual immunosuppressive agents and their ability to prevent dnDSA production. Induction therapy with rabbit antithymocyte globulin may achieve a short-term decrease in dnDSA production in moderately sensitized patients. Rituximab induction may be beneficial in sensitized patients, and in abrogating rebound antibody response in patients undergoing desensitization or treatment for antibody-mediated rejection. Use of bortezomib for induction therapy in at-risk patients is of interest, but the benefits are unproven. In maintenance regimens, nonadherent and previously sensitized patients are not suitable for aggressive weaning protocols, particularly early calcineurin inhibitor withdrawal without lymphocyte-depleting induction. Early conversion to mammalian target of rapamycin inhibitor monotherapy has been reported to increase the risk of dnDSA formation, but a combination of mammalian target of rapamycin inhibitor and reduced-exposure calcineurin inhibitor does not appear to alter the risk. Early steroid therapy withdrawal in standard-risk patients after induction has no known dnDSA penalty. The available data do not demonstrate a consistent effect of mycophenolic acid on dnDSA production. Risk minimization for dnDSA requires monitoring of adherence, appropriate risk stratification, risk-based immunosuppression intensity, and prospective DSA surveillance. PMID:26680372

GDC-0941 inhibits metastatic characteristics of thyroid carcinomas by targeting both the phosphoinositide-3 kinase (PI3K) and hypoxia-inducible factor-1α (HIF-1α) pathways.

PubMed

Burrows, Natalie; Babur, Muhammad; Resch, Julia; Ridsdale, Sophie; Mejin, Melissa; Rowling, Emily J; Brabant, Georg; Williams, Kaye J

2011-12-01

Phosphoinositide 3-kinase (PI3K) regulates the transcription factor hypoxia-inducible factor-1 (HIF-1) in thyroid carcinoma cells. Both pathways are associated with aggressive phenotype in thyroid carcinomas. Our objective was to assess the effects of the clinical PI3K inhibitor GDC-0941 and genetic inhibition of PI3K and HIF on metastatic behavior of thyroid carcinoma cells in vitro and in vivo. Vascular endothelial growth factor ELISA, HIF activity assays, proliferation studies, and scratch-wound migration and cell spreading assays were performed under various O(2) tensions [normoxia, hypoxia (1 and 0.1% O(2)), and anoxia] with or without GDC-0941 in a panel of four thyroid carcinoma cell lines (BcPAP, WRO, FTC133, and 8505c). Genetic inhibition was achieved by overexpressing phosphatase and tensin homolog (PTEN) into PTEN-null cells and by using a dominant-negative variant of HIF-1α (dnHIF). In vivo, human enhanced green fluorescence protein-expressing follicular thyroid carcinomas (FTC) were treated with GDC-0941 (orally). Spontaneous lung metastasis was confirmed by viewing enhanced green fluorescence protein-positive colonies cultured from lung tissue. GDC-0941 inhibited hypoxia/anoxia-induced HIF-1α and HIF-2α expression and HIF activity in thyroid carcinoma cells. Basal (three of four cell lines) and/or hypoxia-induced (four of four) secreted vascular endothelial growth factor was inhibited by GDC-0941, whereas selective HIF targeting predominantly affected hypoxia/anoxia-mediated secretion (P < 0.05-0.0001). Antiproliferative effects of GDC-0941 were more pronounced in PTEN mutant compared with PTEN-restored cells (P < 0.05). Hypoxia increased migration in papillary cells and cell spreading/migration in FTC cells (P < 0.01). GDC-0941 reduced spreading and migration in all O(2) conditions, whereas dnHIF had an impact only on hypoxia-induced migration (P < 0.001). In vivo, GDC-0941 reduced expression of HIF-1α, phospho-AKT, GLUT-1, and lactate dehydrogenase A in FTC xenografts. DnHIF expression and GDC-0941 reduced FTC tumor growth and metastatic lung colonization (P < 0.05). PI3K plays a prominent role in the metastatic behavior of thyroid carcinoma cells irrespective of O(2) tension and appears upstream of HIF activation. GDC-0941 significantly inhibited the metastatic phenotype, supporting the clinical development of PI3K inhibition in thyroid carcinomas.

Effects of consumption of a fermented dairy product containing the probiotic Lactobacillus casei DN-114 001 on common respiratory and gastrointestinal infections in shift workers in a randomized controlled trial.

PubMed

Guillemard, Eric; Tanguy, Jérôme; Flavigny, Ann'Laure; de la Motte, Stephan; Schrezenmeir, Juergen

2010-10-01

The risk of infection may be increased in people under stress such as shift workers. This study examined the effect of a fermented dairy product containing the probiotic Lactobacillus casei DN-114 001 (verum) on the incidence of respiratory and gastrointestinal common infectious diseases (CIDs) and on immune functions in healthy shift workers. The study was single-center, randomized, double-blind, and controlled. Volunteers received 200 g/day of verum (n = 500) or control product (n = 500) for 3 months; 1-month follow-up was carried out. The cumulated number of CIDs (primary outcome) was not significantly different between groups. Because the Poisson distribution of the primary parameter did not fully fit the observed data, a post hoc categorical analysis was applied and showed a significantly lower cumulated number of CIDs in the verum group during the product consumption phase (odds ratio [OR] = 0.75, 95% confidence interval [CI] 0.59-0.95, p = 0.017). Verum also reduced the proportion of volunteers experiencing at least 1 CID (43% vs. 51%, p = 0.005), increased the time to the first occurrence of CID (p = 0.017) in the whole population, and reduced the cumulated number of CIDs in the subgroup of smokers (p = 0.033). In the course of CID, cumulated duration of fever was lower in the verum group (in the whole study phase) (p = 0.022), and an increase in leukocyte, neutrophil, and natural killer (NK) cell counts and activity (p = 0.047 to p < 0.001) was observed compared with control group. Verum was safe and well tolerated. The results indicate that daily consumption of a fermented dairy product containing Lactobacillus casei DN-114 001 could reduce the risk of common infections in stressed individuals such as shift workers.

Evaluation of Populus and Salix continuously irrigated with landfill leachate I. Genotype-specific elemental phytoremediation

Treesearch

Ronald S., Jr. Zalesny; Edmund O. Bauer

2007-01-01

There is a need for the identification and selection of specific tree genotypes that can sequester elements from contaminated soils, with elevated rates of uptake. We irrigated Populus (DN17, DN182, DN34, NM2, NM6) and Salix (94003, 94012, S287, S566, SX61) genotypes planted in large soil-filled containers with landfill leachate or...

Evaluation of Populus and Salix continuously irrigated with landfill leachate II. Soils and early tree development

Treesearch

Ronald S., Jr. Zalesny; Edmund O. Bauer

2007-01-01

Soil contaminant levels and early tree growth data are helpful for assessing phytoremediation systems. Populus (DN17, DN182, DN34, NM2, and NM6) and Salix (94003, 94012, S287, S566, and SX61) genotypes were irrigated with landfill leachate or municipal water and tested for differences in 1) element concentrations (P, K, Ca, Mg, S,...

An Automatic Drag-and-Drop Assistive Program Developed to Assistive People with Developmental Disabilities to Improve Drag-and-Drop Efficiency

ERIC Educational Resources Information Center

Shih, Ching-Hsiang; Huang, Hsun-Chin; Liao, Yung-Kun; Shih, Ching-Tien; Chiang, Ming-Shan

2010-01-01

The latest researches adopted software technology to improve pointing performance; however, Drag-and-Drop (DnD) operation is also commonly used in modern GUI programming. This study evaluated whether two children with developmental disabilities would be able to improve their DnD performance, through an Automatic DnD Assistive Program (ADnDAP). At…

Hypocellularity in the Murine Model for Down Syndrome Ts65Dn Is Not Affected by Adult Neurogenesis

PubMed Central

López-Hidalgo, Rosa; Ballestín, Raul; Vega, Jessica; Blasco-Ibáñez, José M.; Crespo, Carlos; Gilabert-Juan, Javier; Nácher, Juan; Varea, Emilio

2016-01-01

Down syndrome (DS) is caused by the presence of an extra copy of the chromosome 21 and it is the most common aneuploidy producing intellectual disability. Neural mechanisms underlying this alteration may include defects in the formation of neuronal networks, information processing and brain plasticity. The murine model for DS, Ts65Dn, presents reduced adult neurogenesis. This reduction has been suggested to underlie the hypocellularity of the hippocampus as well as the deficit in olfactory learning in the Ts65Dn mice. Similar alterations have also been observed in individuals with DS. To determine whether the impairment in adult neurogenesis is, in fact, responsible for the hypocellularity in the hippocampus and physiology of the olfactory bulb, we have analyzed cell proliferation and neuronal maturation in the two major adult neurogenic niches in the Ts656Dn mice: the subgranular zone (SGZ) of the hippocampus and the subventricular zone (SVZ). Additionally, we carried out a study to determine the survival rate and phenotypic fate of newly generated cells in both regions, injecting 5′BrdU and sacrificing the mice 21 days later, and analyzing the number and phenotype of the remaining 5′BrdU-positive cells. We observed a reduction in the number of proliferating (Ki67 positive) cells and immature (doublecortin positive) neurons in the subgranular and SVZ of Ts65Dn mice, but we did not observe changes in the number of surviving cells or in their phenotype. These data correlated with a lower number of apoptotic cells (cleaved caspase 3 positive) in Ts65Dn. We conclude that although adult Ts65Dn mice have a lower number of proliferating cells, it is compensated by a lower level of cell death. This higher survival rate in Ts65Dn produces a final number of mature cells similar to controls. Therefore, the reduction of adult neurogenesis cannot be held responsible for the neuronal hypocellularity in the hippocampus or for the olfactory learning deficit of Ts65Dn mice. PMID:26973453

The Impact of Diabetic Neuropathy on Balance and on the Risk of Falls in Patients with Type 2 Diabetes Mellitus: A Cross-Sectional Study.

PubMed

Timar, Bogdan; Timar, Romulus; Gaiță, Laura; Oancea, Cristian; Levai, Codrina; Lungeanu, Diana

2016-01-01

Diabetic neuropathy (DN) is a prevalent complication of Type 2 Diabetes Mellitus (T2DM) with a major impact on the health of the affected patient. We hypothesized that mediated by the dysfunctionalities associated with DN's three major components: sensitive (lack of motion associated sensory), motor (impairments in movement coordination) and autonomic (the presence of postural hypotension), the presence of DN may impair the balance in the affected patients. Our study's main aim is to evaluate the possible association between the presence and severity of DN and both the balance impairment and the risk of falls in patients with T2DM. In this cross-sectional study we enrolled, according to a consecutive-case population-based setting 198 patients with T2DM. The presence and severity of DN was evaluated using the Michigan Neuropathy Screening Instrument, a tool which allows both diagnosing and severity staging of DN. The balance impairment and the risk of falls were evaluated using four validated and standardized tools: Berg Balance Scale (BBS), Timed-up and Go test (TUG), Single Leg Stand test (SLS) and Fall Efficacy Scale (FES-I). The presence of DN was associated with significant decreases in the BBS score (40.5 vs. 43.7 points; p<0.001) and SLS time (9.3 vs. 10.3 seconds; p = 0.003) respectively increases in TUG time (8.9 vs. 7.6 seconds; p = 0.002) and FES-I score (38 vs. 33 points; p = 0.034). The MNSI score was reverse and significantly correlated with both BBS score (Spearman's r = -0.479; p<0.001) and SLS time (Spearman's r = -0.169; p = 0.017). In the multivariate regression model, we observed that patient's age, DN severity and depression's symptoms acted as independent, significant predictors for the risk of falls in patients with T2DM. The presence of DN in patients with DM is associated with impaired balance and with a consecutively increase in the risk of falls.

The curious case of SN 2011dn: A very peculiar type Ia supernova?

NASA Astrophysics Data System (ADS)

Rachubo, Alisa

Type Ia supernovae (SNe Ia) are excellent cosmological distance indicators due to the uniformity in their light curves, which led to the major discovery of the accelerated expansion of the universe. However, SNe Ia are not so uniform as one may expect, as there are many peculiar SNe Ia that exhibit differences in their photometric and spectroscopic behavior from normal SNe Ia. One of the goals of supernova cosmology today is to produce a cleaner sample of SNe Ia without these peculiar SNe Ia. Here we consider SN 2011dn, a peculiar SN Ia candidate. In 2011, Salvo, et al. carried out a preliminary analysis of a subset of the data prescribed here, and identified spectral and photometric peculiarities in this object's evolution that warranted further analysis. Here, we present a complete re-reduction and reanalysis of B, V,R, and I photometry of SN 2011dn obtained at Mount Laguna Observatory, spanning from 7 days before maximum light in B to 88 days past maximum light. In addition, we also consider total flux spectra from 9 days before maximum light to 4 days after maximum light, along with ultraviolet (UV) photometry obtained with the Swift telescope. From SN 2011dn's optical spectra, we find that SN 2011dn most closely resembles a SN 1991T-like type Ia supernova ('91T-like SN Ia). Such SNe Ia are typically more luminous than normal SNe Ia, and possess broader (i.e., they decline less rapidly than normal from maximum light) light curves. Their Deltam15(B) (drop in B magnitude 15 days after maximum light) are typically significantly less than the canonical value of 1.1, and can be as low as 0.8. In the earlier preliminary analysis, Salvo et al. measured a surprisingly high Deltam15(B) value for SN 2011dn, of ˜ 1.1. Since SN 2011dn was embedded in UGC 11501 (its host galaxy), however, it is possible that some of the light from the host galaxy was included in the photometric aperture, resulting in inaccurate photometric measurements. Here, in order to better isolate the supernova light from its host galaxy, we employ galaxy-subtraction techniques to generate more precise light curves. From these data, we obtain an updated Deltam15( B) value of 1.01 +/- 0.02, which suggests that SN 2011dn is indeed slightly overluminous compared to normal SNe Ia, but perhaps not as overluminous as '91T-like SNe Ia. However, despite this apparent resolution of the spectral and photometric conflict, we find SN 2011dn to still exhibit some unique features. For instance, its near-maximum and especially its post-maximum spectra exhibit an unusually weak Si II lambda6355 feature, even considering that '91T-like SNe Ia spectra tend to have shallow silicon features. Furthermore, we find that SN 2011dn exhibits some unusual UV-optical color evolution, though its early-time UV excess may be linked to unburned carbon in SN 2011dn's ejecta, as indicated by the C III lambda4649 feature in its pre-maximum spectra. Altogether, after a careful reanalysis of the spectral and photometric properties of SN 2011dn, we classify it as slightly overluminous, with '91T-like pre-maximum and near-maximum spectra, but exhibiting some atypical features. SN 2011dn is not as peculiar as anticipated, but still has some characteristics that are unique to it.

The relationship between solar keratoses and squamous cell carcinomas among Japanese.

PubMed

Takemiya, M; Ohtsuka, H; Miki, Y

1990-06-01

Between 1976 and 1988, 135 patients with solar keratosis (SK) and 53 patients with squamous cell carcinoma (SCC) on the sun-exposed skin, but without apparent preceding diseases such as burn scars, chronic radiodermatitis, chronic arsenic poisoning, or xeroderma pigmentosum, were encountered. Sixteen of the SCC patients also had SK on other areas of sun-exposed skin. There were 31 SCC patients also showing SK (SK-SCC) and 22 SCC not showing SK (DN-SCC) within the same histologic sections. The mean ages of the patients with SK-SCC and with DN-SCC were similar. Metastases to regional lymph nodes were observed in 5 SK-SCC patients, of whom 3 died of the disease, and in 5 DN-SCC patients, of whom 4 died of the disease. The five-year post-operative survival rates were 70% in SK-SCC and 74% in DN-SCC; the ten-year post-operative survival rates were 70% in SK-SCC and 44% in DN-SCC.

Mexican humanitarian assistance system.

DTIC Science & Technology

2016-05-26

Stabilization Mission in Haiti, SEDENA, Plan-DN-III- E , international relief system, Cluster system, Organization of American States, Conference of American...strategic plan for disaster relief—Plan DN-III- E . The plan contains annexes with specific instructions to different military actors and, because of...2FSArticuloSinPaginaLayout. 9 “Gaceta Parlamentaria 22 Apr 2010.” 10 Estado Mayor Defensa Nacional, Plan DN-III- E : Auxilio a La Poblacion Civil En Casos

Child dental neglect: is it a neglected area in the UK?

PubMed

Sarri, G; Marcenes, W

2012-08-01

This commentary focuses on the condition of dental neglect (DN) in children in the UK. It is divided into three sections: the first section defines DN in children and its consequences, the second section discusses who may be responsible for dental diseases in children as a result of neglect and the third section proposes a holistic approach to address DN in children in the UK.

Diabetic Neuropathy and Oxidative Stress: Therapeutic Perspectives

PubMed Central

Hosseini, Asieh; Abdollahi, Mohammad

2013-01-01

Diabetic neuropathy (DN) is a widespread disabling disorder comprising peripheral nerves' damage. DN develops on a background of hyperglycemia and an entangled metabolic imbalance, mainly oxidative stress. The majority of related pathways like polyol, advanced glycation end products, poly-ADP-ribose polymerase, hexosamine, and protein kinase c all originated from initial oxidative stress. To date, no absolute cure for DN has been defined; although some drugs are conventionally used, much more can be found if all pathophysiological links with oxidative stress would be taken into account. In this paper, although current therapies for DN have been reviewed, we have mainly focused on the links between DN and oxidative stress and therapies on the horizon, such as inhibitors of protein kinase C, aldose reductase, and advanced glycation. With reference to oxidative stress and the related pathways, the following new drugs are under study such as taurine, acetyl-L-carnitine, alpha lipoic acid, protein kinase C inhibitor (ruboxistaurin), aldose reductase inhibitors (fidarestat, epalrestat, ranirestat), advanced glycation end product inhibitors (benfotiamine, aspirin, aminoguanidine), the hexosamine pathway inhibitor (benfotiamine), inhibitor of poly ADP-ribose polymerase (nicotinamide), and angiotensin-converting enzyme inhibitor (trandolapril). The development of modern drugs to treat DN is a real challenge and needs intensive long-term comparative trials. PMID:23738033

Silencing of Histone Deacetylase 9 Expression in Podocytes Attenuates Kidney Injury in Diabetic Nephropathy

PubMed Central

Liu, Feng; Zong, Ming; Wen, Xiaofei; Li, Xuezhu; Wang, Jun; Wang, Yi; Jiang, Wei; Li, Xiaojun; Guo, Zhongliang; Qi, Hualin

2016-01-01

Podocyte dysfunction is important in the onset and development of diabetic nephropathy (DN). Histone deacetylases (HDACs) have been recently proved to play critical roles in the pathogenesis of DN. As one subtype of the class IIa HDACs, HDAC9 is capable to repress/de-repress their target genes in tumor, inflammation, atherosclerosis and metabolic diseases. In the present study, we investigate whether HDAC9 is involved in the pathophysiologic process of DN, especially the podocyte injury. Firstly, we explored the expression patterns and localization of HDAC9 and found that HDAC9 expression was significantly up-regulated in high glucose (HG)-treated mouse podocytes, as well as kidney tissues from diabetic db/db mice and patients with DN. Secondly, knockdown of HDAC9 in mouse podocytes significantly suppressed HG-induced reactive oxygen species (ROS) generation, cell apoptosis and inflammation through JAK2/STAT3 pathway and reduced the podocytes injury by decreasing the expression levels of Nephrin and Podocin. Moreover, in diabetic db/db mice, silencing of HDAC9 attenuated the glomerulosclerosis, inflammatory cytokine release, podocyte apoptosis and renal injury. Collectively, these data indicate that HDAC9 may be involved in the process of DN, especially podocyte injury. Our study suggest that inhibition of HDAC9 may have a therapeutic potential in DN treatment. PMID:27633396

Cardiac hypertrophy limits infarct expansion after myocardial infarction in mice.

PubMed

Iismaa, Siiri E; Li, Ming; Kesteven, Scott; Wu, Jianxin; Chan, Andrea Y; Holman, Sara R; Calvert, John W; Haq, Ahtesham Ul; Nicks, Amy M; Naqvi, Nawazish; Husain, Ahsan; Feneley, Michael P; Graham, Robert M

2018-04-17

We have previously demonstrated that adult transgenic C57BL/6J mice with CM-restricted overexpression of the dominant negative W v mutant protein (dn-c-kit-Tg) respond to pressure overload with robust cardiomyocyte (CM) cell cycle entry. Here, we tested if outcomes after myocardial infarction (MI) due to coronary artery ligation are improved in this transgenic model. Compared to non-transgenic littermates (NTLs), adult male dn-c-kit-Tg mice displayed CM hypertrophy and concentric left ventricular (LV) hypertrophy in the absence of an increase in workload. Stroke volume and cardiac output were preserved and LV wall stress was markedly lower than that in NTLs, leading to a more energy-efficient heart. In response to MI, infarct size in adult (16-week old) dn-c-kit-Tg hearts was similar to that of NTL after 24 h but was half that in NTL hearts 12 weeks post-MI. Cumulative CM cell cycle entry was only modestly increased in dn-c-kit-Tg hearts. However, dn-c-kit-Tg mice were more resistant to infarct expansion, adverse LV remodelling and contractile dysfunction, and suffered no early death from LV rupture, relative to NTL mice. Thus, pre-existing cardiac hypertrophy lowers wall stress in dn-c-kit-Tg hearts, limits infarct expansion and prevents death from myocardial rupture.

Development potential of the Dauin geothermal prospect, Negros Oriental, Philippines

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bayrante, L.F.; Hermoso, D.Z.; Candelaria, M.R.

1997-12-31

The Dauin geothermal prospect, situated 5 km southeast of the Palinpinon I and II sectors, was drilled between 1982 and 1983 to test its viability for development. Drilling results indicated that DN-1 was drilled closer to the source region than DN-2 where permeability, temperature, and alteration mineralogy were generally unpromising. DN-1 encountered temperatures of at least 240{degrees}C and a neutral-pH fluid with reservoir chloride of 3000 mg/kg. In particular, the presence of sulphur in the DN-1 discharge provoked debates and many speculation on the nature of the fluid in the area. The area was re-evaluated in 1996 for the followingmore » reasons: (1) Renewed interests on other geothermal prospects within Negros Island from an economic point of view and the success of modular plant developments are Pal II and other areas in the Philippines; (2) Reinterpretation of the genesis of sulphur contained in the DN-1 discharge fluid; (3) Encouraging temperature, permeability and neutral-pH alterations at depth and the neutral character of DN-1 discharge fluid; and (4) Reinterpretation of the hydrological model from a geochemical and geological point of view. The study indicates good potential for modular power development.« less

Effects of Temperature on Chronic Trapezius Myofascial Pain Syndrome during Dry Needling Therapy

PubMed Central

2014-01-01

The purpose of this study was to investigate the effects of temperature on chronic trapezius myofascial pain syndrome during dry needling therapy. Sixty patients were randomized into two groups of dry needling (DN) alone (group A) and DN combined with heat therapy group (group B). Each patient was treated once and the therapeutic effect was assessed by the visual analogue scale (VAS), pressure pain threshold (PPT), and the 36-item short form health survey (SF-36) at seven days, one month, and three months after treatment. Evaluation based on VAS and PPT showed that the pain of patients in groups A and B was significantly (P < 0.05) relieved at seven days, one month, and three months after treatment Compared to before treatment. There was significantly (P < 0.05) less pain in group B than group A at one and three months after treatment. The SF-36 evaluation demonstrated that the physical condition of patients in both groups showed significant (P < 0.05) improvement at one month and three months after treatment than before treatment. Our study suggests that both DN and DN heating therapy were effective in the treatment of trapezius MPS, and that DN heating therapy had better long-term effects than DN therapy. PMID:25383083

Identification of Type VI Collagen Synthesizing Cells in Human Diabetic Glomerulosclerosis Using Renal Biopsy Sections

PubMed Central

Razzaque, Mohammed Shawkat; Koji, Takehiko; Harada, Takashi; Taguchi, Takashi

1997-01-01

Although the role of extracellular matrices in the development of glomerulosclerosis has been discussed widely, the cellular origin of type VI collagen in diabetic nephropathy (DN) has remained relatively unexplored. This study reports the distribution and cellular origin of type VI collagen in DN. Type VI collagen‐specific oligonucleotide probes and monoclonal antibody were used to assess the relative expression of mRNA for \\alpha1 (VI) chain and its translated protein in paraffin‐embedded renal biopsy sections of DN. By immunohistochemistry, compared to the control, increased deposition of type VI collagen was noted in the diffuse and nodular lesions of diabetic glomeruli. For cellular localization of type VI collagen mRNA, paraffin‐embedded renal sections of the control and DN were hybridized in situ with digoxigenin (Dig)‐labeled antisense oligo‐DNA probe complementary to a part of \\alpha1 (VI) mRNA. In comparison to the control kidney sections, increased numbers of intraglomerular cells (both mesangial and epithelial cells) were positive for α1 (VI) mRNA in renal biopsy sections of DN. From the results, we conclude that overexpression of type VI collagen by intraglomerular cells with its increased deposition might significantly contribute to the glomerulosclerosis found in DN. PMID:9497854

Emotional and cognitive stimuli differentially engage the default network during inductive reasoning.

PubMed

Eldaief, Mark C; Deckersbach, Thilo; Carlson, Lindsay E; Beucke, Jan C; Dougherty, Darin D

2012-04-01

The brain's default network (DN) is comprised of several cortical regions demonstrating robust intrinsic connectivity at rest. The authors sought to examine the differential effects of emotional reasoning and reasoning under certainty upon the DN through the employment of an event-related fMRI design in healthy participants. Participants were presented with syllogistic arguments which were organized into a 2 × 2 factorial design in which the first factor was emotional salience and the second factor was certainty/uncertainty. We demonstrate that regions of the DN were activated both during reasoning that is emotionally salient and during reasoning which is more certain, suggesting that these processes are neurally instantiated on a network level. In addition, we present evidence that emotional reasoning preferentially activates the dorsomedial (dMPFC) subsystem of the DN, whereas reasoning in the context of certainty activates areas specific to the DN's medial temporal (MTL) subsystem. We postulate that emotional reasoning mobilizes the dMPFC subsystem of the DN because this type of reasoning relies upon the recruitment of introspective and self-relevant data such as personal bias and temperament. In contrast, activation of the MTL subsystem during certainty argues that this form of reasoning involves the recruitment of mnemonic and semantic associations to derive conclusions.

Diabetic nephropathy research in China: Data analysis and review from the National Natural Science Foundation of China.

PubMed

Wan, Qiang; Xu, Yanying; Dong, Erdan

2015-05-01

As the largest funding agency of natural science of China, the National Natural Science Foundation of China (NSFC) has made great efforts in promoting the development of diabetic nephropathy (DN) research in recent years. The aim of the current study is to summarize the diabetic nephropathy research in China by analyzing NSFC-funded projects. Data on all projects in the DN field funded by NSFC from 1986 to 2013 were collected. The funding tendency, funding areas, and hotspots in the DN field, and major research institutions, were analyzed. As one output of this support, outstanding research groups in China, and their representative studies, are also highlighted. From 1986 to 2013, the NSFC has funded a total of 248 projects in the DN field, with a total funding amount of 91.5 million RMB (US$14.9 million). A rapid increase could be seen in the past 5 years, with an average annual 30% increase in projects numbers and a 52% increase in funding amount. All fields in DN research have been covered by the NSFC, including etiology, pathophysiology, diagnostics, and therapeutics. Along with increased funding of the DN research, there has been a growth in the papers published in Science Citation Index journals by Chinese scholars. In the past decade, the funding scale and funding budget have increased dramatically. Benefiting from this, DN research in China has also made considerable progression. © 2015 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.

Maternal choline supplementation programs greater activity of the phosphatidylethanolamine N-methyltransferase (PEMT) pathway in adult Ts65Dn trisomic mice.

PubMed

Yan, Jian; Ginsberg, Stephen D; Powers, Brian; Alldred, Melissa J; Saltzman, Arthur; Strupp, Barbara J; Caudill, Marie A

2014-10-01

Maternal choline supplementation (MCS) induces lifelong cognitive benefits in the Ts65Dn mouse, a trisomic mouse model of Down syndrome and Alzheimer's disease. To gain insight into the mechanisms underlying these beneficial effects, we conducted a study to test the hypothesis that MCS alters choline metabolism in adult Ts65Dn offspring. Deuterium-labeled methyl-d9-choline was administered to adult Ts65Dn and disomic (2N) female littermates born to choline-unsupplemented or choline-supplemented Ts65Dn dams. Enrichment of d9-choline metabolites (derived from intact choline) and d3 + d6-choline metabolites [produced when choline-derived methyl groups are used by phosphatidylethanolamine N-methyltransferase (PEMT)] was measured in harvested tissues. Adult offspring (both Ts65Dn and 2N) of choline-supplemented (vs. choline-unsupplemented) dams exhibited 60% greater (P≤0.007) activity of hepatic PEMT, which functions in de novo choline synthesis and produces phosphatidylcholine (PC) enriched in docosahexaenoic acid. Higher (P<0.001) enrichment of PEMT-derived d3 and d6 metabolites was detected in liver, plasma, and brain in both genotypes but to a greater extent in the Ts65Dn adult offspring. MCS also yielded higher (P<0.05) d9 metabolite enrichments in liver, plasma, and brain. These data demonstrate that MCS exerts lasting effects on offspring choline metabolism, including up-regulation of the hepatic PEMT pathway and enhanced provision of choline and PEMT-PC to the brain. © FASEB.

What if? Neural activity underlying semantic and episodic counterfactual thinking.

PubMed

Parikh, Natasha; Ruzic, Luka; Stewart, Gregory W; Spreng, R Nathan; De Brigard, Felipe

2018-05-25

Counterfactual thinking (CFT) is the process of mentally simulating alternative versions of known facts. In the past decade, cognitive neuroscientists have begun to uncover the neural underpinnings of CFT, particularly episodic CFT (eCFT), which activates regions in the default network (DN) also activated by episodic memory (eM) recall. However, the engagement of DN regions is different for distinct kinds of eCFT. More plausible counterfactuals and counterfactuals about oneself show stronger activity in DN regions compared to implausible and other- or object-focused counterfactuals. The current study sought to identify a source for this difference in DN activity. Specifically, self-focused counterfactuals may also be more plausible, suggesting that DN core regions are sensitive to the plausibility of a simulation. On the other hand, plausible and self-focused counterfactuals may involve more episodic information than implausible and other-focused counterfactuals, which would imply DN sensitivity to episodic information. In the current study, we compared episodic and semantic counterfactuals generated to be plausible or implausible against episodic and semantic memory reactivation using fMRI. Taking multivariate and univariate approaches, we found that the DN is engaged more during episodic simulations, including eM and all eCFT, than during semantic simulations. Semantic simulations engaged more inferior temporal and lateral occipital regions. The only region that showed strong plausibility effects was the hippocampus, which was significantly engaged for implausible CFT but not for plausible CFT, suggestive of binding more disparate information. Consequences of these findings for the cognitive neuroscience of mental simulation are discussed. Published by Elsevier Inc.

AGED DOMINANT NEGATIVE p38α MAPK MICE ARE RESISTANT TO AGE-DEPENDENT DECLINE IN ADULT-NEUROGENESIS AND CONTEXT DISCRIMINATION FEAR CONDITIONING

PubMed Central

Cortez, IbDanelo; Bulavin, Dmitry V.; Wu, Ping; McGrath, Erica L; Cunningham, Kathryn A; Wakamiya, Maki; Papaconstantinou, John; Dineley, Kelly T

2018-01-01

A major aspect of mammalian aging is the decline in functional competence of many self-renewing cell types, including adult-born neuronal precursors. Since age-related senescence of self-renewal occurs simultaneously with chronic up-regulation of the p38MAPKalpha (p38α) signaling pathway, we used the dominant negative mouse model for attenuated p38α activity (DN-p38αAF/+ ) in which Thr180 and Tyr182 are mutated (T→A/Y→F) to prevent phosphorylation activation (DN-p38αAF/+) and kinase activity. As a result, aged DN-p38αAF/+ mice are resistant to age-dependent decline in proliferation and regeneration of several peripheral tissue progenitors when compared to wild-type littermates. Aging is the major risk factor for non-inherited forms of Alzheimer’s disease (AD); environmental and genetic risk factors that accelerate the senescence phenotype are thought to contribute to an individual’s relative risk. In the present study, we evaluated aged DN-p38αAF/+ and wildtype littermates in a series of behavioral paradigms to test if p38α mutant mice exhibit altered baseline abnormalities in neurological reflexes, locomotion, anxiety-like behavior, and age-dependent cognitive decline. While aged DN-p38αAF/+ and wildtype littermates appear equal in all tested baseline neurological and behavioral parameters, DN-p38αAF/+ exhibit superior context discrimination fear conditioning. Context discrimination is a cognitive task that is supported by proliferation and differentiation of adult-born neurons in the dentate gyrus of the hippocampus. Consistent with enhanced context discrimination in aged DN-p38αAF/+, we discovered enhanced production of adult-born neurons in the dentate gyrus of DN-p38αAF/+ mice compared to wildtype littermates. Our findings support the notion that p38α inhibition has therapeutic utility in aging diseases that affect cognition, such as AD. PMID:27765672

A polymorphism in the gene encoding carnosinase (CNDP1) as a predictor of mortality and progression from nephropathy to end-stage renal disease in type 1 diabetes mellitus.

PubMed

Alkhalaf, A; Bakker, S J L; Bilo, H J G; Gans, R O B; Navis, G J; Postmus, D; Forsblom, C; Groop, P H; Vionnet, N; Hadjadj, S; Marre, M; Parving, H H; Rossing, P; Tarnow, L

2010-12-01

Homozygosity for a five leucine repeat (5L-5L) in the carnosinase gene (CNDP1) has been found to be cross-sectionally associated with a low frequency of diabetic nephropathy (DN), mainly in type 2 diabetes. We prospectively investigated in patients with type 1 diabetes whether: (1) 5L-5L is associated with mortality; (2) there is an interaction of 5L-5L with DN or sex for prediction of mortality; and (3) 5L-5L is associated with progression to end-stage renal disease (ESRD). In this prospective study in white European patients with type 1 diabetes, individuals with DN were defined by persistent albuminuria ≥ 300 mg/24 h. Controls without nephropathy were defined by persistent (>15 years) normoalbuminuria < 30 mg/24 h. Leucine repeats were assessed with a fluorescent DNA analysis system. Onset of ESRD was defined by need to start chronic dialysis or kidney transplantation. The study involved 916 patients with DN and 1,170 controls. During follow-up for 8.8 years, 107 patients (14%) with 5L-5L died compared with 182 patients (13.8%) with other genotypes (p = 0.99). There was no significant interaction of 5L-5L with DN for prediction of mortality (p = 0.57), but a trend towards interaction with sex (p = 0.08). In patients with DN, HR for ESRD in 5L-5L vs other genotypes was not constant over time, with increased risk for 5L-5L beyond 8 years of follow-up (p = 0.03). CNDP1 polymorphism was not associated with mortality, and nor was there an interaction of this polymorphism with DN for prediction of mortality in patients with type 1 diabetes. CNDP1 polymorphism predicts progression to ESRD in patients with DN, but only late after baseline measurements.

Further evidence for a locus for cutaneous malignant melanoma-dysplastic nevus (CMM/DN) on chromosome Ip, and evidence for genetic heterogeneity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Goldstein, A.M.; Fraser, M.C.; McBride, O.W.

Assignment of a susceptibility locus for cutaneous malignant melanoma-dysplastic nevus (CMM/DN) to chromosome 1p remains controversial. The authors examined the relationship between CMM/DN and markers D1S47, PND, and D1S160 on seven new families (set B) plus updated versions of six previously reported families (set A). Three linkage analyses were performed: (1) CMM alone - all individuals without confirmed melanoma or borderline lesions were considered unaffected (model I); (2) CMM/DN with variable age at onset and sporadics (model II); and (3) CMM/DN using the model of Bale et al. (model III). For CMM alone and D1S47, Z[sub max] = 3.12 atmore » [theta] = .10. For D1S160 and CMM alone, Z[sub max] = 1.76 at [theta] = .10. PND showed no evidence for linkage to CMM alone. Models II and III showed strong evidence for linkage to D1S47, D1S160, and PND in the set A pedigrees but not in the set B families. The authors tested for homogeneity of CMM/DN (model II) by splitting families into two groups on the basis of (1) the proportion of CMM/DN cases and (2) the occurrence of immune-related tumors. In group 1 there was significant evidence of heterogeneity with both D1S47 and D1S160, and in group 2 there was significant evidence of heterogeneity with D1S160. Thus, diagnostic, clinical, and genetic heterogeneity are the likely reasons that previous studies have failed to confirm linkage of CMM/DN to chromosome 1p. The results showed significant evidence for a CMM locus linked to D1S47, as well as significant evidence for heterogeneity with only a subset of the families appearing linked to chromosome 1p. 38 refs., 1 fig., 5 tabs.« less

AMPKα2 deficiency uncovers time dependency in the regulation of contraction-induced palmitate and glucose uptake in mouse muscle.

PubMed

Abbott, Marcia J; Bogachus, Lindsey D; Turcotte, Lorraine P

2011-07-01

AMP-activated protein kinase (AMPK) is a fuel sensor in skeletal muscle with multiple downstream signaling targets that may be triggered by increases in intracellular Ca(2+) concentration ([Ca(2+)]). The purpose of this study was to determine whether increases in intracellular [Ca(2+)] induced by caffeine act solely via AMPKα(2) and whether AMPKα(2) is essential to increase glucose uptake, fatty acid (FA) uptake, and FA oxidation in contracting skeletal muscle. Hindlimbs from wild-type (WT) or AMPKα(2) dominant-negative (DN) transgene mice were perfused during rest (n = 11), treatment with 3 mM caffeine (n = 10), or muscle contraction (n = 11). Time-dependent effects on glucose and FA uptake were uncovered throughout the 20-min muscle contraction perfusion period (P < 0.05). Glucose uptake rates did not increase in DN mice during muscle contraction until the last 5 min of the protocol (P < 0.05). FA uptake rates were elevated at the onset of muscle contraction and diminished by the end of the protocol in DN mice (P < 0.05). FA oxidation rates were abolished in the DN mice during muscle contraction (P < 0.05). The DN transgene had no effect on caffeine-induced FA uptake and oxidation (P > 0.05). Glucose uptake rates were blunted in caffeine-treated DN mice (P < 0.05). The DN transgene resulted in a greater use of intramuscular triglycerides as a fuel source during muscle contraction. The DN transgene did not alter caffeine- or contraction-mediated changes in the phosphorylation of Ca(2+)/calmodulin-dependent protein kinase I or ERK1/2 (P > 0.05). These data suggest that AMPKα(2) is involved in the regulation of substrate uptake in a time-dependent manner in contracting muscle but is not necessary for regulation of FA uptake and oxidation during caffeine treatment.

Rapeseed protein-derived antioxidant peptide RAP alleviates renal fibrosis through MAPK/NF-κB signaling pathways in diabetic nephropathy.

PubMed

Zhang, Mingyan; Yan, Zhibin; Bu, Lili; An, Chunmei; Wang, Dan; Liu, Xin; Zhang, Jianfeng; Yang, Wenle; Deng, Bochuan; Xie, Junqiu; Zhang, Bangzhi

2018-01-01

Kidney fibrosis is the main pathologic change in diabetic nephropathy (DN), which is the major cause of end-stage renal disease. Current therapeutic strategies slow down but cannot reverse the progression of renal dysfunction in DN. Plant-derived bioactive peptides in foodstuffs are widely used in many fields because of their potential pharmaceutical and nutraceutical benefits. However, this type of peptide has not yet been studied in renal fibrosis of DN. Previous studies have indicated that the peptide YWDHNNPQIR (named RAP), a natural peptide derived from rapeseed protein, has an antioxidative stress effect. The oxidative stress is believed to be associated with DN. The aim of this study was to evaluate the pharmacologic effects of RAP against renal fibrosis of DN and high glucose (HG)-induced mesangial dysfunction. Diabetes was induced by streptozotocin and high-fat diet in C57BL/6 mice and these mice were treated by subcutaneous injection of different doses of RAP (0.1 mg/kg and 0.5 mg/kg, every other day) or PBS for 12 weeks. Later, functional and histopathologic analyses were performed. Parallel experiments verifying the molecular mechanism by which RAP alleviates DN were carried out in HG-induced mesangial cells (MCs). RAP improved the renal function indices, including 24-h albuminuria, triglyceride, serum creatinine, and blood urea nitrogen levels, but did not lower blood glucose levels in DN mice. RAP also simultaneously attenuated extracellular matrix accumulation in DN mice and HG-induced MCs. Furthermore, RAP reduced HG-induced cell proliferation, but it showed no toxicity in MCs. Additionally, RAP inhibited the mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) signaling pathways. RAP can attenuate fibrosis in vivo and in vitro by antagonizing the MAPK and NF-κB pathways.

Linking a dermal permeation and an inhalation model to a simple pharmacokinetic model to study airborne exposure to di(n-butyl) phthalate.

PubMed

Lorber, Matthew; Weschler, Charles J; Morrison, Glenn; Bekö, Gabriel; Gong, Mengyan; Koch, Holger M; Salthammer, Tunga; Schripp, Tobias; Toftum, Jørn; Clausen, Geo

2017-11-01

Six males clad only in shorts were exposed to high levels of airborne di(n-butyl) phthalate (DnBP) and diethyl phthalate (DEP) in chamber experiments conducted in 2014. In two 6 h sessions, the subjects were exposed only dermally while breathing clean air from a hood, and both dermally and via inhalation when exposed without a hood. Full urine samples were taken before, during, and for 48 h after leaving the chamber and measured for key DnBP and DEP metabolites. The data clearly demonstrated high levels of DnBP and DEP metabolite excretions while in the chamber and during the first 24 h once leaving the chamber under both conditions. The data for DnBP were used in a modeling exercise linking dose models for inhalation and transdermal permeation with a simple pharmacokinetic model that predicted timing and mass of metabolite excretions. These models were developed and calibrated independent of these experiments. Tests included modeling of the "hood-on" (transdermal penetration only), "hood-off" (both inhalation and transdermal) scenarios, and a derived "inhalation-only" scenario. Results showed that the linked model tended to duplicate the pattern of excretion with regard to timing of peaks, decline of concentrations over time, and the ratio of DnBP metabolites. However, the transdermal model tended to overpredict penetration of DnBP such that predictions of metabolite excretions were between 1.1 and 4.5 times higher than the cumulative excretion of DnBP metabolites over the 54 h of the simulation. A similar overprediction was not seen for the "inhalation-only" simulations. Possible explanations and model refinements for these overpredictions are discussed. In a demonstration of the linked model designed to characterize general population exposures to typical airborne indoor concentrations of DnBP in the United States, it was estimated that up to one-quarter of total exposures could be due to inhalation and dermal uptake.

Comparison of del Nido and St Thomas Cardioplegia Solutions in Pediatric Patients: A Prospective Randomized Clinical Trial.

PubMed

Talwar, Sachin; Bhoje, Amolkumar; Sreenivas, Vishnubhatla; Makhija, Neeti; Aarav, Sudheer; Choudhary, Shiv Kumar; Airan, Balram

2017-01-01

We conducted a prospective randomized trial to compare del Nido (DN) cardioplegia with conventional cold blood cardioplegia (St Thomas [STH]) in pediatric patients. We randomized 100 pediatric patients aged ≤12 years undergoing elective repair of ventricular septal defects and tetralogy of Fallot to the DN and the STH groups. In the DN group, a 20 mL/kg single dose was administered. In the STH group, a 30 mL/kg dose was administered, followed by repeated doses at 25- to 30-minute intervals. The primary outcome was cardiac index that was measured 4 times intra- and postoperatively. Troponin-I, interleukin-6, and tissue necrosis factor-alpha were measured. Myocardial biopsy was obtained to assess electron-microscopic ultrastructural changes. Cardiac indices were significantly higher in the DN group than in the STH group 2 hours after termination of cardiopulmonary bypass (P = 0.0006), after 6 hours (P = 0.0006), and after 24 hours (P ≤ 0.0001). On repeated measure regression analysis, the cardiac index was on an average 0.50 L/min/m 2 higher in the DN group than in the STH group at any time point (P = 0.002). Duration of mechanical ventilation (P = 0.01), intensive care unit stay (P = 0.01), and hospital stay (P = 0.0007) was significantly lower in the DN group. Patients in the DN group exhibited lower troponin-I release 24 hours following cardiopulmonary bypass (P = 0.021). Electron microscopic studies showed more myofibrillar disarray in the STH group (P = 0.02). Use of long-acting DN cardioplegia solution was associated with better preservation of cardiac index, lesser troponin-I release, and decreased morbidity. Ultrastructural changes showed better preservation of myofibrillar architecture. Copyright © 2017 Elsevier Inc. All rights reserved.

Whole-exome sequencing in obsessive-compulsive disorder identifies rare mutations in immunological and neurodevelopmental pathways

PubMed Central

Cappi, C; Brentani, H; Lima, L; Sanders, S J; Zai, G; Diniz, B J; Reis, V N S; Hounie, A G; Conceição do Rosário, M; Mariani, D; Requena, G L; Puga, R; Souza-Duran, F L; Shavitt, R G; Pauls, D L; Miguel, E C; Fernandez, T V

2016-01-01

Studies of rare genetic variation have identified molecular pathways conferring risk for developmental neuropsychiatric disorders. To date, no published whole-exome sequencing studies have been reported in obsessive-compulsive disorder (OCD). We sequenced all the genome coding regions in 20 sporadic OCD cases and their unaffected parents to identify rare de novo (DN) single-nucleotide variants (SNVs). The primary aim of this pilot study was to determine whether DN variation contributes to OCD risk. To this aim, we evaluated whether there is an elevated rate of DN mutations in OCD, which would justify this approach toward gene discovery in larger studies of the disorder. Furthermore, to explore functional molecular correlations among genes with nonsynonymous DN SNVs in OCD probands, a protein–protein interaction (PPI) network was generated based on databases of direct molecular interactions. We applied Degree-Aware Disease Gene Prioritization (DADA) to rank the PPI network genes based on their relatedness to a set of OCD candidate genes from two OCD genome-wide association studies (Stewart et al., 2013; Mattheisen et al., 2014). In addition, we performed a pathway analysis with genes from the PPI network. The rate of DN SNVs in OCD was 2.51 × 10−8 per base per generation, significantly higher than a previous estimated rate in unaffected subjects using the same sequencing platform and analytic pipeline. Several genes harboring DN SNVs in OCD were highly interconnected in the PPI network and ranked high in the DADA analysis. Nearly all the DN SNVs in this study are in genes expressed in the human brain, and a pathway analysis revealed enrichment in immunological and central nervous system functioning and development. The results of this pilot study indicate that further investigation of DN variation in larger OCD cohorts is warranted to identify specific risk genes and to confirm our preliminary finding with regard to PPI network enrichment for particular biological pathways and functions. PMID:27023170

Inhibition of glycogen synthase kinase 3beta during heart failure is protective.

PubMed

Hirotani, Shinichi; Zhai, Peiyong; Tomita, Hideharu; Galeotti, Jonathan; Marquez, Juan Pablo; Gao, Shumin; Hong, Chull; Yatani, Atsuko; Avila, Jesús; Sadoshima, Junichi

2007-11-26

Glycogen synthase kinase (GSK)-3, a negative regulator of cardiac hypertrophy, is inactivated in failing hearts. To examine the histopathological and functional consequence of the persistent inhibition of GSK-3beta in the heart in vivo, we generated transgenic mice with cardiac-specific overexpression of dominant negative GSK-3beta (Tg-GSK-3beta-DN) and tetracycline-regulatable wild-type GSK-3beta. GSK-3beta-DN significantly reduced the kinase activity of endogenous GSK-3beta, inhibited phosphorylation of eukaryotic translation initiation factor 2B epsilon, and induced accumulation of beta-catenin and myeloid cell leukemia-1, confirming that GSK-3beta-DN acts as a dominant negative in vivo. Tg-GSK-3beta-DN exhibited concentric hypertrophy at baseline, accompanied by upregulation of the alpha-myosin heavy chain gene and increases in cardiac function, as evidenced by a significantly greater Emax after dobutamine infusion and percentage of contraction in isolated cardiac myocytes, indicating that inhibition of GSK-3beta induces well-compensated hypertrophy. Although transverse aortic constriction induced a similar increase in hypertrophy in both Tg-GSK-3beta-DN and nontransgenic mice, Tg-GSK-3beta-DN exhibited better left ventricular function and less fibrosis and apoptosis than nontransgenic mice. Induction of the GSK-3beta transgene in tetracycline-regulatable wild-type GSK-3beta mice induced left ventricular dysfunction and premature death, accompanied by increases in apoptosis and fibrosis. Overexpression of GSK-3beta-DN in cardiac myocytes inhibited tumor necrosis factor-alpha-induced apoptosis, and the antiapoptotic effect of GSK-3beta-DN was abrogated in the absence of myeloid cell leukemia-1. These results suggest that persistent inhibition of GSK-3beta induces compensatory hypertrophy, inhibits apoptosis and fibrosis, and increases cardiac contractility and that the antiapoptotic effect of GSK-3beta inhibition is mediated by myeloid cell leukemia-1. Thus, downregulation of GSK-3beta during heart failure could be compensatory.

Aged dominant negative p38α MAPK mice are resistant to age-dependent decline in adult-neurogenesis and context discrimination fear conditioning.

PubMed

Cortez, IbDanelo; Bulavin, Dmitry V; Wu, Ping; McGrath, Erica L; Cunningham, Kathryn A; Wakamiya, Maki; Papaconstantinou, John; Dineley, Kelly T

2017-03-30

A major aspect of mammalian aging is the decline in functional competence of many self-renewing cell types, including adult-born neuronal precursors. Since age-related senescence of self-renewal occurs simultaneously with chronic up-regulation of the p38MAPKalpha (p38α) signaling pathway, we used the dominant negative mouse model for attenuated p38α activity (DN-p38α AF/+ ) in which Thr180 and Tyr182 are mutated (T→A/Y→F) to prevent phosphorylation activation (DN-p38α AF/+ ) and kinase activity. As a result, aged DN-p38α AF/+ mice are resistant to age-dependent decline in proliferation and regeneration of several peripheral tissue progenitors when compared to wild-type littermates. Aging is the major risk factor for non-inherited forms of Alzheimer's disease (AD); environmental and genetic risk factors that accelerate the senescence phenotype are thought to contribute to an individual's relative risk. In the present study, we evaluated aged DN-p38α AF/+ and wildtype littermates in a series of behavioral paradigms to test if p38α mutant mice exhibit altered baseline abnormalities in neurological reflexes, locomotion, anxiety-like behavior, and age-dependent cognitive decline. While aged DN-p38α AF/+ and wildtype littermates appear equal in all tested baseline neurological and behavioral parameters, DN-p38α AF/+ exhibit superior context discrimination fear conditioning. Context discrimination is a cognitive task that is supported by proliferation and differentiation of adult-born neurons in the dentate gyrus of the hippocampus. Consistent with enhanced context discrimination in aged DN-p38α AF/+ , we discovered enhanced production of adult-born neurons in the dentate gyrus of DN-p38α AF/+ mice compared to wildtype littermates. Our findings support the notion that p38α inhibition has therapeutic utility in aging diseases that affect cognition, such as AD. Copyright © 2016 Elsevier B.V. All rights reserved.

Maternal choline supplementation in a mouse model of Down syndrome: effects on attention and nucleus basalis/substantia innominata neuron morphology in adult offspring

PubMed Central

Powers, Brian E.; Kelley, Christy M.; Velazquez, Ramon; Ash, Jessica A.; Strawderman, Myla S.; Alldred, Melissa J.; Ginsberg, Stephen D.; Mufson, Elliott J.; Strupp, Barbara J.

2016-01-01

The Ts65Dn mouse model of Down syndrome (DS) and Alzheimer’s disease (AD) exhibits cognitive impairment and degeneration of basal forebrain cholinergic neurons (BFCNs). Our prior studies demonstrated that maternal choline supplementation (MCS) improves attention and spatial cognition in Ts65Dn offspring, normalizes hippocampal neurogenesis, and lessens BFCN degeneration in the medial septal nucleus (MSN). Here we determined whether (i) BFCN degeneration contributes to attentional dysfunction, and (ii) whether the attentional benefits of perinatal MCS are due to changes in BFCN morphology. Ts65Dn dams were fed either a choline-supplemented or standard diet during pregnancy and lactation. Ts65Dn and disomic (2N) control offspring were tested as adults (12–17 months of age) on a series of operant attention tasks, followed by morphometric assessment of BFCNs. Ts65Dn mice demonstrated impaired learning and attention relative to 2N mice, and MCS significantly improved these functions in both genotypes. We also found, for the first time, that the number of BFCNs in the nucleus basalis of Meynert/substantia innominata (NBM/SI) was significantly increased in Ts65Dn mice relative to controls. In contrast, the number of BFCNs in the MSN was significantly decreased. Another novel finding was that the volume of BFCNs in both basal forebrain regions was significantly larger in Ts65Dn mice. MCS did not normalize any of these morphological abnormalities in the NBM/SI or MSN. Finally, correlational analysis revealed that attentional performance was inversely associated with BFCN volume, and positively associated with BFCN density. These results support the lifelong attentional benefits of MCS for Ts65Dn and 2N offspring and have profound implications for translation to human DS and pathology attenuation in AD. PMID:27840230

Maternal choline supplementation in a mouse model of Down syndrome: Effects on attention and nucleus basalis/substantia innominata neuron morphology in adult offspring.

PubMed

Powers, Brian E; Kelley, Christy M; Velazquez, Ramon; Ash, Jessica A; Strawderman, Myla S; Alldred, Melissa J; Ginsberg, Stephen D; Mufson, Elliott J; Strupp, Barbara J

2017-01-06

The Ts65Dn mouse model of Down syndrome (DS) and Alzheimer's disease (AD) exhibits cognitive impairment and degeneration of basal forebrain cholinergic neurons (BFCNs). Our prior studies demonstrated that maternal choline supplementation (MCS) improves attention and spatial cognition in Ts65Dn offspring, normalizes hippocampal neurogenesis, and lessens BFCN degeneration in the medial septal nucleus (MSN). Here we determined whether (i) BFCN degeneration contributes to attentional dysfunction, and (ii) whether the attentional benefits of perinatal MCS are due to changes in BFCN morphology. Ts65Dn dams were fed either a choline-supplemented or standard diet during pregnancy and lactation. Ts65Dn and disomic (2N) control offspring were tested as adults (12-17months of age) on a series of operant attention tasks, followed by morphometric assessment of BFCNs. Ts65Dn mice demonstrated impaired learning and attention relative to 2N mice, and MCS significantly improved these functions in both genotypes. We also found, for the first time, that the number of BFCNs in the nucleus basalis of Meynert/substantia innominata (NBM/SI) was significantly increased in Ts65Dn mice relative to controls. In contrast, the number of BFCNs in the MSN was significantly decreased. Another novel finding was that the volume of BFCNs in both basal forebrain regions was significantly larger in Ts65Dn mice. MCS did not normalize any of these morphological abnormalities in the NBM/SI or MSN. Finally, correlational analysis revealed that attentional performance was inversely associated with BFCN volume, and positively associated with BFCN density. These results support the lifelong attentional benefits of MCS for Ts65Dn and 2N offspring and have profound implications for translation to human DS and pathology attenuation in AD. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Presentation, pathology and prognosis of renal disease in type 2 diabetes

PubMed Central

Tan, Jasmine; Zwi, L Jonathan; Collins, John F; Marshall, Mark R; Cundy, Tim

2017-01-01

Objective Non-diabetic renal disease (NDRD) is common in patients with type 2 diabetes (T2D), but the relationship between its presentation and prognosis is unknown. Research design and methods In a retrospective cohort study, we compared renal and patient survival among 263 patients with T2D who had native renal biopsies between 2002 and 2008 from three Auckland hospitals in New Zealand. The presence of diabetic nephropathy (DN), NDRD or mixed (DN and NDRD) was determined from biopsy. We examined clinical associations according to NDRD etiologies and mode of presentation—acute (defined by acute kidney injury (AKI)) or non-acute. Patients were followed until end-stage renal disease, death or December 2015. Survival was compared using Log-rank test. Results 94 (36%) patients had DN, 72 (27%) had NDRD, and 97 (37%) had mixed pathologies. Obesity-related focal segmental glomerulosclerosis was the most common NDRD (46%) in patients with non-acute presentations, whereas interstitial nephritis or immune-complex glomerulonephritides were the most prevalent in those with acute presentations (60%). DN was commonly associated with AKI (p<0.001). The prevalence of DN increased with diabetes duration (p<0.001), but NDRD was still found in 55% of subjects with ≥14 years T2D. NDRD was strongly associated with the absence of retinopathy (p<0.001). Renal survival was best in the NDRD group (p<0.001). Among those with DN, renal prognosis was worse in those with more advanced DN lesions and those with an acute presentation (p<0.001). The proportion of all-cause mortality was similar in all three groups, but overall survival was poorest in the DN group (p=0.025). Conclusions Renal disease in patients with T2D is heterogeneous. The renal prognosis differs markedly according to histopathological diagnosis and mode of presentation. PMID:28878938

Abnormal MicroRNA Expression in Ts65Dn Hippocampus and Whole Blood: Contributions to Down Syndrome Phenotypes

PubMed Central

Keck-Wherley, Jennifer; Grover, Deepak; Bhattacharyya, Sharmistha; Xu, Xiufen; Holman, Derek; Lombardini, Eric D.; Verma, Ranjana; Biswas, Roopa; Galdzicki, Zygmunt

2011-01-01

Down syndrome (DS; trisomy 21) is one of the most common genetic causes of intellectual disability, which is attributed to triplication of genes located on chromosome 21. Elevated levels of several microRNAs (miRNAs) located on chromosome 21 have been reported in human DS heart and brain tissues. The Ts65Dn mouse model is the most investigated DS model with a triplicated segment of mouse chromosome 16 harboring genes orthologous to those on human chromosome 21. Using ABI TaqMan miRNA arrays, we found a set of miRNAs that were significantly up- or downregulated in the Ts65Dn hippocampus compared to euploid controls. Furthermore, miR-155 and miR-802 showed significant overexpression in the Ts65Dn hippocampus, thereby confirming results of previous studies. Interestingly, miR-155 and miR-802 were also overexpressed in the Ts65Dn whole blood but not in lung tissue. We also found overexpression of the miR-155 precursors, pri- and pre-miR-155 derived from the miR-155 host gene, known as B cell integration cluster, suggesting enhanced biogenesis of miR-155. Bioinformatic analysis revealed that neurodevelopment, differentiation of neuroglia, apoptosis, cell cycle, and signaling pathways including ERK/MAPK, protein kinase C, phosphatidylinositol 3-kinase, m-TOR and calcium signaling are likely targets of these miRNAs. We selected some of these potential gene targets and found downregulation of mRNA encoding Ship1, Mecp2 and Ezh2 in Ts65Dn hippocampus. Interestingly, the miR-155 target gene Ship1 (inositol phosphatase) was also downregulated in Ts65Dn whole blood but not in lung tissue. Our findings provide insights into miRNA-mediated gene regulation in Ts65Dn mice and their potential contribution to impaired hippocampal synaptic plasticity and neurogenesis, as well as hemopoietic abnormalities observed in DS. PMID:22042248

A new pathological scoring system by the Japanese classification to predict renal outcome in diabetic nephropathy.

PubMed

Hoshino, Junichi; Furuichi, Kengo; Yamanouchi, Masayuki; Mise, Koki; Sekine, Akinari; Kawada, Masahiro; Sumida, Keiichi; Hiramatsu, Rikako; Hasegawa, Eiko; Hayami, Noriko; Suwabe, Tatsuya; Sawa, Naoki; Hara, Shigeko; Fujii, Takeshi; Ohashi, Kenichi; Kitagawa, Kiyoki; Toyama, Tadashi; Shimizu, Miho; Takaichi, Kenmei; Ubara, Yoshifumi; Wada, Takashi

2018-01-01

The impact of the newly proposed pathological classification by the Japan Renal Pathology Society (JRPS) on renal outcome is unclear. So we evaluated that impact and created a new pathological scoring to predict outcome using this classification. A multicenter cohort of 493 biopsy-proven Japanese patients with diabetic nephropathy (DN) were analyzed. The association between each pathological factor-Tervaert' and JRPS classifications-and renal outcome (dialysis initiation or 50% eGFR decline) was estimated by adjusted Cox regression. The overall pathological risk score (J-score) was calculated, whereupon its predictive ability for 10-year risk of renal outcome was evaluated. The J-scores of diffuse lesion classes 2 or 3, GBM doubling class 3, presence of mesangiolysis, polar vasculosis, and arteriolar hyalinosis were, respectively, 1, 2, 4, 1, and 2. The scores of IFTA classes 1, 2, and 3 were, respectively, 3, 4, and 4, and those of interstitial inflammation classes 1, 2, and 3 were 5, 5, and 4 (J-score range, 0-19). Renal survival curves, when dividing into four J-score grades (0-5, 6-10, 11-15, and 16-19), were significantly different from each other (p<0.01, log-rank test). After adjusting clinical factors, the J-score was a significant predictor of renal outcome. Ability to predict 10-year renal outcome was improved when the J-score was added to the basic model: c-statistics from 0.661 to 0.685; category-free net reclassification improvement, 0.154 (-0.040, 0.349, p = 0.12); and integrated discrimination improvement, 0.015 (0.003, 0.028, p = 0.02). Mesangiolysis, polar vasculosis, and doubling of GBM-features of the JRPS system-were significantly associated with renal outcome. Prediction of DN patients' renal outcome was better with the J-score than without it.

The Inhibitory Effect of Rapamycin on Toll Like Receptor 4 and Interleukin 17 in the Early Stage of Rat Diabetic Nephropathy.

PubMed

Yu, Ruichao; Bo, Hong; Villani, Vincenzo; Spencer, Philip J; Fu, Ping

2016-01-01

There is increasing evidence showing that innate immune responses and inflammatory processes play an important role in the development and progression of diabetic nephropathy (DN). The potential effect of innate immunity in the early stage of DN is still unclear. Toll-Like-Receptor 4 (TLR4) is vigorously involved in the progress of kidney diseases in a sterile environment. The activation of the interleukin 17 (IL-17) pathway produces inflammatory cytokines, appearing in various kidney diseases. Unfortunately the relationship between TLR4 and IL-17 has not been investigated in diabetic nephropathy to date. The aim of this study is to investigate whether mammalian target of rapamycin (mTOR) inhibition may be dependent on TLR4 signaling and the pro-inflammatory factor IL-17 to delay the progression of DN. Streptozotocin (STZ)-induced diabetic rats were randomly assigned to 3 experimental groups: a diabetic nephropathy group (DN, n = 6); and a diabetic nephropathy treated with rapamycin group (Rapa, n = 6) and a control group (Control, n =6). Body weight, fasting blood sugar, and 24h urine albumin were assessed at week 2, week 4 and week 8. Renal tissues were harvested for H&E, PAS staining, as well as an immunohistochemistry assay for TLR4 and IL-17. TLR4 quantitative expression was measured by Western-Blot analysis and RT-PCR. Our results demonstrated that the expression of both TLR4 and IL-17 were upregulated in early stage DN and reduced by rapamycin. TLR4 and IL-17 both increased and positively related to 24h urinary albumin and kidney/weight ratio. However, neither TLR4 nor IL-17 made a significant difference on fasting blood sugar. Taken together, our results confirm and extend previous studies identifying the significance of the TLR4 and Th17 pathways in development of early stage DN. Furthermore, we suggest this overexpression of TLR4 might be involved in the immunopathogenesis of DN through activation of Th17 cells. Rapamycin may attenuate DN via reduction of the TLR4 signaling pathway and Th17 cells signaling. Although the underlying mechanisms need to be explored, the observed increase of TLR4 and IL-17 during the early stages of DN and their suppression with rapamycin treatment suggest the importance of TLR4 and IL-17 in DN pathophysiology. © 2016 The Author(s) Published by S. Karger AG, Basel.

The Role of Liuwei Dihuang Pills and Ginkgo Leaf Tablets in Treating Diabetic Complications.

PubMed

Zhao, Yue; Yu, Jiangyi; Liu, Jingshun; An, Xiaofei

2016-01-01

Objective. To observe the clinical prophylactic and therapeutic efficacy of Liuwei Dihuang Pills and Ginkgo Leaf Tablets for type 2 diabetic vascular complications. Methods. It was a randomized, double-blind and placebo-controlled clinical trial. 140 outpatients with type 2 diabetes were recruited and randomly divided into the treatment group and control group. The two groups were given basic therapy (management of blood sugar, blood pressure, etc.). Additionally, the treatment group was given Liuwei Dihuang Pills and Ginkgo Leaf Tablets, while the control group was given Liuwei Dihuang Pills and Ginkgo Leaf Tablets placebos. All subjects were followed up for consecutive 36 months and observed monthly. The clinical data as urinary microalbumin to urinary creatinine ratio (Umalb/cr), carotid intima-media thickness (IMT), diabetic nephropathy (DN) and diabetic retinopathy (DR) prevalence, cardiovascular and cerebrovascular events, blood glucose, and blood pressure were collected and analyzed statistically. Results. After 36-month treatment, the Umalb/cr level and DN and DR prevalence in treatment group were all significantly lower than control group ( P < 0.05). However, the IMT level and the incidence of cardiovascular and cerebrovascular events were not significantly different between the two groups ( P > 0.05). Conclusions. Liuwei Dihuang Pills and Ginkgo Leaf Tablets are beneficial to diabetic microvascular complications, while the efficacy to diabetic macrovascular complications needs more observations.

Effect of yogurt containing Bifidobacterium animalis subsp . lactis DN-173010 probiotic on dental plaque and saliva in orthodontic patients.

PubMed

Pinto, G S; Cenci, M S; Azevedo, M S; Epifanio, M; Jones, M H

2014-01-01

To assess how consumption of yogurt containing Bifidobacterium animalis subsp. lactis DN-173010 probiotic for a period of 2 weeks affects salivary and dental plaque levels of mutans streptococci and lactobacilli in patients undergoing orthodontic treatment. A crossover, double-blind, randomized and placebo-controlled clinical trial was performed with 26 volunteers. The study was divided into four periods. During periods 2 and 4, the volunteers ingested yogurt containing probiotic or control yogurt daily for 2 weeks. Periods 1 and 3 were a 1-week run-in period and 4-week washout period, respectively. Saliva and dental plaque samples were collected from each participant at the end of each period. Mutans streptococci, lactobacilli, and total cultivable microorganisms were counted. Values were compared between groups and across periods with the Wilcoxon's test. There was no difference between the yogurt containing probiotic and the control yogurt for any of the studied variables (all p > 0.05). A reduction in counts of total cultivable microorganisms was observed in dental plaque samples after ingestion of either yogurts (both p < 0.05 vs. baseline), but not in saliva (p < 0.05). Daily ingestion of yogurt with or without B. animalis subsp. lactis for a period of 2 weeks was beneficial in reducing total microbial counts in dental plaque. Therefore, no additional benefits were achieved by the use of the tested probiotic strain.

From the cradle to the grave: activities of GATA-3 throughout T cell development and differentiation

PubMed Central

Hosoya, Tomonori; Maillard, Ivan; Engel, James Douglas

2010-01-01

Summary GATA family transcription factors play multiple vital roles in hematopoiesis in many cell lineages, and in particular, T cells require GATA-3 for execution of several developmental steps. Transcriptional activation of the Gata3 gene is observed throughout T-cell development and differentiation in stage-specific fashion. GATA-3 has been described as a master regulator of T-helper 2 (Th2) cell differentiation in mature CD4+ T cells. During T-cell development in the thymus, its roles in the CD4 vs. CD8 lineage choice and at the β-selection checkpoint are the best characterized. In contrast, its importance prior to β-selection has been obscured both by the developmental heterogeneity of double negative (DN) 1 thymocytes and the paucity of early T-lineage progenitors (ETPs), a subpopulation of DN1 cells that contains the most immature thymic progenitors that retain potent T-lineage developmental potential. By examining multiple lines of in vivo evidence procured through the analysis of Gata3 mutant mice, we have recently demonstrated that GATA-3 is additionally required at the earliest stage of thymopoiesis for the development of the ETP population. Here, we review the characterized functions of GATA-3 at each stage of T-cell development and discuss hypothetical molecular pathways that mediate these functions. PMID:20969588

Effect of vitamin D on proteinuria in type 2 diabetic patients.

PubMed

Momeni, Ali; Mirhosseini, Mahmood; Kabiri, Mohsen; Kheiri, Soleiman

2017-01-01

Vitamin D (Vit D) deficiency is a common disorder in diabetic patients and may be a risk factor for ischemic heart disease and exacerbation of diabetic nephropathy(DN). The aim of this study was to evaluate the effect of Vit D3 therapy on protein uriain type 2 diabetic patients with deficient or insufficient serum Vit D. In a double blind clinical trial, 60 type 2 diabetic patients with proteinuria greater than 150 mg/day who had Vit D deficiency or insufficiency were randomly enrolled in two equal groups. Pearl of Vit D as 50 000 IU/week and placebo (1 tablet per week) were prescribed in patients of case and control groups respectively for 8 weeks. At the beginning and 2 months later, 24 hours urine protein was checked in all patients. There is no difference between serums Vit D level in case and control group at the beginning of the study, however at the end of the study serum Vit D level was significantly higher in the case group. There is no difference in proteinuria between case and control group at the beginning and the end of the study, while a significant difference between the changes of proteinuria before and after the study was seen in two groups ( P = 0.028). Vit D deficiency may exacerbate protein uric and DN, hence correction of Vit D deficiency may decrease proteinuria in diabetic patients with nephropathy.

Neural Responses to Heartbeats in the Default Network Encode the Self in Spontaneous Thoughts.

PubMed

Babo-Rebelo, Mariana; Richter, Craig G; Tallon-Baudry, Catherine

2016-07-27

The default network (DN) has been consistently associated with self-related cognition, but also to bodily state monitoring and autonomic regulation. We hypothesized that these two seemingly disparate functional roles of the DN are functionally coupled, in line with theories proposing that selfhood is grounded in the neural monitoring of internal organs, such as the heart. We measured with magnetoencephalograhy neural responses evoked by heartbeats while human participants freely mind-wandered. When interrupted by a visual stimulus at random intervals, participants scored the self-relatedness of the interrupted thought. They evaluated their involvement as the first-person perspective subject or agent in the thought ("I"), and on another scale to what degree they were thinking about themselves ("Me"). During the interrupted thought, neural responses to heartbeats in two regions of the DN, the ventral precuneus and the ventromedial prefrontal cortex, covaried, respectively, with the "I" and the "Me" dimensions of the self, even at the single-trial level. No covariation between self-relatedness and peripheral autonomic measures (heart rate, heart rate variability, pupil diameter, electrodermal activity, respiration rate, and phase) or alpha power was observed. Our results reveal a direct link between selfhood and neural responses to heartbeats in the DN and thus directly support theories grounding selfhood in the neural monitoring of visceral inputs. More generally, the tight functional coupling between self-related processing and cardiac monitoring observed here implies that, even in the absence of measured changes in peripheral bodily measures, physiological and cognitive functions have to be considered jointly in the DN. The default network (DN) has been consistently associated with self-processing but also with autonomic regulation. We hypothesized that these two functions could be functionally coupled in the DN, inspired by theories according to which selfhood is grounded in the neural monitoring of internal organs. Using magnetoencephalography, we show that heartbeat-evoked responses (HERs) in the DN covary with the self-relatedness of ongoing spontaneous thoughts. HER amplitude in the ventral precuneus covaried with the "I" self-dimension, whereas HER amplitude in the ventromedial prefrontal cortex encoded the "Me" self-dimension. Our experimental results directly support theories rooting selfhood in the neural monitoring of internal organs. We propose a novel functional framework for the DN, where self-processing is coupled with physiological monitoring. Copyright © 2016 Babo-Rebelo et al.

Neural Responses to Heartbeats in the Default Network Encode the Self in Spontaneous Thoughts

PubMed Central

Babo-Rebelo, Mariana; Richter, Craig G.

2016-01-01

The default network (DN) has been consistently associated with self-related cognition, but also to bodily state monitoring and autonomic regulation. We hypothesized that these two seemingly disparate functional roles of the DN are functionally coupled, in line with theories proposing that selfhood is grounded in the neural monitoring of internal organs, such as the heart. We measured with magnetoencephalograhy neural responses evoked by heartbeats while human participants freely mind-wandered. When interrupted by a visual stimulus at random intervals, participants scored the self-relatedness of the interrupted thought. They evaluated their involvement as the first-person perspective subject or agent in the thought (“I”), and on another scale to what degree they were thinking about themselves (“Me”). During the interrupted thought, neural responses to heartbeats in two regions of the DN, the ventral precuneus and the ventromedial prefrontal cortex, covaried, respectively, with the “I” and the “Me” dimensions of the self, even at the single-trial level. No covariation between self-relatedness and peripheral autonomic measures (heart rate, heart rate variability, pupil diameter, electrodermal activity, respiration rate, and phase) or alpha power was observed. Our results reveal a direct link between selfhood and neural responses to heartbeats in the DN and thus directly support theories grounding selfhood in the neural monitoring of visceral inputs. More generally, the tight functional coupling between self-related processing and cardiac monitoring observed here implies that, even in the absence of measured changes in peripheral bodily measures, physiological and cognitive functions have to be considered jointly in the DN. SIGNIFICANCE STATEMENT The default network (DN) has been consistently associated with self-processing but also with autonomic regulation. We hypothesized that these two functions could be functionally coupled in the DN, inspired by theories according to which selfhood is grounded in the neural monitoring of internal organs. Using magnetoencephalography, we show that heartbeat-evoked responses (HERs) in the DN covary with the self-relatedness of ongoing spontaneous thoughts. HER amplitude in the ventral precuneus covaried with the “I” self-dimension, whereas HER amplitude in the ventromedial prefrontal cortex encoded the “Me” self-dimension. Our experimental results directly support theories rooting selfhood in the neural monitoring of internal organs. We propose a novel functional framework for the DN, where self-processing is coupled with physiological monitoring. PMID:27466329

Increased 4-hydroxynonenal protein adducts in male GSTA4–4/PPAR-alpha double knockout mice enhance injury during early stages of alcoholic liver disease

USDA-ARS?s Scientific Manuscript database

To test the significance of lipid peroxidation in the development of alcoholic liver injury, an ethanol (EtOH) liquid diet was fed to male wild type 129/SvJ mice, and glutathione S-transferase A4-4 null (GSTA4-/-) mice for 40 d. GSTA4-/- mice were also crossed with peroxisome proliferator-activated ...

Maize opaque5 Encodes Monogalactosyldiacylglycerol Synthase and Specifically Affects Galactolipids Necessary for Amyloplast and Chloroplast Function[C][W][OA

PubMed Central

Myers, Alan M.; James, Martha G.; Lin, Qiaohui; Yi, Gibum; Stinard, Philip S.; Hennen-Bierwagen, Tracie A.; Becraft, Philip W.

2011-01-01

The maize (Zea mays) opaque5 (o5) locus was shown to encode the monogalactosyldiacylglycerol synthase MGD1. Null and point mutations of o5 that affect the vitreous nature of mature endosperm engendered an allelic series of lines with stepwise reductions in gene function. C18:3/C18:2 galactolipid abundance in seedling leaves was reduced proportionally, without significant effects on total galactolipid content. This alteration in polar lipid composition disrupted the organization of thylakoid membranes into granal stacks. Total galactolipid abundance in endosperm was strongly reduced in o5- mutants, causing developmental defects and changes in starch production such that the normal simple granules were replaced with compound granules separated by amyloplast membrane. Complete loss of MGD1 function in a null mutant caused kernel lethality owing to failure in both endosperm and embryo development. The data demonstrate that low-abundance galactolipids with five double bonds serve functions in plastid membranes that are not replaced by the predominant species with six double bonds. Furthermore, the data identify a function of amyloplast membranes in the development of starch granules. Finally, the specific changes in lipid composition suggest that MGD1 can distinguish the constituency of acyl groups on its diacylglycerol substrate based upon the degree of desaturation. PMID:21685260

EFFECTS OF LONG-TERM MEMANTINE ON MEMORY AND NEUROPATHOLOGY IN TS65DN MICE, A MODEL FOR DOWN SYNDROME

PubMed Central

Lockrow, Jason; Boger, Heather; Bimonte-Nelson, Heather; Granholm, Ann-Charlotte

2010-01-01

Memantine is a partial NMDA receptor antagonist that has been shown to improve learning and memory in several animal models, and is approved for the treatment of Alzheimer’s disease. Chronic treatments using memantine in animal models of Alzheimer’s disease show disease-modifying effects and suggest a potential neuroprotective function. The present study assessed the effects of both short- and long-term memantine treatment in a mouse model of Down syndrome, the Ts65Dn mouse. The Ts65Dn mouse contains a partial trisomy of murine chromosome 16, and exhibits hippocampal-dependent memory deficits, as well as progressive degeneration of basal forebrain cholinergic neurons. Ts65Dn mice were treated with memantine for a period of six months, beginning at four months of age. At the end of treatment the mice underwent memory testing using novel object recognition and water radial arm maze tasks, and then histologically analyzed for markers of neurodegeneration. Memantine treatment improved spatial and recognition memory performance in the Ts65Dn mice, though not to the level of normosomic littermate controls. Despite these memory improvements, histological analysis found no morphological signs of neuroprotection of basal forebrain cholinergic or locus coeruleus neurons in memantine-treated Ts65Dn mice. However, memantine treatment of Ts65Dn mice gave rise to elevated brain-derived neurotrophic factor expression in the hippocampus and frontal cortex, suggesting a mechanism of behavioral modification. Thus, our findings provide further evidence for memory facilitation of memantine, but suggest pharmacological rather than neuroprotective effects of memantine both after acute and chronic treatment in this mouse model. PMID:20363261

DN1(p) circadian neurons coordinate acute light and PDF inputs to produce robust daily behavior in Drosophila.

PubMed

Zhang, Luoying; Chung, Brian Y; Lear, Bridget C; Kilman, Valerie L; Liu, Yixiao; Mahesh, Guruswamy; Meissner, Rose-Anne; Hardin, Paul E; Allada, Ravi

2010-04-13

Daily behaviors in animals are determined by the interplay between internal timing signals from circadian clocks and environmental stimuli such as light. How these signals are integrated to produce timely and adaptive behavior is unclear. The fruit fly Drosophila exhibits clock-driven activity increases that anticipate dawn and dusk and free-running rhythms under constant conditions. Flies also respond to the onset of light and dark with acute increases in activity. Mutants of a novel ion channel, narrow abdomen (na), lack a robust increase in activity in response to light and show reduced anticipatory behavior and free-running rhythms, providing a genetic link between photic responses and circadian clock function. We used tissue-specific rescue of na to demonstrate a role for approximately 16-20 circadian pacemaker neurons, a subset of the posterior dorsal neurons 1 (DN1(p)s), in mediating the acute response to the onset of light as well as morning anticipatory behavior. Circadian pacemaker neurons expressing the neuropeptide PIGMENT-DISPERSING FACTOR (PDF) are especially important for morning anticipation and free-running rhythms and send projections to the DN1(p)s. We also demonstrate that DN1(p)Pdfr expression is sufficient to rescue, at least partially, Pdfr morning anticipation defects as well as defects in free-running rhythms, including those in DN1 molecular clocks. Additionally, these DN1 clocks in wild-type flies are more strongly reset to timing changes in PDF clocks than other pacemaker neurons, suggesting that they are direct targets. Taking these results together, we demonstrate that the DN1(p)s lie at the nexus of PDF and photic signaling to produce appropriate daily behavior.

On the onset of secondary flow and unsteady solutions through a loosely coiled rectangular duct for large aspect ratio

NASA Astrophysics Data System (ADS)

Shaha, Poly Rani; Rudro, Sajal Kanti; Poddar, Nayan Kumar; Mondal, Rabindra Nath

2016-07-01

The study of flows through coiled ducts and channels has attracted considerable attention not only because of their ample applications in Chemical, Mechanical, Civil, Nuclear and Biomechanical engineering but also because of their ample applications in other areas, such as blood flow in the veins and arteries of human and other animals. In this paper, a numerical study is presented for the fully developed two-dimensional flow of viscous incompressible fluid through a loosely coiled rectangular duct of large aspect ratio. Numerical calculations are carried out by using a spectral method, and covering a wide range of the Dean number, Dn, for two types of curvatures of the duct. The main concern of the present study is to find out effects of curvature as well as formation of secondary vortices on unsteady solutions whether the unsteady flow is steady-state, periodic, multi-periodic or chaotic, if Dn is increased. Time evolution calculations as well as their phase spaces are performed with a view to study the non-linear behavior of the unsteady solutions, and it is found that the steady-state flow turns into chaotic flow through various flow instabilities, if Dn is increased no matter what the curvature is. It is found that the unsteady flow is a steady-state solution for small Dn's and oscillates periodically or non-periodically (chaotic) between two- and twelve-vortex solutions, if Dn is increased. It is also found that the chaotic solution is weak for small Dn's but strong as Dn becomes large. Axial flow distribution is also investigated and shown in contour plots.

Increased Sparsity of Hippocampal CA1 Neuronal Ensembles in a Mouse Model of Down Syndrome Assayed by Arc Expression

PubMed Central

Smith-Hicks, Constance L.; Cai, Peiling; Savonenko, Alena V.; Reeves, Roger H.; Worley, Paul F.

2017-01-01

Down syndrome (DS) is the leading chromosomal cause of intellectual disability, yet the neural substrates of learning and memory deficits remain poorly understood. Here, we interrogate neural networks linked to learning and memory in a well-characterized model of DS, the Ts65Dn mouse. We report that Ts65Dn mice exhibit exploratory behavior that is not different from littermate wild-type (WT) controls yet behavioral activation of Arc mRNA transcription in pyramidal neurons of the CA1 region of the hippocampus is altered in Ts65Dn mice. In WT mice, a 5 min period of exploration of a novel environment resulted in Arc mRNA transcription in 39% of CA1 neurons. By contrast, the same period of exploration resulted in only ~20% of CA1 neurons transcribing Arc mRNA in Ts65Dn mice indicating increased sparsity of the behaviorally induced ensemble. Like WT mice the CA1 pyramidal neurons of Ts65Dn mice reactivated Arc transcription during a second exposure to the same environment 20 min after the first experience, but the size of the reactivated ensemble was only ~60% of that in WT mice. After repeated daily exposures there was a further decline in the size of the reactivated ensemble in Ts65Dn and a disruption of reactivation. Together these data demonstrate reduction in the size of the behaviorally induced network that expresses Arc in Ts65Dn mice and disruption of the long-term stability of the ensemble. We propose that these deficits in network formation and stability contribute to cognitive symptoms in DS. PMID:28217086

Mangiferin prevents diabetic nephropathy progression and protects podocyte function via autophagy in diabetic rat glomeruli.

PubMed

Wang, Xiaodan; Gao, Lihui; Lin, Hua; Song, Jingling; Wang, Jinwen; Yin, Yumin; Zhao, Jianghu; Xu, Xiangwei; Li, Zhenkun; Li, Ling

2018-04-05

Diabetic nephropathy (DN) is one of the most severe microangiopathies of diabetes mellitus and is a leading cause of end stage renal disease. Numerous studies suggest that podocyte injury contributes to progressive proteinuria. Podocytes are highly specialized, terminally differentiated cells that are unable to proliferate, autophagy plays a key role in maintaining the structure and function of podocytes. Autophagy impairment is involved in the pathogenesis of podocyte loss, which leads to massive proteinuria in DN. In the present study, we investigated the effects of mangiferin on nephropathy in streptozotocin (STZ)-induced diabetic rats; we focused on pathological factors related to autophagy in podocytes and the AMPK-mTOR-ULK1 pathway. The results showed that chronic treatment with mangiferin significantly decreased albuminuria, inhibited glomerular extracellular matrix expansion and restored the expression of nephrin, a podocyte marker, in diabetic rats; these results suggest that mangiferin delayed the process of DN and protected the podocytes. In addition, mangiferin induced autophagy, as shown by the up-regulation of LC3 II and the down-regulation of p62 in both DN rats and podocytes. Transmission electron microscope analyses showed that mangiferin increased the number of autophagosomes in the podocytes of DN rats. This underlying mechanism was associated with the up-regulation of AMPK phosphorylation, the down-regulation of mTOR phosphorylation and the up-regulation of p-ULK1. Taken together, mangiferin delayed the progression of DN and protected the podocytes by enhancing autophagy under diabetic conditions via the AMPK-mTOR-ULK1 pathway. These findings provide new insights into the molecular mechanisms underlying the renoprotective effects of mangiferin in DN. Copyright © 2018 Elsevier B.V. All rights reserved.

Dominant negative Ras attenuates pathological ventricular remodeling in pressure overload cardiac hypertrophy

PubMed Central

Ramos-Kuri, Manuel; Rapti, Kleopatra; Mehel, Hind; Zhang, Shihong; Dhandapany, Perundurai S.; Liang, Lifan; García-Carrancá, Alejandro; Bobe, Regis; Fischmeister, Rodolphe; Adnot, Serge; Lebeche, Djamel; Hajjar, Roger J.; Lipskaia, Larissa; Chemaly, Elie R.

2015-01-01

The importance of the oncogene Ras in cardiac hypertrophy is well appreciated. The hypertrophic effects of the constitutively active mutant Ras-Val12 are revealed by clinical syndromes due to the Ras mutations and experimental studies. We examined the possible anti-hypertrophic effect of Ras inhibition in vitro using rat neonatal cardiomyocytes (NRCM) and in vivo in the setting of pressure-overload left ventricular (LV) hypertrophy (POH) in rats. Ras functions were modulated via adenovirus directed gene transfer of active mutant Ras-Val12 or dominant negative mutant N17-DN-Ras (DN-Ras). Ras-Val12 expression in vitro activates NFAT resulting in pro-hypertrophic and cardio-toxic effects on NRCM beating and Z-line organization. In contrast, the DN-Ras was antihypertrophic on NRCM, inhibited NFAT and exerted cardio-protective effects attested by preserved NRCM beating and Z line structure. Additional experiments with silencing H-Ras gene strategy corroborated the antihypertrophic effects of siRNA-H-Ras on NRCM. In vivo, with the POH model, both Ras mutants were associated with similar hypertrophy two weeks after simultaneous induction of POH and Ras-mutant gene transfer. However, LV diameters were higher and LV fractional shortening lower in the Ras-Val12 group compared to control and DN-Ras. Moreover, DN-Ras reduced the cross-sectional area of cardiomyocytes in vivo, and decreased the expression of markers of pathologic cardiac hypertrophy. In isolated adult cardiomyocytes after 2 weeks of POH and Ras-mutant gene transfer, DN-Ras improved sarcomere shortening and calcium transients compared to Ras-Val12. Overall, DN-Ras promotes a more physiological form of hypertrophy, suggesting an interesting therapeutic target for pathological cardiac hypertrophy. PMID:26260012

Adaptive mesh refinement for characteristic grids

NASA Astrophysics Data System (ADS)

Thornburg, Jonathan

2011-05-01

I consider techniques for Berger-Oliger adaptive mesh refinement (AMR) when numerically solving partial differential equations with wave-like solutions, using characteristic (double-null) grids. Such AMR algorithms are naturally recursive, and the best-known past Berger-Oliger characteristic AMR algorithm, that of Pretorius and Lehner (J Comp Phys 198:10, 2004), recurses on individual "diamond" characteristic grid cells. This leads to the use of fine-grained memory management, with individual grid cells kept in two-dimensional linked lists at each refinement level. This complicates the implementation and adds overhead in both space and time. Here I describe a Berger-Oliger characteristic AMR algorithm which instead recurses on null slices. This algorithm is very similar to the usual Cauchy Berger-Oliger algorithm, and uses relatively coarse-grained memory management, allowing entire null slices to be stored in contiguous arrays in memory. The algorithm is very efficient in both space and time. I describe discretizations yielding both second and fourth order global accuracy. My code implementing the algorithm described here is included in the electronic supplementary materials accompanying this paper, and is freely available to other researchers under the terms of the GNU general public license.

Dentate nucleus iron deposition is a potential biomarker for tremor-dominant Parkinson’s disease

PubMed Central

He, Naying; Huang, Pei; Ling, Huawei; Langley, Jason; Liu, Chunlei; Ding, Bei; Huang, Juan; Xu, Hongmin; Zhang, Yong; Zhang, Zhongping; Hu, Xiaoping; Chen, Shengdi; Yan, Fuhua

2016-01-01

Parkinson disease (PD) is a heterogeneous neurodegenerative disorder with variable clinicopathologic phenotypes and underlying neuropathologic mechanisms. Each clinical phenotype has a unique set of motor symptoms. Tremor is the most frequent initial motor symptom of PD and is the most difficult symptom to treat. The dentate nucleus (DN) is a deep iron rich nucleus in the cerebellum and may be involved in PD tremor. In this study, we test the hypothesis that DN iron may be elevated in tremor dominant PD patients using quantitative susceptibility mapping. Forty-three patients with PD [19 tremor dominant (TD)/24 akinetic-rigid dominant (AR)] and 48 healthy gender- and age-matched controls were recruited. Multi-echo gradient echo data were collected for each subject on a 3.0 T MR system. Inter-group susceptibility differences in bilateral DN were investigated and correlations of clinical features with susceptibility were also examined. In contrast to the AR group, the TD group was found to have increased susceptibility in the bilateral DN, when compared to healthy controls. In addition, susceptibility was positively correlated with tremor score in drug naive PD patients. These findings indicate that iron load within DN may make an important contribution to motor phenotypes in PD. Moreover, our results suggest that TD and AR phenotypes of PD can be differentiated on the basis of the susceptibility of the DN at least on the group level. PMID:27192177

Effects of cell penetrating Notch inhibitory peptide conjugated to elastin-like polypeptide on glioblastoma cells.

PubMed

Opačak-Bernardi, Teuta; Ryu, Jung Su; Raucher, Drazen

2017-07-01

Notch pathway was found to be activated in most glioblastomas (GBMs), underlining the importance of Notch in formation and recurrence of GBM. In this study, a Notch inhibitory peptide, dominant negative MAML (dnMAML), was conjugated to elastin-like polypeptide (ELP) for tumor targeted delivery. ELP is a thermally responsive polypeptide that can be actively and passively targeted to the tumor site by localized application of hyperthermia. This complex was further modified with the addition of a cell penetrating peptide, SynB1, for improved cellular uptake and blood-brain barrier penetration. The SynB1-ELP1-dnMAML was examined for its cellular uptake, cytotoxicity, apoptosis, cell cycle inhibition and the inhibition of target genes' expression. SynB1-ELP1-dnMAML inhibited the growth of D54 and U251 cells by inducing apoptosis and cell cycle arrest, especially in the presence of hyperthermia. Hyperthermia increased overall uptake of the polypeptide by the cells and enhanced the resulting pharmacological effects of dnMAML, showing the inhibition of targets of Notch pathway such as Hes-1 and Hey-L. These results confirm that dnMAML is an effective Notch inhibitor and combination with ELP may allow thermal targeting of the SynB1-ELP1-dnMAML complex in cancer cells while avoiding the dangers of systemic Notch inhibition.

A DWARF NOVA IN THE GLOBULAR CLUSTER M13

DOE Office of Scientific and Technical Information (OSTI.GOV)

Servillat, M.; Van den Berg, M.; Grindlay, J.

Dwarf novae (DNe) in globular clusters (GCs) seem to be rare with only 13 detections in the 157 known Galactic GCs. We report the identification of a new DN in M13, the 14th DN identified in a GC to date. Using the 2 m Faulkes Telescope North, we conducted a search for stars in M13 that show variability over a year (2005-2006) on timescales of days and months. This led to the detection of one DN showing several outbursts. A Chandra X-ray source is coincident with this DN and shows both a spectrum and variability consistent with that expected frommore » a DN, thus supporting the identification. We searched for a counterpart in Hubble Space Telescope Advanced Camera for Surveys/Wide Field Camera archived images and found at least 11 candidates, of which we could characterize only the 7 brightest, including one with a 3{sigma} H{alpha} excess and a faint blue star. The detection of one DN when more could have been expected likely indicates that our knowledge of the global Galactic population of cataclysmic variables is too limited. The proportion of DNe may be lower than found in catalogs, or they may have a much smaller mean duty cycle ({approx}1%) as proposed by some population synthesis models and recent observations in the field.« less

Application of the ReNuMa model in the Sha He river watershed: tools for watershed environmental management.

PubMed

Sha, Jian; Liu, Min; Wang, Dong; Swaney, Dennis P; Wang, Yuqiu

2013-07-30

Models and related analytical methods are critical tools for use in modern watershed management. A modeling approach for quantifying the source apportionment of dissolved nitrogen (DN) and associated tools for examining the sensitivity and uncertainty of the model estimates were assessed for the Sha He River (SHR) watershed in China. The Regional Nutrient Management model (ReNuMa) was used to infer the primary sources of DN in the SHR watershed. This model is based on the Generalized Watershed Loading Functions (GWLF) and the Net Anthropogenic Nutrient Input (NANI) framework, modified to improve the characterization of subsurface hydrology and septic system loads. Hydrochemical processes of the SHR watershed, including streamflow, DN load fluxes, and corresponding DN concentration responses, were simulated following calibrations against observations of streamflow and DN fluxes. Uncertainty analyses were conducted with a Monte Carlo analysis to vary model parameters for assessing the associated variations in model outputs. The model performed accurately at the watershed scale and provided estimates of monthly streamflows and nutrient loads as well as DN source apportionments. The simulations identified the dominant contribution of agricultural land use and significant monthly variations. These results provide valuable support for science-based watershed management decisions and indicate the utility of ReNuMa for such applications. Copyright © 2013 Elsevier Ltd. All rights reserved.

Adult-Onset Fluoxetine Treatment Does Not Improve Behavioral Impairments and May Have Adverse Effects on the Ts65Dn Mouse Model of Down Syndrome

PubMed Central

Heinen, Markus; Hettich, Moritz M.; Ryan, Devon P.; Schnell, Susanne; Paesler, Katharina; Ehninger, Dan

2012-01-01

Down syndrome is caused by triplication of chromosome 21 and is associated with neurocognitive phenotypes ranging from severe intellectual disability to various patterns of more selective neuropsychological deficits, including memory impairments. In the Ts65Dn mouse model of Down syndrome, excessive GABAergic neurotransmission results in local over-inhibition of hippocampal circuits, which dampens hippocampal synaptic plasticity and contributes to cognitive impairments. Treatments with several GABAA receptor antagonists result in increased plasticity and improved memory deficits in Ts65Dn mice. These GABAA receptor antagonists are, however, not suitable for clinical applications. The selective serotonin reuptake inhibitor fluoxetine, in contrast, is a widely prescribed antidepressant that can also enhance plasticity in the adult rodent brain by lowering GABAergic inhibition. For these reasons, we wondered if an adult-onset 4-week oral fluoxetine treatment restores spatial learning and memory impairments in Ts65Dn mice. Fluoxetine did not measurably improve behavioral impairments of Ts65Dn mice. On the contrary, we observed seizures and mortality in fluoxetine-treated Ts65Dn mice, raising the possibility of a drug × genotype interaction with respect to these adverse treatment outcomes. Future studies should re-address this in larger animal cohorts and determine if fluoxetine treatment is associated with adverse treatment effects in individuals with Down syndrome. PMID:22848851

Effect of the consumption of a fermented dairy product containing Bifidobacterium lactis DN-173 010 on constipation in childhood: a multicentre randomised controlled trial (NTRTC: 1571).

PubMed

Tabbers, Merit M; Chmielewska, Ania; Roseboom, Maaike G; Boudet, Claire; Perrin, Catherine; Szajewska, Hania; Benninga, Marc A

2009-03-18

Constipation is a frustrating symptom affecting 3% of children worldwide. Randomised controlled trials show that both polyethylene glycol and lactulose are effective in increasing defecation frequency in children with constipation. However, in 30-50%, these children reported abdominal pain, bloating, flatulence, diarrhoea, nausea and bad taste of the medication. Two recent studies have shown that the fermented dairy product containing Bifidobacterium lactis strain DN-173 010 is effective in increasing stool frequency in constipation-predominant irritable bowel syndrome patients with a defecation frequency < 3/week and in constipated women with a defecation frequency < 3/week. Goal of this study is to determine whether this fermented dairy product is effective in the treatment of constipated children with a defecation frequency < 3/week. It is a two nation (The Netherlands and Poland) double-blind, placebo-controlled randomised multicentre trial in which 160 constipated children (age 3-16 years) with a defecation frequency <3/week will be randomly allocated to consume a fermented dairy product containing Bifidobacterium lactis DN-173 010 or a control product, twice a day, for 3 weeks. During the study all children are instructed to try to defecate on the toilet for 5-10 minutes after each meal (3 times a day) and daily complete a standardized bowel diary. Primary endpoint is stool frequency. Secondary endpoints are stool consistency, faecal incontinence frequency, pain during defecation, digestive symptoms (abdominal pain, flatulence), adverse effects (nausea, diarrhoea, bad taste) and intake of rescue medication (Bisacodyl). Rate of success and rate of responders are also evaluated, with success defined as > or = 3 bowel movements per week and < or =1 faecal incontinence episode over the last 2 weeks of product consumption and responder defined as a subject reporting a stool frequency > or = 3 on the last week of product consumption. To demonstrate that the success percentage in the intervention group will be 35% and the success percentage in the control group (acidified milk without ferments, toilet training, bowel diary) will be 15%, with alpha 0.05 and power 80%, a total sample size of 160 patients was calculated. This study is aimed to show that the fermented dairy product containing Bifidobacterium lactis strain DN-173 010 is effective in increasing stool frequency after 3 weeks of product consumption in children with functional constipation and a defecation frequency < 3/week.

Effect of the consumption of a fermented dairy product containing Bifidobacterium lactis DN-173 010 on constipation in childhood: a multicentre randomised controlled trial (NTRTC: 1571)

PubMed Central

Tabbers, Merit M; Chmielewska, Ania; Roseboom, Maaike G; Boudet, Claire; Perrin, Catherine; Szajewska, Hania; Benninga, Marc A

2009-01-01

Background Constipation is a frustrating symptom affecting 3% of children worldwide. Randomised controlled trials show that both polyethylene glycol and lactulose are effective in increasing defecation frequency in children with constipation. However, in 30–50%, these children reported abdominal pain, bloating, flatulence, diarrhoea, nausea and bad taste of the medication. Two recent studies have shown that the fermented dairy product containing Bifidobacterium lactis strain DN-173 010 is effective in increasing stool frequency in constipation-predominant irritable bowel syndrome patients with a defecation frequency < 3/week and in constipated women with a defecation frequency < 3/week. Goal of this study is to determine whether this fermented dairy product is effective in the treatment of constipated children with a defecation frequency < 3/week. Methods/design It is a two nation (The Netherlands and Poland) double-blind, placebo-controlled randomised multicentre trial in which 160 constipated children (age 3–16 years) with a defecation frequency <3/week will be randomly allocated to consume a fermented dairy product containing Bifidobacterium lactis DN-173 010 or a control product, twice a day, for 3 weeks. During the study all children are instructed to try to defecate on the toilet for 5–10 minutes after each meal (3 times a day) and daily complete a standardized bowel diary. Primary endpoint is stool frequency. Secondary endpoints are stool consistency, faecal incontinence frequency, pain during defecation, digestive symptoms (abdominal pain, flatulence), adverse effects (nausea, diarrhoea, bad taste) and intake of rescue medication (Bisacodyl). Rate of success and rate of responders are also evaluated, with success defined as ≥ 3 bowel movements per week and ≤1 faecal incontinence episode over the last 2 weeks of product consumption and responder defined as a subject reporting a stool frequency ≥ 3 on the last week of product consumption. To demonstrate that the success percentage in the intervention group will be 35% and the success percentage in the control group (acidified milk without ferments, toilet training, bowel diary) will be 15%, with alpha 0.05 and power 80%, a total sample size of 160 patients was calculated. Conclusion This study is aimed to show that the fermented dairy product containing Bifidobacterium lactis strain DN-173 010 is effective in increasing stool frequency after 3 weeks of product consumption in children with functional constipation and a defecation frequency < 3/week. PMID:19296845

Bubble growth as a means to measure dissolved nitrogen concentration in aerated water

NASA Astrophysics Data System (ADS)

Ando, Keita; Yamashita, Tatsuya

2017-11-01

Controlling the amount of dissolved gases in water is important, for example, to food processing; it is essential to quantitatively evaluate dissolved gas concentration. The concentration of dissolved oxygen (DO) can be measured by commercial DO meters, but that of dissolved nitrogen (DN) cannot be obtained easily. Here, we propose a means to measure DN concentration based on Epstein-Plesset-type analysis of bubble growth under dissolved gas supersaturation. DO supersaturation in water is produced by oxygen microbubble aeration. The diffusion-driven growth of bubbles nucleated at glass surfaces in contact with the aerated water is first observed. The observed growth is then compared to the extended Epstein-Plesset theory that considers Fick's mass transfer of both DO and DN across bubble interfaces; in this comparison, the unknown DN concentration is treated as a fitting parameter. Comparisons between the experiment and the theory suggest, as expected, that DN can be effectively purged by oxygen microbubble aeration. This study was supported in part by the Mizuho Foundation for the Promotion of Science and by a MEXT Grant-in-Aid for the Program for Leading Graduate Schools.

The effects of GLP-1 analogues, DPP-4 inhibitors and SGLT2 inhibitors on the renal system.

PubMed

Schernthaner, Guntram; Mogensen, Carl Erik; Schernthaner, Gerit-Holger

2014-09-01

Diabetic nephropathy (DN) affects an estimated 20%-40% of patients with type 2 diabetes mellitus (T2DM). Key modifiable risk factors for DN are albuminuria, anaemia, dyslipidaemia, hyperglycaemia and hypertension, together with lifestyle factors, such as smoking and obesity. Early detection and treatment of these risk factors can prevent DN or slow its progression, and may even induce remission in some patients. DN is generally preceded by albuminuria, which frequently remains elevated despite treatment in patients with T2DM. Optimal treatment and prevention of DN may require an early, intensive, multifactorial approach, tailored to simultaneously target all modifiable risk factors. Regular monitoring of renal function, including urinary albumin excretion, creatinine clearance and glomerular filtration rate, is critical for following any disease progression and making treatment adjustments. Dipeptidyl peptidase (DPP)-4 inhibitors and sodium-glucose cotransporter 2 (SGLT2) inhibitors lower blood glucose levels without additional risk of hypoglycaemia, and may also reduce albuminuria. Further investigation of the potential renal benefits of DPP-4 and SGLT2 inhibitors is underway. © The Author(s) 2014.

The effects of GLP-1 analogues, DPP-4 inhibitors and SGLT2 inhibitors on the renal system

PubMed Central

Mogensen, Carl Erik; Schernthaner, Gerit-Holger

2014-01-01

Diabetic nephropathy (DN) affects an estimated 20%–40% of patients with type 2 diabetes mellitus (T2DM). Key modifiable risk factors for DN are albuminuria, anaemia, dyslipidaemia, hyperglycaemia and hypertension, together with lifestyle factors, such as smoking and obesity. Early detection and treatment of these risk factors can prevent DN or slow its progression, and may even induce remission in some patients. DN is generally preceded by albuminuria, which frequently remains elevated despite treatment in patients with T2DM. Optimal treatment and prevention of DN may require an early, intensive, multifactorial approach, tailored to simultaneously target all modifiable risk factors. Regular monitoring of renal function, including urinary albumin excretion, creatinine clearance and glomerular filtration rate, is critical for following any disease progression and making treatment adjustments. Dipeptidyl peptidase (DPP)-4 inhibitors and sodium-glucose cotransporter 2 (SGLT2) inhibitors lower blood glucose levels without additional risk of hypoglycaemia, and may also reduce albuminuria. Further investigation of the potential renal benefits of DPP-4 and SGLT2 inhibitors is underway. PMID:25116004

Epithelial-to-Mesenchymal Transition in Diabetic Nephropathy: Fact or Fiction?

PubMed

Loeffler, Ivonne; Wolf, Gunter

2015-10-09

The pathophysiology of diabetic nephropathy (DN), one of the most serious complications in diabetic patients and the leading cause of end-stage renal disease worldwide, is complex and not fully elucidated. A typical hallmark of DN is the excessive deposition of extracellular matrix (ECM) proteins in the glomerulus and in the renal tubulointerstitium, eventually leading to glomerulosclerosis and interstitial fibrosis. Although it is obvious that myofibroblasts play a major role in the synthesis and secretion of ECM, the origin of myofibroblasts in DN remains the subject of controversial debates. A number of studies have focused on epithelial-to-mesenchymal transition (EMT) as one source of matrix-generating fibroblasts in the diseased kidney. EMT is characterized by the acquisition of mesenchymal properties by epithelial cells, preferentially proximal tubular cells and podocytes. In this review we comprehensively review the literature and discuss arguments both for and against a function of EMT in renal fibrosis in DN. While the precise extent of the contribution to nephrotic fibrosis is certainly arduous to quantify, the picture that emerges from this extensive body of literature suggests EMT as a major source of myofibroblasts in DN.

Nuclear science experiments with a bright neutron source from fusion reactions on the OMEGA Laser System

NASA Astrophysics Data System (ADS)

Forrest, C. J.; Knauer, J. P.; Schroeder, W. U.; Glebov, V. Yu.; Radha, P. B.; Regan, S. P.; Sangster, T. C.; Sickles, M.; Stoeckl, C.; Szczepanski, J.

2018-04-01

Subnanosecond impulses of 1013 to 1014 neutrons, produced in direct-drive laser inertial confinement fusion implosions, have been used to irradiate deuterated targets at the OMEGA Laser System (Boehly et al., 1997). The target compounds include heavy water (D2O) and deuterated benzene (C6D6). Yields and energy spectra of neutrons from D(n,2n)p to study the breakup reaction have been measured at a forward angle of θlab = 3 .5∘ ± 3.5° with a sensitive, high-dynamic-range neutron time-of-flight spectrometer to infer the double-differential breakup cross section d2 σ/dE d Ω for 14-MeV D-T fusion neutrons.

Spectroscopic Classification of ASASSN-13dn

NASA Astrophysics Data System (ADS)

Martini, P.; Elias, J.; Points, S.; Prieto, J. L.; Shappee, B. J.; Stanek, K. Z.; Kochanek, C. S.; Holoien, T. W.-S.; Jencson, J.; Basu, U.; Beacom, J. F.; Szczygiel, D.; Pojmanski, G.; Brimacombe, J.; Bersier, D.

2013-12-01

We obtained optical spectra of ASASSN-13dn (ATel #5665). The candidate was confirmed with the new KOSMOS instrument (Kitt Peak Ohio State Multi-Object Spectrograph), which is presently being commissioned at the KPNO 4-m Mayall telescope. Observations were obtained with both the blue and red VPH grisms (50 min each) for a combined wavelength range of 380nm to 965nm at R ~ 2000. The spectrum of ASASSN-13dn is characteristic of a Type II SN at the redshift of its host galaxy (z=0.023).

Exaggerated NMDA Mediated LTD in a Mouse Model of Down Syndrome and Pharmacological Rescuing by Memantine

ERIC Educational Resources Information Center

Scott-McKean, Jonah J.; Costa, Alberto C. S.

2011-01-01

The Ts65Dn mouse is the best-studied animal model for Down syndrome. In the experiments described here, NMDA-mediated or mGluR-mediated LTD was induced in the CA1 region of hippocampal slices from Ts65Dn and euploid control mice by bath application of 20 [mu]M NMDA for 3 min and 50 [mu]M DHPG for 5 min, respectively. We found that Ts65Dn mice…

Analysis of the Drosophila Clock promoter reveals heterogeneity in expression between subgroups of central oscillator cells and identifies a novel enhancer region.

PubMed

Gummadova, Jennet Orazmuradovna; Coutts, Graham Andrew; Glossop, Nicholas Robert John

2009-10-01

The CLOCK-CYCLE (CLK-CYC) heterodimer lies at the heart of the circadian oscillator mechanism in Drosophila, yet little is known about the identity of transcription factors that regulate the expression of Clk and/or cyc. Here, the authors have used a transgenic approach to isolate regions of the Clk locus that are necessary for expression in central oscillator neurons in the adult fly brain. This analysis shows that central clock cells can be subdivided into 2 distinct groups based on Clk gene regulation. Expression in the lateral neuron (LN), dorsal neuron 1 anterior (DN1a) and 2 (DN2) clusters requires cis-elements located in a 122 base-pair (bp) region (-206 to -84) of the Clk promoter. Expression in the remaining dorsal neurons, 1 posterior (DN1p) and 3 (DN3) and the lateral posterior neurons (LPN), requires regulatory elements located in the -856 to -206 region. In addition, expression in photoreceptors of the compound eye is enhanced by cis-elements located in a 3rd region of the Clk locus (-1982 to -856). This region also enhances expression in nonoscillator cells in the brain including the Kenyon cells, but expression in these neurons is suppressed by regulatory sites located further upstream of -1982. The authors' analysis reveals clear heterogeneity in Clk gene expression in the adult brain and provides a necessary focus to isolate novel transcription factors that bind at the Clk locus to regulate expression in different oscillator neuron subgroups. These results also suggest that the DN1a/DN2 neurons may have more molecular commonality with the LNs than they do with the DN1p/DN3/LPN neurons. Finally, this analysis has generated new transgenic lines that will enable genes to be misexpressed in subgroups of central oscillator cells that have previously been resistant to discrete genetic manipulation. Hence, these lines provide important new tools to facilitate a more complete dissection of the neural network that regulates output rhythms in physiology and behavior.

Racial differences in the development of de-novo donor-specific antibodies and treated antibody-mediated rejection after heart transplantation.

PubMed

Cole, Robert Townsend; Gandhi, Jonathan; Bray, Robert A; Gebel, Howard M; Yin, Michael; Shekiladze, Nikolaz; Young, An; Grant, Aubrey; Mahoney, Ian; Laskar, S Raja; Gupta, Divya; Bhatt, Kunal; Book, Wendy; Smith, Andrew; Nguyen, Duc; Vega, J David; Morris, Alanna A

2018-04-01

Despite improvements in outcomes after heart transplantation, black recipients have worse survival compared with non-black recipients. The source of such disparate outcomes remains largely unknown. We hypothesize that a propensity to generate de-novo donor-specific antibodies (dnDSA) and subsequent antibody-mediated rejection (AMR) may account for racial differences in sub-optimal outcomes after heart transplant. In this study we aimed to determine the role of dnDSA and AMR in racial disparities in post-transplant outcomes. This study was a single-center, retrospective analysis of 137 heart transplant recipients (81% male, 48% black) discharged from Emory University Hospital. Patients were classified as black vs non-black for the purpose of our analysis. Kaplan-Meier and Cox regression analyses were used to evaluate the association between race and selected outcomes. The primary outcome was the development of dnDSA. Secondary outcomes included treated AMR and a composite of all-cause graft dysfunction or death. After 3.7 years of follow-up, 39 (28.5%) patients developed dnDSA and 19 (13.8%) were treated for AMR. In multivariable models, black race was associated with a higher risk of developing dnDSA (hazard ratio [HR] 3.65, 95% confidence interval [CI] 1.54 to 8.65, p = 0.003) and a higher risk of treated AMR (HR 4.86, 95% CI 1.26 to 18.72, p = 0.021) compared with non-black race. Black race was also associated with a higher risk of all-cause graft dysfunction or death in univariate analyses (HR 2.10, 95% CI 1.02 to 4.30, p = 0.044). However, in a multivariable model incorporating dnDSA, black race was no longer a significant risk factor. Only dnDSA development was significantly associated with all-cause graft dysfunction or death (HR 4.85, 95% CI 1.89 to 12.44, p = 0.001). Black transplant recipients are at higher risk for the development of dnDSA and treated AMR, which may account for racial disparities in outcomes after heart transplantation. Copyright © 2018 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Fatigue, insomnia and nervousness: gender disparities and roles of individual characteristics and lifestyle factors among economically active people.

PubMed

Peretti-Watel, Patrick; Legleye, Stéphane; Baumann, Michèle; Choquet, Marie; Falissard, Bruno; Chau, Nearkasen

2009-09-01

Individuals with certain personal, family and job characteristics are at elevated risk of poor mental health. Yet, the respective role of obesity, smoking, alcohol abuse, low education, income, living and family conditions, and socio-occupational category in fatigue/insomnia (FI), nervousness (N) and frequent drug use for those disorders (DFI and DN) among men and women and in gender disparities are not well known. We studied gender differences in FI, N, DFI, DN, and in their correlated, and whether the gender differences were mediated by individual and lifestyle factors among 3,450 active subjects aged 18-64, randomly selected from North-eastern France. Subjects completed a post-mailed questionnaire. Data were analyzed via adjusted odds ratio (ORa) computed with the logistic regression model. Women were more affected than men for FI (21.3 vs. 13.1%, OR adjusted for age ORa 1.80, 95% CI 1.50-2.16), DFI (11.6 vs. 7.1%, ORa 1.74, 1.38-2.21), N (14.7 vs. 9.9%, ORa 1.58, 1.28-1.94), and for DN (12.1 vs. 5.7%, ORa 2.29, 1.79-2.94). These differences were not mediated by the individual characteristics studied. Multivariate analysis showed that the risk patterns varied between the two sexes. Smoking was related to N in men as well as in women; alcohol abuse to DFI in men only; lack of family support to all outcome variables in men and women; low educational level to DFI in men only; low income to FI, N and DN in men and to FI and DN in women; being unmarried to DN in men; being divorced/separated to N and DN in women; being a manual worker to FI and being a farmer to DFI in men; and being a manual worker to DN and being an employee to FI in women (1.50

Toward improved target conformity for two spot scanning proton therapy delivery systems using dynamic collimation

PubMed Central

Moignier, Alexandra; Gelover, Edgar; Smith, Blake R.; Wang, Dongxu; Flynn, Ryan T.; Kirk, Maura L.; Lin, Liyong; Solberg, Timothy D.; Lin, Alexander; Hyer, Daniel E.

2016-01-01

Purpose: To quantify improvement in target conformity in brain and head and neck tumor treatments resulting from the use of a dynamic collimation system (DCS) with two spot scanning proton therapy delivery systems (universal nozzle, UN, and dedicated nozzle, DN) with median spot sizes of 5.2 and 3.2 mm over a range of energies from 100 to 230 MeV. Methods: Uncollimated and collimated plans were calculated with both UN and DN beam models implemented within our in-house treatment planning system for five brain and ten head and neck datasets in patients previously treated with spot scanning proton therapy. The prescription dose and beam angles from the clinical plans were used for both the UN and DN plans. The average reduction of the mean dose to the 10-mm ring surrounding the target between the uncollimated and collimated plans was calculated for the UN and the DN. Target conformity was analyzed using the mean dose to 1-mm thickness rings surrounding the target at increasing distances ranging from 1 to 10 mm. Results: The average reductions of the 10-mm ring mean dose for the UN and DN plans were 13.7% (95% CI: 11.6%–15.7%; p < 0.0001) and 11.5% (95% CI: 9.5%–13.5%; p < 0.0001) across all brain cases and 7.1% (95% CI: 4.4%–9.8%; p < 0.001) and 6.3% (95% CI: 3.7%–9.0%; p < 0.001), respectively, across all head and neck cases. The collimated UN plans were either more conformal (all brain cases and 60% of the head and neck cases) than or equivalent (40% of the head and neck cases) to the uncollimated DN plans. The collimated DN plans offered the highest conformity. Conclusions: The DCS added either to the UN or DN improved the target conformity. The DCS may be of particular interest for sites with UN systems looking for a more economical solution than upgrading the nozzle to improve the target conformity of their spot scanning proton therapy system. PMID:26936726

Differential presentation and survival of de novo and recurrent metastatic breast cancer over time: 1990-2010.

PubMed

Malmgren, Judith A; Mayer, Musa; Atwood, Mary K; Kaplan, Henry G

2018-01-01

Differences in de novo (dnMBC) and recurrent metastatic breast cancer (rMBC) presentation and survival over time have not been adequately described. A retrospective cohort study, 1990-2010, with follow up through 2015 of dnMBC patients (stage IV at diagnosis) and rMBC patients with subsequent distant metastatic recurrence (stage I-III initial diagnosis) [dnMBC = 247, rMBC = 911)]. Analysis included Chi squared tests of categorical variables, Kaplan-Meier survival estimates, and Cox proportional adjusted hazard ratios (HzR) and 95% confidence intervals (CI). Disease specific survival (DSS) was time from diagnosis or distant recurrence to BC death. Over time, 1990-1998, 1999-2004, and 2005-2010, dnMBC incidence was constant (3%) and rMBC incidence decreased [18% to 7% (p < 0.001)] with no change in dnMBC hormone receptor (HR) or her2-neu (HER2) status but a decrease in rMBC HER2-positive cases and increase in triple negative breast cancer (HR-negative/HER2-negative) (p = 0.049). Five-year dnMBC DSS was 44% vs. 21% for rMBC (p < 0.001). Five-year dnMBC DSS improved over time [28% to 55% (p = 0.008)] and rMBC worsened [23% to 13%, p = 0.065)]. Worse DSS was associated with HR-negative status (HzR = 1.63; 1.41, 1.89), rMBC (HzR = 1.88; 1.58, 2.23), older age (70 +) (HzR = 1.88; 1.58, 2.24), > 1 distant metastases (HzR 1.39; 1.20, 1.62), and visceral dominant disease (HzR 1.22; 1.05, 1.43). After 1998, HER2-positive disease was associated with better DSS (HzR = 0.72, 95% CI 0.56, 0.93). Factors associated with the widening survival gap and non-equivalence between dnMBC and rMBC and decreased rMBC incidence warrant further study.

Metabolomics study of cadmium-induced diabetic nephropathy and protective effect of caffeic acid phenethyl ester using UPLC-Q-TOF-MS combined with pattern recognition.

PubMed

Gong, Pin; Chang, Xiangna; Chen, Xuefeng; Bai, Xiaohuan; Wen, He; Pi, Sihui; Yang, Wenjuan; Wang, Lan; Chen, Fuxin

2017-09-01

Diabetic nephropathy (DN) is the most severe complication of diabetes and multiple factors are involved in the pathogenesis of DN. Among them, cadmium (Cd) acts as a risk factor inducing the occurrence of DN. The present study focused on investigating the protective role of caffeic acid phenethyl ester (CAPE), an active component of propolis from honeybee hives, against Cd-induced DN in mice based on ultra performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS)and pattern recognition. Serum and urine biochemical indexes were detected and histopathological observation has been done to evaluate the damage of Cd on animals. Moreover, the global serum profiles of different groups were distinguished by UPLC-Q-TOF-MS and principal component analysis (PCA) were applied for group differentiation and marker selection. Moreover, the influence of Cd on the oxidative status in DN mice were also evaluated by assessing the parameters of oxidative stress, proinflammatory cytokines and antioxidant competence. As shown in the scores plots, the distinct clustering among controls, DN and CAPE groups were observed, significant changes in serum levels of LysoPC(18:1(11Z)), 2,3-dinor-8-iso-PGF2a, PS(18:1(9Z)/18:1(9Z)), DG(17:0/22:4 (7Z,10Z, 13Z, 16Z)/0:0) and Arachidonic acid(AA) were noted and identified as potential biomarkers, the effect of CAPE reverted them back to near normalcy. Further, It was observed a significant improvement in lipid peroxides (LPO) and protein carbonyls (PCO) levels in Cd-induced DN kidneys along with a significant decline in superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (GSH) levels, however, CAPE relieved these changes. In conclusion, the study suggested that the pathogenesis of DN caused by Cd probably owes to the perturbations of lipid metabolism and AA metabolism; CAPE seems to be effective agent and may be related to its potent antioxidant, anti-inflammatory properties and action as an Nrf2 activator. Copyright © 2017 Elsevier B.V. All rights reserved.

Evaluation of Multimodal Imaging Biomarkers of Prostate Cancer

DTIC Science & Technology

2015-09-01

and PET images. Figure 2 highlights the dynamic uptake of TSPO as compared to muscle. Across 60 minutes the %ID/cc continues to increase which is...p53 double null mutant mouse model. Towards that end, we have successfully acquired anatomic MRI and PET data in orthotopic tumors within the Pten...castration resistant prostate cancer, MRI, PET , FDHT, image optimization 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES

Semaphorin3a Promotes Advanced Diabetic Nephropathy

PubMed Central

Aggarwal, Pardeep K.; Veron, Delma; Thomas, David B.; Siegel, Dionicio; Moeckel, Gilbert; Kashgarian, Michael

2015-01-01

The onset of diabetic nephropathy (DN) is highlighted by glomerular filtration barrier abnormalities. Identifying pathogenic factors and targetable pathways driving DN is crucial to developing novel therapies and improving the disease outcome. Semaphorin3a (sema3a) is a guidance protein secreted by podocytes. Excess sema3a disrupts the glomerular filtration barrier. Here, using immunohistochemistry, we show increased podocyte SEMA3A in renal biopsies from patients with advanced DN. Using inducible, podocyte-specific Sema3a gain-of-function (Sema3a+) mice made diabetic with streptozotocin, we demonstrate that sema3a is pathogenic in DN. Diabetic Sema3a+ mice develop massive proteinuria, renal insufficiency, and extensive nodular glomerulosclerosis, mimicking advanced DN in humans. In diabetic mice, Sema3a+ exacerbates laminin and collagen IV accumulation in Kimmelstiel-Wilson-like glomerular nodules and causes diffuse podocyte foot process effacement and F-actin collapse via nephrin, αvβ3 integrin, and MICAL1 interactions with plexinA1. MICAL1 knockdown and sema3a inhibition render podocytes not susceptible to sema3a-induced shape changes, indicating that MICAL1 mediates sema3a-induced podocyte F-actin collapse. Moreover, sema3a binding inhibition or podocyte-specific plexinA1 deletion markedly ameliorates albuminuria and abrogates renal insufficiency and the diabetic nodular glomerulosclerosis phenotype of diabetic Sema3a+ mice. Collectively, these findings indicate that excess sema3a promotes severe diabetic nephropathy and identifies novel potential therapeutic targets for DN. PMID:25475434

Evaluation of genetic association and expression reduction of TRPC1 in the development of diabetic nephropathy.

PubMed

Zhang, Dongying; Freedman, Barry I; Flekac, Milan; Santos, Elisabete; Hicks, Pamela J; Bowden, Donald W; Efendic, Suad; Brismar, Kerstin; Gu, Harvest F

2009-01-01

The TRPC1 gene on chromosome 3q22-24 resides within the linkage region for diabetic nephropathy (DN) in type 1 (T1D) and type 2 diabetes mellitus (T2D). A recent study has demonstrated that TRPC1 expression is reduced in the kidney of diabetic ZDF- and STZ-treated rats. The present study aimed to evaluate the genetic and functional role of TRPC1 in the development of DN. Genetic association study was performed with two independent cohorts, including 1,177 T1D European Americans with or without DN from GoKinD population and 850 African-American subjects with T2D-associated end-stage renal disease (ESRD), or with hypertensive (non-diabetic) ESRD, and nondiabetic controls. Seven tag SNP markers derived from HapMap data (phase II) were genotyped. TRPC1 gene expression was examined using real time RT-PCR. No significant association of TRPC1 DNA polymorphisms with DN or ERSD was found in GoKinD and African-American populations. TRPC1 gene mRNA expression in kidney was found to be trendily reduced in 12-week and significantly in 26-week-old db/db mice. TRPC1 genetic polymorphism may not fundamentally contribute to the development of DN, while reduction of the gene expression in kidney may be a late phenomenon of DN as seen in diabetic animal models. 2008 S. Karger AG, Basel.

Genomewide Linkage Scan for Diabetic Renal Failure and Albuminuria: The FIND Study

PubMed Central

Igo, Robert P.; Iyengar, Sudha K.; Nicholas, Susanne B.; Goddard, Katrina A.B.; Langefeld, Carl D.; Hanson, Robert L.; Duggirala, Ravindranath; Divers, Jasmin; Abboud, Hanna; Adler, Sharon G.; Arar, Nedal H.; Horvath, Amanda; Elston, Robert C.; Bowden, Donald W.; Guo, Xiuqing; Ipp, Eli; Kao, W.H. Linda; Kimmel, Paul L.; Knowler, William C.; Meoni, Lucy A.; Molineros, Julio; Nelson, Robert G.; Pahl, Madeline V.; Parekh, Rulan S.; Rasooly, Rebekah S.; Schelling, Jeffrey R.; Shah, Vallabh O.; Smith, Michael W.; Winkler, Cheryl A.; Zager, Philip G.; Sedor, John R.; Freedman, Barry I.

2011-01-01

Background Diabetic nephropathy (DN) is a leading cause of mortality and morbidity in patients with type 1 and type 2 diabetes. The multicenter FIND consortium aims to identify genes for DN and its associated quantitative traits, e.g. the urine albumin:creatinine ratio (ACR). Herein, the results of whole-genome linkage analysis and a sparse association scan for ACR and a dichotomous DN phenotype are reported in diabetic individuals. Methods A genomewide scan comprising more than 5,500 autosomal single nucleotide polymorphism markers (average spacing of 0.6 cM) was performed on 1,235 nuclear and extended pedigrees (3,972 diabetic participants) ascertained for DN from African-American (AA), American-Indian (AI), European-American (EA) and Mexican-American (MA) populations. Results Strong evidence for linkage to DN was detected on chromosome 6p (p = 8.0 × 10−5, LOD = 3.09) in EA families as well as suggestive evidence for linkage to chromosome 7p in AI families. Regions on chromosomes 3p in AA, 7q in EA, 16q in AA and 22q in MA displayed suggestive evidence of linkage for urine ACR. The linkage peak on chromosome 22q overlaps the MYH9/APOL1 gene region, previously implicated in AA diabetic and nondiabetic nephropathies. Conclusion These results strengthen the evidence for previously identified genomic regions and implicate several novel loci potentially involved in the pathogenesis of DN. PMID:21454968

Dentate nucleus iron deposition is a potential biomarker for tremor-dominant Parkinson's disease.

PubMed

He, Naying; Huang, Pei; Ling, Huawei; Langley, Jason; Liu, Chunlei; Ding, Bei; Huang, Juan; Xu, Hongmin; Zhang, Yong; Zhang, Zhongping; Hu, Xiaoping; Chen, Shengdi; Yan, Fuhua

2017-04-01

Parkinson's disease (PD) is a heterogeneous neurodegenerative disorder with variable clinicopathologic phenotypes and underlying neuropathologic mechanisms. Each clinical phenotype has a unique set of motor symptoms. Tremor is the most frequent initial motor symptom of PD and is the most difficult symptom to treat. The dentate nucleus (DN) is a deep iron-rich nucleus in the cerebellum and may be involved in PD tremor. In this study, we test the hypothesis that DN iron may be elevated in tremor-dominant PD patients using quantitative susceptibility mapping. Forty-three patients with PD [19 tremor dominant (TD)/24 akinetic rigidity (AR) dominant] and 48 healthy gender- and age-matched controls were recruited. Multi-echo gradient echo data were collected for each subject on a 3.0-T MR system. Inter-group susceptibility differences in the bilateral DN were investigated and correlations of clinical features with susceptibility were also examined. In contrast with the AR-dominant group, the TD group was found to have increased susceptibility in the bilateral DN when compared with healthy controls. In addition, susceptibility was positively correlated with tremor score in drug-naive PD patients. These findings indicate that iron load within the DN may make an important contribution to motor phenotypes in PD. Moreover, our results suggest that TD and AR-dominant phenotypes of PD can be differentiated on the basis of the susceptibility of the DN, at least at the group level. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kuncharin, Yanin; Sangphech, Naunpun; Kueanjinda, Patipark

The Notch signaling pathway plays important roles in tumorigenesis in a context-dependent manner. In human cervical cancer, alterations in Notch signaling have been reported, and both tumor-suppressing and tumor-promoting roles of Notch signaling have been proposed; however, the precise molecular mechanisms governing these roles in cervical cancer remain controversial. MAML is a transcriptional co-activator originally identified by its role in Notch signaling. Recent evidence suggests that it also plays a role in other signaling pathways, such as the p53 and {beta}-catenin pathways. MAML is required for stable formation of Notch transcriptional complexes at the promoters of Notch target genes. Chromosomalmore » translocations affecting MAML have been shown to promote tumorigenesis. In this study, we used a truncated dominant-negative MAML1 (DN-MAML) to investigate the role of MAML in HPV-positive cervical cancer cell lines. Three human cervical cancer cell lines (HeLa, SiHa and CaSki) expressed all Notch receptors and the Notch target genes Hes1 and MAML1. Among these 3 cell lines, constitutive appearance of cleaved Notch1 was found only in CaSki cells, which suggests that Notch1 is constitutively activated in this cell line. Gamma secretase inhibitor (GSI) treatment, which suppresses Notch receptor activation, completely abrogated this form of Notch1 but had no effect on cell viability. Overexpression of DN-MAML by retroviral transduction in CaSki cells resulted in significant decreases in the mRNA levels of Hes1 and Notch1 but had no effects on the levels of MAML1, p53 or HPV E6/E7. DN-MAML expression induced increased viability of CaSki cells without any effect on cell cycle progression or cell proliferation. In addition, clonogenic assay experiments revealed that overexpression of DN-MAML resulted in increased colony formation compared to the overexpression of the control vector. When the status of the NF-{kappa}B pathway was investigated, CaSki cells overexpressing DN-MAML exhibited loss of phospho-I{kappa}B{alpha}, decreased total I{kappa}B{alpha} and nuclear localization of NF-{kappa}B p65, which suggests that the NF-{kappa}B pathway is hyperactivated. Furthermore, increased level of cleaved Notch1 was detected when DN-MAML was expressed. When DN-MAML-overexpressing cells were treated with GSI, significantly decreased cell viability was observed, indicating that inhibition of Notch signaling using GSI treatment and DN-MAML expression negatively affects cell viability. Taken together, targeting Notch signaling using DN-MAML and GSI treatment may present a novel method to control cell viability in cervical cancer cells.« less

Relationship between fibrillin-1 genotype and severity of cardiovascular involvement in Marfan syndrome.

PubMed

Franken, Romy; Teixido-Tura, Gisela; Brion, Maria; Forteza, Alberto; Rodriguez-Palomares, Jose; Gutierrez, Laura; Garcia Dorado, David; Pals, Gerard; Mulder, Barbara Jm; Evangelista, Artur

2017-11-01

The effect of FBN1 mutation type on the severity of cardiovascular manifestations in patients with Marfan syndrome (MFS) has been reported with disparity results. This study aims to determine the impact of the FBN1 mutation type on aortic diameters, aortic dilation rates and on cardiovascular events (ie, aortic dissection and cardiovascular mortality). MFS patients with a pathogenic FBN1 mutation followed at two specialised units were included. FBN1 mutations were classified as being dominant negative (DN; incorporation of non-mutated and mutated fibrillin-1 in the extracellular matrix) or having haploinsufficiency (HI; only incorporation of non-mutated fibrillin-1, thus a decreased amount of fibrillin-1 protein). Aortic diameters and the aortic dilation rate at the level of the aortic root, ascending aorta, arch, descending thoracic aorta and abdominal aorta by echocardiography and clinical endpoints comprising dissection and death were compared between HI and DN patients. Two hundred and ninety patients with MFS were included: 113 (39%) with an HI- FBN1 mutation and 177 (61%) with a DN- FBN1 . At baseline, patients with HI- FBN1 had a larger aortic root diameter than patients with DN- FBN1 (HI: 39.3±7.2 mm vs DN: 37.3±6.8 mm, p=0.022), with no differences in age or body surface area. After a mean follow-up of 4.9±2.0 years, aortic root and ascending dilation rates were increased in patients with HI- FBN1 (HI: 0.57±0.8 vs DN: 0.28±0.5 mm/year, p=0.004 and HI: 0.59±0.9 vs DN: 0.30±0.7 mm/year, p=0.032, respectively). Furthermore, patients with HI- FBN1 tended to be at increased risk for the combined endpoint of dissection and death compared with patients with DN- FBN1 (HR: 3.3, 95% CI 1.0 to 11.4, p=0.060). Patients with an HI mutation had a more severely affected aortic phenotype, with larger aortic root diameters and a more rapid dilation rate, and tended to have an increased risk of death and dissections compared with patients with a DN mutation. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Epigallocatechin-3-gallate (EGCG) consumption in the Ts65Dn model of Down syndrome fails to improve behavioral deficits and is detrimental to skeletal phenotypes.

PubMed

Stringer, Megan; Abeysekera, Irushi; Thomas, Jared; LaCombe, Jonathan; Stancombe, Kailey; Stewart, Robert J; Dria, Karl J; Wallace, Joseph M; Goodlett, Charles R; Roper, Randall J

2017-08-01

Down syndrome (DS) is caused by three copies of human chromosome 21 (Hsa21) and results in phenotypes including intellectual disability and skeletal deficits. Ts65Dn mice have three copies of ~50% of the genes homologous to Hsa21 and display phenotypes associated with DS, including cognitive deficits and skeletal abnormalities. DYRK1A is found in three copies in humans with Trisomy 21 and in Ts65Dn mice, and is involved in a number of critical pathways including neurological development and osteoclastogenesis. Epigallocatechin-3-gallate (EGCG), the main polyphenol in green tea, inhibits Dyrk1a activity. We have previously shown that EGCG treatment (~10mg/kg/day) improves skeletal abnormalities in Ts65Dn mice, yet the same dose, as well as ~20mg/kg/day did not rescue deficits in the Morris water maze spatial learning task (MWM), novel object recognition (NOR) or balance beam task (BB). In contrast, a recent study reported that an EGCG-containing supplement with a dose of 2-3mg per day (~40-60mg/kg/day) improved hippocampal-dependent task deficits in Ts65Dn mice. The current study investigated if an EGCG dosage similar to that study would yield similar improvements in either cognitive or skeletal deficits. Ts65Dn mice and euploid littermates were given EGCG [0.4mg/mL] or a water control, with treatments yielding average daily intakes of ~50mg/kg/day EGCG, and tested on the multivariate concentric square field (MCSF)-which assesses activity, exploratory behavior, risk assessment, risk taking, and shelter seeking-and NOR, BB, and MWM. EGCG treatment failed to improve cognitive deficits; EGCG also produced several detrimental effects on skeleton in both genotypes. In a refined HPLC-based assay, its first application in Ts65Dn mice, EGCG treatment significantly reduced kinase activity in femora but not in the cerebral cortex, cerebellum, or hippocampus. Counter to expectation, 9-week-old Ts65Dn mice exhibited a decrease in Dyrk1a protein levels in Western blot analysis in the cerebellum. The lack of beneficial therapeutic behavioral effects and potentially detrimental skeletal effects of EGCG found in Ts65Dn mice emphasize the importance of identifying dosages of EGCG that reliably improve DS phenotypes and linking those effects to actions of EGCG (or EGCG-containing supplements) in specific targets in brain and bone. Copyright © 2017 Elsevier Inc. All rights reserved.

Gene therapy of uterine leiomyomas: adenovirus-mediated expression of dominant negative estrogen receptor inhibits tumor growth in nude mice.

PubMed

Al-Hendy, Ayman; Lee, Eun J; Wang, Hui Q; Copland, John A

2004-11-01

Leiomyomas (fibroids) are common estrogen-dependent uterine tumors with no effective medicinal treatment; hysterectomy is the mainstay of management. This study was undertaken to investigate a potential therapy for leiomyoma; we used a mutated dominant-negative estrogen receptor gene delivered via an adenoviral vector (Ad-ER-DN). Ad-ER-DN transduction, in both human and rat leiomyoma cell lines, induced an increase in both caspase-3 levels and BAX/Bcl-2 ratio with evident apoptosis in the TdT-mediated dUTP nick-end labeling assay. In nude mice, rat leiomyoma cells ex vivo transduced with Ad-ER-DN supported significantly smaller tumors compared with Ad-LacZ-treated cells 5 weeks after implantation. In mice treated by direct intratumor injection into preexisting lesions, Ad-ER-DN caused immediate overall arrest of tumor growth. The Ad-ER-DN-treated tumors demonstrated severely inhibited cell proliferation (BrdU index) and a marked increase in the number of apoptotic cells (TdT-mediated dUTP nick-end labeling index). Dominant-negative estrogen receptor gene therapy may provide a nonsurgical treatment option for women with symptomatic uterine fibroids who want to preserve their uteri.

Beyond a Gaussian Denoiser: Residual Learning of Deep CNN for Image Denoising.

PubMed

Zhang, Kai; Zuo, Wangmeng; Chen, Yunjin; Meng, Deyu; Zhang, Lei

2017-07-01

The discriminative model learning for image denoising has been recently attracting considerable attentions due to its favorable denoising performance. In this paper, we take one step forward by investigating the construction of feed-forward denoising convolutional neural networks (DnCNNs) to embrace the progress in very deep architecture, learning algorithm, and regularization method into image denoising. Specifically, residual learning and batch normalization are utilized to speed up the training process as well as boost the denoising performance. Different from the existing discriminative denoising models which usually train a specific model for additive white Gaussian noise at a certain noise level, our DnCNN model is able to handle Gaussian denoising with unknown noise level (i.e., blind Gaussian denoising). With the residual learning strategy, DnCNN implicitly removes the latent clean image in the hidden layers. This property motivates us to train a single DnCNN model to tackle with several general image denoising tasks, such as Gaussian denoising, single image super-resolution, and JPEG image deblocking. Our extensive experiments demonstrate that our DnCNN model can not only exhibit high effectiveness in several general image denoising tasks, but also be efficiently implemented by benefiting from GPU computing.

Review of the origin of sulphur in DN-1 discharge and its implication for future development, Dauin prospect, central Philippines

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bayrante, L.F.; Hermoso, D.Z.; Candelaria, M.R.

1997-12-31

Well DN-1, the first exploratory well of the Dauin geothermal prospect discharged in 1983 substantial quantities of sulphur with a near-neutral pH fluid (pH 6.4 to 7.2) containing maximum chloride levels of 3,300 mg/kg, SO{sub 4} of 300 mg/kg; and high CO{sub 2} and H{sub 2}S relative to the production wells in Palinpinon Field to the north. The chemistry of DN-1 discharge-fluid and the origin of sulphur have been the cause of apprehension for any future development due to concerns on the presence of a possible acid resource southeast of Cuernos de Negros. A reinterpretation of the previous and newmore » surface data was undertaken in 1992 and 1996, including the origin of sulphur, to evaluate the potential of Dauin for development. The results indicate that the sulphur in DN-1 is formed from partial oxidation of hydrogen sulphide derived from the neutralised-acid fluids formed by sulphur hydrolysis at shallow levels but distant from DN-1. The study argues for the presence of near neutral exploitable resource in the prospect area.« less

Local Thermonuclear Runaways in Dwarf Novae?

NASA Astrophysics Data System (ADS)

Shara, Michael

2012-10-01

We have no hope of understanding the structure and evolution of a class of astrophysical objects if we cannot identify the dominant energy source of those objects.The Disk Instability Model {DIM} postulates that Dwarf Nova {DN} outbursts are powered by runaway accretion from an accretion disk onto a White Dwarf {WD} in a red dwarf-WD mass transferring binary. Ominously, HST observations {e.g. Sion et al. 2001} of WD surface abundances hint at a significant shortcoming of the DIM. The data from the present proposal will be able to unequivocally demonstrate if the observed highly Carbon-depleted and Nitrogen-enhanced abundances on WD surfaces {NOT predicted by DIM} vary with binary orbital phase, or throughout a DN quiescence cycle, or from cycle to cycle. These same data will test if predicted {but never observed} Local Thermonuclear Runaways {"Nuclear-powered mini-novas"} occur on the WDs of DN. Such events could trigger or even power DN, providing the long-sought physical mechanism of DN eruptions that DIM lacks. As a "free" bonus, the same data may also directly detect the diffusion of accreted metals in a WD atmosphere for the first time, or provide significant limits on the diffusion rate.

Effect of CYP3A perpetrators on ibrutinib exposure in healthy participants.

PubMed

de Jong, Jan; Skee, Donna; Murphy, Joe; Sukbuntherng, Juthamas; Hellemans, Peter; Smit, Johan; de Vries, Ronald; Jiao, Juhui James; Snoeys, Jan; Mannaert, Erik

2015-08-01

Ibrutinib (PCI-32765), a potent covalent inhibitor of Bruton's tyrosine kinase, has shown efficacy against a variety of B-cell malignancies. Given the prominent role of CYP3A in ibrutinib metabolism, effect of coadministration of CYP3A perpetrators with ibrutinib was evaluated in healthy adults. Ibrutinib (120 mg [Study 1, fasted], 560 mg [studies 2 (fasted), and 3 (nonfasted)]) was given alone and with ketoconazole [Study 1; 400 mg q.d.], rifampin [Study 2; 600 mg q.d.], and grapefruit juice [GFJ, Study 3]. Lower doses of ibrutinib were used together with CYP3A inhibitors [Study 1: 40 mg; Study 3: 140 mg], as safety precaution. Under fasted condition, ketoconazole increased ibrutinib dose-normalized (DN) exposure [DN-AUClast: 24-fold; DN-C max: 29-fold], rifampin decreased ibrutinib exposure [C max: 13-fold; AUClast: 10-fold]. Under nonfasted condition, GFJ caused a moderate increase [DN-C max: 3.5-fold; DN-AUC: 2.2-fold], most likely through inhibition of intestinal CYP3A. Half-life was not affected by CYP perpetrators indicating the interaction was mainly on first-pass extraction. All treatments were well-tolerated.

Investigation of mechanisms of mesenchymal stem cells for treatment of diabetic nephropathy via construction of a miRNA-TF-mRNA network

PubMed Central

Yang, Hailing; Zhang, Xiaofei; Xin, Guangda

2018-01-01

Abstract Background: Recent studies have reported that mesenchymal stem cells (MSCs) exert therapeutic effects on the treatment of diabetic nephropathy (DN), but the underlying mechanisms remain unclear. Methods: A dataset GSE65561 was obtained from Gene Expression Omnibus (GEO) database, which contained four healthy control samples (group 1), four healthy controls samples co-cultured with MSCs (group 2), five DN samples (group 3) and five DN samples co-cultured with MSCs (group 4). The differentially expressed genes (DEGs) between group 3 vs. group 1 and group 4 vs. group 2 were constructed using Linear Models for Microarray (LIMMA) package package. Then, DAVID was used to analyze the functional enrichment of DEGs. Based on STRING database the protein-protein interaction (PPI) network was visualized by the Cytoscape plug-in CytoNCA. Besides, the hub miRNAs and transcription factors (TFs) regulating DEGs were predicted using Webgestalt. Results: Totally, 303 up-regulated and 88 down-regulated DEGs were shared in group 3 vs. group 1 and group 4 vs. group 2. Besides, the up-regulated DEGs were mainly enriched in ‘translation’ and ‘translational elongation’, while the down-regulated genes were only enriched in ‘protein kinase activity’. RPS27A and RPLP0 had a higher degree in the PPI network and they were regulated by EIF3M. In addition, ETF1 was predicted to be an important gene, which was regulated by miR-150, miR-134 and EIF2S1. Conclusions: RPS27A, RPLP0 and ETF1 may be potential targets for MSCs on the treatment of DN.HighlightsRPS27A and RPLP0 may be important genes in the treatment of MSCs for DN.TF EIF3M may play a key role in the treatment of MSCs for DN.MiR-150 and miR-134 may be essential microRNAs in the treatment of MSCs for DN. PMID:29532746

Developmental excitatory-to-inhibitory GABA polarity switch is delayed in Ts65Dn mice, a genetic model of Down syndrome.

PubMed

Lysenko, Larisa V; Kim, Jeesun; Madamba, Francisco; Tyrtyshnaia, Anna A; Ruparelia, Aarti; Kleschevnikov, Alexander M

2018-07-01

Down syndrome (DS) is the most frequent genetic cause of developmental abnormalities leading to intellectual disability. One notable phenomenon affecting the formation of nascent neural circuits during late developmental periods is developmental switch of GABA action from depolarizing to hyperpolarizing mode. We examined properties of this switch in DS using primary cultures and acute hippocampal slices from Ts65Dn mice, a genetic model of DS. Cultures of DIV3-DIV13 Ts65Dn and control normosomic (2 N) neurons were loaded with FURA-2 AM, and GABA action was assessed using local applications. In 2 N cultures, the number of GABA-activated cells dropped from ~100% to 20% between postnatal days 3-13 (P3-P13) reflecting the switch in GABA action polarity. In Ts65Dn cultures, the timing of this switch was delayed by 2-3 days. Next, microelectrode recordings of multi-unit activity (MUA) were performed in CA3 slices during bath application of the GABA A agonist isoguvacine. MUA frequency was increased in P8-P12 and reduced in P14-P22 slices reflecting the switch of GABA action from excitatory to inhibitory mode. The timing of this switch was delayed in Ts65Dn by approximately 2 days. Finally, frequency of giant depolarizing potentials (GDPs), a form of primordial neural activity, was significantly increased in slices from Ts65Dn pups at P12 and P14. These experimental evidences show that GABA action polarity switch is delayed in Ts65Dn model of DS, and that these changes lead to a delay in maturation of nascent neural circuits. These alterations may affect properties of neural circuits in adult animals and, therefore, represent a prospective target for pharmacotherapy of cognitive impairment in DS. Copyright © 2018 Elsevier Inc. All rights reserved.

Roux-en-Y Esophagojejunostomy Ameliorates Renal Function Through Reduction of Renal Inflammatory and Fibrotic Markers in Diabetic Nephropathy.

PubMed

Wang, Cuifang; He, Bing; Piao, Dongxu; Han, Ping

2016-07-01

Roux-en-Y bariatric surgery has been shown to have a remarkable and sustainable improvement in type 2 diabetes. Recent clinical studies have shown that bariatric surgery can improve or halt the development of diabetic microvascular complications such as nephropathy. However, the exact underlying mechanisms of surgical procedures are unknown. Here, we have investigated the effects of Roux-en-Y esophagojejunostomy (RYEJ) on renal function and inflammation and fibrosis biomarkers for renal injury in type 2 diabetic rats. Sprague-Dawley rats with high fat diet and streptozotocin (STZ)-induced diabetes were randomly assigned into four groups: diabetic nephropathy (DN), DN treated with food restriction (DN-FR), DN treated with RYEJ surgery (DN-RYEJ), and DN-RYEJ sham (n = 6/group). Age-matched normal rats were assigned as control group. RYEJ and sham surgeries were performed. Hyperinsulinemic-euglycemic clamps with tracer infusion were completed to assess insulin sensitivity. Twenty-four hour urine albumin excretion rate (UAER) and glomerular filtration rate (GFR) were measured. The renal pathological injury was assessed by hematoxylin and eosin (HE) staining. Kidney messenger RNA (mRNA) and/or protein content/distribution of phospho-c-Jun NH2-terminal kinase (JNK), monocyte chemoattractant protein (MCP)-1, transforming growth factor (TGF)-β1, and mitogen-activated protein kinase phosphatase 5 (MKP5) were evaluated by real-time PCR and/or Western blotting/immunohistochemistry. Roux-en-Y esophagojejunostomy improved insulin sensitivity. RYEJ ameliorated renal function by improving UAER and GFR and attenuated glomerular hypertrophy after surgery. RYEJ also significantly downregulated the levels of JNK-mediated inflammatory response and upregulated the level of the anti-inflammatory mediator MKP5. Roux-en-Y esophagojejunostomy alleviates insulin resistance. RYEJ surgery ameliorated renal function and attenuated glomerular hypertrophy in a DN rat model. The considerable nephroprotective function may be mainly attributed to the reduced inflammatory and fibrotic biomarkers after RYEJ. The improvements in renal function and inflammation are not wholly dependent on the magnitude of weight loss.

Reflection statistics of weakly disordered optical medium when its mean refractive index is different from an outside medium

NASA Astrophysics Data System (ADS)

Pradhan, Prabhakar; John Park, Daniel; Capoglu, Ilker; Subramanian, Hariharan; Damania, Dhwanil; Cherkezyan, Lusik; Taflove, Allen; Backman, Vadim

2017-06-01

Statistical properties of light waves reflected from a one-dimensional (1D) disordered optical medium [n(x) = n0+ dn(x), =0] have been well studied, however, most of the studies have focused on the situation when the mean refractive index of the optical medium matched with the outside medium, i.e., n0= nout=1. Further, considering dn(x) as a Gaussian color noise refractive index medium with exponential spatial correlation decay length lc and k as the incident wave vector, it has been shown that for smaller correlation length limit, i.e., klc <<1, both the mean reflection coefficient and std of r, σ(r), have same value, and they follow the relation = σ(r) ∝ lc. However, when the refractive index of the sample medium is different from the outside medium, the reflection statistics may have interesting features, which has not been well studied or understood. We studied the reflection statistics of a 1D weakly disordered optical medium with the mean background refractive index n0 being different from the outside medium nout (≠n0), to see the effect of mismatching (i.e., value of n0- nout) on the reflection statistics. In the mismatched case, the results show that the mean reflection coefficient follows a form similar to that of the matched refractive-index case, i.e., ∝ lc, with a linear increased shift, which is due to 1D uniform background reflection from a slab. However, σ(r) is shown to be σ(r) ∝ (lc)1/2, which is different from the matched case. This change in std of r is attributed to the interference between the mismatched-crerated edge mediated multiple scattering that are coupled with the random scattering. Applications to light scattering from random layered media and biological cells are discussed.

Digastric Muscle Phenotypes of the Ts65Dn Mouse Model of Down Syndrome

PubMed Central

Connor, Nadine P.

2016-01-01

Down syndrome is frequently associated with complex difficulties in oromotor development, feeding, and swallowing. However, the muscle phenotypes underlying these deficits are unclear. We tested the hypotheses that the Ts65Dn mouse model of DS has significantly altered myosin heavy chain (MyHC) isoform profiles of the muscles involved in feeding and swallowing, as well as reductions in the speed of these movements during behavioral assays. SDS-PAGE, immunofluorescence, and qRT-PCR were used to assess MyHC isoform expression in pertinent muscles, and functional feeding and swallowing performance were quantified through videofluoroscopy and mastication assays. We found that both the anterior digastric (ADG) and posterior digastric (PDG) muscles in 11-day old and 5–6 week old Ts65Dn groups showed significantly lower MyHC 2b protein levels than in age-matched euploid control groups. In videofluoroscopic and videotape assays used to quantify swallowing and mastication performance, 5–6 week old Ts65Dn and euploid controls showed similar swallow rates, inter-swallow intervals, and mastication rates. In analysis of adults, 10–11 week old Ts65Dn mice revealed significantly less MyHC 2b mRNA expression in the posterior digastric, but not the anterior digastric muscle as compared with euploid controls. Analysis of MyHC 2b protein levels across an adult age range (10–53 weeks of age) revealed lower levels of MyHC 2b protein in the PDG of Ts65Dn than in euploids, but similar levels of MyHC 2b in the ADG. Cumulatively, these results indicate biochemical differences in some, but not all, muscles involved in swallowing and jaw movement in Ts65Dn mice that manifest early in post-natal development, and persist into adulthood. These findings suggest potential utility of this model for future investigations of the mechanisms of oromotor difficulties associated with Down syndrome. PMID:27336944

Treatment with corn oil improves neurogenesis and cognitive performance in the Ts65Dn mouse model of Down syndrome.

PubMed

Giacomini, Andrea; Stagni, Fiorenza; Emili, Marco; Guidi, Sandra; Salvalai, Maria Elisa; Grilli, Mariagrazia; Vidal-Sanchez, Veronica; Martinez-Cué, Carmen; Bartesaghi, Renata

2018-06-20

Individuals with Down syndrome (DS), a genetic condition due to triplication of Chromosome 21, are characterized by intellectual disability that worsens with age. Since impairment of neurogenesis and dendritic maturation are very likely key determinants of intellectual disability in DS, interventions targeted to these defects may translate into a behavioral benefit. While most of the neurogenesis enhancers tested so far in DS mouse models may pose some caveats due to possible side effects, substances naturally present in the human diet may be regarded as therapeutic tools with a high translational impact. Linoleic acid and oleic acid are major constituents of corn oil that positively affect neurogenesis and neuron maturation. Based on these premises, the goal of the current study was to establish whether treatment with corn oil improves hippocampal neurogenesis and hippocampus-dependent memory in the Ts65Dn model of DS. Four-month-old Ts65Dn and euploid mice were treated with saline or corn oil for 30 days. Evaluation of behavior at the end of treatment showed that Ts65Dn mice treated with corn oil underwent a large improvement in hippocampus-dependent learning and memory. Evaluation of neurogenesis and dendritogenesis showed that in treated Ts65Dn mice the number of new granule cells of the hippocampal dentate gyrus and their dendritic pattern became similar to those of euploid mice. In addition, treated Ts65Dn mice underwent an increase in body and brain weight. This study shows for the first time that fatty acids have a positive impact on the brain of the Ts65Dn mouse model of DS. These results suggest that a diet that is rich in fatty acids may exert beneficial effects on cognitive performance in individuals with DS without causing adverse effects. Copyright © 2018. Published by Elsevier Inc.

Protein Dynamics Associated with Failed and Rescued Learning in the Ts65Dn Mouse Model of Down Syndrome

PubMed Central

Ahmed, Md. Mahiuddin; Dhanasekaran, A. Ranjitha; Block, Aaron; Tong, Suhong; Costa, Alberto C. S.; Stasko, Melissa; Gardiner, Katheleen J.

2015-01-01

Down syndrome (DS) is caused by an extra copy of human chromosome 21 (Hsa21). Although it is the most common genetic cause of intellectual disability (ID), there are, as yet, no effective pharmacotherapies. The Ts65Dn mouse model of DS is trisomic for orthologs of ∼55% of Hsa21 classical protein coding genes. These mice display many features relevant to those seen in DS, including deficits in learning and memory (L/M) tasks requiring a functional hippocampus. Recently, the N-methyl-D-aspartate (NMDA) receptor antagonist, memantine, was shown to rescue performance of the Ts65Dn in several L/M tasks. These studies, however, have not been accompanied by molecular analyses. In previous work, we described changes in protein expression induced in hippocampus and cortex in control mice after exposure to context fear conditioning (CFC), with and without memantine treatment. Here, we extend this analysis to Ts65Dn mice, measuring levels of 85 proteins/protein modifications, including components of MAP kinase and MTOR pathways, and subunits of NMDA receptors, in cortex and hippocampus of Ts65Dn mice after failed learning in CFC and after learning was rescued by memantine. We show that, compared with wild type littermate controls, (i) of the dynamic responses seen in control mice in normal learning, >40% also occur in Ts65Dn in failed learning or are compensated by baseline abnormalities, and thus are considered necessary but not sufficient for successful learning, and (ii) treatment with memantine does not in general normalize the initial protein levels but instead induces direct and indirect responses in approximately half the proteins measured and results in normalization of the endpoint protein levels. Together, these datasets provide a first view of the complexities associated with pharmacological rescue of learning in the Ts65Dn. Extending such studies to additional drugs and mouse models of DS will aid in identifying pharmacotherapies for effective clinical trials. PMID:25793384

An extract of Pueraria tuberosa tubers attenuates diabetic nephropathy by upregulating matrix metalloproteinase-9 expression in the kidney of diabetic rats.

PubMed

Tripathi, Yamini B; Shukla, Rashmi; Pandey, Nidhi; Pandey, Vivek; Kumar, Mohan

2017-02-01

Currently, no drug is available to directly target the signaling molecules involved in the pathogenesis of diabetic nephropathy (DN); only antihypertensive and antidiabetic drugs are in clinical use. In the present study, the therapeutic effects of a active fraction of tubers from Pueraria tuberosa (hereafter referred to as PTY-2) were investigated in streptozotocin (STZ)-diabetic rats with DN, with particular emphasis on its effects on extracellular matrix (ECM) accumulation and matrix metalloproteinase (Mmp)-9 expression in kidney tissue. Rats were injected with 55 mg/kg, i.p., STZ. After 40 days, rats were divided into groups as follows (n = 6 per group): Group 1, age-matched rats not injected with STZ (non-diabetic control); Group 2, STZ-diabetic DN rats; and Group 3, PTY-2 (30 mg/100 g, p.o.)-treated DN rats. After 20 days treatment, the effects of PTY-2 on serum urea and creatinine concentrations, urinary levels of glucose, creatinine, protein, and ketone bodies, and urine pH were determined. Kidney tissue was evaluated for Mmp-9 expression and histological changes. Blood glucose, serum urea, creatinine, and urine protein levels were significantly higher, and creatinine clearance was significantly lower, in Group 2 versus Group 1 rats. There was a higher degree of glomerulosclerosis, expansion of the mesangial matrix, and excess ECM deposition and eosinophilic casts in kidneys from Group 2 versus Group 1 rats. Furthermore, Mmp-9 activity and expression were significantly reduced in kidney homogenate of Group 2 versus Group 1 rats. Interestingly, PTY-2 treatment significantly reversed all these changes in DN rats. Treatment of DN rats with PTY-2 significantly attenuated the severity of DN by increasing the expression and activity of Mmp-9, consequently degrading the ECM accumulated in kidney tissue. © 2016 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.

Ras Family GTPases Control Growth of Astrocyte Processes

PubMed Central

Kalman, Daniel; Gomperts, Stephen N.; Hardy, Stephen; Kitamura, Marina; Bishop, J. Michael

1999-01-01

Astrocytes in neuron-free cultures typically lack processes, although they are highly process-bearing in vivo. We show that basic fibroblast growth factor (bFGF) induces cultured astrocytes to grow processes and that Ras family GTPases mediate these morphological changes. Activated alleles of rac1 and rhoA blocked and reversed bFGF effects when introduced into astrocytes in dissociated culture and in brain slices using recombinant adenoviruses. By contrast, dominant negative (DN) alleles of both GTPases mimicked bFGF effects. A DN allele of Ha-ras blocked bFGF effects but not those of Rac1-DN or RhoA-DN. Our results show that bFGF acting through c-Ha-Ras inhibits endogenous Rac1 and RhoA GTPases thereby triggering astrocyte process growth, and they provide evidence for the regulation of this cascade in vivo by a yet undetermined neuron-derived factor. PMID:10233170

Relevance of β-delayed neutron data for reactor, nuclear physics and astrophysics applications

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kratz, Karl-Ludwig

Initially, yields (or abundances) and branching ratios of β-delayed neutrons (βdn) from fission products (P{sub n}-values) have had their main importance in nuclear reactor control. At that time, the six-group mathematical approximation of the time-dependence of βdn-data in terms of the so-called 'Keepin groups' was generally accepted. Later, with the development of high-resolution neutron spectroscopy, βdn data have provided important information on nuclear-structure properties at intermediate excitation energy in nuclei far from stability, as well as in nuclear astrophysics. In this paper, I will present some examples of the βdn-studies performed by the Kernchemie Mainz group during the past threemore » decades. This work has been recognized as an example of 'broad scientific diversity' which has led to my nomination for the 2014 Hans A. Bethe prize.« less

The topological matter of holonomy displacement on the principal U(n) -bundle over Dn,m , related to complex surfaces

NASA Astrophysics Data System (ADS)

Byun, Taechang

2018-04-01

Consider U(n) → U(n , m) / U(m) → π Dn,m , where Dn,m = U(n , m) /(U(n) × U(m)) . Given a nontrivial X ∈Mm×n(C) and g ∈ U(n , m) , consider a complete oriented surface S = S(X , g) with a complex structure in Dn,m and a "new" area form ω (X , g) on the surface S . Let c : [ 0 , 1 ] → S be a smooth, simple, closed, orientation-preserving curve and c ˆ : [ 0 , 1 ] → U(n , m) / U(m) its horizontal lift. Then the holonomy displacement is given by the right action of eΨ for some Ψ ∈SpanR { i(X∗ X)k }k=1p ⊂ u(n) , p =the number of distinct positiveeigenvalues ofX∗ X , such that

The integrable quantum group invariant A2n-1(2) and Dn+1(2) open spin chains

NASA Astrophysics Data System (ADS)

Nepomechie, Rafael I.; Pimenta, Rodrigo A.; Retore, Ana L.

2017-11-01

A family of A2n(2) integrable open spin chains with Uq (Cn) symmetry was recently identified in arxiv:arXiv:1702.01482. We identify here in a similar way a family of A2n-1(2) integrable open spin chains with Uq (Dn) symmetry, and two families of Dn+1(2) integrable open spin chains with Uq (Bn) symmetry. We discuss the consequences of these symmetries for the degeneracies and multiplicities of the spectrum. We propose Bethe ansatz solutions for two of these models, whose completeness we check numerically for small values of n and chain length N. We find formulas for the Dynkin labels in terms of the numbers of Bethe roots of each type, which are useful for determining the corresponding degeneracies. In an appendix, we briefly consider Dn+1(2) chains with other integrable boundary conditions, which do not have quantum group symmetry.

Biotransformation of Tributyltin chloride by Pseudomonas stutzeri strain DN2

PubMed Central

Khanolkar, Dnyanada S.; Naik, Milind Mohan; Dubey, Santosh Kumar

2014-01-01

A bacterial isolate capable of utilizing tributyltin chloride (TBTCl) as sole carbon source was isolated from estuarine sediments of west coast of India and identified as Pseudomonas stutzeri based on biochemical tests and Fatty acid methyl ester (FAME) analysis. This isolate was designated as strain DN2. Although this bacterial isolate could resist up to 3 mM TBTCl level, it showed maximum growth at 2 mM TBTCl in mineral salt medium (MSM). Pseudomonas stutzeri DN2 exposed to 2 mM TBTCl revealed significant alteration in cell morphology as elongation and shrinkage in cell size along with roughness of cell surface. FTIR and NMR analysis of TBTCl degradation product extracted using chloroform and purified using column chromatography clearly revealed biotransformation of TBTCl into Dibutyltin dichloride (DBTCl2) through debutylation process. Therefore, Pseudomonas stutzeri strain DN2 may be used as a potential bacterial strain for bioremediation of TBTCl contaminated aquatic environmental sites. PMID:25763027

Antagonism of NMDA receptors as a potential treatment for Down syndrome: a pilot randomized controlled trial

PubMed Central

Boada, R; Hutaff-Lee, C; Schrader, A; Weitzenkamp, D; Benke, T A; Goldson, E J; Costa, A C S

2012-01-01

Down syndrome (DS) is the most common genetic cause of intellectual disability. The N-methyl-D-aspartate (NMDA) receptor uncompetitive antagonist, memantine hydrochloride (memantine), has been shown to improve learning/memory and rescue one form of hippocampus synaptic plasticity dysfunction in the best-studied mouse model of DS available, the Ts65Dn mouse. Given the status of memantine as a treatment for Alzheimer's disease (AD) approved by the Food and Drug Administration, the preclinical evidence of potential efficacy in Ts65Dn mice, and the favorable safety profile of memantine, we designed a study to investigate whether the findings in the mouse model could be translated to individuals with DS. In this pilot, proof-of-principle study we hypothesized that memantine therapy would improve test scores of young adults with DS on measures of episodic and spatial memory, which are generally considered to be hippocampus dependent. Accordingly, in this randomized, double-blind, placebo-controlled trial, we compared the effect of 16-week treatment with either memantine or placebo on cognitive and adaptive functions of 40 young adults with DS using a carefully selected set of neuropsychological outcome measures. Safety and tolerability were also monitored. Although no significant differences were observed between the memantine and placebo groups on the two primary outcome measures, we found a significant improvement in the memantine group in one of the secondary measures associated with the primary hypothesis. Only infrequent and mild adverse events were noted. PMID:22806212

Altered default network resting state functional connectivity in patients with a first episode of psychosis.

PubMed

Alonso-Solís, Anna; Corripio, Iluminada; de Castro-Manglano, Pilar; Duran-Sindreu, Santiago; Garcia-Garcia, Manuel; Proal, Erika; Nuñez-Marín, Fidel; Soutullo, Cesar; Alvarez, Enric; Gómez-Ansón, Beatriz; Kelly, Clare; Castellanos, F Xavier

2012-08-01

Default network (DN) abnormalities have been identified in patients with chronic schizophrenia using "resting state" functional magnetic resonance imaging (R-fMRI). Here, we examined the integrity of the DN in patients experiencing their first episode of psychosis (FEP) compared with sex- and age-matched healthy controls. We collected R-fMRI data from 19 FEP patients (mean age 24.9 ± 4.8 yrs, 14 males) and 19 healthy controls (26.1 ± 4.8 yrs, 14 males) at 3T. Following standard preprocessing, we examined the functional connectivity (FC) of two DN subsystems and the two DN hubs (P<0.0045, corrected). Patients with FEP exhibited abnormal FC that appeared largely restricted to the dorsomedial prefrontal cortex (dMPFC) DN subsystem. Relative to controls, FEP patients exhibited weaker positive FC between dMPFC and posterior cingulate cortex (PCC) and precuneus, extending laterally through the parietal lobe to the posterior angular gyrus. Patients with FEP exhibited weaker negative FC between the lateral temporal cortex and the intracalcarine cortex, bilaterally. The PCC and temporo-parietal junction also exhibited weaker negative FC with the right fusiform gyrus extending to the lingual gyrus and lateral occipital cortex, in FEP patients, compared to controls. By contrast, patients with FEP showed stronger negative FC between the temporal pole and medial motor cortex, anterior precuneus and posterior mid-cingulate cortex. Abnormalities in the dMPFC DN subsystem in patients with a FEP suggest that FC patterns are altered even in the early stages of psychosis. Copyright © 2012 Elsevier B.V. All rights reserved.

Iron-based magnetic molecular imprinted polymers and their application in removal and determination of di-n-pentyl phthalate in aqueous media

PubMed Central

Zhou, Qingxiang; Yuan, Yongyong; Wu, Yalin

2017-01-01

Iron-based magnetic molecular imprinted polymers (Fe@SiO2@MIP) were synthesized for highly selective removal and recognition of di-n-pentyl phthalate (DnPP) from water. Well-defined core-shell Fe@SiO2 nanoparticles (less than 70 nm) were decorated on MIPs reticular layers to endow DnPP-MIPs with magnetic property for the first time. Five other phthalic acid esters including dimethyl phthalate, diethyl phthalate, dipropyl phthalate, di-n-butyl phthalate and di-iso-octyl phthalate were used to investigate the adsorptive selectivity to DnPP. The designed experiments were carried out to explore the adsorption kinetics, isotherms and thermodynamics and the results demonstrated that the adsorption was a spontaneous, exothermal and physical adsorption process. The materials were proved to be excellent adsorbents in removal of DnPP with an adsorption capacity as high as 194.15 mg g−1 in optimal condition. Furthermore, a magnetic solid phase extraction with Fe@SiO2@MIP coupled to high-performance liquid chromatography method was successfully developed for the determination of DnPP, and the proposed method achieved a good linear range of 0.5–250 µg l−1 with a correlation coefficient (R2) of 0.999 and low limit of detection (LOD) of 0.31 µg l−1. These materials exhibited excellent capacity in removal and highly sensitive identification of DnPP from aqueous environment samples, and opened a valuable direction for developing new adsorbents for the removal and enrichment of important pollutants. PMID:28879009

Iron-based magnetic molecular imprinted polymers and their application in removal and determination of di-n-pentyl phthalate in aqueous media.

PubMed

Li, Jing; Zhou, Qingxiang; Yuan, Yongyong; Wu, Yalin

2017-08-01

Iron-based magnetic molecular imprinted polymers (Fe@SiO 2 @MIP) were synthesized for highly selective removal and recognition of di- n -pentyl phthalate (DnPP) from water. Well-defined core-shell Fe@SiO 2 nanoparticles (less than 70 nm) were decorated on MIPs reticular layers to endow DnPP-MIPs with magnetic property for the first time. Five other phthalic acid esters including dimethyl phthalate, diethyl phthalate, dipropyl phthalate, di- n -butyl phthalate and di-iso-octyl phthalate were used to investigate the adsorptive selectivity to DnPP. The designed experiments were carried out to explore the adsorption kinetics, isotherms and thermodynamics and the results demonstrated that the adsorption was a spontaneous, exothermal and physical adsorption process. The materials were proved to be excellent adsorbents in removal of DnPP with an adsorption capacity as high as 194.15 mg g -1 in optimal condition. Furthermore, a magnetic solid phase extraction with Fe@SiO 2 @MIP coupled to high-performance liquid chromatography method was successfully developed for the determination of DnPP, and the proposed method achieved a good linear range of 0.5-250 µg l -1 with a correlation coefficient ( R 2 ) of 0.999 and low limit of detection (LOD) of 0.31 µg l -1 . These materials exhibited excellent capacity in removal and highly sensitive identification of DnPP from aqueous environment samples, and opened a valuable direction for developing new adsorbents for the removal and enrichment of important pollutants.

Nitric oxide system and diabetic nephropathy

PubMed Central

2014-01-01

About 30% of patients with type 2 diabetes mellitus develop clinically overt nephropathy. Hyperglycemia is necessary, but not sufficient, to cause the renal damage that leads to kidney failure. Diabetic nephropathy (DN) is a multifactorial disorder that results from interaction between environmental and genetic factors. In the present article we will review the role of the nitric oxide synthase (NOS) in the pathogenesis of DN. Nitric oxide (NO) is a short-lived gaseous lipophilic molecule produced in almost all tissues, and it has three distinct genes that encode three NOS isoforms: neuronal (nNOS), inducible (iNOS) and endothelial (eNOS). The correct function of the endothelium depends on NO, participating in hemostasis control, vascular tone regulation, proliferation of vascular smooth muscle cells and blood pressure homeostasis, among other features. In the kidney, NO plays many different roles, including control of renal and glomerular hemodynamics. The net effect of NO in the kidney is to promote natriuresis and diuresis, along with renal adaptation to dietary salt intake. The eNOS gene has been considered a potential candidate gene for DN susceptibility. Three polymorphisms have been extensively researched: G894T missense mutation (rs1799983), a 27-bp repeat in intron 4, and the T786C single nucleotide polymorphism (SNP) in the promoter (rs2070744). However, the potential link between eNOS gene variants and the induction and progression of DN yielded contradictory results in the literature. In conclusion, NOS seems to be involve in the development and progression of DN. Despite the discrepant results of many studies, the eNOS gene is also a good candidate gene for DN. PMID:24520999

Deficits in cognition and synaptic plasticity in a mouse model of Down syndrome ameliorated by GABAB receptor antagonists

PubMed Central

Kleschevnikov, A.M.; Belichenko, P.V.; Faizi, M.; Jacobs, L.F.; Htun, K.; Shamloo, M.; Mobley, W.C.

2012-01-01

Cognitive impairment in Down syndrome (DS) is characterized by deficient learning and memory. Mouse genetic models of DS exhibit impaired cognition in hippocampally mediated behavioral tasks and reduced synaptic plasticity of hippocampal pathways. Enhanced efficiency of GABAergic neurotransmission was implicated in those changes. We have recently shown that signaling through postsynaptic GABAB receptors is significantly increased in the dentate gyrus (DG) of Ts65Dn mice, a genetic model of DS. Here we examined a role for GABAB receptors in cognitive deficits in DS by defining the effect of selective GABAB receptor antagonists on behavior and synaptic plasticity of adult Ts65Dn mice. Treatment with the GABAB receptor antagonist CGP55845 restored memory of Ts65Dn mice in the novel place recognition, novel object recognition and contextual fear conditioning tasks, but did not affect locomotion and performance in T-maze. The treatment increased hippocampal levels of brain-derived neurotrophic factor (BDNF), equally in 2N and Ts65Dn mice. In hippocampal slices, treatment with the GABAB receptor antagonists CGP55845 or CGP52432 enhanced long-term potentiation (LTP) in the Ts65Dn DG. The enhancement of LTP was accompanied by an increase in the NMDA receptor-mediated component of the tetanus-evoked responses. These findings are evidence for a contribution of GABAB receptors to changes in hippocampal-based cognition in the Ts65Dn mouse. The ability to rescue cognitive performance through treatment with selective GABAB receptor antagonists motivates studies to further explore the therapeutic potential of these compounds in people with DS. PMID:22764230

Altered Default Network Resting State Functional Connectivity in Patients with a First Episode of Psychosis

PubMed Central

Alonso-Solís, Anna; Corripio, Iluminada; de Castro-Manglano, Pilar; Duran-Sindreu, Santiago; Garcia-Garcia, Manuel; Proal, Erika; Nuñez-Marín, Fidel; Soutullo, Cesar; Alvarez, Enric; Gómez-Ansón, Beatriz; Kelly, Clare; Castellanos, F. Xavier

2012-01-01

Background Default network (DN) abnormalities have been identified in patients with chronic schizophrenia using “resting state” functional magnetic resonance imaging (R-fMRI). Here, we examined the integrity of the DN in patients experiencing their first episode of psychosis (FEP) compared with sex- and age-matched healthy controls. Methods We collected R-fMRI data from 19 FEP patients (mean age 24.9±4.8 yrs, 14 males) and 19 healthy controls (26.1±4.8 yrs, 14 males) at 3 Tesla. Following standard preprocessing, we examined the functional connectivity (FC) of two DN subsystems and the two DN hubs (P<0.0045, corrected). Results Patients with FEP exhibited abnormal FC that appeared largely restricted to the dorsomedial prefrontal cortex (dMPFC) DN subsystem. Relative to controls, FEP patients exhibited weaker positive FC between dMPFC and posterior cingulate cortex (PCC) and precuneus, extending laterally through the parietal lobe to the posterior angular gyrus. Patients with FEP exhibited weaker negative FC between the lateral temporal cortex and the intracalcarine cortex, bilaterally. The PCC and temporo-parietal junction also exhibited weaker negative FC with the right fusiform gyrus extending to the lingual gyrus and lateral occipital cortex, in FEP patients, compared to controls. By contrast, patients with FEP showed stronger negative FC between the temporal pole and medial motor cortex, anterior precuneus and posterior mid-cingulate cortex. Conclusions Abnormalities in the dMPFC DN subsystem in patients with a FEP suggest that FC patterns are altered even in the early stages of psychosis. PMID:22633527

Improved confinement in highly powered high performance scenarios on DIII-D

NASA Astrophysics Data System (ADS)

Petrie, T. W.; Osborne, T.; Fenstermacher, M. E.; Ferron, J.; Groebner, R.; Grierson, B.; Holcomb, C.; Lasnier, C.; Leonard, A.; Luce, T.; Makowski, M.; Turco, F.; Solomon, W.; Victor, B.; Watkins, J.

2017-08-01

DIII-D has recently demonstrated improved energy confinement by injecting neutral deuterium gas into high performance near-double null divertor (DND) plasmas during high power operation. Representative parameters for these plasmas are: q 95  =  6, P IN up to 15 MW, H 98  =  1.4-1.8, and β N  =  2.5-4.0. The ion B   ×  \

Methylation of Gibberellins by Arabidopsis GAMT1 and GAMT2[W

PubMed Central

Varbanova, Marina; Yamaguchi, Shinjiro; Yang, Yue; McKelvey, Katherine; Hanada, Atsushi; Borochov, Roy; Yu, Fei; Jikumaru, Yusuke; Ross, Jeannine; Cortes, Diego; Ma, Choong Je; Noel, Joseph P.; Mander, Lew; Shulaev, Vladimir; Kamiya, Yuji; Rodermel, Steve; Weiss, David; Pichersky, Eran

2007-01-01

Arabidopsis thaliana GAMT1 and GAMT2 encode enzymes that catalyze formation of the methyl esters of gibberellins (GAs). Ectopic expression of GAMT1 or GAMT2 in Arabidopsis, tobacco (Nicotiana tabacum), and petunia (Petunia hybrida) resulted in plants with GA deficiency and typical GA deficiency phenotypes, such as dwarfism and reduced fertility. GAMT1 and GAMT2 are both expressed mainly in whole siliques (including seeds), with peak transcript levels from the middle until the end of silique development. Within whole siliques, GAMT2 was previously shown to be expressed mostly in developing seeds, and we show here that GAMT1 expression is also localized mostly to seed, suggesting a role in seed development. Siliques of null single GAMT1 and GAMT2 mutants accumulated high levels of various GAs, with particularly high levels of GA1 in the double mutant. Methylated GAs were not detected in wild-type siliques, suggesting that methylation of GAs by GAMT1 and GAMT2 serves to deactivate GAs and initiate their degradation as the seeds mature. Seeds of homozygous GAMT1 and GAMT2 null mutants showed reduced inhibition of germination, compared with the wild type, when placed on plates containing the GA biosynthesis inhibitor ancymidol, with the double mutant showing the least inhibition. These results suggest that the mature mutant seeds contained higher levels of active GAs than wild-type seeds. PMID:17220201

Disruption of insulin-like growth factor-II imprinting during embryonic development rescues the dwarf phenotype of mice null for pregnancy-associated plasma protein-A.

PubMed

Bale, Laurie K; Conover, Cheryl A

2005-08-01

Pregnancy-associated plasma protein-A (PAPP-A), an insulin-like growth factor-binding protein (IGFBP) protease, increases insulin-like growth factor (IGF) activity through cleavage of inhibitory IGFBP-4 and the consequent release of IGF peptide for receptor activation. Mice homozygous for targeted disruption of the PAPP-A gene are born as proportional dwarfs and exhibit retarded bone ossification during fetal development. Phenotype and in vitro data support a model in which decreased IGF-II bioavailability during embryogenesis results in growth retardation and reduction in overall body size. To test the hypothesis that an increase in IGF-II during embryogenesis would overcome the growth deficiencies, PAPP-A-null mice were crossed with DeltaH19 mutant mice, which have increased IGF-II expression and fetal overgrowth due to disruption of IgfII imprinting. DeltaH19 mutant mice were 126% and PAPP-A-null mice were 74% the size of controls at birth. These size differences were evident at embryonic day 16.5. Importantly, double mutants were indistinguishable from controls both in terms of size and skeletal development. Body size programmed during embryo development persisted post-natally. Thus, disruption of IgfII imprinting and consequent elevation in IGF-II during fetal development was associated with rescue of the dwarf phenotype and ossification defects of PAPP-A-null mice. These data provide strong genetic evidence that PAPP-A plays an essential role in determining IGF-II bioavailability for optimal fetal growth and development.

High internal inductance for steady-state operation in ITER and a reactor

DOE PAGES

Ferron, John R.; Holcomb, Christopher T.; Luce, Timothy C.; ...

2015-06-26

Increased confinement and ideal stability limits at relatively high values of the internal inductance (more » $${{\\ell}_{i}}$$ ) have enabled an attractive scenario for steady-state tokamak operation to be demonstrated in DIII-D. Normalized plasma pressure in the range appropriate for a reactor has been achieved in high elongation and triangularity double-null divertor discharges with $${{\\beta}_{\\text{N}}}\\approx 5$$ at $${{\\ell}_{i}}\\approx 1.3$$ , near the ideal $n=1$ kink stability limit calculated without the effect of a stabilizing vacuum vessel wall, with the ideal-wall limit still higher at $${{\\beta}_{\\text{N}}}>5.5$$ . Confinement is above the H-mode level with $${{H}_{98\\left(\\text{y},2\\right)}}\\approx 1.8$$ . At $${{q}_{95}}\\approx 7.5$$ , the current is overdriven, with bootstrap current fraction $${{f}_{\\text{BS}}}\\approx 0.8$$ , noninductive current fraction $${{f}_{\\text{NI}}}>1$$ and negative surface voltage. For ITER (which has a single-null divertor shape), operation at $${{\\ell}_{i}}\\approx 1$$ is a promising option with $${{f}_{\\text{BS}}}\\approx 0.5$$ and the remaining current driven externally near the axis where the electron cyclotron current drive efficiency is high. This scenario has been tested in the ITER shape in DIII-D at $${{q}_{95}}=4.8$$ , so far reaching $${{f}_{\\text{NI}}}=0.7$$ and $${{f}_{\\text{BS}}}=0.4$$ at $${{\\beta}_{\\text{N}}}\\approx 3.5$$ with performance appropriate for the ITER Q=5 mission, $${{H}_{89}}{{\\beta}_{\\text{N}}}/q_{95}^{2}\\approx 0.3$$ . Modeling studies explored how increased current drive power for DIII-D could be applied to maintain a stationary, fully noninductive high $${{\\ell}_{i}}$$ discharge. Lastly, stable solutions in the double-null shape are found without the vacuum vessel wall at $${{\\beta}_{\\text{N}}}=4$$ , $${{\\ell}_{i}}=1.07$$ and $${{f}_{\\text{BS}}}=0.5$$ , and at $${{\\beta}_{\\text{N}}}=5$$ with the vacuum vessel wall.« less

SPINAL AND PERIPHERAL DRY NEEDLING VERSUS PERIPHERAL DRY NEEDLING ALONE AMONG INDIVIDUALS WITH A HISTORY OF LATERAL ANKLE SPRAIN: A RANDOMIZED CONTROLLED TRIAL

PubMed Central

Rossi, Ainsley; Blaustein, Sara; Brown, Joshua; Dieffenderfer, Kari; Ervin, Elaine; Griffin, Steven; Frierson, Elizabeth; Geist, Kathleen

2017-01-01

Background In addition to established interventions, dry needling may reduce impairments leading to greater functional abilities for individuals following ankle sprain. Hypothesis/Purpose The purpose of this study was to compare effects of spinal and peripheral dry needling (DN) with peripheral DN alone on impairments and functional performance among individuals with a history of lateral ankle sprain. Study Design Randomized controlled trial. Methods Twenty individuals with a history of lateral ankle sprain (18 bilateral, 2 unilateral) participated in this study (4 males, 16 females; mean age 28.9 + /- 9.2 years). During the first of two sessions, participants completed the Foot and Ankle Disability Index (FADI) and the Cumberland Ankle Instability Tool (CAIT) and their strength, unilateral balance, and unilateral hop test performance was assessed. Participants were randomly assigned to a spinal and peripheral DN group (SPDN), or a peripheral only DN group (PDN). Participants in the SPDN site group received DN to bilateral L5 multifidi and fibularis longus and brevis muscles on the involved lower extremity. Participants in the PDN group received DN to the fibularis muscles alone. Participants’ strength, balance and hop test performance were reassessed immediately following the intervention, and at follow-up 6-7 days later, all outcome measures were reassessed. Three-way mixed model ANOVAs and Mann-Whitney U tests assessed between group differences for outcome variables with normal distributions and non-normal distributions, respectively. Results ANOVAs showed significant group by time interaction (p<0.05) for invertor strength, significant side by group and time by group interactions (p<0.05) for plantarflexor-evertor strength, no significant findings for dorsiflexor-invertor strength, significant side by time interaction (p<0.05) for unilateral balance, significant main effect of time (p<0.05) for triple hop for distance test, and significant main effect of side (p<0.05) for the CAIT. Mann-Whitney U tests showed no significance (p>0.05) for the side hop test or FADI. Conclusion The results suggest that DN of the multifidi in addition to fibularis muscles does not result in improvements in strength, unilateral balance or unilateral hop test performance, compared to DN the fibularis muscles alone among individuals with a history of ankle sprain. PMID:29234555

Random trinomial tree models and vanilla options

NASA Astrophysics Data System (ADS)

Ganikhodjaev, Nasir; Bayram, Kamola

2013-09-01

In this paper we introduce and study random trinomial model. The usual trinomial model is prescribed by triple of numbers (u, d, m). We call the triple (u, d, m) an environment of the trinomial model. A triple (Un, Dn, Mn), where {Un}, {Dn} and {Mn} are the sequences of independent, identically distributed random variables with 0 < Dn < 1 < Un and Mn = 1 for all n, is called a random environment and trinomial tree model with random environment is called random trinomial model. The random trinomial model is considered to produce more accurate results than the random binomial model or usual trinomial model.

Superposition of elliptic functions as solutions for a large number of nonlinear equations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Khare, Avinash; Saxena, Avadh

2014-03-15

For a large number of nonlinear equations, both discrete and continuum, we demonstrate a kind of linear superposition. We show that whenever a nonlinear equation admits solutions in terms of both Jacobi elliptic functions cn(x, m) and dn(x, m) with modulus m, then it also admits solutions in terms of their sum as well as difference. We have checked this in the case of several nonlinear equations such as the nonlinear Schrödinger equation, MKdV, a mixed KdV-MKdV system, a mixed quadratic-cubic nonlinear Schrödinger equation, the Ablowitz-Ladik equation, the saturable nonlinear Schrödinger equation, λϕ{sup 4}, the discrete MKdV as well asmore » for several coupled field equations. Further, for a large number of nonlinear equations, we show that whenever a nonlinear equation admits a periodic solution in terms of dn{sup 2}(x, m), it also admits solutions in terms of dn {sup 2}(x,m)±√(m) cn (x,m) dn (x,m), even though cn(x, m)dn(x, m) is not a solution of these nonlinear equations. Finally, we also obtain superposed solutions of various forms for several coupled nonlinear equations.« less

A comparative profile of methanol extracts of Allium cepa and Allium sativum in diabetic neuropathy in mice

PubMed Central

Bhanot, Abhishek; Shri, Richa

2010-01-01

Introduction: Diabetic Neuropathy (DN) is a major microvascular complication of uncontrolled diabetes. This may result from increased oxidative stress that accompanies diabetes. Hence plants with antioxidant action play an important role in management of diabetes and its complications. Materials and Methods: This study was designed to evaluate preventive as well as curative effect of methanol extracts of outer scales and edible portions of two plants with established antioxidant action - Allium cepa and Allium sativum, in induced DN in albino mice. Mice were divided into control, diabetic and test extracts treated groups. Test extracts were administered daily at a dose of 200 mg/kg p.o. for 21 days, in the preventive group prior to onset of DN, and in the curative group after the onset of DN. Hyperalgesia and oxidative stress markers were assessed. STZ-diabetic mice showed a significant thermal hyperalgesia (as assessed by the tail-flick test), indicating development of DN. Results: Treatment with test extracts prevented loss in body weight, decreased plasma glucose level, and significantly ameliorated the hyperalgesia, TBARS, serum nitrite and GSH levels in diabetic mice. Conclusion: Methanol extract of outer scales of onion has shown most significant improvement; may be due to higher content of phenolic compounds in outer scales of A. cepa. PMID:21713142

Emotional and cognitive stimuli differentially engage the default network during inductive reasoning

PubMed Central

Deckersbach, Thilo; Carlson, Lindsay E.; Beucke, Jan C.; Dougherty, Darin D.

2012-01-01

The brain’s default network (DN) is comprised of several cortical regions demonstrating robust intrinsic connectivity at rest. The authors sought to examine the differential effects of emotional reasoning and reasoning under certainty upon the DN through the employment of an event-related fMRI design in healthy participants. Participants were presented with syllogistic arguments which were organized into a 2 × 2 factorial design in which the first factor was emotional salience and the second factor was certainty/uncertainty. We demonstrate that regions of the DN were activated both during reasoning that is emotionally salient and during reasoning which is more certain, suggesting that these processes are neurally instantiated on a network level. In addition, we present evidence that emotional reasoning preferentially activates the dorsomedial (dMPFC) subsystem of the DN, whereas reasoning in the context of certainty activates areas specific to the DN’s medial temporal (MTL) subsystem. We postulate that emotional reasoning mobilizes the dMPFC subsystem of the DN because this type of reasoning relies upon the recruitment of introspective and self-relevant data such as personal bias and temperament. In contrast, activation of the MTL subsystem during certainty argues that this form of reasoning involves the recruitment of mnemonic and semantic associations to derive conclusions. PMID:21296864

Interactive effects of genotype x environment on the live weight of GIFT Nile tilapias.

PubMed

Oliveira, Sheila N DE; Ribeiro, Ricardo P; Oliveira, Carlos A L DE; Alexandre, Luiz; Oliveira, Aline M S; Lopera-Barrero, Nelson M; Santander, Victor F A; Santana, Renan A C

2017-01-01

In this paper, the existence of a genotype x environment interaction for the average daily weight in GIFT Nile tilapia (Oreochromis niloticus) in different regions in the state of Paraná (Brazil) was analyzed. The heritability results were high in the uni-characteristic analysis: 0.71, 0.72 and 0.67 for the cities of Palotina (PL), Floriano (FL) and Diamond North (DN), respectively. Genetic correlations estimated in bivariate analyzes were weak with values between 0.12 for PL-FL, 0.06 for PL and 0.23 for DN-FL-DN. The Spearman correlation values were low, which indicated a change in ranking in the selection of animals in different environments in the study. There was heterogeneity in the phenotypic variance among the three regions and heterogeneity in the residual variance between PL and DN. The direct genetic gain was greater for the region with a DN value gain of 198.24 g/generation, followed by FL (98.73 g/generation) and finally PL (98.73 g/generation). The indirect genetic gains were lower than 0.37 and greater than 0.02 g/generation. The evidence of the genotype x environment interaction was verified, which indicated the phenotypic heterogeneity of the variances among the three regions, weak genetic correlation and modified rankings in the different environments.

IL-6 signaling in diabetic nephropathy: From pathophysiology to therapeutic perspectives.

PubMed

Feigerlová, Eva; Battaglia-Hsu, Shyue-Fang

2017-10-01

Diabetic nephropathy (DN) is a leading cause of chronic kidney disease (CKD). Interleukin-6 (IL-6) signaling participates in inflammation responses central to the progression of DN. Current evidence suggests that these IL-6 responses are mediated via gp130-STAT3 dependent mechanisms which, on one hand, trigger globally the transition from innate to adaptive immune response, and on the other hand act locally for tissue remodeling and immune cell infiltration. In diabetic conditions the role of IL-6 is not well elucidated. Both IL-6 classical signaling pathway via receptor IL-6R (IL-6R) and IL-6 trans-signaling pathway via soluble IL-6R (sIL-6R) were shown to participate in the pathogenesis and progression of DN, and IL-6 appears to influence renal cells also in an autocrine manner. To date, evidence is limited. The goal of this review is to provide an overview of our current understanding on the role of IL-6 signaling in DN and to delineate challenges for future research. Putative sequential events related to IL-6 secretion by different cell populations in diabetic conditions are outlined. Further, we discuss potential applications of anti-IL-6 therapy in the context of DN. Copyright © 2017 Elsevier Ltd. All rights reserved.

Rogue periodic waves of the modified KdV equation

NASA Astrophysics Data System (ADS)

Chen, Jinbing; Pelinovsky, Dmitry E.

2018-05-01

Rogue periodic waves stand for rogue waves on a periodic background. Two families of travelling periodic waves of the modified Korteweg–de Vries (mKdV) equation in the focusing case are expressed by the Jacobian elliptic functions dn and cn. By using one-fold and two-fold Darboux transformations of the travelling periodic waves, we construct new explicit solutions for the mKdV equation. Since the dn-periodic wave is modulationally stable with respect to long-wave perturbations, the new solution constructed from the dn-periodic wave is a nonlinear superposition of an algebraically decaying soliton and the dn-periodic wave. On the other hand, since the cn-periodic wave is modulationally unstable with respect to long-wave perturbations, the new solution constructed from the cn-periodic wave is a rogue wave on the cn-periodic background, which generalizes the classical rogue wave (the so-called Peregrine’s breather) of the nonlinear Schrödinger equation. We compute the magnification factor for the rogue cn-periodic wave of the mKdV equation and show that it remains constant for all amplitudes. As a by-product of our work, we find explicit expressions for the periodic eigenfunctions of the spectral problem associated with the dn and cn periodic waves of the mKdV equation.

Sialidases affect the host cell adherence and epsilon toxin-induced cytotoxicity of Clostridium perfringens type D strain CN3718.

PubMed

Li, Jihong; Sayeed, Sameera; Robertson, Susan; Chen, Jianming; McClane, Bruce A

2011-12-01

Clostridium perfringens type B or D isolates, which cause enterotoxemias or enteritis in livestock, produce epsilon toxin (ETX). ETX is exceptionally potent, earning it a listing as a CDC class B select toxin. Most C. perfringens strains also express up to three different sialidases, although the possible contributions of those enzymes to type B or D pathogenesis remain unclear. Type D isolate CN3718 was found to carry two genes (nanI and nanJ) encoding secreted sialidases and one gene (nanH) encoding a cytoplasmic sialidase. Construction in CN3718 of single nanI, nanJ and nanH null mutants, as well as a nanI/nanJ double null mutant and a triple sialidase null mutant, identified NanI as the major secreted sialidase of this strain. Pretreating MDCK cells with NanI sialidase, or with culture supernatants of BMC206 (an isogenic CN3718 etx null mutant that still produces sialidases) enhanced the subsequent binding and cytotoxic effects of purified ETX. Complementation of BMC207 (an etx/nanH/nanI/nanJ null mutant) showed this effect is mainly attributable to NanI production. Contact between BMC206 and certain mammalian cells (e.g., enterocyte-like Caco-2 cells) resulted in more rapid sialidase production and this effect involved increased transcription of BMC206 nanI gene. BMC206 was shown to adhere to some (e.g. Caco-2 cells), but not all mammalian cells, and this effect was dependent upon sialidase, particularly NanI, expression. Finally, the sialidase activity of NanI (but not NanJ or NanH) could be enhanced by trypsin. Collectively these in vitro findings suggest that, during type D disease originating in the intestines, trypsin may activate NanI, which (in turn) could contribute to intestinal colonization by C. perfringens type D isolates and also increase ETX action.

Characterization of eight Russian wheat aphid (Hemiptera: Aphididae) biotypes using two-category resistant-susceptible plant responses.

PubMed

Puterka, G J; Nicholson, S J; Brown, M J; Cooper, W R; Peairs, F B; Randolph, T L

2014-06-01

Eight biotypes of the Russian wheat aphid, Diuraphis noxia (Kurdjumov), have been discovered in the United States since 2003. Biotypes are identified by the distinct feeding damage responses they produce on wheat carrying different Russian wheat aphid resistance genes, namely, from Dn1 to Dn9. Each Russian wheat aphid biotype has been named using plant damage criteria and virulence categories that have varied between studies. The study was initiated to compare the plant damage caused by all the eight known Russian wheat aphid biotypes, and analyze the results to determine how Russian wheat aphid virulence should be classified. Each Russian wheat aphid biotype was evaluated on 16 resistant or susceptible cereal genotypes. Plant damage criteria included leaf roll, leaf chlorosis, and plant height. The distribution of chlorosis ratings followed a bimodal pattern indicating two categories of plant responses, resistant or susceptible. Correlations were significant between chlorosis ratings and leaf roll (r(2) = 0.72) and between chlorosis ratings and plant height (r(2) = 0.48). The response of 16 cereal genotypes to feeding by eight Russian wheat aphid biotypes found RWA1, RWA2, RWA6, and RWA8 to differ in virulence, while Russian wheat aphid biotypes RWA3, RWA4, RWA5, and RWA7 produced similar virulence profiles. These biotypes have accordingly been consolidated to what is hereafter referred to as RWA3/7. Our results indicated that the five main biotypes RWA1, RWA2, RWA3/7, RWA6, and RWA8 can be identified using only four wheat genotypes containing Dn3, Dn4, Dn6, and Dn9.

The relationship between urban combined traffic noise and annoyance: an investigation in Dalian, north of China.

PubMed

Di, Guoqing; Liu, Xiaoyi; Lin, Qili; Zheng, Yue; He, Lingjiao

2012-08-15

Several residential areas in Dalian, north of China, were selected to investigate the influence of combined traffic noise pollution on urban residents. The software Cadna/A was used to estimate the day-night equivalent noise level (L(dn)) at 1m from the windows of each building, which were modified according to the actual data. Annoyance has been identified as the most important psychological impact of noise. A face-to-face survey on annoyance was carried out among 1536 local residents between the ages of 15 and 75 years. In this study, the relationship between the percentage of "highly annoyed" persons (%HA) and L(dn) was determined. The L(dn) was measured and identified as railway dominant noise, road traffic dominant noise or road-rail combined traffic noise. We find that when L(dn)>63.5 dB, the %HA due to the road-rail combined traffic noise was significantly higher than that due to the one dominant noise source with the same L(dn). Thus, it is suggested that the planning permission buildings whose L(dn) of road-rail combined traffic noise exceeds 63.5-dB be reviewed more strictly. The relationships between %HA induced by different traffic noise and the distance to transportation artery (s) were analyzed. The results showed that as the distance to transportation artery increased, the %HA due to different traffic noise gradually decreased. Furthermore, the %HA due to the road traffic dominant noise at close range (1 m≤s≤50 m) was lower than that at a more remote location (51 m≤s≤100 m), which might be ascribed to the greater tolerance of the noise by the residents. Copyright © 2012 Elsevier B.V. All rights reserved.

AMP-activated Protein Kinase Mediates Apoptosis in Response to Bioenergetic Stress through Activation of the Pro-apoptotic Bcl-2 Homology Domain-3-only Protein BMF*

PubMed Central

Kilbride, Seán M.; Farrelly, Angela M.; Bonner, Caroline; Ward, Manus W.; Nyhan, Kristine C.; Concannon, Caoimhín G.; Wollheim, Claes B.; Byrne, Maria M.; Prehn, Jochen H. M.

2010-01-01

Heterozygous loss-of-function mutations in the hepatocyte nuclear factor 1A (HNF1A) gene result in the pathogenesis of maturity-onset diabetes-of-the-young type 3, (HNF1A-MODY). This disorder is characterized by a primary defect in metabolism-secretion coupling and decreased beta cell mass, attributed to excessive beta cell apoptosis. Here, we investigated the link between energy stress and apoptosis activation following HNF1A inactivation. This study employed single cell fluorescent microscopy, flow cytometry, gene expression analysis, and gene silencing to study the effects of overexpression of dominant-negative (DN)-HNF1A expression on cellular bioenergetics and apoptosis in INS-1 cells. Induction of DN-HNF1A expression led to reduced ATP levels and diminished the bioenergetic response to glucose. This was coupled with activation of the bioenergetic stress sensor AMP-activated protein kinase (AMPK), which preceded the onset of apoptosis. Pharmacological activation of AMPK using aminoimidazole carboxamide ribonucleotide (AICAR) was sufficient to induce apoptosis in naive cells. Conversely, inhibition of AMPK with compound C or AMPKα gene silencing protected against DN-HNF1A-induced apoptosis. Interestingly, AMPK mediated the induction of the pro-apoptotic Bcl-2 homology domain-3-only protein Bmf (Bcl-2-modifying factor). Bmf expression was also elevated in islets of DN-HNF1A transgenic mice. Furthermore, knockdown of Bmf expression in INS-1 cells using siRNA was sufficient to protect against DN-HNF1A-induced apoptosis. Our study suggests that overexpression of DN-HNF1A induces bioenergetic stress and activation of AMPK. This in turn mediates the transcriptional activation of the pro-apoptotic Bcl-2-homology protein BMF, coupling prolonged energy stress to apoptosis activation. PMID:20841353

Angiotensin II initiates tyrosine kinase Pyk2-dependent signalings leading to activation of Rac1-mediated c-Jun NH2-terminal kinase.

PubMed

Murasawa, S; Matsubara, H; Mori, Y; Masaki, H; Tsutsumi, Y; Shibasaki, Y; Kitabayashi, I; Tanaka, Y; Fujiyama, S; Koyama, Y; Fujiyama, A; Iba, S; Iwasaka, T

2000-09-01

Ca(2+)-sensitive tyrosine kinase Pyk2 was shown to be involved in angiotensin (Ang) II-mediated activation of extracellular signal-regulated kinase (ERK) via transactivation of epidermal growth factor receptor (EGF-R). In this study, we tested the involvement of Pyk2 and EGF-R in Ang II-induced activation of JNK and c-Jun in cardiac fibroblasts. Ang II markedly stimulated JNK activities, which were abolished by genistein and intracellular Ca(2+) chelators but partially by protein kinase C depletion. Inhibition of EGF-R did not affect Pyk2 and JNK activation by Ang II. Stable transfection with a dominant negative (DN) mutant for Pyk2 (PKM) completely blocked JNK activation by Ang II. DN mutants of Rac1 (DN-Rac1) and MEK kinase (DN-MEKK1) also abolished it, whereas those of Cdc42, RhoA, and Ha-Ras had no effect. Induction of c-Jun gene transcription by Ang II was abolished in PKM, DN-Rac1, and DN-MEKK1, in which Ang II-induced binding of ATF2/c-Jun heterodimer to the activator protein-1 sequence at -190 played a key role. These results suggest that 1) in cardiac fibroblasts activation of JNK and c-Jun by Ang II is initiated by Pyk2-dependent signalings but not by downstream signals of EGF-R or Ras, 2) Rac1 but not Cdc42 is required for JNK activation by Ang II upstream of MEKK1, and 3) ATF-2/c-Jun binding to the activator protein-1 sequence at -190 plays a key role for induction of c-Jun gene by Ang II.

Maternal choline supplementation differentially alters the basal forebrain cholinergic system of young-adult Ts65Dn and disomic mice.

PubMed

Kelley, Christy M; Powers, Brian E; Velazquez, Ramon; Ash, Jessica A; Ginsberg, Stephen D; Strupp, Barbara J; Mufson, Elliott J

2014-04-15

Down syndrome (DS), trisomy 21, is a multifaceted condition marked by intellectual disability and early presentation of Alzheimer's disease (AD) neuropathological lesions including degeneration of the basal forebrain cholinergic neuron (BFCN) system. Although DS is diagnosable during gestation, there is no treatment option for expectant mothers or DS individuals. Using the Ts65Dn mouse model of DS that displays age-related degeneration of the BFCN system, we investigated the effects of maternal choline supplementation on the BFCN system in adult Ts65Dn mice and disomic (2N) littermates at 4.3-7.5 months of age. Ts65Dn dams were maintained on a choline-supplemented diet (5.1 g/kg choline chloride) or a control, unsupplemented diet with adequate amounts of choline (1 g/kg choline chloride) from conception until weaning of offspring; post weaning, offspring were fed the control diet. Mice were transcardially perfused with paraformaldehyde, and brains were sectioned and immunolabeled for choline acetyltransferase (ChAT) or p75-neurotrophin receptor (p75(NTR) ). BFCN number and size, the area of the regions, and the intensity of hippocampal labeling were determined. Ts65Dn-unsupplemented mice displayed region- and immunolabel-dependent increased BFCN number, larger areas, smaller BFCNs, and overall increased hippocampal ChAT intensity compared with 2N unsupplemented mice. These effects were partially normalized by maternal choline supplementation. Taken together, the results suggest a developmental imbalance in the Ts65Dn BFCN system. Early maternal-diet choline supplementation attenuates some of the genotype-dependent alterations in the BFCN system, suggesting this naturally occurring nutrient as a treatment option for pregnant mothers with knowledge that their offspring is trisomy 21. Copyright © 2013 Wiley Periodicals, Inc.

Neuroscience education in addition to trigger point dry needling for the management of patients with mechanical chronic low back pain: A preliminary clinical trial.

PubMed

Téllez-García, Mario; de-la-Llave-Rincón, Ana I; Salom-Moreno, Jaime; Palacios-Ceña, Maria; Ortega-Santiago, Ricardo; Fernández-de-Las-Peñas, César

2015-07-01

The objective of the current study was to determine the short-term effects of trigger point dry needling (TrP-DN) alone or combined with neuroscience education on pain, disability, kinesiophobia and widespread pressure sensitivity in patients with mechanical low back pain (LBP). Twelve patients with LBP were randomly assigned to receive either TrP-DN (TrP-DN) or TrP-DN plus neuroscience education (TrP-DN + EDU). Pain intensity (Numerical Pain Rating Scale, 0-10), disability (Roland-Morris Disability Questionnaire-RMQ-, Oswestry Low Back Pain Disability Index-ODI), kinesiophobia (Tampa Scale of Kinesiophobia-TSK), and pressure pain thresholds (PPT) over the C5-C6 zygapophyseal joint, transverse process of L3 vertebra, second metacarpal, and tibialis anterior muscle were collected at baseline and 1-week after the intervention. Patients treated with TrP-DN + EDU experienced a significantly greater reduction of kinesiophobia (P = 0.008) and greater increases in PPT over the transverse process of L3 (P = 0.049) than those patients treated only with TrP-DN. Both groups experienced similar decreases in pain, ODI and RMQ, and similar increases in PPT over the C5/C6 joint, second metacarpal, and tibialis anterior after the intervention (all, P > 0.05). The results suggest that TrP-DN was effective for improving pain, disability, kinesiophobia and widespread pressure sensitivity in patients with mechanical LBP at short-term. The inclusion of a neuroscience educational program resulted in a greater improvement in kinesiophobia. Copyright © 2014 Elsevier Ltd. All rights reserved.

Formoterol, a long-acting β2 adrenergic agonist, improves cognitive function and promotes dendritic complexity in a mouse model of Down syndrome.

PubMed

Dang, Van; Medina, Brian; Das, Devsmita; Moghadam, Sarah; Martin, Kara J; Lin, Bill; Naik, Priyanka; Patel, Devan; Nosheny, Rachel; Wesson Ashford, John; Salehi, Ahmad

2014-02-01

Down syndrome is associated with significant failure in cognitive function. Our previous investigation revealed age-dependent degeneration of locus coeruleus, a major player in contextual learning, in the Ts65Dn mouse model of Down syndrome. We studied whether drugs already available for use in humans can be used to improve cognitive function in these mice. We studied the status of β adrenergic signaling in the dentate gyrus of the Ts65Dn mouse model of Down syndrome. Furthermore, we used fear conditioning to study learning and memory in these mice. Postmortem analyses included the analysis of synaptic density, dendritic arborization, and neurogenesis. We found significant atrophy of dentate gyrus and failure of β adrenergic signaling in the hippocampus of Ts65Dn mice. Our behavioral analyses revealed that formoterol, a long-acting β2 adrenergic receptor agonist, caused significant improvement in the cognitive function in Ts65Dn mice. Postmortem analyses revealed that the use of formoterol was associated with a significant improvement in the synaptic density and increased complexity of newly born dentate granule neurons in the hippocampus of Ts65Dn mice. Our data suggest that targeting β2 adrenergic receptors is an effective strategy for restoring synaptic plasticity and cognitive function in these mice. Considering its widespread use in humans and positive effects on cognition in Ts65Dn mice, formoterol or similar β2 adrenergic receptor agonists with ability to cross the blood brain barrier might be attractive candidates for clinical trials to improve cognitive function in individuals with Down syndrome. Published by Elsevier Inc.

A noradrenergic lesion exacerbates neurodegeneration in a Down syndrome mouse model.

PubMed

Lockrow, Jason; Boger, Heather; Gerhardt, Greg; Aston-Jones, Gary; Bachman, David; Granholm, Ann-Charlotte

2011-01-01

Individuals with Down syndrome (DS) acquire Alzheimer's-like dementia (AD) and associated neuropathology earlier and at significantly greater rates than age-matched normosomic individuals. However, biological mechanisms have not been discovered and there is currently limited therapy for either DS- or AD-related dementia. Segmental trisomy 16 (Ts65Dn) mice provide a useful model for many of the degenerative changes which occur with age in DS including cognitive deficits, neuroinflammation, and degeneration of basal forebrain cholinergic neurons. Loss of noradrenergic locus coeruleus (LC) neurons is an early event in AD and in DS, and may contribute to the neuropathology. We report that Ts65Dn mice exhibit progressive loss of norepinephrine (NE) phenotype in LC neurons. In order to determine whether LC degeneration contributes to memory loss and neurodegeneration in Ts65Dn mice, we administered the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4; 2 doses of 50 mg/kg, i.p.) to Ts65Dn mice at four months of age, prior to working memory loss. At eight months of age, Ts65Dn mice treated with DSP-4 exhibited an 80% reduction in hippocampal NE, coupled with a marked increase in hippocampal neuroinflammation. Noradrenergic depletion also resulted in accelerated cholinergic neuron degeneration and a further impairment of memory function in Ts65Dn mice. In contrast, DSP-4 had minimal effects on normosomic littermates, suggesting a disease-modulated vulnerability to NE loss in the DS mouse model. These data suggest that noradrenergic degeneration may play a role in the progressive memory loss, neuroinflammation, and cholinergic loss occurring in DS individuals, providing a possible therapeutic avenue for future clinical studies.

Inhibition of MCU forces extramitochondrial adaptations governing physiological and pathological stress responses in heart

PubMed Central

Rasmussen, Tyler P.; Wu, Yuejin; Joiner, Mei-ling A.; Koval, Olha M.; Wilson, Nicholas R.; Luczak, Elizabeth D.; Wang, Qinchuan; Chen, Biyi; Gao, Zhan; Zhu, Zhiyong; Wagner, Brett A.; Soto, Jamie; McCormick, Michael L.; Kutschke, William; Weiss, Robert M.; Yu, Liping; Boudreau, Ryan L.; Abel, E. Dale; Zhan, Fenghuang; Spitz, Douglas R.; Buettner, Garry R.; Song, Long-Sheng; Zingman, Leonid V.; Anderson, Mark E.

2015-01-01

Myocardial mitochondrial Ca2+ entry enables physiological stress responses but in excess promotes injury and death. However, tissue-specific in vivo systems for testing the role of mitochondrial Ca2+ are lacking. We developed a mouse model with myocardial delimited transgenic expression of a dominant negative (DN) form of the mitochondrial Ca2+ uniporter (MCU). DN-MCU mice lack MCU-mediated mitochondrial Ca2+ entry in myocardium, but, surprisingly, isolated perfused hearts exhibited higher O2 consumption rates (OCR) and impaired pacing induced mechanical performance compared with wild-type (WT) littermate controls. In contrast, OCR in DN-MCU–permeabilized myocardial fibers or isolated mitochondria in low Ca2+ were not increased compared with WT, suggesting that DN-MCU expression increased OCR by enhanced energetic demands related to extramitochondrial Ca2+ homeostasis. Consistent with this, we found that DN-MCU ventricular cardiomyocytes exhibited elevated cytoplasmic [Ca2+] that was partially reversed by ATP dialysis, suggesting that metabolic defects arising from loss of MCU function impaired physiological intracellular Ca2+ homeostasis. Mitochondrial Ca2+ overload is thought to dissipate the inner mitochondrial membrane potential (ΔΨm) and enhance formation of reactive oxygen species (ROS) as a consequence of ischemia-reperfusion injury. Our data show that DN-MCU hearts had preserved ΔΨm and reduced ROS during ischemia reperfusion but were not protected from myocardial death compared with WT. Taken together, our findings show that chronic myocardial MCU inhibition leads to previously unanticipated compensatory changes that affect cytoplasmic Ca2+ homeostasis, reprogram transcription, increase OCR, reduce performance, and prevent anticipated therapeutic responses to ischemia-reperfusion injury. PMID:26153425

Phloretin either alone or in combination with duloxetine alleviates the STZ-induced diabetic neuropathy in rats.

PubMed

Balaha, Mohamed; Kandeel, Samah; Kabel, Ahmed

2018-05-01

Diabetic neuropathy (DN) is one of most disabling disorder complicating diabetes mellites (DM), which affects more than 50% of the all diabetic patients during the disease course. Duloxetine (DX) is one of the first-line medication that approved by FDA for management of DN, nevertheless, it is too costly and has many adverse effects. Recently, phloretin (PH) exhibited powerful euglycemic, antihyperlipidemic, antioxidant, and anti-inflammatory activities. Therefore, we investigated the in vivo possible antineuropathic activity of phloretin, besides, its modulating effects on duloxetine potency, in a rat model of DN. Twelve-week-old male Wistar rats received a single intraperitoneal injection of 55 mg/kg STZ to induce DM. Either DX (30 or 15 mg/kg dissolved in distilled water), PH (50 0r 25 mg/kg dissolved in 0.5% DMSO) or a combination of 15 mg/kg DX and 25 mg/kg PH, used daily orally for 4 weeks to treat DN, starting from the end of the 4 th week of DM development, when DN confirmed. Our finding showed that both DX and PH dose-dependently improved behavioral parameters (with the superiority of DX), sciatic nerve tissue antioxidant state, and suppressed tissue inflammatory cytokine, besides, they abrogated the tissue histopathological changes (with the superiority of PH). Moreover, DX augmented the DM metabolic disturbance and hepatic dysfunction, however, PH effectively amended these disorders. Furthermore, the low-dose combination of both, had the merits of both medications, with the alleviation of their disadvantages. Therefore, phloretin could be a promising agent in the management of DN either alone or in combination with duloxetine. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

High glucose induces podocyte epithelial-to-mesenchymal transition by demethylation-mediated enhancement of MMP9 expression

PubMed Central

Ling, Li; Chen, Libo; Zhang, Changning; Gui, Shuyan; Zhao, Haiyan; Li, Zhengzhang

2018-01-01

Abnormal expression of matrix metalloproteinase 9 (MMP9) is correlated with podocyte epithelial-to-mesenchymal transition (EMT) in diabetic nephropathy (DN). However, the mechanisms underlying this process are not well defined. Site-specific demethylation may sustain high expression levels of target genes. In the present study, in order to investigate the association between DNA demethylation of MMP9 promoter and podocyte EMT in DN, human podocytes were cultured in high-glucose (HG) medium and a rat model of DN was established by intraperitoneal injection of streptozotocin (STZ) to determine whether site-specific demethylation of the MMP9 promoter was involved in regulating podocyte EMT in DN. The MTT assay was used to assess the effects of HG culture on the growth of podocytes, and the demethylation status of the MMP9 promoter was assessed by bisulfite sequencing polymerase chain reaction. mRNA and protein expression levels of MMP9, α-smooth muscle actin (α-SMA), podocalyxin and fibronectin-1 in podocytes were assessed by reverse transcription-quantitative PCR (RT-qPCR) and western blot analyses. The results demonstrated that HG treatment up regulated the expression of MMP9, α-SMA and fibronectin-1, but down regulated the expression of podocalyxin in podocytes. The MMP9 promoter region was revealed to contain a variety of demethylated CpG sites, and HG treatment reduced the rate of MMP9 promotermethylation, which, in turn, enhanced its promoter activity. In summary, these data suggested that demethylation of the MMP9 promoter may serve an important role in podocyte EMT in DN. The demethylation status of the MMP9 promoter maybe used as an important prognostic marker of DN in clinic. PMID:29436620

The influence of light on temperature preference in Drosophila

PubMed Central

Head, Lauren M.; Tang, Xin; Hayley, Sean E.; Goda, Tadahiro; Umezaki, Yujiro; Chang, Elaine C.; Leslie, Jennifer R.; Fujiwara, Mana; Garrity, Paul A.; Hamada, Fumika N.

2015-01-01

Ambient light affects multiple physiological functions and behaviors, such as circadian rhythms, sleep-wake activities, and development from flies to mammals [1–6]. Mammals exhibit a higher body temperature when exposed to acute light compared to when they are exposed to dark, but the underlying mechanisms are largely unknown [7–10]. The body temperature of small ecotherms, such as Drosophila, rely on the temperature of their surrounding environment and these animals exhibit a robust temperature preference behavior [11–13]. Here, we demonstrate that Drosophila prefer a one-degree higher temperature when exposed to acute light rather than dark. This acute light response, light dependent temperature preference (LDTP), was observed regardless of the time of day, suggesting that LDTP is regulated separately from the circadian clock. However, screening of eye and circadian clock mutants suggests that the circadian clock neurons, posterior dorsal neurons 1 (DN1ps) and pigment-dispersing factor receptor (pdfr) play a role in LDTP. To further investigate the role of DN1ps in LDTP, pdfr in DN1ps was knocked down, resulting in an abnormal LDTP. The phenotype of the pdfr mutant was sufficiently rescued by expressing pdfr in DN1ps, indicating that pdfr expression in DN1ps is responsible for LDTP. These results suggest that light positively influences temperature preference via the circadian clock neurons, DN1ps, which may result from the integration of light and temperature information. Given that both Drosophila and mammals respond to acute light by increasing their body temperature, the effect of acute light on temperature regulation may be conserved evolutionarily between flies and humans. PMID:25866391

Delay activity of saccade-related neurons in the caudal dentate nucleus of the macaque cerebellum

PubMed Central

Sommer, Marc A.

2013-01-01

The caudal dentate nucleus (DN) in lateral cerebellum is connected with two visual/oculomotor areas of the cerebrum: the frontal eye field and lateral intraparietal cortex. Many neurons in frontal eye field and lateral intraparietal cortex produce “delay activity” between stimulus and response that correlates with processes such as motor planning. Our hypothesis was that caudal DN neurons would have prominent delay activity as well. From lesion studies, we predicted that this activity would be related to self-timing, i.e., the triggering of saccades based on the internal monitoring of time. We recorded from neurons in the caudal DN of monkeys (Macaca mulatta) that made delayed saccades with or without a self-timing requirement. Most (84%) of the caudal DN neurons had delay activity. These neurons conveyed at least three types of information. First, their activity was often correlated, trial by trial, with saccade initiation. Correlations were found more frequently in a task that required self-timing of saccades (53% of neurons) than in a task that did not (27% of neurons). Second, the delay activity was often tuned for saccade direction (in 65% of neurons). This tuning emerged continuously during a trial. Third, the time course of delay activity associated with self-timed saccades differed significantly from that associated with visually guided saccades (in 71% of neurons). A minority of neurons had sensory-related activity. None had presaccadic bursts, in contrast to DN neurons recorded more rostrally. We conclude that caudal DN neurons convey saccade-related delay activity that may contribute to the motor preparation of when and where to move. PMID:23365182

Trichloroethylene Exposure Reduces Liver Injury in a Mouse Model of Primary Biliary Cholangitis

PubMed Central

Ray, Jessica L.; Kopec, Anna K.; Joshi, Nikita; Cline-Fedewa, Holly; Lash, Lawrence H.; Williams, Kurt J.; Leung, Patrick S.; Gershwin, M. Eric

2017-01-01

Abstract Trichloroethylene (TCE) is a persistent environmental contaminant proposed to contribute to autoimmune disease. Experimental studies in lupus-prone MRL+/+ mice have suggested that TCE exposure can trigger autoimmune hepatitis. The vast majority of studies examining the connection between TCE and autoimmunity utilize this model, and the impact of TCE exposure in other established models of autoimmune liver disease is not known. We tested the hypothesis that TCE exposure exacerbates experimental hepatic autoimmunity in dominant negative transforming growth factor beta receptor type II (dnTGFBRII) mice, which develop serological and histological features resembling human primary biliary cholangitis. Female 8-week-old wild-type and dnTGFBRII mice were exposed to TCE (0.5 mg/ml) or vehicle (1% ethoxylated castor oil) in the drinking water for 12 or 22 weeks. Liver histopathology in 20- and 30-week-old wild-type mice was unremarkable irrespective of treatment. Mild portal inflammation was observed in vehicle-exposed 20-week-old dnTGFBRII mice and was not exacerbated by TCE exposure. Vehicle-exposed 30-week-old dnTGFBRII mice developed anti-mitochondrial antibodies, marked hepatic inflammation with necrosis, and hepatic accumulation of both B and T lymphocytes. To our surprise, TCE exposure dramatically reduced hepatic parenchymal inflammation and injury in 30-week-old dnTGFBRII mice, reflected by changes in hepatic proinflammatory gene expression, serum chemistry, and histopathology. Interestingly, TCE did not affect hepatic B cell accumulation or induction of the anti-inflammatory cytokine IL10. These data indicate that TCE exposure reduces autoimmune liver injury in female dnTGFBRII mice and suggests that the precise effect of environmental chemicals in autoimmunity depends on the experimental model. PMID:28115651

Renoprotective effects of berberine and its potential effect on the expression of β-arrestins and intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in streptozocin-diabetic nephropathy rats.

PubMed

Tang, Li-Qin; Ni, Wei-Jian; Cai, Ming; Ding, Hai-Hua; Liu, Sheng; Zhang, Shan-Tang

2016-09-01

Berberine has been shown to exert protective effects against diabetic nephropathy (DN), but the mechanisms involved have not been fully characterized. The aim of the present study was to explore the effects of berberine on the expression of β-arrestins, intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in DN rat kidneys and investigate the underlying molecular mechanisms. To create the DN model, rats fed a high-fat and high-glucose diet were injected with a single dose of streptozotocin (35 mg/kg, i.p.). Then, DN rats were either treated or not with berberine (50, 100, 200 mg/kg per day, i.g., 8 weeks). Periodic acid-Schiff staining was used to evaluate renal histopathological changes. Renal tissue levels of β-arrestin 1 and β-arrestin 2 were determined by Western blot analysis, whereas immunohistochemistry was used to determine renal ICAM-1 and VCAM-1 levels. Berberine (100, 200 mg/kg) ameliorated the histopathological changes in the diabetic kidney. Western blot analysis revealed significant increases in ICAM-1 and VCAM-1 levels in the kidneys of DN rats, which were reversed by treatment with 100 and 200 mg/kg berberine. In addition, berberine treatment (50, 100, 200 mg/kg) increased diabetic-induced decreases in β-arrestin 1 and β-arrestin 2. Berberine exhibited renoprotective effects in DN rats. The underlying molecular mechanisms may be associated with changes in the levels and regulation of β-arrestin expression, as well as ICAM-1 and VCAM-1 levels in the rat kidney. © 2015 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.

Intramuscular nerve damage in lacerated skeletal muscles may direct the inflammatory cytokine response during recovery.

PubMed

Pereira, Barry P; Tan, Bee Leng; Han, Hwan Chour; Zou, Yu; Aung, Khin Zarchi; Leong, David T

2012-07-01

The expression of inflammatory cytokines and growth factors in surgically repaired lacerated muscles over a 12-week recovery phase was investigated. We hypothesized that these expression levels are influenced by both neural and muscular damage within lacerated muscles. Microarrays were confirmed with reverse transcription-polymerase chain reaction assays and histology of biopsies at the lesion of three simulated lacerated muscle models in 130 adult rats. The lacerated medial gastrocnemius with the main intramuscular nerve branch either cut (DN), crushed but leaving an intact nerve sheath (RN); or preserved intact (PN) were compared. At 4 weeks, DN had a higher number of interleukins up-regulated. DN and RN also had a set of Bmp genes significantly expressed between 2 and 8 weeks (P ≤ 0.05). By 12 weeks, DN had a poorer and slower myogenic recovery and greater fibrosis formation correlating with an up-regulation of the Tgf-β gene family. DN also showed poorer re-innervation with higher mRNA expression levels of nerve growth factor (Ngf) and brain-derived neurotrophin growth factor (Bdnf) over RN and PN. This study demonstrates that the inflammatory response over 12 weeks in lacerated muscles may be directed by the type of intramuscular nerve damage, which can influence the recovery at the lesion site. Inflammatory-related genes associated to the type of intramuscular nerve damage include Gas-6, Artemin, Fgf10, Gdf8, Cntf, Lif, and Igf-2. qPCR also found up-regulation of Bdnf (1-week), neurotrophin-3 (2w), Lif (4w), and Ngf (4w, 8w) mRNA expressions in DN, making them possible candidates for therapeutic treatment to arrest the poor recovery in muscle lacerations (250). Copyright © 2012 Wiley Periodicals, Inc.

Mismatch repair proteins and AID deaminase activity are required for the dominant negative function of C terminally-deleted AID in class switching

PubMed Central

Ucher, Anna J.; Ranjit, Sanjay; Kadungure, Tatenda; Linehan, Erin K.; Khair, Lyne; Xie, Elaine; Limauro, Jennifer; Rauch, Katherina S.; Schrader, Carol E.; Stavnezer, Janet

2014-01-01

Activation-induced cytidine deaminase (AID) is essential for class switch recombination (CSR) and somatic hypermutation (SHM) of Ig genes. The AID C terminus is required for CSR but not for S region DNA DSBs during CSR, and it is not required for SHM. AID lacking the C terminus (ΔAID) is a dominant negative (DN) mutant, as human patients heterozygous for this mutant fail to undergo CSR. In agreement, we show that ΔAID is a DN mutant when expressed in AID-sufficient mouse splenic B cells. In order to have DN function,ΔAID must have deaminase activity, suggesting that its ability to induce DSBs is important for the DN function. Supporting this hypothesis, Msh2-Msh6 have previously been shown to contribute to DSB formation in S regions, and here we find that Msh2 is required for the DN activity, as ΔAID is not a DN mutant in msh2−/− cells. Our results suggest that the DNA DSBs induced by ΔAID are unable to participate in CSR, and might interfere with the ability of full-length AID to participate in CSR. We propose thatΔAID is impaired in its ability to recruit non-homologous end joining (NHEJ) repair factors, resulting in accumulation of DSBs that undergo aberrant resection. Supporting this hypothesis, we find that the S-S junctions induced by ΔAID have longer microhomologies than those induced by full-length AID. In addition, our data suggest that AID binds Sµ regions in vivo as a monomer. PMID:24973444

Urinary Liver-Type Fatty Acid–Binding Protein and Progression of Diabetic Nephropathy in Type 1 Diabetes

PubMed Central

Panduru, Nicolae M.; Forsblom, Carol; Saraheimo, Markku; Thorn, Lena; Bierhaus, Angelika; Humpert, Per M.; Groop, Per-Henrik

2013-01-01

OBJECTIVE Diabetic nephropathy (DN) has mainly been considered a glomerular disease, although tubular dysfunction may also play a role. This study assessed the predictive value for progression of a tubular marker, urinary liver-type fatty acid–binding protein (L-FABP), at all stages of DN. RESEARCH DESIGN AND METHODS At baseline, 1,549 patients with type 1 diabetes had an albumin excretion rate (AER) within normal reference ranges, 334 had microalbuminuria, and 363 had macroalbuminuria. Patients were monitored for a median of 5.8 years (95% CI 5.7–5.9). In addition, 208 nondiabetic subjects were studied. L-FABP was measured by ELISA and normalized with urinary creatinine. Different Cox proportional hazard models for the progression at every stage of DN were used to evaluate the predictive value of L-FABP. The potential benefit of using L-FABP alone or together with AER was assessed by receiver operating characteristic curve analyses. RESULTS L-FABP was an independent predictor of progression at all stages of DN. As would be expected, receiver operating characteristic curves for the prediction of progression were significantly larger for AER than for L-FABP, except for patients with baseline macroalbuminuria, in whom the areas were similar. Adding L-FABP to AER in the models did not significantly improve risk prediction of progression in favor of the combination of L-FABP plus AER compared with AER alone. CONCLUSIONS L-FABP is an independent predictor of progression of DN irrespective of disease stage. L-FABP used alone or together with AER may not improve the risk prediction of DN progression in patients with type 1 diabetes, but further studies are needed in this regard. PMID:23378622

Maternal choline supplementation differentially alters the basal forebrain cholinergic system of young-adult Ts65Dn and disomic mice

PubMed Central

Kelley, Christy M.; Powers, Brian E.; Velazquez, Ramon; Ash, Jessica A.; Ginsberg, Stephen D.; Strupp, Barbara J.; Mufson, Elliott J.

2014-01-01

Down syndrome (DS), trisomy 21, is a multifaceted condition marked by intellectual disability and early presentation of Alzheimer’s disease (AD) neuropathological lesions including degeneration of the basal forebrain cholinergic neuron (BFCN) system. While DS is diagnosable during gestation, there is no treatment option for expectant mothers or DS individuals. Using the Ts65Dn mouse model of DS that displays age-related degeneration of the BFCN system, we investigated the effects of maternal choline supplementation on the BFCN system in adult Ts65Dn mice and disomic (2N) littermates at 4.3–7.5 mos of age. Ts65Dn dams were maintained on a choline supplemented diet (5.1 g/kg choline chloride) or a control, unsupplemented diet with adequate amounts of choline (1 g/kg choline chloride) from conception until weaning of offspring; postweaning, offspring were fed the control diet. Mice were transcardially perfused with paraformaldehyde, brains were sectioned, and immunolabeled for choline acetyltransferase (ChAT) or p75-neurotrophin receptor (p75NTR). BFCN number and size, the area of the regions, and the intensity of hippocampal labeling were determined. Ts65Dn unsupplemented mice displayed region- and immunolabel-dependent increased BFCN number, larger areas, smaller BFCNs, and overall increased hippocampal ChAT intensity compared with 2N unsupplemented mice. These effects were partially normalized by maternal choline supplementation. Taken together, the results suggest a developmental imbalance in the Ts65Dn BFCN system. Early maternal-diet choline supplementation attenuates some of the genotype-dependent alterations in the BFCN system, suggesting this naturally occurring nutrient as a treatment option for pregnant mothers with knowledge that their offspring is trisomy 21. PMID:24178831

A Noradrenergic Lesion Exacerbates Neurodegeneration in a Down Syndrome Mouse Model

PubMed Central

Lockrow, Jason; Boger, Heather; Gerhardt, Greg; Aston-Jones, Gary; Bachman, David; Granholm, Ann-Charlotte

2012-01-01

Individuals with Down syndrome (DS) acquire Alzheimer’s-like dementia (AD) and associated neuropathology earlier and at significantly greater rates than age-matched normosomic individuals. However, biological mechanisms have not been discovered and there is currently limited therapy for either DS- or AD-related dementia. Segmental trisomy 16 (Ts65Dn) mice provide a useful model for many of the degenerative changes which occur with age in DS including cognitive deficits, neuroinflammation, and degeneration of basal forebrain cholinergic neurons. Loss of noradrenergic locus coeruleus (LC) neurons is an early event in AD and in DS, and may contribute to the neuropathology. We report that Ts65Dn mice exhibit progressive loss of norepinephrine (NE) phenotype in LC neurons. In order to determine whether LC degeneration contributes to memory loss and neurodegeneration in Ts65Dn mice, we administered the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4; 2 doses of 50 mg/kg, i.p.) to Ts65Dn mice at four months of age, prior to working memory loss. At eight months of age, Ts65Dn mice treated with DSP-4 exhibited an 80% reduction in hippocampal NE, coupled with a marked increase in hippocampal neuroinflammation. Noradrenergic depletion also resulted in accelerated cholinergic neuron degeneration and a further impairment of memory function in Ts65Dn mice. In contrast, DSP-4 had minimal effects on normosomic littermates, suggesting a disease-modulated vulnerability to NE loss in the DS mouse model. These data suggest that noradrenergic degeneration may play a role in the progressive memory loss, neuroinflammation, and cholinergic loss occurring in DS individuals, providing a possible therapeutic avenue for future clinical studies. PMID:21098982

Electrical silencing of PDF neurons advances the phase of non-PDF clock neurons in Drosophila.

PubMed

Wu, Ying; Cao, Guan; Nitabach, Michael N

2008-04-01

Drosophila clock neurons exhibit self-sustaining cellular oscillations that rely in part on rhythmic transcriptional feedback loops. We have previously determined that electrical silencing of the pigment dispersing factor (PDF)-expressing lateral-ventral (LN(V)) pacemaker subset of fly clock neurons via expression of an inward-rectifier K(+) channel (Kir2.1) severely disrupts free-running rhythms of locomotor activity-most flies are arrhythmic and those that are not exhibit weak short-period rhythms-and abolishes LN(V) molecular oscillation in constant darkness. PDF is known to be an important LN(V) output signal. Here we examine the effects of electrical silencing of the LN(V) pacemakers on molecular rhythms in other, nonsilenced, subsets of clock neurons. In contrast to previously described cell-autonomous abolition of free-running molecular rhythms, we find that electrical silencing of the LN(V) pacemakers via Kir2.1 expression does not impair molecular rhythms in LN(D), DN1, and DN2 subsets of clock neurons. However, free-running molecular rhythms in these non-LN(V) clock neurons occur with advanced phase. Electrical silencing of LN(V)s phenocopies PDF null mutation (pdf (01) ) at both behavioral and molecular levels except for the complete abolition of free-running cellular oscillation in the LN(V)s themselves. LN(V) electrically silenced or pdf 01 flies exhibit weak free-running behavioral rhythms with short period, and the molecular oscillation in non-LN(V) neurons phase advances in constant darkness. That LN( V) electrical silencing leads to the same behavioral and non-LN( V) molecular phenotypes as pdf 01 suggests that persistence of LN(V) molecular oscillation in pdf 01 flies has no functional effect, either on behavioral rhythms or on non-LN(V) molecular rhythms. We thus conclude that functionally relevant signals from LN(V)s to non-LN(V) clock neurons and other downstream targets rely both on PDF signaling and LN(V) electrical activity, and that LN( V)s do not ordinarily send functionally relevant signals via PDF-independent mechanisms.

The neurophysiological effects of dry needling in patients with upper trapezius myofascial trigger points: study protocol of a controlled clinical trial

PubMed Central

Abbaszadeh-Amirdehi, Maryam; Ansari, Noureddin Nakhostin; Naghdi, Soofia; Olyaei, Gholamreza; Nourbakhsh, Mohammad Reza

2013-01-01

Introduction Dry needling (DN) is an effective method for the treatment of myofascial trigger points (MTrPs). There is no report on the neurophysiological effects of DN in patients with MTrPs. The aim of the present study will be to assess the immediate neurophysiological efficacy of deep DN in patients with upper trapezius MTrPs. Methods and analysis A prospective, controlled clinical trial was designed to include patients with upper trapezius MTrPs and volunteered healthy participants to receive one session of DN. The primary outcome measures are neuromuscular junction response and sympathetic skin response. The secondary outcomes are pain intensity and pressure pain threshold. Data will be collected at baseline and immediately after intervention. Ethics and dissemination This study protocol has been approved by the Research Council, School of Rehabilitation and the Ethics Committee of Tehran University of Medical Sciences. The results of the study will be disseminated in a peer-reviewed journal and presented at international congresses. PMID:23793673

Diabetic nephropathy among Mexican Americans.

PubMed

Debnath, Subrata; Thameem, Farook; Alves, Tahira; Nolen, Jacqueline; Al-Shahrouri, Hania; Bansal, Shweta; Abboud, Hanna E; Fanti, Paolo

2012-04-01

The incidence of diabetic nephropathy (DN) is growing rapidly worldwide as a consequence of the rising prevalence of Type 2 diabetes mellitus (T2DM). Among U.S. ethnic groups, Mexican Americans have a disproportionately high incidence and prevalence of DN and associated end-stage renal disease (ESRD). In communities bordering Mexico, as many as 90% of Mexican American patients with ESRD also suffer from T2DM compared to only 50% of non-Hispanic Whites (NHW). Both socio-economic factors and genetic predisposition appear to have a strong influence on this association. In addition, certain pathogenetic and clinical features of T2DM and DN are different in Mexican Americans compared to NHW, raising questions as to whether the diagnostic and treatment strategies that are standard practice in the NHW patient population may not be applicable in Mexican Americans. This article reviews the epidemiology of DN in Mexican Americans, describes the pathophysiology and associated risk factors, and identifies gaps in our knowledge and understanding that needs to be addressed by future investigations.

Parametric study of the lubrication of thrust loaded 120-mm bore ball bearings to 3 million DN

NASA Technical Reports Server (NTRS)

Signer, H.; Bamberger, E. N.; Zaretsky, E. V.

1973-01-01

A parametric study was performed with 120-mm bore angular-contact ball bearings under varying thrust loads, bearing and lubricant temperatures, and cooling and lubricant flow rates. Contact angles were nominally 20 and 24 deg with bearing speeds to 3 million DN. Endurance tests were run at 3 million DN and a temperature of 492 K (425 F) with 10 bearings having a nominal 24 deg contact angle at a thrust load of 22241 N (5000 lb). Bearing operating temperature, differences in temperatures between the inner and outer races, and bearing power consumption can be tuned to any desirable operating requirement by varying 4 parameters. These parameters are outer-race cooling, inner-race cooling, lubricant flow to the inner race, and oil inlet temperature. Preliminary endurance tests at 3 million DN and 492 K (425 F) indicate that long term bearing operation can be achieved with a high degree of reliability.

Epstein-Plesset theory based measurements of concentration of nitrogen gases dissolved in aerated water

NASA Astrophysics Data System (ADS)

Sasaki, Masashi; Yamashita, Tatsuya; Ando, Keita

2016-11-01

Microbubble aeration is used to dissolved gases into water and is an important technique in agriculture and industry. We can measure concentration of dissolved oxygen (DO) in aerated water by commercial DO meters. However, there do not exist commercially available techniques to measure concentration to dissolved nitrogen (DN). In the present study, we propose the method to measure DN in aerated water with the aid of Epstein-Plesset-type analysis. Gas-supersaturated tap water is produced by applying aeration with micro-sized air bubbles and is then stored in a glass container open to the atmosphere. Diffusion-driven growth of bubbles nucleated at the container surface is recorded with a video camera. The bubble growth rate is compare to the extended Epstein-Plesset theory that models mass transfer of both DO and DN into the surface-attached bubbles base on the diffusion equation. Given the DO measurements, we can obtain the DN level by fitting in the comparison.

Diabetic nephropathy among Mexican Americans

PubMed Central

Debnath, Subrata; Thameem, Farook; Alves, Tahira; Nolen, Jacqueline; Al-Shahrouri, Hania; Bansal, Shweta; Abboud, Hanna E.; Fanti, Paolo

2012-01-01

The incidence of diabetic nephropathy (DN) is growing rapidly worldwide as a consequence of the rising prevalence of Type 2 diabetes mellitus (T2DM). Among U.S. ethnic groups, Mexican Americans have a disproportionately high incidence and prevalence of DN and associated end-stage renal disease (ESRD). In communities bordering Mexico, as many as 90% of Mexican American patients with ESRD also suffer from T2DM compared to only 50% of non-Hispanic Whites (NHW). Both socio-economic factors and genetic predisposition appear to have a strong influence on this association. In addition, certain pathogenetic and clinical features of T2DM and DN are different in Mexican Americans compared to NHW, raising questions as to whether the diagnostic and treatment strategies that are standard practice in the NHW patient population may not be applicable in Mexican Americans. This article reviews the epidemiology of DN in Mexican Americans, describes the pathophysiology and associated risk factors, and identifies gaps in our knowledge and understanding that needs to be addressed by future investigations. PMID:22445478

Endurance and failure characteristics of main-shaft jet engine bearings at 3x10 to the 6th power DN

NASA Technical Reports Server (NTRS)

Bamberger, E. N.; Zaretsky, E. V.; Signer, H.

1976-01-01

Groups of thirty 120-mm bore angular contact ball bearings were endurance tested at a speed of 12,000 and 25,000 rpm and a thrust load of 66 721 N. The bearings were manufactured from a single heat of VIM-VAR AISI M-50 steel. At 1.44X1 million and 3.0x1 million DN, 84 483 and 74 800 bearing test hours were accumulated, respectively. Test results were compared with similar bearings made from CVM AISI M-50 steel run under the same conditions. Bearing lives at speeds of 3x1 million DN with the VIM-VAR AISI M-50 steel were nearly equivalent to those obtained at lower speeds. A combined processing and material life factor of 44 was found for VIM-VAR AISI M-50 steel. Continuous running after a spall has occurred at 3.0x1 million DN can result in a destructive fracture of the bearing inner race.

Climate variability and extremes, interacting with nitrogen storage, amplify eutrophication risk

USGS Publications Warehouse

Lee, Minjin; Shevliakova, Elena; Malyshev, Sergey; Milly, P.C.D.; Jaffe, Peter R.

2016-01-01

Despite 30 years of basin-wide nutrient-reduction efforts, severe hypoxia continues to be observed in the Chesapeake Bay. Here we demonstrate the critical influence of climate variability, interacting with accumulated nitrogen (N) over multidecades, on Susquehanna River dissolved nitrogen (DN) loads, known precursors of the hypoxia in the Bay. We used the process model LM3-TAN (Terrestrial and Aquatic Nitrogen), which is capable of capturing both seasonal and decadal-to-century changes in vegetation-soil-river N storage, and produced nine scenarios of DN-load distributions under different short-term scenarios of climate variability and extremes. We illustrate that after 1 to 3 yearlong dry spells, the likelihood of exceeding a threshold DN load (56 kt yr−1) increases by 40 to 65% due to flushing of N accumulated throughout the dry spells and altered microbial processes. Our analyses suggest that possible future increases in climate variability/extremes—specifically, high precipitation occurring after multiyear dry spells—could likely lead to high DN-load anomalies and hypoxia.

Long-term effect of neonatal inhibition of APP gamma-secretase on hippocampal development in the Ts65Dn mouse model of Down syndrome.

PubMed

Stagni, Fiorenza; Raspanti, Alessandra; Giacomini, Andrea; Guidi, Sandra; Emili, Marco; Ciani, Elisabetta; Giuliani, Alessandro; Bighinati, Andrea; Calzà, Laura; Magistretti, Jacopo; Bartesaghi, Renata

2017-07-01

Neurogenesis impairment is considered a major determinant of the intellectual disability that characterizes Down syndrome (DS), a genetic condition caused by triplication of chromosome 21. Previous evidence obtained in the Ts65Dn mouse model of DS showed that the triplicated gene APP (amyloid precursor protein) is critically involved in neurogenesis alterations. In particular, excessive levels of AICD (amyloid precursor protein intracellular domain) resulting from APP cleavage by gamma-secretase increase the transcription of Ptch1, a Sonic Hedgehog (Shh) receptor that keeps the mitogenic Shh pathway repressed. Previous evidence showed that neonatal treatment with ELND006, an inhibitor of gamma-secretase, reinstates the Shh pathway and fully restores neurogenesis in Ts65Dn pups. In the framework of potential therapies for DS, it is extremely important to establish whether the positive effects of early intervention are retained after treatment cessation. Therefore, the goal of the current study was to establish whether early treatment with ELND006 leaves an enduring trace in the brain of Ts65Dn mice. Ts65Dn and euploid pups were treated with ELND006 in the postnatal period P3-P15 and the outcome of treatment was examined at ~one month after treatment cessation. We found that in treated Ts65Dn mice the pool of proliferating cells in the hippocampal dentate gyrus (DG) and total number of granule neurons were still restored as was the number of pre- and postsynaptic terminals in the stratum lucidum of CA3, the site of termination of the mossy fibers from the DG. Accordingly, patch-clamp recording from field CA3 showed functional normalization of the input to CA3. Unlike in field CA3, the number of pre- and postsynaptic terminals in the DG of treated Ts65Dn mice was no longer fully restored. The finding that many of the positive effects of neonatal treatment were retained after treatment cessation provides proof of principle demonstration of the efficacy of early inhibition of gamma-secretase for the improvement of brain development in DS. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Reed, S.A.; Senf, S.M.; Cornwell, E.W.

Research highlights: {yields} Independent inhibition of Foxo, IKK{alpha} and IKK{beta} activities does not alter muscle fiber size in weight bearing muscles. {yields} Inhibition of Foxo activity plus IKK{alpha} or IKK{beta} activities increases muscle fiber size. {yields} Independent inhibition of Foxo and IKK{beta} activities attenuates cast immobilization-induced muscle fiber atrophy. {yields} Disuse muscle fiber atrophy is abolished by inhibition of Foxo activity plus IKK{alpha} or IKK{beta} activities. -- Abstract: Two transcription factor families that are activated during multiple conditions of skeletal muscle wasting are nuclear factor {kappa}B (NF-{kappa}B) and forkhead box O (Foxo). There is clear evidence that both NF-{kappa}B andmore » Foxo activation are sufficient to cause muscle fiber atrophy and they are individually required for at least half of the fiber atrophy during muscle disuse, but there is no work determining the combined effect of inhibiting these factors during a physiological condition of muscle atrophy. Here, we determined whether inhibition of Foxo activation plus inhibition of NF-{kappa}B activation, the latter by blocking the upstream inhibitor of kappaB kinases (IKK{alpha} and IKK{beta}), would prevent muscle atrophy induced by 7 days of cast immobilization. Results were based on measurements of mean fiber cross-sectional area (CSA) from 72 muscles transfected with 5 different mutant expression plasmids or plasmid combinations. Immobilization caused a 47% decrease in fiber CSA in muscles injected with control plasmids. Fibers from immobilized muscles transfected with dominant negative (d.n.) IKK{alpha}-EGFP, d.n. IKK{beta}-EGFP or d.n. Foxo-DsRed showed a 22%, 57%, and 76% inhibition of atrophy, respectively. Co-expression of d.n. IKK{alpha}-EGFP and d.n. Foxo-DsRed significantly inhibited 89% of the immobilization-induced fiber atrophy. Similarly, co-expression of d.n. IKK{beta}-EGFP and d.n. Foxo-DsRed inhibited the immobilization-induced fiber atrophy by 95%. These findings demonstrate that the combined effects of inhibiting immobilization-induced NF-{kappa}B and Foxo transcriptional activity has an additive effect on preventing immobilization-induced atrophy, indicating that NF-{kappa}B and Foxo have a cumulative effect on atrophy signaling and/or atrophy gene expression.« less

LincRNA-Gm4419 knockdown ameliorates NF-κB/NLRP3 inflammasome-mediated inflammation in diabetic nephropathy.

PubMed

Yi, Hong; Peng, Rui; Zhang, Lu-Yu; Sun, Yan; Peng, Hui-Min; Liu, Han-Deng; Yu, Li-Juan; Li, Ai-Ling; Zhang, Ya-Juan; Jiang, Wen-Hao; Zhang, Zheng

2017-02-02

Diabetic nephropathy (DN) as the primary cause of end-stage kidney disease is a common complication of diabetes. Recent researches have shown the activation of nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) and NACHT, LRR and PYD domain-containing protein 3 (NLRP3) inflammasome are associated with inflammation in the progression of DN, but the exact mechanism is unclear. Long noncoding RNAs (lncRNAs) have roles in the development of many diseases including DN. However, the relationship between lncRNAs and inflammation in DN remains largely unknown. Our previous study has revealed that 14 lncRNAs are abnormally expressed in DN by RNA sequencing and real-time quantitative PCR (qRT-PCR) in the renal tissues of db/db DN mice. In this study, these lncRNAs were verified their expressions by qRT-PCR in mesangial cells (MCs) cultured under high- and low-glucose conditions. Twelve lncRNAs displayed the same expressional tendencies in both renal tissues and MCs. In particular, long intergenic noncoding RNA (lincRNA)-Gm4419 was the only one associating with NF-κB among these 12 lncRNAs by bioinformatics methods. Moreover, Gm4419 knockdown could obviously inhibit the expressions of pro-inflammatory cytokines and renal fibrosis biomarkers, and reduce cell proliferation in MCs under high-glucose condition, whereas overexpression of Gm4419 could increase the inflammation, fibrosis and cell proliferation in MCs under low-glucose condition. Interestingly, our results showed that Gm4419 could activate the NF-κB pathway by directly interacting with p50, the subunit of NF-κB. In addition, we found that p50 could interact with NLRP3 inflammasome in MCs. In conclusion, our findings suggest lincRNA-Gm4419 may participate in the inflammation, fibrosis and proliferation in MCs under high-glucose condition through NF-κB/NLRP3 inflammasome signaling pathway, and may provide new insights into the regulation of Gm4419 during the progression of DN.

Urinary Exosomal miRNA Signature in Type II Diabetic Nephropathy Patients

PubMed Central

Delić, Denis; Eisele, Claudia; Schmid, Ramona; Baum, Patrick; Wiech, Franziska; Gerl, Martin; Zimdahl, Heike; Pullen, Steven S.; Urquhart, Richard

2016-01-01

MicroRNAs (miRNAs) are short non-coding RNA species which are important post-transcriptional regulators of gene expression and play an important role in the pathogenesis of diabetic nephropathy. miRNAs are present in urine in a remarkably stable form packaged in extracellular vesicles, predominantly exosomes. In the present study, urinary exosomal miRNA profiling was conducted in urinary exosomes obtained from 8 healthy controls (C), 8 patients with type II diabetes (T2D) and 8 patients with type II diabetic nephropathy (DN) using Agilent´s miRNA microarrays. In total, the expression of 16 miRNA species was deregulated (>2-fold) in DN patients compared to healthy donors and T2D patients: the expression of 14 miRNAs (miR-320c, miR-6068, miR-1234-5p, miR-6133, miR-4270, miR-4739, miR-371b-5p, miR-638, miR-572, miR-1227-5p, miR-6126, miR-1915-5p, miR-4778-5p and miR-2861) was up-regulated whereas the expression of 2 miRNAs (miR-30d-5p and miR-30e-5p) was down-regulated. Most of the deregulated miRNAs are involved in progression of renal diseases. Deregulation of urinary exosomal miRNAs occurred in micro-albuminuric DN patients but not in normo-albuminuric DN patients. We used qRT-PCR based analysis of the most strongly up-regulated miRNAs in urinary exosomes from DN patients, miRNAs miR-320c and miR-6068. The correlation of miRNA expression and micro-albuminuria levels could be replicated in a confirmation cohort. In conclusion, urinary exosomal miRNA content is altered in type II diabetic patients with DN. Deregulated miR-320c, which might have an impact on the TGF-β-signaling pathway via targeting thrombospondin 1 (TSP-1) shows promise as a novel candidate marker for disease progression in type II DN that should be evaluated in future studies. PMID:26930277

78 FR 115 - Certain Wireless Communications Equipment and Articles Therein; Notice of Receipt of Complaint...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-01-02

... INTERNATIONAL TRADE COMMISSION [DN 2926] Certain Wireless Communications Equipment and Articles... complaint entitled Certain Wireless Communications Equipment and Articles Therein, DN 2926; the Commission... communications equipment and articles therein. The complaint names as respondents Ericsson Inc. of TX and...

76 FR 66750 - Certain Automotive GPS Navigation Systems, Components Thereof, and Products Containing Same...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-10-27

... INTERNATIONAL TRADE COMMISSION [DN 2850] Certain Automotive GPS Navigation Systems, Components... given that the U.S. International Trade Commission has received a complaint entitled In Re Certain Automotive GPS Navigation Systems, Components Thereof, And Products Containing Same, DN 2850; the Commission...

URINARY METABOLITES OF DI-N-OCTYL PHTHALATE IN RATS

EPA Science Inventory

Di-n-octyl phthalate (DnOP) is a plasticizer used in polyvinyl chloride plastics, cellulose esters, and polystyrene resins. The metabolism of DnOP results in the hydrolysis of one ester linkage to produce mono-n-octyl phthalate (MnOP), which subsequently metabolizes to form oxida...

Intraindividual Analysis of Signal Intensity Changes in the Dentate Nucleus After Consecutive Serial Applications of Linear and Macrocyclic Gadolinium-Based Contrast Agents.

PubMed

Radbruch, Alexander; Weberling, Lukas D; Kieslich, Pascal J; Hepp, Johanna; Kickingereder, Philipp; Wick, Wolfgang; Schlemmer, Heinz-Peter; Bendszus, Martin

2016-11-01

Recent studies reported an increase in the dentate nucleus (DN)-to-pons signal intensity (SI) ratio (DN-pons SI ratio) on unenhanced T1-weighted images in patients who received consecutive serial injections of linear gadolinium-based contrast agents (GBCAs). In contrast, most studies found no increase in the DN-pons SI ratio when patients were treated with consecutive serial injections of macrocyclic GBCAs. However, the potential difference between macrocyclic and linear GBCAs has never been assessed in individuals who received subsequent applications of both contrast agents. In this retrospective study, we assessed the evolution of the DN-pons SI ratio change in patients that were treated with a comparable number of serial consecutive injections of the linear GBCA gadopentetate dimeglumine and subsequent serial injections of the macrocyclic GBCAs gadobutrol and gadoterate meglumine. Data of 36 patients was analyzed. All patients underwent at least 5 consecutive administrations of the linear GBCA gadopentetate dimeglumine followed by an equal number of consecutive administrations of the macrocyclic GBCA gadobutrol. In 12 of the 36 patients, 5 or more final consecutive injections of the macrocyclic GBCA gadoterate meglumine were analyzed additionally. The difference of DN-pons SI ratios on unenhanced T1-weighted images was calculated by subtracting the ratio at the first examination from the ratio at the last examination in each of the 3 periods. The mean DN-pons SI ratio difference in the gadopentetate dimeglumine period was significantly greater than 0 (mean ± SD, 0.0448 ± 0.0345; P < 0.001), whereas the mean DN-pons SI ratio difference in the subsequent gadobutrol and gadoterate meglumine period was significantly smaller than 0 (gadobutrol: -0.0178 ± 0.0459, P = 0.026; gadoterate meglumine: -0.0250 ± 0.0284, P = 0.011). In this observational study, the application of the linear GBCA gadopentetate dimeglumine was associated with a DN-pons SI ratio increase, whereas subsequent applications of the macrocyclic GBCAs gadobutrol or gadoterate meglumine in the same patients were not. Rather, the current data tentatively suggest a decrease in preexisting hyperintensities over time when linear GBCAs are changed to macrocyclic GBCAs, potentially indicating a washout effect or precipitation of gadolinium. Future patient studies need to include control groups to replicate the present results, and additional animal studies should be conducted to clarify the underlying mechanism of the proposed SI decrease.

The Bone Morphogenetic Protein Type Ib Receptor Is a Major Mediator of Glial Differentiation and Cell Survival in Adult Hippocampal Progenitor Cell Culture

PubMed Central

Brederlau, A.; Faigle, R.; Elmi, M.; Zarebski, A.; Sjöberg, S.; Fujii, M.; Miyazono, K.; Funa, K.

2004-01-01

Bone morphogenetic proteins (BMPs) act as growth regulators and inducers of differentiation. They transduce their signal via three different type I receptors, termed activin receptor-like kinase 2 (Alk2), Alk3, or bone morphogenetic protein receptor Ia (BMPRIa) and Alk6 or BMPRIb. Little is known about functional differences between the three type I receptors. Here, we have investigated consequences of constitutively active (ca) and dominant negative (dn) type I receptor overexpression in adult-derived hippocampal progenitor cells (AHPs). The dn receptors have a nonfunctional intracellular but functional extracellular domain. They thus trap BMPs that are endogenously produced by AHPs. We found that effects obtained by overexpression of dnAlk2 and dnAlk6 were similar, suggesting similar ligand binding patterns for these receptors. Thus, cell survival was decreased, glial fibrillary acidic protein (GFAP) expression was reduced, whereas the number of oligodendrocytes increased. No effect on neuronal differentiation was seen. Whereas the expression of Alk2 and Alk3 mRNA remained unchanged, the Alk6 mRNA was induced after impaired BMP signaling. After dnAlk3 overexpression, cell survival and astroglial differentiation increased in parallel to augmented Alk6 receptor signaling. We conclude that endogenous BMPs mediate cell survival, astroglial differentiation and the suppression of oligodendrocytic cell fate mainly via the Alk6 receptor in AHP culture. PMID:15194807

Prevalence of nephropathy in type 1 diabetes in the Arab world: A systematic review and meta-analysis.

PubMed

Abdel-Motal, Ussama M; G, Akila; Abdelalim, Essam M; Ponnuraja, Chinnaiyan; Iken, Khadija; Jahromi, Mohamed; Doss, George Priya; El Bekay, Rajaa; Zayed, Hatem

2018-05-17

The aim of this study was to conduct a systematic review and meta-analysis and determine the prevalence of diabetic nephropathy (DN) among Arab patients with T1D. A systematic literature search was conducted using 4 different literature databases (PubMed, ScienceDirect, Web of Science, and Embase) to capture all relevant data about Arab patients with T1D that had DN. Meta-analysis and systematic review were performed using the random effect model, and the heterogeneity of the studies was assessed using the Q-test, I2, and Tau-squared statistics. Publication bias was assessed using the funnel-plot test. Our search strategy captured 372 studies in only 10 out of the 22 Arab countries in a period of 48 years (1969-2017); of which, 41 met our inclusion criteria for full article analysis, of those, 15 were eligible for meta-analysis. We estimated the prevalence of DN among Arab people with T1D to be 18.2% (95% confidence interval 13.1%-24.8%). In conclusion, DN prevalence is underexplored among Arab patients with T1D and represents a significant risk for the well-being of Arab patients with T1D. Therefore, there is an urgent need for comprehensive epidemiological studies for DN among Arab patients with T1D. Copyright © 2018 John Wiley & Sons, Ltd.

Assessment of reproductive and developmental effects of DINP, DnHP and DCHP using quantitative weight of evidence.

PubMed

Dekant, Wolfgang; Bridges, James

2016-11-01

Quantitative weight of evidence (QWoE) methodology utilizes detailed scoring sheets to assess the quality/reliability of each publication on toxicity of a chemical and gives numerical scores for quality and observed toxicity. This QWoE-methodology was applied to the reproductive toxicity data on diisononylphthalate (DINP), di-n-hexylphthalate (DnHP), and dicyclohexylphthalate (DCHP) to determine if the scientific evidence for adverse effects meets the requirements for classification as reproductive toxicants. The scores for DINP were compared to those when applying the methodology DCHP and DnHP that have harmonized classifications. Based on the quality/reliability scores, application of the QWoE shows that the three databases are of similar quality; but effect scores differ widely. Application of QWoE to DINP studies resulted in an overall score well below the benchmark required to trigger classification. For DCHP, the QWoE also results in low scores. The high scores from the application of the QWoE methodology to the toxicological data for DnHP represent clear evidence for adverse effects and justify a classification of DnHP as category 1B for both development and fertility. The conclusions on classification based on the QWoE are well supported using a narrative assessment of consistency and biological plausibility. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

On the Distribution of Protein Refractive Index Increments

PubMed Central

Zhao, Huaying; Brown, Patrick H.; Schuck, Peter

2011-01-01

The protein refractive index increment, dn/dc, is an important parameter underlying the concentration determination and the biophysical characterization of proteins and protein complexes in many techniques. In this study, we examine the widely used assumption that most proteins have dn/dc values in a very narrow range, and reappraise the prediction of dn/dc of unmodified proteins based on their amino acid composition. Applying this approach in large scale to the entire set of known and predicted human proteins, we obtain, for the first time, to our knowledge, an estimate of the full distribution of protein dn/dc values. The distribution is close to Gaussian with a mean of 0.190 ml/g (for unmodified proteins at 589 nm) and a standard deviation of 0.003 ml/g. However, small proteins <10 kDa exhibit a larger spread, and almost 3000 proteins have values deviating by more than two standard deviations from the mean. Due to the widespread availability of protein sequences and the potential for outliers, the compositional prediction should be convenient and provide greater accuracy than an average consensus value for all proteins. We discuss how this approach should be particularly valuable for certain protein classes where a high dn/dc is coincidental to structural features, or may be functionally relevant such as in proteins of the eye. PMID:21539801

Inhibition of elastase-pulmonary emphysema in dominant-negative MafB transgenic mice.

PubMed

Aida, Yasuko; Shibata, Yoko; Abe, Shuichi; Inoue, Sumito; Kimura, Tomomi; Igarashi, Akira; Yamauchi, Keiko; Nunomiya, Keiko; Kishi, Hiroyuki; Nemoto, Takako; Sato, Masamichi; Sato-Nishiwaki, Michiko; Nakano, Hiroshi; Sato, Kento; Kubota, Isao

2014-01-01

Alveolar macrophages (AMs) play important roles in the pathogenesis of chronic obstructive pulmonary disease (COPD). We previously demonstrated upregulation of the transcription factor MafB in AMs of mice exposed to cigarette smoke. The aim of this study was to elucidate the roles of MafB in the development of pulmonary emphysema. Porcine pancreatic elastase was administered to wild-type (WT) and dominant-negative (DN)-MafB transgenic (Tg) mice in which MafB activity was suppressed only in macrophages. We measured the mean linear intercept and conducted cell differential analysis of bronchoalveolar lavage (BAL) cells, surface marker analysis using flow cytometry, and immunohistochemical staining using antibodies to matrix metalloproteinase (MMP)-9 and MMP-12. Airspace enlargement of the lungs was suppressed significantly in elastase-treated DN-MafB Tg mice compared with treated WT mice. AMs with projected pseudopods were decreased in DN-MafB Tg mice. The number of cells intermediately positive for F4/80 and weakly or intermediately positive for CD11b, which are considered cell subsets of matured AMs, decreased in the BAL of DN-MafB Tg mice. Furthermore, MMP-9 and -12 were significantly downregulated in BAL cells of DN-MafB Tg mice. Because MMPs exacerbate emphysema, MafB may be involved in pulmonary emphysema development through altered maturation of macrophages and MMP expression.

On the distribution of protein refractive index increments.

PubMed

Zhao, Huaying; Brown, Patrick H; Schuck, Peter

2011-05-04

The protein refractive index increment, dn/dc, is an important parameter underlying the concentration determination and the biophysical characterization of proteins and protein complexes in many techniques. In this study, we examine the widely used assumption that most proteins have dn/dc values in a very narrow range, and reappraise the prediction of dn/dc of unmodified proteins based on their amino acid composition. Applying this approach in large scale to the entire set of known and predicted human proteins, we obtain, for the first time, to our knowledge, an estimate of the full distribution of protein dn/dc values. The distribution is close to Gaussian with a mean of 0.190 ml/g (for unmodified proteins at 589 nm) and a standard deviation of 0.003 ml/g. However, small proteins <10 kDa exhibit a larger spread, and almost 3000 proteins have values deviating by more than two standard deviations from the mean. Due to the widespread availability of protein sequences and the potential for outliers, the compositional prediction should be convenient and provide greater accuracy than an average consensus value for all proteins. We discuss how this approach should be particularly valuable for certain protein classes where a high dn/dc is coincidental to structural features, or may be functionally relevant such as in proteins of the eye. Copyright © 2011 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Both LOV1 and LOV2 domains of phototropin2 function as the photosensory domain for hypocotyl phototropic responses in Arabidopsis thaliana (Brassicaceae).

PubMed

Suetsugu, Noriyuki; Kong, Sam-Geun; Kasahara, Masahiro; Wada, Masamitsu

2013-01-01

Phototropins (phot) are blue light receptor proteins that mediate phototropism and control photomovement responses, such as chloroplast photorelocation movement and stomatal opening. Arabidopsis thaliana has two phototropins, phot1 and phot2. Although both phot1 and phot2 redundantly mediate photomovement responses, phot2 uniquely regulates phototropism and the chloroplast avoidance response under high-intensity blue light. However, compared to that of phot1, the mechanistic basis of phot2 function is poorly understood, and in particular, the importance of the LOV2 domain in phot2 function has not been clearly demonstrated. Indeed, photocycle-deficient LOV2 transgenic lines expressing phot2 in a phot1phot2 mutant background retained phototropism, although with less sensitivity than wild-type plants. We isolated 11 alleles of phot2 mutants and determined the molecular lesion in each allele. We analyzed hypocotyl phototropism, chloroplast photorelocation movement, and leaf flattening in the phot2 mutant and the respective phot1phot2 double mutant plants. We demonstrated that unlike the phot2 null mutant, the phot2-10 mutant, which has the defective phot2 LOV2 domain, retained the phototropic response and had unusual chloroplast movement. Mutants phot2-2 and phot2-6, which have a missense mutation in the kinase activation loop of phot2, had the phot2-null mutant phenotype. Furthermore, we convincingly demonstrated that the commonly used phot2-1 mutant allele is a phot2-null mutant. The analyses of the multiple phot2 mutant alleles provided strong evidence for the importance of both LOV domains and the kinase activation loop of phot2 in phototropism and other phot-dependent responses and also demonstrated that phot2-1 allele is a null mutant.

RNA interference can target pre-mRNA: consequences for gene expression in a Caenorhabditis elegans operon.

PubMed Central

Bosher, J M; Dufourcq, P; Sookhareea, S; Labouesse, M

1999-01-01

In nematodes, flies, trypanosomes, and planarians, introduction of double-stranded RNA results in sequence-specific inactivation of gene function, a process termed RNA interference (RNAi). We demonstrate that RNAi against the Caenorhabditis elegans gene lir-1, which is part of the lir-1/lin-26 operon, induced phenotypes very different from a newly isolated lir-1 null mutation. Specifically, lir-1(RNAi) induced embryonic lethality reminiscent of moderately strong lin-26 alleles, whereas the lir-1 null mutant was viable. We show that the lir-1(RNAi) phenotypes resulted from a severe loss of lin-26 gene expression. In addition, we found that RNAi directed against lir-1 or lin-26 introns induced similar phenotypes, so we conclude that lir-1(RNAi) targets the lir-1/lin-26 pre-mRNA. This provides direct evidence that RNA interference can prevent gene expression by targeting nuclear transcripts. Our results highlight that caution may be necessary when interpreting RNA interference without the benefit of mutant alleles. PMID:10545456

Selenium and Prostate Cancer Prevention: Insights from the Selenium and Vitamin E Cancer Prevention Trial (SELECT)

PubMed Central

Nicastro, Holly L.; Dunn, Barbara K.

2013-01-01

The Selenium and Vitamin E Cancer Prevention Trial (SELECT) was conducted to assess the efficacy of selenium and vitamin E alone, and in combination, on the incidence of prostate cancer. This randomized, double-blind, placebo-controlled, 2 × 2 factorial design clinical trial found that neither selenium nor vitamin E reduced the incidence of prostate cancer after seven years and that vitamin E was associated with a 17% increased risk of prostate cancer compared to placebo. The null result was surprising given the strong preclinical and clinical evidence suggesting chemopreventive activity of selenium. Potential explanations for the null findings include the agent formulation and dose, the characteristics of the cohort, and the study design. It is likely that only specific subpopulations may benefit from selenium supplementation; therefore, future studies should consider the baseline selenium status of the participants, age of the cohort, and genotype of specific selenoproteins, among other characteristics, in order to determine the activity of selenium in cancer prevention. PMID:23552052

77 FR 14423 - Certain Food Containers, Cups, Plates, Cutlery, and Related Items, and Packaging Thereof; Notice...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-09

... INTERNATIONAL TRADE COMMISSION [DN 2883] Certain Food Containers, Cups, Plates, Cutlery, and... Containers, Cups, Plates, Cutlery, and Related Items, and Packaging Thereof, DN 2883; the Commission is... importation of certain food containers, cups, plates, cutlery, and related items, and packaging thereof. The...

MONO-(3-CARBOXYPROPYL) PHTHALATE, A METABOLITE OF DI-N-OCTYL PHTHALATE

EPA Science Inventory

Di-n-octyl phthalate (DnOP) is found as a component of mixed C6–C10 linear-chain phthalates used as plasticizers in various polyvinyl chloride applications, including flooring and carpet tiles. Following exposure and absorption, DnOP is metabolized to its hydrolytic monoester, mo...

77 FR 19032 - Certain Semiconductor Integrated Circuit Devices and Products Containing Same Notice of Receipt...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-29

... INTERNATIONAL TRADE COMMISSION [DN 2888] Certain Semiconductor Integrated Circuit Devices and... Integrated Circuit Devices and Products Containing Same, DN 2888; the Commission is soliciting comments on... Commission's electronic docket (EDIS) at http://edis.usitc.gov , and will be available for inspection during...

RETRACTED: Relationship between the ACE I/D gene polymorphism and T1DN susceptibility/risk of T1DM developing into T1DN in the Caucasian population.

PubMed

Zhou, Tian-Biao; Guo, Xue-Feng; Jiang, Zongpei; Li, Hong-Yan

2015-12-01

The following article has been included in a multiple retraction: Tian-Biao Zhou, Xue-Feng Guo, Zongpei Jiang, and Hong-Yan Li Relationship between the ACE I/D gene polymorphism and T1DN susceptibility/risk of T1DM developing into T1DN in the Caucasian population Journal of Renin-Angiotensin-Aldosterone System 1470320314563425, first published on February 1, 2015 doi: 10.1177/1470320314563425 This article has been retracted at the request of the Editors and the Publisher. After conducting a thorough investigation, SAGE found that the submitting authors of a number of papers published in the Journal of the Renin-Angiotensin Aldosterone System ( JRAAS) (listed below) had supplied fabricated contact details for their nominated reviewers. The Editors accepted these papers based on the reports supplied by the individuals using these fake reviewer email accounts. After concluding that the peer review process was therefore seriously compromised, SAGE and the journal Editors have decided to retract all affected articles. Online First articles (these articles will not be published in an issue) Wenzhuang Tang, Tian-Biao Zhou, and Zongpei Jiang Association of the angiotensinogen M235T gene polymorphism with risk of diabetes mellitus developing into diabetic nephropathy Journal of Renin-Angiotensin-Aldosterone System 1470320314563426, first published on December 18, 2014 doi: 10.1177/1470320314563426 Tian-Biao Zhou, Hong-Yan Li, Zong-Pei Jiang, Jia-Fan Zhou, Miao-Fang Huang, and Zhi-Yang Zhou Role of renin-angiotensin-aldosterone system inhibitors in radiation nephropathy Journal of Renin-Angiotensin-Aldosterone System 1470320314563424, first published on December 18, 2014 doi: 10.1177/1470320314563424 Weiqiang Zhong, Zongpei Jiang, and Tian-Biao Zhou Association between the ACE I/D gene polymorphism and T2DN susceptibility: The risk of T2DM developing into T2DN in the Asian population Journal of Renin-Angiotensin-Aldosterone System 1470320314566019, first published on January 26, 2015 doi: 10.1177/1470320314566019 Tian-Biao Zhou, Xue-Feng Guo, Zongpei Jiang, and Hong-Yan Li Relationship between the ACE I/D gene polymorphism and T1DN susceptibility/risk of T1DM developing into T1DN in the Caucasian population Journal of Renin-Angiotensin-Aldosterone System 1470320314563425, first published on February 1, 2015 doi: 10.1177/1470320314563425 Chun-Hua Yang and Tian-Biao Zhou Relationship between the angiotensinogen A1166C gene polymorphism and the risk of diabetes mellitus developing into diabetic nephropathy Journal of Renin-Angiotensin-Aldosterone System 1470320314566221, first published on February 1, 2015 doi: 10.1177/1470320314566221 Chun-Hua Yang and Tian-Biao Zhou Association of the ACE I/D gene polymorphism with sepsis susceptibility and sepsis progression Journal of Renin-Angiotensin-Aldosterone System 1470320314568521, first published on February 3, 2015 doi: 10.1177/1470320314568521 Articles published in an issue Guohui Liu, Tian-Biao Zhou, Zongpei Jiang, and Dongwen Zheng Association of ACE I/D gene polymorphism with T2DN susceptibility and the risk of T2DM developing into T2DN in a Caucasian population Journal of Renin-Angiotensin-Aldosterone System March 2015 16: 165-171, first published on November 14, 2014 doi: 10.1177/1470320314557849 Weiqiang Zhong, Zhongliang Huang, Yong Wu, Zongpei Jiang, and Tian-Biao Zhou Association of aldosterone synthase (CYP11B2) gene polymorphism with IgA nephropathy risk and progression of IgA nephropathy Journal of Renin-Angiotensin-Aldosterone System September 2015 16: 660-665, first published on August 20, 2014 doi: 10.1177/1470320314524011.

RETRACTED: Association between the ACE I/D gene polymorphism and T2DN susceptibility: The risk of T2DM developing into T2DN in the Asian population.

PubMed

Zhong, Weiqiang; Jiang, Zongpei; Zhou, Tian-Biao

2015-12-01

This article has been included in a multiple retraction: Weiqiang Zhong, Zongpei Jiang, and Tian-Biao Zhou Association between the ACE I/D gene polymorphism and T2DN susceptibility: The risk of T2DM developing into T2DN in the Asian population Journal of Renin-Angiotensin-Aldosterone System 1470320314566019, first published on January 26, 2015 doi: 10.1177/1470320314566019 This article has been retracted at the request of the Editors and the Publisher. After conducting a thorough investigation, SAGE found that the submitting authors of a number of papers published in the Journal of the Renin-Angiotensin Aldosterone System ( JRAAS) (listed below) had supplied fabricated contact details for their nominated reviewers. The Editors accepted these papers based on the reports supplied by the individuals using these fake reviewer email accounts. After concluding that the peer review process was therefore seriously compromised, SAGE and the journal Editors have decided to retract all affected articles. Online First articles (these articles will not be published in an issue) Wenzhuang Tang, Tian-Biao Zhou, and Zongpei Jiang Association of the angiotensinogen M235T gene polymorphism with risk of diabetes mellitus developing into diabetic nephropathy Journal of Renin-Angiotensin-Aldosterone System 1470320314563426, first published on December 18, 2014 doi: 10.1177/1470320314563426 Tian-Biao Zhou, Hong-Yan Li, Zong-Pei Jiang, Jia-Fan Zhou, Miao-Fang Huang, and Zhi-Yang Zhou Role of renin-angiotensin-aldosterone system inhibitors in radiation nephropathy Journal of Renin-Angiotensin-Aldosterone System 1470320314563424, first published on December 18, 2014 doi: 10.1177/1470320314563424 Weiqiang Zhong, Zongpei Jiang, and Tian-Biao Zhou Association between the ACE I/D gene polymorphism and T2DN susceptibility: The risk of T2DM developing into T2DN in the Asian population Journal of Renin-Angiotensin-Aldosterone System 1470320314566019, first published on January 26, 2015 doi: 10.1177/1470320314566019 Tian-Biao Zhou, Xue-Feng Guo, Zongpei Jiang, and Hong-Yan Li Relationship between the ACE I/D gene polymorphism and T1DN susceptibility/risk of T1DM developing into T1DN in the Caucasian population Journal of Renin-Angiotensin-Aldosterone System 1470320314563425, first published on February 1, 2015 doi: 10.1177/1470320314563425 Chun-Hua Yang and Tian-Biao Zhou Relationship between the angiotensinogen A1166C gene polymorphism and the risk of diabetes mellitus developing into diabetic nephropathy Journal of Renin-Angiotensin-Aldosterone System 1470320314566221, first published on February 1, 2015 doi: 10.1177/1470320314566221 Chun-Hua Yang and Tian-Biao Zhou Association of the ACE I/D gene polymorphism with sepsis susceptibility and sepsis progression Journal of Renin-Angiotensin-Aldosterone System 1470320314568521, first published on February 3, 2015 doi: 10.1177/1470320314568521 Articles published in an issue Guohui Liu, Tian-Biao Zhou, Zongpei Jiang, and Dongwen Zheng Association of ACE I/D gene polymorphism with T2DN susceptibility and the risk of T2DM developing into T2DN in a Caucasian population Journal of Renin-Angiotensin-Aldosterone System March 2015 16: 165-171, first published on November 14, 2014 doi: 10.1177/1470320314557849 Weiqiang Zhong, Zhongliang Huang, Yong Wu, Zongpei Jiang, and Tian-Biao Zhou Association of aldosterone synthase (CYP11B2) gene polymorphism with IgA nephropathy risk and progression of IgA nephropathy Journal of Renin-Angiotensin-Aldosterone System September 2015 16: 660-665, first published on August 20, 2014 doi: 10.1177/1470320314524011.

Nuclear science experiments with a bright neutron source from fusion reactions on the OMEGA Laser System

DOE Office of Scientific and Technical Information (OSTI.GOV)

Forrest, C. J.; Knauer, J. P.; Schroeder, W. U.

Subnanosecond impulses of 10 13 to 10 14 neutrons, produced in direct-drive laser inertial confinement fusion implosions, have been used to irradiate deuterated targets at the OMEGA Laser System [T. R. Boehly et al., Opt. Commun. 133, 495 (1997)]. The target compounds include heavy water (D 2O) and deuterated benzene (C 6D 6). Yields and energy spectra of neutrons from D(n,2n)p to study the breakup reaction have been measured at a forward angle of θlab = 3.5 degrees plus/minus 3.5 degrees with a sensitive, high-dynamic-range neutron time-of-flight spectrometer to infer the double-differential breakup cross section d2sigma/dEdomega for 14-MeV D–T fusionmore » neutrons.« less

Nuclear science experiments with a bright neutron source from fusion reactions on the OMEGA Laser System

DOE PAGES

Forrest, C. J.; Knauer, J. P.; Schroeder, W. U.; ...

2018-01-31

Subnanosecond impulses of 10 13 to 10 14 neutrons, produced in direct-drive laser inertial confinement fusion implosions, have been used to irradiate deuterated targets at the OMEGA Laser System [T. R. Boehly et al., Opt. Commun. 133, 495 (1997)]. The target compounds include heavy water (D 2O) and deuterated benzene (C 6D 6). Yields and energy spectra of neutrons from D(n,2n)p to study the breakup reaction have been measured at a forward angle of θlab = 3.5 degrees plus/minus 3.5 degrees with a sensitive, high-dynamic-range neutron time-of-flight spectrometer to infer the double-differential breakup cross section d2sigma/dEdomega for 14-MeV D–T fusionmore » neutrons.« less

Dietary Restriction and Fasting Arrest B and T Cell Development and Increase Mature B and T Cell Numbers in Bone Marrow

PubMed Central

Shushimita, Shushimita; de Bruijn, Marjolein J. W.; de Bruin, Ron W. F.; IJzermans, Jan N. M.; Hendriks, Rudi W.; Dor, Frank J. M. F.

2014-01-01

Dietary restriction (DR) delays ageing and extends life span. Both long- and short-term DR, as well as short-term fasting provide robust protection against many “neuronal and surgery related damaging phenomena” such as Parkinson’s disease and ischemia-reperfusion injury. The exact mechanism behind this phenomenon has not yet been elucidated. Its anti-inflammatory actions prompted us to thoroughly investigate the consequences of DR and fasting on B and T cell compartments in primary and secondary lymphoid organs of male C57Bl/6 mice. In BM we found that DR and fasting cause a decrease in the total B cell population and arrest early B cell development, while increasing the number of recirculating mature B cells. In the fasting group, a significant reduction in peripheral B cell counts was observed in both spleen and mesenteric lymph nodes (mLN). Thymopoiesis was arrested significantly at double negative DN2 stage due to fasting, whereas DR resulted in a partial arrest of thymocyte development at the DN4 stage. Mature CD3+ T cell populations were increased in BM and decreased in both spleen and mLN. Thus, DR arrests B cell development in the BM but increases the number of recirculating mature B cells. DR also arrests maturation of T cells in thymus, resulting in depletion of mature T cells from spleen and mLN while recruiting them to the BM. The functional relevance in relation to protection against organ damage needs to be determined. PMID:24504160

The Green Bank North Celestial Cap Pulsar Survey. III. 45 New Pulsar Timing Solutions

NASA Astrophysics Data System (ADS)

Lynch, Ryan S.; Swiggum, Joseph K.; Kondratiev, Vlad I.; Kaplan, David L.; Stovall, Kevin; Fonseca, Emmanuel; Roberts, Mallory S. E.; Levin, Lina; DeCesar, Megan E.; Cui, Bingyi; Cenko, S. Bradley; Gatkine, Pradip; Archibald, Anne M.; Banaszak, Shawn; Biwer, Christopher M.; Boyles, Jason; Chawla, Pragya; Dartez, Louis P.; Day, David; Ford, Anthony J.; Flanigan, Joseph; Hessels, Jason W. T.; Hinojosa, Jesus; Jenet, Fredrick A.; Karako-Argaman, Chen; Kaspi, Victoria M.; Leake, Sean; Lunsford, Grady; Martinez, José G.; Mata, Alberto; McLaughlin, Maura A.; Noori, Hind Al; Ransom, Scott M.; Rohr, Matthew D.; Siemens, Xavier; Spiewak, Renée; Stairs, Ingrid H.; van Leeuwen, Joeri; Walker, Arielle N.; Wells, Bradley L.

2018-06-01

We provide timing solutions for 45 radio pulsars discovered by the Robert C. Byrd Green Bank Telescope. These pulsars were found in the Green Bank North Celestial Cap pulsar survey, an all-GBT-sky survey being carried out at a frequency of 350 {MHz}. We include pulsar timing data from the Green Bank Telescope and Low Frequency Array. Our sample includes five fully recycled millisecond pulsars (MSPs, three of which are in a binary system), a new relativistic double neutron star system, an intermediate-mass binary pulsar, a mode-changing pulsar, a 138 ms pulsar with a very low magnetic field, and several nulling pulsars. We have measured two post-Keplerian parameters and thus the masses of both objects in the double neutron star system. We also report a tentative companion mass measurement via Shapiro delay in a binary MSP. Two of the MSPs can be timed with high precision and have been included in pulsar timing arrays being used to search for low-frequency gravitational waves, while a third MSP is a member of the black widow class of binaries. Proper motion is measurable in five pulsars, and we provide an estimate of their space velocity. We report on an optical counterpart to a new black widow system and provide constraints on the optical counterparts to other binary MSPs. We also present a preliminary analysis of nulling pulsars in our sample. These results demonstrate the scientific return of long timing campaigns on pulsars of all types.

Effects of shear on the magnetic footprint and stochastic layer in double-null divertor tokamak

NASA Astrophysics Data System (ADS)

Farhat, Hamidullah; Punjabi, Alkesh; Ali, Halima

2006-10-01

We have developed a new area-preserving map, called the Adjustable Shear Map, to calculate effects of shear on the magnetic footprint and stochastic layer in double-null divertor tokamak. The map is given by equationsxn+1=xn-kyn[(1-yn^2 )(1+syn)+sxn+1^2 ),yn+1=yn+kxn+1[1+s(xn+1^2 +yn^2 )]. k is the map parameter and s is the shear parameter. O-point of the map is (0, 0), and the X-points are (0, 1), and (0, -1). For s=0, k=0.6, the last good surface is y=0.9918 with q ˜3. Here we will report on the effects of shear on the stochastic layer and magnetic footprint as the shear parameter is varied from 0 to -1. Here we will report the preliminary results on the effect of shear on the magnetic foot print and the stochastic layer where the shear parameter s has values between -1 and 0. using method of maps [1-4]. This work is done under the DOE grant number DE-FG02-01ER54624. 1. A. Punjabi, A. Boozer, and A. Verma, Phys. Rev. lett., 69, 3322 (1992). 2. H. Ali, A. Punjabi, and A. Boozer, Phys. Plasmas 11, 4527 (2004). 3. A. Punjabi, H. Ali, and A. Boozer, Phys. Plasmas 10, 3992 (2003). 4. A. Punjabi, H. Ali, and A. Boozer, Phys. Plasmas 4, 337 (1997).

Divergence of IL-1, IL-18, and cell death in NLRP3 inflammasomopathies

PubMed Central

Brydges, Susannah D.; Broderick, Lori; McGeough, Matthew D.; Pena, Carla A.; Mueller, James L.; Hoffman, Hal M.

2013-01-01

The inflammasome is a cytoplasmic multiprotein complex that promotes proinflammatory cytokine maturation in response to host- and pathogen-derived signals. Missense mutations in cryopyrin (NLRP3) result in a hyperactive inflammasome that drives overproduction of the proinflammatory cytokines IL-1β and IL-18, leading to the cryopyrin-associated periodic syndromes (CAPS) disease spectrum. Mouse lines harboring CAPS-associated mutations in Nlrp3 have elevated levels of IL-1β and IL-18 and closely mimic human disease. To examine the role of inflammasome-driven IL-18 in murine CAPS, we bred Nlrp3 mutations onto an Il18r-null background. Deletion of Il18r resulted in partial phenotypic rescue that abolished skin and visceral disease in young mice and normalized serum cytokines to a greater extent than breeding to Il1r-null mice. Significant systemic inflammation developed in aging Nlrp3 mutant Il18r-null mice, indicating that IL-1 and IL-18 drive pathology at different stages of the disease process. Ongoing inflammation in double-cytokine knockout CAPS mice implicated a role for caspase-1–mediated pyroptosis and confirmed that CAPS is inflammasome dependent. Our results have important implications for patients with CAPS and residual disease, emphasizing the need to explore other NLRP3-mediated pathways and the potential for inflammasome-targeted therapy. PMID:24084736

Cyclin A2 promotes DNA repair in the brain during both development and aging.

PubMed

Gygli, Patrick E; Chang, Joshua C; Gokozan, Hamza N; Catacutan, Fay P; Schmidt, Theresa A; Kaya, Behiye; Goksel, Mustafa; Baig, Faisal S; Chen, Shannon; Griveau, Amelie; Michowski, Wojciech; Wong, Michael; Palanichamy, Kamalakannan; Sicinski, Piotr; Nelson, Randy J; Czeisler, Catherine; Otero, José J

2016-07-01

Various stem cell niches of the brain have differential requirements for Cyclin A2. Cyclin A2 loss results in marked cerebellar dysmorphia, whereas forebrain growth is retarded during early embryonic development yet achieves normal size at birth. To understand the differential requirements of distinct brain regions for Cyclin A2, we utilized neuroanatomical, transgenic mouse, and mathematical modeling techniques to generate testable hypotheses that provide insight into how Cyclin A2 loss results in compensatory forebrain growth during late embryonic development. Using unbiased measurements of the forebrain stem cell niche, we parameterized a mathematical model whereby logistic growth instructs progenitor cells as to the cell-types of their progeny. Our data was consistent with prior findings that progenitors proliferate along an auto-inhibitory growth curve. The growth retardation inCCNA2-null brains corresponded to cell cycle lengthening, imposing a developmental delay. We hypothesized that Cyclin A2 regulates DNA repair and that CCNA2-null progenitors thus experienced lengthened cell cycle. We demonstrate that CCNA2-null progenitors suffer abnormal DNA repair, and implicate Cyclin A2 in double-strand break repair. Cyclin A2's DNA repair functions are conserved among cell lines, neural progenitors, and hippocampal neurons. We further demonstrate that neuronal CCNA2 ablation results in learning and memory deficits in aged mice.

Human dental pulp pluripotent-like stem cells promote wound healing and muscle regeneration.

PubMed

Martínez-Sarrà, Ester; Montori, Sheyla; Gil-Recio, Carlos; Núñez-Toldrà, Raquel; Costamagna, Domiziana; Rotini, Alessio; Atari, Maher; Luttun, Aernout; Sampaolesi, Maurilio

2017-07-27

Dental pulp represents an easily accessible autologous source of adult stem cells. A subset of these cells, named dental pulp pluripotent-like stem cells (DPPSC), shows high plasticity and can undergo multiple population doublings, making DPPSC an appealing tool for tissue repair or maintenance. DPPSC were harvested from the dental pulp of third molars extracted from young patients. Growth factors released by DPPSC were analysed using antibody arrays. Cells were cultured in specific differentiation media and their endothelial, smooth and skeletal muscle differentiation potential was evaluated. The therapeutic potential of DPPSC was tested in a wound healing mouse model and in two genetic mouse models of muscular dystrophy (Scid/mdx and Sgcb-null Rag2-null γc-null). DPPSC secreted several growth factors involved in angiogenesis and extracellular matrix deposition and improved vascularisation in all three murine models. Moreover, DPPSC stimulated re-epithelialisation and ameliorated collagen deposition and organisation in healing wounds. In dystrophic mice, DPPSC engrafted in the skeletal muscle of both dystrophic murine models and showed integration in muscular fibres and vessels. In addition, DPPSC treatment resulted in reduced fibrosis and collagen content, larger cross-sectional area of type II fast-glycolytic fibres and infiltration of higher numbers of proangiogenic CD206 + macrophages. Overall, DPPSC represent a potential source of stem cells to enhance the wound healing process and slow down dystrophic muscle degeneration.

Electric Dipole Moment of the Neutron from 2+1 Flavor Lattice QCD.

PubMed

Guo, F-K; Horsley, R; Meissner, U-G; Nakamura, Y; Perlt, H; Rakow, P E L; Schierholz, G; Schiller, A; Zanotti, J M

2015-08-07

We compute the electric dipole moment d(n) of the neutron from a fully dynamical simulation of lattice QCD with 2+1 flavors of clover fermions and nonvanishing θ term. The latter is rotated into a pseudoscalar density in the fermionic action using the axial anomaly. To make the action real, the vacuum angle θ is taken to be purely imaginary. The physical value of dd(n) is obtained by analytic continuation. We find d(n)=-3.9(2)(9)×10(-16) θ  e cm, which, when combined with the experimental limit on d(n), leads to the upper bound |θ|≲7.4×10(-11).

Conductance oscillations in molecularly linked Au nanoparticle film-superconductor systems.

PubMed

Dunford, Jeffrey L; Dhirani, Al-Amin

2008-01-16

Charge transport across a disordered normal-superconductor (DN-S) interface was studied using a macroscopic, molecularly linked Au nanoparticle film as the DN component. Low-temperature conductance versus voltage and magnetic field exhibit zero-bias and zero-field peaks, respectively. Importantly, the latter typically exhibit superimposed oscillations. Such oscillations are rarely seen in other DN-S systems and are remarkable given their robustness in these macroscopic films and interfaces. A number of observations indicate that conductance peaks and oscillations arise due to a 'reflectionless tunnelling' process. Scattering length scales extracted from the data using a reflectionless tunnelling picture are consistent with literature values. Factors resulting in the observation of oscillations in this system are discussed.

Isotopically exchangeable organic hydrogen in coal relates to thermal maturity and maceral composition

USGS Publications Warehouse

Mastalerz, Maria; Schimmelmann, A.

2002-01-01

Hydrogen isotopic exchangeability (Hex) and ??Dn values of non-exchangeable organic hydrogen were investigated in coal kerogens ranging in rank from lignite to graphite. The relative abundance of Hex is highest in lignite with about 18% of total hydrogen being exchangeable, and decreases to around 2.5% in coals with Ro of 1.7 to ca. 5.7%. At Still higher rank (Ro > 6%), Hex increases slightly, although the abundance of total hydrogen decreases. ??Dn is influenced by original biochemical D/H ratios and by thermal maturation in contact with water. Therefore, ??Dn does not show an overall consistent trend with maturity. ?? 2002 Elsevier Science Ltd. All rights reserved.

NanI Sialidase, CcpA, and CodY Work Together To Regulate Epsilon Toxin Production by Clostridium perfringens Type D Strain CN3718.

PubMed

Li, Jihong; Freedman, John C; McClane, Bruce A

2015-10-01

Clostridium perfringens type D strains are usually associated with diseases of livestock, and their virulence requires the production of epsilon toxin (ETX). We previously showed (J. Li, S. Sayeed, S. Robertson, J. Chen, and B. A. McClane, PLoS Pathog 7:e1002429, 2011, http://dx.doi.org/10.1371/journal.ppat.1002429) that BMC202, a nanI null mutant of type D strain CN3718, produces less ETX than wild-type CN3718 does. The current study proved that the lower ETX production by strain BMC202 is due to nanI gene disruption, since both genetic and physical (NanI or sialic acid) complementation increased ETX production by BMC202. Furthermore, a sialidase inhibitor that interfered with NanI activity also reduced ETX production by wild-type CN3718. The NanI effect on ETX production was shown to involve reductions in codY and ccpA gene transcription levels in BMC202 versus wild-type CN3718. Similar to CodY, CcpA was found to positively control ETX production. A double codY ccpA null mutant produced even less ETX than a codY or ccpA single null mutant. CcpA bound directly to sequences upstream of the etx or codY start codon, and bioinformatics identified putative CcpA-binding cre sites immediately upstream of both the codY and etx start codons, suggesting possible direct CcpA regulatory effects. A ccpA mutation also decreased codY transcription, suggesting that CcpA effects on ETX production can be both direct and indirect, including effects on codY transcription. Collectively, these results suggest that NanI, CcpA, and CodY work together to regulate ETX production, with NanI-generated sialic acid from the intestines possibly signaling type D strains to upregulate their ETX production and induce disease. Clostridium perfringens NanI was previously shown to increase ETX binding to, and cytotoxicity for, MDCK host cells. The current study demonstrates that NanI also regulates ETX production via increased transcription of genes encoding the CodY and CcpA global regulators. Results obtained using single ccpA or codY null mutants and a ccpA codY double null mutant showed that codY and ccpA regulate ETX production independently of one another but that ccpA also affects codY transcription. Electrophoretic mobility shift assays and bioinformatic analyses suggest that both CodY and CcpA may directly regulate etx transcription. Collectively, results of this study suggest that sialic acid generated by NanI from intestinal sources signals ETX-producing C. perfringens strains, via CcpA and CodY, to upregulate ETX production and cause disease. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Explaining Human Behavior.

ERIC Educational Resources Information Center

Olson, Alton T.; And Others

The Deductive-Nomological (D-N) model of human behavior is useful and provides the most objective explanation when it is appropriate but it is not necessarily an all-inclusive statement. For instance, explaining human behavior is always an act that entails languages and theories that are value laden and reveal human choices; however the D-N model…

The Philosophy of Science and Technology in China: Political and Ideological Influences

ERIC Educational Resources Information Center

Guo, Yuanlin

2014-01-01

In China, the philosophy of science and technology (PST) is derived from "Dialectics of Nature" (DN), which is based on Engels' unfinished book "Dialektik der Natur." DN as a political ideology provides political guidance for scientists and engineers. Therefore, since 1981, "Introduction to Dialectics of Nature" (IDN)…

Fenofibrate attenuates diabetic nephropathy in experimental diabetic rat's model via suppression of augmented TGF-β1/Smad3 signaling pathway.

PubMed

Al-Rasheed, Nouf Mohamed; Al-Rasheed, Nawal Mohamed; Al-Amin, Maha Abdelrahman; Hasan, Iman Huesein; Al-Ajmi, Hanaa Najeeb; Mohammad, Raeesa Ahmed; Attia, Hala Aboulfotooh

2016-10-01

Fibrates, the ligands of peroxisome profileferator-activated receptor-α have been shown to have a renal protective action in diabetic nephropathy (DN). This study aimed to elucidate the effect of fenofibrate on renal transforming growth factor-β1 (TGF-β1) and Smad3 in Streptozotocin (STZ)-induced DN. Diabetes was induced in rats by a single intraperitoneal injection of streptozotocin (55 mg/kg). Diabetic rats were given fenofibrate (100 mg/kg, p.o.). After 12 weeks, diabetic nephropathy biomarkers were assessed. The mRNA expression of collage I and III, TGF-β1 and Smad3 and were detected by RT-PCR. Fenofibrate reduced significantly serum creatinine, kidney/body weight ratio, serum albumin excretion Collage I & III, TGF-β1 and Smad3 mRNA expression. Our results give further insights into the mechanisms underlying the protective role of fenofibrate in DN, suggesting that interference with TGF-β1/Smad3 signaling pathway may be a useful therapeutic approach to prevent DN.

Discovery of 1-(4-((3-(4-methylpiperazin-1-yl)propyl)amino)benzyl)-5-(trifluoromethyl)pyridin-2(1H)-one, an orally active multi-target agent for the treatment of diabetic nephropathy.

PubMed

Chen, Jun; Peng, Zhangzhe; Lu, Miaomiao; Xiong, Xuan; Chen, Zhuo; Li, Qianbin; Cheng, Zeneng; Jiang, Dejian; Tao, Lijian; Hu, Gaoyun

2018-01-15

Oxidative stress, inflammation and fibrosis can cause irreversible damage on cell structure and function of kidney and are key pathological factors in Diabetic Nephropathy (DN). Therefore, multi-target agents are urgently need for the clinical treatment of DN. Using Pirfenidone as a lead compound and based on the previous research, two novel series (5-trifluoromethyl)-2(1H)-pyridone analogs were designed and synthesized. SAR of (5-trifluoromethyl)-2(1H)-pyridone derivatives containing nitrogen heterocyclic ring have been established for in vitro potency. In addition, compound 8, a novel agent that act on multiple targets of anti-DN with IC 50 of 90μM in NIH3T3 cell lines, t 1/2 of 4.89±1.33h in male rats and LD 50 >2000mg/kg in mice, has been advanced to preclinical studies as an oral treatment for DN. Copyright © 2017 Elsevier Ltd. All rights reserved.

Experimental evaluation of 150-millimeter bore ball bearing to 3 million DN using either solid or drilled balls

NASA Technical Reports Server (NTRS)

Scibbe, H. W.; Munson, H. E.

1973-01-01

Seven 150-mm bore ball bearings were run under 8900 Newton (2000 lb) thrust load at speeds from 6670 to 20,000 rpm (1 to 3 million DN). Four of the bearings had conventional solid balls and three bearing had drilled (cylindrically hollow) balls with 50 percent mass reduction. The bearings were under-race cooled and slot-lubricated with Type 2 ester oil at flow rates from 4.35 to 5.80 liters per minute (1.15 to 1.57 gal min). Friction torque and temperatures were measured on all bearings. No significant difference in torque was noted, between the solid and drilled ball bearings. One bearing of each type was rerun at 17,800 Newtons (4000 lb) thrust load. The solid ball bearings performed satisfactorily at 3 million DN. However, at about 2 million DN the drilled ball bearing experienced a broken ball and cracks appeared in two other balls as the result of flexure fatigue. Metallurgical examination of the cracked balls indicated a brittle structure in the bore of the drilled balls.

Thermal lensing compensation optics for high power lasers

NASA Astrophysics Data System (ADS)

Scaggs, Michael; Haas, Gil

2011-03-01

Athermalization of focusing objectives is a common technique for optimizing imaging systems in the infrared where thermal effects are a major concern. The athermalization is generally done within the spectrum of interest and not generally applied to a single wavelength. The predominate glass used with high power infrared lasers in the near infrared of one micron, such as Nd:YAG and fiber lasers, is fused silica which has excellent thermal properties. All glasses, however, have a temperature coefficient of index of refraction (dn/dT) where as the glass heats up its index of refraction changes. Most glasses, fused silica included, have a positive dn/dT. A positive dn/dT will cause the focal length of the lens to decrease with a temperature rise. Many of the fluoride glasses, like CaF2, BaF2, LiF2, etc. have a negative dn/dT. By applying athermalization techniques of glass selection and optical design, the thermal lensing in a laser objective of a high power laser system can be substantially mitigated. We describe a passive method for minimizing thermal lensing of high power laser optics.

The Phoenix TECP Relative Humidity Sensor: Revised Results

NASA Technical Reports Server (NTRS)

Zent, Aaron

2014-01-01

The original calibration function of the RH sensor on the Phoenix mission's Thermal and Electrical Conductivity Sensor (TECP), has been revised to correct the erroneously-published original calibration equation, to demonstrate the value of this unique data set, and to improve characterization of H2O exchange between the martian regolith and atmosphere. TECP returned two data streams, the temperature of the electronics analog board (Tb) and the digital 12-bit output of the RH sensor (DN), both of which are required to uniquely specify the H2O abundance. Because the original flight instrument calibration was performed against a pair of hygrometers that measured frost point (Tf), the revised calibration equation is also cast in terms of frost point. The choice of functional form for the calibration function is minimally constrained. A series of profiles across the calibration data cloud at constant DN and Tb does not reveal any evidence of a complex functional form. Therefore, a series of polynomials in both DN and Tb was investigated, along with several non-linear functions of DN and Tb.

Cutaneous malignant melanoma and familial dysplastic nevi: evidence for autosomal dominance and pleiotropy.

PubMed Central

Bale, S J; Chakravarti, A; Greene, M H

1986-01-01

Segregation of familial cutaneous melanoma has been shown to be compatible with autosomal dominant transmission with incomplete penetrance. However, the combined phenotype of melanoma and a known melanoma-precursor lesion, the dysplastic nevus (DN), has not previously been found to fit a Mendelian model of inheritance using complex segregation analysis. Employing a life-table and disease-free survival analysis approach, we estimated the lifetime incidence of melanoma in the sibs and offspring of DN-affected individuals to be 46%, consistent with a highly penetrant, autosomal dominant mode of inheritance. To further elucidate the relationship between the two traits, we conducted a linkage analysis between the melanoma locus and a hypothetical DN locus, and obtained a maximum lod score of 3.857 at theta = .08. Furthermore, all families giving evidence for linkage were in the coupling phase and the maximum likelihood estimate of theta was not significantly different from 0 (P = .1). This provides evidence that the DN and melanoma traits may represent pleiotropic effects of a single, highly penetrant gene behaving in an autosomal dominant manner. PMID:3456198

Tongxinluo ameliorates renal structure and function by regulating miR-21-induced epithelial-to-mesenchymal transition in diabetic nephropathy.

PubMed

Wang, Jin-yang; Gao, Yan-bin; Zhang, Na; Zou, Da-wei; Xu, Li-ping; Zhu, Zhi-yao; Li, Jiao-yang; Zhou, Sheng-nan; Cui, Fang-qiang; Zeng, Xiang-jun; Geng, Jian-guo; Yang, Jin-kui

2014-03-01

Diabetic nephropathy (DN) is one of the most important diabetic microangiopathies. The epithelial-to-mesenchymal transition (EMT) plays an important role in DN. The physiological role of microRNA-21 (miR-21) was closely linked to EMT. However, it remained elusive whether tongxinluo (TXL) ameliorated renal structure and function by regulating miR-21-induced EMT in DN. This study aimed to determine the effect of TXL on miR-21-induced renal tubular EMT and to explore the relationship between miR-21 and TGF-β1/smads signals. Real-time RT-PCR, cell transfection, in situ hybridization (ISH), and laser confocal microscopy were used, respectively. Here, we revealed that TXL dose dependently lowered miR-21 expression in tissue, serum, and cells. Overexpression of miR-21 can enhance α-smooth muscle actin (SMA) expression and decrease E-cadherin expression by upregulating smad3/p-smad3 expression and downregulating smad7 expression. Interestingly, TXL also increased E-cadherin expression and decreased α-SMA expression by regulating miR-21 expression. More importantly, TXL decreased collagen IV, fibronectin, glomerular basement membrane, glomerular area, and the albumin/creatinine ratio, whereas it increased the creatinine clearance ratio. The results demonstrated that TXL ameliorated renal structure and function by regulating miR-21-induced EMT, which was one of the mechanisms to protect against DN, and that miR-21 may be one of the therapeutic targets for TXL in DN.

Maternal choline supplementation improves spatial learning and adult hippocampal neurogenesis in the Ts65Dn mouse model of Down syndrome.

PubMed

Velazquez, Ramon; Ash, Jessica A; Powers, Brian E; Kelley, Christy M; Strawderman, Myla; Luscher, Zoe I; Ginsberg, Stephen D; Mufson, Elliott J; Strupp, Barbara J

2013-10-01

In addition to intellectual disability, individuals with Down syndrome (DS) exhibit dementia by the third or fourth decade of life, due to the early onset of neuropathological changes typical of Alzheimer's disease (AD). Deficient ontogenetic neurogenesis contributes to the brain hypoplasia and hypocellularity evident in fetuses and children with DS. A murine model of DS and AD (the Ts65Dn mouse) exhibits key features of these disorders, notably deficient ontogenetic neurogenesis, degeneration of basal forebrain cholinergic neurons (BFCNs), and cognitive deficits. Adult hippocampal (HP) neurogenesis is also deficient in Ts65Dn mice and may contribute to the observed cognitive dysfunction. Herein, we demonstrate that supplementing the maternal diet with additional choline (approximately 4.5 times the amount in normal rodent chow) dramatically improved the performance of the adult trisomic offspring in a radial arm water maze task. Ts65Dn offspring of choline-supplemented dams performed significantly better than unsupplemented Ts65Dn mice. Furthermore, adult hippocampal neurogenesis was partially normalized in the maternal choline supplemented (MCS) trisomic offspring relative to their unsupplemented counterparts. A significant correlation was observed between adult hippocampal neurogenesis and performance in the water maze, suggesting that the increased neurogenesis seen in the supplemented trisomic mice contributed functionally to their improved spatial cognition. These findings suggest that supplementing the maternal diet with additional choline has significant translational potential for DS. Copyright © 2013 Elsevier Inc. All rights reserved.

Nitrosonifedipine Ameliorates the Progression of Type 2 Diabetic Nephropathy by Exerting Antioxidative Effects

PubMed Central

Ishizawa, Keisuke; Izawa-Ishizawa, Yuki; Yamano, Noriko; Urushihara, Maki; Sakurada, Takumi; Imanishi, Masaki; Fujii, Shoko; Nuno, Asami; Miyamoto, Licht; Kihira, Yoshitaka; Ikeda, Yasumasa; Kagami, Shoji; Kobori, Hiroyuki; Tsuchiya, Koichiro; Tamaki, Toshiaki

2014-01-01

Diabetic nephropathy (DN) is the major cause of end-stage renal failure. Oxidative stress is implicated in the pathogenesis of DN. Nitrosonifedipine (NO-NIF) is a weak calcium channel blocker that is converted from nifedipine under light exposure. Recently, we reported that NO-NIF has potential as a novel antioxidant with radical scavenging abilities and has the capacity to treat vascular dysfunction by exerting an endothelial protective effect. In the present study, we extended these findings by evaluating the efficacy of NO-NIF against DN and by clarifying the mechanisms of its antioxidative effect. In a model of type 2 DN (established in KKAy mice), NO-NIF administration reduced albuminuria and proteinuria as well as glomerular expansion without affecting glucose metabolism or systolic blood pressure. NO-NIF also suppressed renal and systemic oxidative stress and decreased the expression of intercellular adhesion molecule (ICAM)-1, a marker of endothelial cell injury, in the glomeruli of the KKAy mice. Similarly, NO-NIF reduced albuminuria, oxidative stress, and ICAM-1 expression in endothelial nitric oxide synthase (eNOS) knockout mice. Moreover, NO-NIF suppressed urinary angiotensinogen (AGT) excretion and intrarenal AGT protein expression in proximal tubular cells in the KKAy mice. On the other hand, hyperglycemia-induced mitochondrial superoxide production was not attenuated by NO-NIF in cultured endothelial cells. These findings suggest that NO-NIF prevents the progression of type 2 DN associated with endothelial dysfunction through selective antioxidative effects. PMID:24489716

Overlapping trisomies for human chromosome 21 orthologs produce similar effects on skull and brain morphology of Dp(16)1Yey and Ts65Dn mice.

PubMed

Starbuck, John M; Dutka, Tara; Ratliff, Tabetha S; Reeves, Roger H; Richtsmeier, Joan T

2014-08-01

Trisomy 21 results in gene-dosage imbalance during embryogenesis and throughout life, ultimately causing multiple anomalies that contribute to the clinical manifestations of Down syndrome. Down syndrome is associated with manifestations of variable severity (e.g., heart anomalies, reduced growth, dental anomalies, shortened life-span). Craniofacial dysmorphology and cognitive dysfunction are consistently observed in all people with Down syndrome. Mouse models are useful for studying the effects of gene-dosage imbalance on development. We investigated quantitative changes in the skull and brain of the Dp(16)1Yey Down syndrome mouse model and compared these mice to Ts65Dn and Ts1Cje mouse models. Three-dimensional micro-computed tomography images of Dp(16)1Yey and euploid mouse crania were morphometrically evaluated. Cerebellar cross-sectional area, Purkinje cell linear density, and granule cell density were evaluated relative to euploid littermates. Skulls of Dp(16)1Yey and Ts65Dn mice displayed similar changes in craniofacial morphology relative to their respective euploid littermates. Trisomy-based differences in brain morphology were also similar in Dp(16)1Yey and Ts65Dn mice. These results validate examination of the genetic basis for craniofacial and brain phenotypes in Dp(16)1Yey mice and suggest that they, like Ts65Dn mice, are valuable tools for modeling the effects of trisomy 21 on development. © 2014 Wiley Periodicals, Inc.

Overlapping Trisomies for Human Chromosome 21 Orthologs Produce Similar Effects on Skull and Brain Morphology of Dp(16)1Yey and Ts65Dn Mice

PubMed Central

Ratliff, Tabetha S.; Reeves, Roger H.; Richtsmeier, Joan T.

2014-01-01

Trisomy 21 results in gene-dosage imbalance during embryogenesis and throughout life, ultimately causing multiple anomalies that contribute to the clinical manifestations of Down syndrome. Down syndrome is associated with manifestations of variable severity (e.g., heart anomalies, reduced growth, dental anomalies, shortened life-span). Craniofacial dysmorphology and cognitive dysfunction are consistently observed in all people with Down syndrome. Mouse models are useful for studying the effects of gene-dosage imbalance on development. We investigated quantitative changes in the skull and brain of the Dp(16) 1Yey Down syndrome mouse model and compared these mice to Ts65Dn and Ts1Cje mouse models. Three-dimensional microcomputed tomography images of Dp(16)1Yey and euploid mouse crania were morphometrically evaluated. Cerebellar cross-sectional area, Purkinje cell linear density, and granule cell density were evaluated relative to euploid littermates. Skulls of Dp(16)1Yey and Ts65Dn mice displayed similar changes in craniofacial morphology relative to their respective euploid littermates. Trisomy-based differences in brain morphology were also similar in Dp(16)1Yey and Ts65Dn mice. These results validate examination of the genetic basis for craniofacial and brain phenotypes in Dp(16)1Yey mice and suggest that they, like Ts65Dn mice, are valuable tools for modeling the effects of trisomy 21 on development. PMID:24788405

Identification of heparin-binding EGF-like growth factor as a target in intercellular regulation of epidermal basal cell growth by suprabasal retinoic acid receptors.

PubMed Central

Xiao, J H; Feng, X; Di, W; Peng, Z H; Li, L A; Chambon, P; Voorhees, J J

1999-01-01

The role of retinoic acid receptors (RARs) in intercellular regulation of cell growth was assessed by targeting a dominant-negative RARalpha mutant (dnRARalpha) to differentiated suprabasal cells of mouse epidermis. dnRARalpha lacks transcriptional activation but not DNA-binding and receptor dimerization functions. Analysis of transgenic mice revealed that dnRARalpha dose-dependently impaired induction of basal cell proliferation and epidermal hyperplasia by all-trans RA (tRA). dnRARalpha formed heterodimers with endogenous retinoid X receptor-alpha (RXRalpha) over RA response elements in competition with remaining endogenous RARgamma-RXRalpha heterodimers, and dose-dependently impaired retinoid-dependent gene transcription. To identify genes regulated by retinoid receptors and involved in cell growth control, we analyzed the retinoid effects on expression of the epidermal growth factor (EGF) receptor, EGF, transforming growth factor-alpha, heparin-binding EGF-like growth factor (HB-EGF) and amphiregulin genes. In normal epidermis, tRA rapidly and selectively induced expression of HB-EGF but not the others. This induction occurred exclusively in suprabasal cells. In transgenic epidermis, dnRARalpha dose-dependently inhibited tRA induction of suprabasal HB-EGF and subsequent basal cell hyperproliferation. Together, our observations suggest that retinoid receptor heterodimers located in differentiated suprabasal cells mediate retinoid induction of HB-EGF, which in turn stimulates basal cell growth via intercellular signaling. These events may underlie retinoid action in epidermal regeneration during wound healing. PMID:10075925

Social Norm, Family Communication, and HBV Screening among Asian Americans.

PubMed

Juon, Hee-Soon; Rimal, Rajiv N; Klassen, Ann; Lee, Sunmin

2017-12-01

Individuals' behaviors are influenced by those of others in their social environment (i.e., descriptive norms), as well as by how individuals perceive they should behave in that environment (e.g., injunctive norms). Although social norms are thought to play an important role in hepatitis B virus (HBV) screening, limited theoretical or empirical guidance exists on how the underlying process works. In addition, norms are social phenomena that are spread through family discussion about the importance of getting HBV screening. Using the theory of normative social behavior (TNSB), this study examined the roles of injunctive norms (IN), descriptive norms (DN), and family discussion in HBV screening behavior among Asian Americans. Data from a survey of Asian Americans in the Baltimore Washington metropolitan area (N = 877) were used to test underlying theoretical propositions. DN and family discussion emerged as key factors in HBV screening behavior among all Asian Americans. IN were associated with HBV screening among Chinese and Korean Americans, but not for Vietnamese Americans. Family discussion moderated the influence of DN on behavior among Chinese and Vietnamese Americans. However, the main effect of DN on screening behavior was not modified by IN (no interactions between DN and IN). The results indicate that family discussion and social norms are integral in enabling Asian Americans to undergo HBV screening and warrant sensitivity in the design and implementation of a liver cancer prevention program in this high-risk group of Asian Americans.

Maternal choline supplementation improves spatial learning and adult hippocampal neurogenesis in the Ts65Dn mouse model of Down syndrome

PubMed Central

Velazquez, Ramon; Ash, Jessica A.; Powers, Brian E.; Kelley, Christy M.; Strawderman, Myla; Luscher, Zoe I.; Ginsberg, Stephen D.; Mufson, Elliott J.; Strupp, Barbara J.

2014-01-01

In addition to intellectual disability, individuals with Down syndrome (DS) exhibit dementia by the third or fourth decade of life, due to the early onset of neuropathological changes typical of Alzheimer’s disease (AD). Deficient ontogenetic neurogenesis contributes to the brain hypoplasia and hypocellularity evident in fetuses and children with DS. A murine model of DS and AD (the Ts65Dn mouse) exhibits key features of these disorders, notably deficient ontogenetic neurogenesis, degeneration of basal forebrain cholinergic neurons (BFCNs), and cognitive deficits. Adult hippocampal (HP) neurogenesis is also deficient in Ts65Dn mice and may contribute to the observed cognitive dysfunction. Herein, we demonstrate that supplementing the maternal diet with additional choline (approximately 4.5 times the amount in normal rodent chow) dramatically improved the performance of the adult trisomic offspring in a radial arm water maze task. Ts65Dn offspring of choline-supplemented dams performed significantly better than unsupplemented Ts65Dn mice. Furthermore, adult hippocampal neurogenesis was partially normalized in the maternal choline supplemented (MCS) trisomic offspring relative to their unsupplemented counterparts. A significant correlation was observed between adult hippocampal neurogenesis and performance in the water maze, suggesting that the increased neurogenesis seen in the supplemented trisomic mice contributed functionally to their improved spatial cognition. These findings suggest that supplementing the maternal diet with additional choline has significant translational potential for DS. PMID:23643842

Association of single nucleotide polymorphisms in the gene encoding GLUT1 and diabetic nephropathy in Brazilian patients with type 1 diabetes mellitus.

PubMed

Marques, T; Patente, T A; Monteiro, M B; Cavaleiro, A M; Queiroz, M S; Nery, M; de Azevedo, M J; Canani, L H; Parisi, M C; Moura-Neto, A; Passarelli, M; Giannella-Neto, D; Machado, U F; Corrêa-Giannella, M L

2015-04-15

Mesangial cells subject to high extracellular glucose concentrations, as occur in hyperglycaemic states, are unable to down regulate glucose influx, resulting in intracellular activation of deleterious biochemical pathways. A high expression of GLUT1 participates in the development of diabetic glomerulopathy. Variants in the gene encoding GLUT1 (SLC2A1) have been associated to this diabetic complication. The aim of this study was to test whether polymorphisms in SLC2A1 confer susceptibility to diabetic nephropathy (DN) in Brazilian type 1 diabetes patients. Four polymorphisms (rs3820589, rs1385129, rs841847 and rs841848) were genotyped in a Brazilian cohort comprised of 452 patients. A prospective analysis was performed in 155 patients. Mean duration of follow-up was 5.6 ± 2.4 years and the incidence of renal events was 18.0%. The rs3820589 presented an inverse association with the prevalence of incipient DN (OR: 0.36, 95% CI: 0.16 - 0.80, p=0.01) and with progression to renal events (HR: 0.20; 95% CI: 0.03 - 0.70; p=0.009). AGGT and AGAC haplotypes were associated with the prevalence of incipient DN and the AGAC haplotype was also associated with the prevalence of established/advanced DN. In conclusion, rs3820589 in the SLC2A1 gene modulates the risk to DN in Brazilian patients with inadequate type 1 diabetes control. Copyright © 2015 Elsevier B.V. All rights reserved.

Is the cardiac monitoring function related to the self in both the default network and right anterior insula?

PubMed

Babo-Rebelo, Mariana; Wolpert, Nicolai; Adam, Claude; Hasboun, Dominique; Tallon-Baudry, Catherine

2016-11-19

The self has been proposed to be rooted in the neural monitoring of internal bodily signals and might thus involve interoceptive areas, notably the right anterior insula (rAI). However, studies on the self consistently showed the involvement of midline default network (DN) nodes, without referring to visceral monitoring. Here, we investigate this apparent discrepancy. We previously showed that neural responses to heartbeats in the DN encode two different self-dimensions, the agentive 'I' and the introspective 'Me', in a whole-brain analysis of magnetoencephalography (MEG) data. Here, we confirm and anatomically refine this result with intracranial recordings (intracranial electroencephalography, iEEG). In two patients, we show a parametric modulation of neural responses to heartbeats by the self-relatedness of thoughts, at the single trial level. A region-of-interest analysis of the insula reveals that MEG responses to heartbeats in the rAI encode the 'I' self-dimension. The effect in rAI was weaker than in the DN and was replicated in iEEG data in one patient out of two. We propose that a common mechanism, the neural monitoring of cardiac signals, underlies the self in both the DN and rAI. This might reconcile studies on the self highlighting the DN, with studies on interoception focusing on the insula.This article is part of the themed issue 'Interoception beyond homeostasis: affect, cognition and mental health'. © 2016 The Authors.

FADD and the NF-κB family member Bcl-3 regulate complementary pathways to control T-cell survival and proliferation

PubMed Central

Rangelova, Svetla; Kirschnek, Susanne; Strasser, Andreas; Häcker, Georg

2008-01-01

Fas-associated protein with death domain/mediator of receptor induced toxicity (FADD/MORT1) was first described as a transducer of death receptor signalling but was later recognized also to be important for proliferation of T cells. B-cell lymphoma 3 (Bcl-3) is a relatively little understood member of the nuclear factor (NF)-κB family of transcription factors. We recently found that Bcl-3 is up-regulated in T cells from mice where FADD function is blocked by a dominant negative transgene (FADD-DN). To understand the importance of this, we generated FADD-DN/bcl-3−/− mice. Here, we report that T cells from these mice show massive cell death and severely reduced proliferation in response to T-cell receptor (TCR) stimulation in vitro. Transgenic co-expression of Bcl-2 (FADD-DN/bcl-3−/−/vav-bcl-2 mice) rescued the survival but not the proliferation of T cells. FADD-DN/bcl-3−/− mice had normal thymocyte numbers but reduced numbers of peripheral T cells despite an increase in cycling T cells in vivo. However, activation of the classical NF-κB and extracellular regulated kinase (ERK) pathways and expression of interleukin (IL)-2 mRNA upon stimulation were normal in T cells from FADD-DN/bcl-3−/− mice. These data suggest that FADD and Bcl-3 regulate separate pathways that both contribute to survival and proliferation in mouse T cells. PMID:18557791

Relationship between serum bilirubin concentrations and diabetic nephropathy in Shanghai Han's patients with type 1 diabetes mellitus.

PubMed

Li, Xu; Zhang, Lei; Chen, Haibing; Guo, Kaifeng; Yu, Haoyong; Zhou, Jian; Li, Ming; Li, Qing; Li, Lianxi; Yin, Jun; Liu, Fang; Bao, Yuqian; Han, Junfeng; Jia, Weiping

2017-03-31

Recent studies highlight a negative association between total bilirubin concentrations and albuminuria in patients with type 2 diabetes mellitus. Our study evaluated the relationship between bilirubin concentrations and the prevalence of diabetic nephropathy (DN) in Chinese patients with type 1 diabetes mellitus (T1DM). A total of 258 patients with T1DM were recruited and bilirubin concentrations were compared between patients with or without diabetic nephropathy. Multiple stepwise regression analysis was used to examine the relationship between bilirubin concentrations and 24 h urinary microalbumin. Binary logistic regression analysis was performed to assess independent risk factors for diabetic nephropathy. Participants were divided into four groups according to the quartile of total bilirubin concentrations (Q1, 0.20-0.60; Q2, 0.60-0.80; Q3, 0.80-1.00; Q4, 1.00-1.90 mg/dL) and the chi-square test was used to compare the prevalence of DN in patients with T1DM. The median bilirubin level was 0.56 (interquartile: 0.43-0.68 mg/dL) in the DN group, significantly lower than in the non-DN group (0.70 [interquartile: 0.58-0.89 mg/dL], P < 0.001). Spearman's correlational analysis showed bilirubin concentrations were inversely correlated with 24 h urinary microalbumin (r = -0.13, P < 0.05) and multiple stepwise regression analysis showed bilirubin concentrations were independently associated with 24 h urinary microalbumin. In logistic regression analysis, bilirubin concentrations were significantly inversely associated with nephropathy. In addition, in stratified analysis, from the first to the fourth quartile group, increased bilirubin concentrations were associated with decreased prevalence of DN from 21.90% to 2.00%. High bilirubin concentrations are independently and negatively associated with albuminuria and the prevalence of DN in patients with T1DM.

Comparing proton treatment plans of pediatric brain tumors in two pencil beam scanning nozzles with different spot sizes

PubMed Central

Kralik, John C.; Xi, Liwen; Solberg, Timothy D.; Simone, Charles B.

2015-01-01

Target coverage and organ‐at‐risk sparing were compared for 22 pediatric patients with primary brain tumors treated using two distinct nozzles in pencil beam scanning (PBS) proton therapy. Consecutive patients treated at our institution using a PBS‐dedicated nozzle (DN) were replanned using a universal nozzle (UN) beam model and the original DN plan objectives. Various cranial sites were treated among the patients to prescription doses ranging from 45 to 54 Gy. Organs at risk (OARs) evaluated were patient‐dependent; 15 unique OARs were analyzed, all of which were assessed in at least 10 patients. Clinical target volume (CTV) coverage and organ sparing were compared for the two nozzles using dose‐volume histogram data. Statistical analysis using a confidence‐interval approach demonstrates that CTV coverage is equivalent for UN and DN plans within ±5% equivalence bounds. In contrast, average mean and maximum doses are significantly higher for nearly all 15 OARs in the UN plans. The average median increase over all OARs and patients is approximately 1.7 Gy, with an increase in the 25%–75% of 1.0–2.3 Gy; the median increase to the pituitary gland, temporal lobes, eyes and cochleas are 1.8, 1.7, 0.7, and 2.7 Gy, respectively. The CTV dose distributions fall off slower for UN than for the DN plans; hence, normal tissue structures in close proximity to CTVs receive higher doses in UN plans than in DN plans. The higher OAR doses in the UN plans are likely due to the larger spot profile in plans created with UN beams. In light of the high rates of toxicities in pediatric patients receiving cranial irradiation and in light of selected brain tumor types having high cure rates, this study suggests the smaller DN beam profile is preferable for the advantage of reducing dose to OARs. PACS number: 87.55.D‐ PMID:26699553

Using exposure prediction tools to link exposure and dosimetry for risk-based decisions: A case study with phthalates.

PubMed

Moreau, Marjory; Leonard, Jeremy; Phillips, Katherine A; Campbell, Jerry; Pendse, Salil N; Nicolas, Chantel; Phillips, Martin; Yoon, Miyoung; Tan, Yu-Mei; Smith, Sherrie; Pudukodu, Harish; Isaacs, Kristin; Clewell, Harvey

2017-10-01

A few different exposure prediction tools were evaluated for use in the new in vitro-based safety assessment paradigm using di-2-ethylhexyl phthalate (DEHP) and dibutyl phthalate (DnBP) as case compounds. Daily intake of each phthalate was estimated using both high-throughput (HT) prediction models such as the HT Stochastic Human Exposure and Dose Simulation model (SHEDS-HT) and the ExpoCast heuristic model and non-HT approaches based on chemical specific exposure estimations in the environment in conjunction with human exposure factors. Reverse dosimetry was performed using a published physiologically based pharmacokinetic (PBPK) model for phthalates and their metabolites to provide a comparison point. Daily intakes of DEHP and DnBP were estimated based on the urinary concentrations of their respective monoesters, mono-2-ethylhexyl phthalate (MEHP) and monobutyl phthalate (MnBP), reported in NHANES (2011-2012). The PBPK-reverse dosimetry estimated daily intakes at the 50th and 95th percentiles were 0.68 and 9.58 μg/kg/d and 0.089 and 0.68 μg/kg/d for DEHP and DnBP, respectively. For DEHP, the estimated median from PBPK-reverse dosimetry was about 3.6-fold higher than the ExpoCast estimate (0.68 and 0.18 μg/kg/d, respectively). For DnBP, the estimated median was similar to that predicted by ExpoCast (0.089 and 0.094 μg/kg/d, respectively). The SHEDS-HT prediction of DnBP intake from consumer product pathways alone was higher at 0.67 μg/kg/d. The PBPK-reverse dosimetry-estimated median intake of DEHP and DnBP was comparable to values previously reported for US populations. These comparisons provide insights into establishing criteria for selecting appropriate exposure prediction tools for use in an integrated modeling platform to link exposure to health effects. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Inhibition of Thrombopoietin/Mpl Signaling in Adult Hematopoiesis Identifies New Candidates for Hematopoietic Stem Cell Maintenance.

PubMed

Kohlscheen, Saskia; Wintterle, Sabine; Schwarzer, Adrian; Kamp, Christel; Brugman, Martijn H; Breuer, Daniel C; Büsche, Guntram; Baum, Christopher; Modlich, Ute

2015-01-01

Thrombopoietin (Thpo) signals via its receptor Mpl and regulates megakaryopoiesis, hematopoietic stem cell (HSC) maintenance and post-transplant expansion. Mpl expression is tightly controlled and deregulation of Thpo/Mpl-signaling is linked to hematological disorders. Here, we constructed an intracellular-truncated, signaling-deficient Mpl protein which is presented on the cell surface (dnMpl). The transplantation of bone marrow cells retrovirally transduced to express dnMpl into wildtype mice induced thrombocytopenia, and a progressive loss of HSC. The aplastic BM allowed the engraftment of a second BM transplant without further conditioning. Functional analysis of the truncated Mpl in vitro and in vivo demonstrated no internalization after Thpo binding and the inhibition of Thpo/Mpl-signaling in wildtype cells due to dominant-negative (dn) effects by receptor competition with wildtype Mpl for Thpo binding. Intracellular inhibition of Mpl could be excluded as the major mechanism by the use of a constitutive-dimerized dnMpl. To further elucidate the molecular changes induced by Thpo/Mpl-inhibition on the HSC-enriched cell population in the BM, we performed gene expression analysis of Lin-Sca1+cKit+ (LSK) cells isolated from mice transplanted with dnMpl transduced BM cells. The gene expression profile supported the exhaustion of HSC due to increased cell cycle progression and identified new and known downstream effectors of Thpo/Mpl-signaling in HSC (namely TIE2, ESAM1 and EPCR detected on the HSC-enriched LSK cell population). We further compared gene expression profiles in LSK cells of dnMpl mice with human CD34+ cells of aplastic anemia patients and identified similar deregulations of important stemness genes in both cell populations. In summary, we established a novel way of Thpo/Mpl inhibition in the adult mouse and performed in depth analysis of the phenotype including gene expression profiling.

Inhibition of Thrombopoietin/Mpl Signaling in Adult Hematopoiesis Identifies New Candidates for Hematopoietic Stem Cell Maintenance

PubMed Central

Schwarzer, Adrian; Kamp, Christel; Brugman, Martijn H.; Breuer, Daniel C.; Büsche, Guntram; Baum, Christopher; Modlich, Ute

2015-01-01

Thrombopoietin (Thpo) signals via its receptor Mpl and regulates megakaryopoiesis, hematopoietic stem cell (HSC) maintenance and post-transplant expansion. Mpl expression is tightly controlled and deregulation of Thpo/Mpl-signaling is linked to hematological disorders. Here, we constructed an intracellular-truncated, signaling-deficient Mpl protein which is presented on the cell surface (dnMpl). The transplantation of bone marrow cells retrovirally transduced to express dnMpl into wildtype mice induced thrombocytopenia, and a progressive loss of HSC. The aplastic BM allowed the engraftment of a second BM transplant without further conditioning. Functional analysis of the truncated Mpl in vitro and in vivo demonstrated no internalization after Thpo binding and the inhibition of Thpo/Mpl-signaling in wildtype cells due to dominant-negative (dn) effects by receptor competition with wildtype Mpl for Thpo binding. Intracellular inhibition of Mpl could be excluded as the major mechanism by the use of a constitutive-dimerized dnMpl. To further elucidate the molecular changes induced by Thpo/Mpl-inhibition on the HSC-enriched cell population in the BM, we performed gene expression analysis of Lin-Sca1+cKit+ (LSK) cells isolated from mice transplanted with dnMpl transduced BM cells. The gene expression profile supported the exhaustion of HSC due to increased cell cycle progression and identified new and known downstream effectors of Thpo/Mpl-signaling in HSC (namely TIE2, ESAM1 and EPCR detected on the HSC-enriched LSK cell population). We further compared gene expression profiles in LSK cells of dnMpl mice with human CD34+ cells of aplastic anemia patients and identified similar deregulations of important stemness genes in both cell populations. In summary, we established a novel way of Thpo/Mpl inhibition in the adult mouse and performed in depth analysis of the phenotype including gene expression profiling. PMID:26147434

Trichloroethylene Exposure Reduces Liver Injury in a Mouse Model of Primary Biliary Cholangitis.

PubMed

Ray, Jessica L; Kopec, Anna K; Joshi, Nikita; Cline-Fedewa, Holly; Lash, Lawrence H; Williams, Kurt J; Leung, Patrick S; Gershwin, M Eric; Luyendyk, James P

2017-04-01

Trichloroethylene (TCE) is a persistent environmental contaminant proposed to contribute to autoimmune disease. Experimental studies in lupus-prone MRL+/+ mice have suggested that TCE exposure can trigger autoimmune hepatitis. The vast majority of studies examining the connection between TCE and autoimmunity utilize this model, and the impact of TCE exposure in other established models of autoimmune liver disease is not known. We tested the hypothesis that TCE exposure exacerbates experimental hepatic autoimmunity in dominant negative transforming growth factor beta receptor type II (dnTGFBRII) mice, which develop serological and histological features resembling human primary biliary cholangitis. Female 8-week-old wild-type and dnTGFBRII mice were exposed to TCE (0.5 mg/ml) or vehicle (1% ethoxylated castor oil) in the drinking water for 12 or 22 weeks. Liver histopathology in 20- and 30-week-old wild-type mice was unremarkable irrespective of treatment. Mild portal inflammation was observed in vehicle-exposed 20-week-old dnTGFBRII mice and was not exacerbated by TCE exposure. Vehicle-exposed 30-week-old dnTGFBRII mice developed anti-mitochondrial antibodies, marked hepatic inflammation with necrosis, and hepatic accumulation of both B and T lymphocytes. To our surprise, TCE exposure dramatically reduced hepatic parenchymal inflammation and injury in 30-week-old dnTGFBRII mice, reflected by changes in hepatic proinflammatory gene expression, serum chemistry, and histopathology. Interestingly, TCE did not affect hepatic B cell accumulation or induction of the anti-inflammatory cytokine IL10. These data indicate that TCE exposure reduces autoimmune liver injury in female dnTGFBRII mice and suggests that the precise effect of environmental chemicals in autoimmunity depends on the experimental model. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Angiotensin II receptor blocker valsartan ameliorates cardiac fibrosis partly by inhibiting miR-21 expression in diabetic nephropathy mice.

PubMed

Wang, Jinyang; Duan, Lijun; Gao, Yanbin; Zhou, Shuhong; Liu, Yongming; Wei, Suhong; An, Siqin; Liu, Jing; Tian, Liming; Wang, Shaocheng

2017-12-09

Cardiac fibrosis with diabetic nephropathy (DN) is one of major diabetic complications. miR-21 and MMP-9 were closely associated with fibrosis diseases. Angiotensin II receptor blockers (ARB) have cardioprotective effects. However, it remains unclear whether miR-21 was involved in the mechanism of cardiac fibrosis with DN by target MMP-9 and ARB ameliorates cardiac fibrosis partly by inhibiting miR-21 expression. In this study, In Situ Hybridization(ISH), RT-PCR, cell transfection, western blotting and laser confocal telescope were used, respectively. ISH showed that miR-21, concentrated in cytoplasmic foci in the proximity of the nucleus, was mainly localized in cardiac fibroblasts and at relatively low levels in cardiomyocytes within cardiac tissue with DN. RT-PCR showed that miR-21 expression was significantly enhanced in cardiac tissue with DN, accompanied by the increase of col-IV, FN, CVF, PVCA, LVMI, HWI and NT-pro-BNP (p < 0.05). Bioinformatics analysis and Luciferase reporter gene assays showed that MMP-9 was a validated target of miR-21. Furthermore, cell transfection experiments showed that miR-21 overexpression directly decreased MMP-9 expression. Interestingly, miR-21 levels in cardiac tissue was positively correlated with ACR (r = -0.870, P = 0.003), whereas, uncorrelated with SBP, HbA1C and T-Cho (p > 0.05). More importantly, ARB can significantly decrease miR-21 expression in cardiac tissue, cardiac fibroblasts and serum. Overall, our results suggested that miR-21 may contribute to the pathogenesis of cardiac fibrosis with DN by target MMP-9, and that miR-21 may be a new possible therapeutic target for ARB in cardiac fibrosis with DN. Copyright © 2017. Published by Elsevier B.V.

The structural basis of the dominant negative phenotype of the Gαi1β1γ2 G203A/A326S heterotrimer

PubMed Central

Liu, Ping; Jia, Ming-zhu; Zhou, X Edward; De Waal, Parker W; Dickson, Bradley M; Liu, Bo; Hou, Li; Yin, Yan-ting; Kang, Yan-yong; Shi, Yi; Melcher, Karsten; Xu, H Eric; Jiang, Yi

2016-01-01

Aim: Dominant negative mutant G proteins have provided critical insight into the mechanisms of G protein-coupled receptor (GPCR) signaling, but the mechanisms underlying the dominant negative characteristics are not completely understood. The aim of this study was to determine the structure of the dominant negative Gαi1β1γ2 G203A/A326S complex (Gi-DN) and to reveal the structural basis of the mutation-induced phenotype of Gαi1β1γ2. Methods: The three subunits of the Gi-DN complex were co-expressed with a baculovirus expression system. The Gi-DN heterotrimer was purified, and the structure of its complex with GDP was determined through X-ray crystallography. Results: The Gi-DN heterotrimer structure revealed a dual mechanism underlying the dominant negative characteristics. The mutations weakened the hydrogen bonding network between GDP/GTP and the binding pocket residues, and increased the interactions in the Gα-Gβγ interface. Concomitantly, the Gi-DN heterotrimer adopted a conformation, in which the C-terminus of Gαi and the N-termini of both the Gβ and Gγ subunits were more similar to the GPCR-bound state compared with the wild type complex. From these structural observations, two additional mutations (T48F and D272F) were designed that completely abolish the GDP binding of the Gi-DN heterotrimer. Conclusion: Overall, the results suggest that the mutations impede guanine nucleotide binding and Gα-Gβγ protein dissociation and favor the formation of the G protein/GPCR complex, thus blocking signal propagation. In addition, the structure provides a rationale for the design of other mutations that cause dominant negative effects in the G protein, as exemplified by the T48F and D272F mutations. PMID:27498775

TREATMENT OF SUBACUTE POSTERIOR KNEE PAIN IN AN ADOLESCENT BALLET DANCER UTILIZING TRIGGER POINT DRY NEEDLING: A CASE REPORT

PubMed Central

Tansey, Kimberly A.; Westrick, Richard B.

2014-01-01

Study Design: Case Report. Background and Purpose: Dry needling (DN) is an increasingly popular intervention used by clinicians as a treatment of regional neuromusculoskeletal pain. DN is an invasive procedure that involves insertion of a thin monofilament needle directly into a muscle trigger point (MTP) with the intent of stimulating a local twitch response. Current evidence is somewhat limited, but recent literature supports the use of this intervention in specific neuromusculoskeletal conditions. The purpose of this case report is to present the outcomes of DN as a primary treatment intervention in an adolescent subject with subacute posterior knee pain. Case Description: The subject was a 16‐year‐old female competitive ballet dancer referred to physical therapy with a two month history of right posterior knee pain. Palpation identified MTPs which reproduced the patient’s primary symptoms. In addition to an exercise program promoting lower extremity flexibility and hip stability, the subject was treated with DN to the right gastrocnemius, soleus, and popliteus muscles. Outcomes: The subject reported being pain free on the Numerical Pain Scale and a +7 improvement in perceived change in recovery on the Global Rating of Change at final follow‐up. Physical examination demonstrated no observed impairments or functional limitations, including normal mobility, full strength, and unrestricted execution of dance maneuvers. Discussion: The patient was able to return to high level dance training and competition without physical limitations and resumed pre‐injury dynamic movement activities including dancing, running, jumping, and pivoting without pain. DN can be an effective and efficient intervention to assist patients in decreasing pain and returning to high intensity physical activity. Additional research is needed to determine if DN is effective for other body regions and has long‐term positive outcomes. Level of Evidence: Level 4 PMID:24567862

[Effects of flavonoids from Pyrrosiae folium on pathological changes and inflammatory response of diabetic nephropathy].

PubMed

Liu, Xu-Lin; Liu, Wen-Ping; Wang, Li-Li; Feng, Liang

2018-06-01

Diabetic nephropathy (DN) is closely related to immune-mediated inflammatory damage. Pyrrosiae folium is used commonly for the urinary system diseases with a good efficacy, which contains abundant flavonoids (SWHT). This study was performed to investigate the therapeutic effect of SWHT on DN and its effect on inflammatory response. In this study, the main active components of SWHT were identified by high performance liquid chromatography (HPLC). The results showed that SWHT mainly contained mangiferin and isomucoside. Rat model of diabetic nephropathy (DN) was established by feeding high glucose & high fat diet and injecting streptozocin (STZ). Then the rats were randomly divided into control group, DN model group, positive control group, and SWHT groups (50, 100, 200 mg·kg⁻¹, ig). The levels of AGEs and RAGE in serum were measured by ELISA after 12 weeks of drug administration. The serum creatinine, blood urea nitrogen and total protein levels were detected by using test kit. HE staining and transmission electron microscopy were applied to observe the pathological changes and structure of renal tissue. Western blot and ELISA were used to detect the protein expression and content levels of interleukin 6 (IL-6), tumor necrosis factor (TNF-α) and IL-1β in renal tissue. Results showed that SWHT significantly decreased serum AGEs and RAGE levels in DN rats; decreased serum creatinine, blood urea nitrogen and total urinary protein levels, improved renal pathological damages and reduced basement membrane thickening in DN rats. In addition, SWHT down-regulated the protein expression levels of inflammatory mediators IL-6, TNF-α and IL-1β. The research studies indicated that SWHT component had a potential anti-diabetic nephropathy activity, and its improvement effect on pathological damages may be related to reducing inflammation. This provides the basis for the scientific and rational application of P. folium, and also provides active components for further development of Chinese medicine for diabetic nephropathy. Copyright© by the Chinese Pharmaceutical Association.

Monoacylglycerol Lipase Inhibitor JZL184 Improves Behavior and Neural Properties in Ts65Dn Mice, a Model of Down Syndrome

PubMed Central

Lysenko, Larisa V.; Kim, Jeesun; Henry, Cassandra; Tyrtyshnaia, Anna; Kohnz, Rebecca A.; Madamba, Francisco; Simon, Gabriel M.; Kleschevnikova, Natalia E.; Nomura, Daniel K.; Ezekowitz, R . Alan B.; Kleschevnikov, Alexander M.

2014-01-01

Genetic alterations or pharmacological treatments affecting endocannabinoid signaling have profound effects on synaptic and neuronal properties and, under certain conditions, may improve higher brain functions. Down syndrome (DS), a developmental disorder caused by triplication of chromosome 21, is characterized by deficient cognition and inevitable development of the Alzheimer disease (AD) type pathology during aging. Here we used JZL184, a selective inhibitor of monoacylglycerol lipase (MAGL), to examine the effects of chronic MAGL inhibition on the behavioral, biochemical, and synaptic properties of aged Ts65Dn mice, a genetic model of DS. In both Ts65Dn mice and their normosomic (2N) controls, JZL184-treatment increased brain levels of 2-arachidonoylglycerol (2-AG) and decreased levels of its metabolites such as arachidonic acid, prostaglandins PGD2, PGE2, PGFα, and PGJ2. Enhanced spontaneous locomotor activity of Ts65Dn mice was reduced by the JZL184-treatement to the levels observed in 2N animals. Deficient long-term memory was also improved, while short-term and working types of memory were unaffected. Furthermore, reduced hippocampal long-term potentiation (LTP) was increased in the JZL184-treated Ts65Dn mice to the levels observed in 2N mice. Interestingly, changes in synaptic plasticity and behavior were not observed in the JZL184-treated 2N mice suggesting that the treatment specifically attenuated the defects in the trisomic animals. The JZL184-treatment also reduced the levels of Aβ40 and Aβ42, but had no effect on the levels of full length APP and BACE1 in both Ts65Dn and 2N mice. These data show that chronic MAGL inhibition improves the behavior and brain functions in a DS model suggesting that pharmacological targeting of MAGL may be considered as a perspective new approach for improving cognition in DS. PMID:25474204

Pharmacotherapy with Fluoxetine Restores Functional Connectivity from the Dentate Gyrus to Field CA3 in the Ts65Dn Mouse Model of Down Syndrome

PubMed Central

Guidi, Sandra; Ciani, Elisabetta; Mangano, Chiara; Calzà, Laura; Bartesaghi, Renata

2013-01-01

Down syndrome (DS) is a high-incidence genetic pathology characterized by severe impairment of cognitive functions, including declarative memory. Impairment of hippocampus-dependent long-term memory in DS appears to be related to anatomo-functional alterations of the hippocampal trisynaptic circuit formed by the dentate gyrus (DG) granule cells - CA3 pyramidal neurons - CA1 pyramidal neurons. No therapies exist to improve cognitive disability in individuals with DS. In previous studies we demonstrated that pharmacotherapy with fluoxetine restores neurogenesis, granule cell number and dendritic morphology in the DG of the Ts65Dn mouse model of DS. The goal of the current study was to establish whether treatment rescues the impairment of synaptic connectivity between the DG and CA3 that characterizes the trisomic condition. Euploid and Ts65Dn mice were treated with fluoxetine during the first two postnatal weeks and examined 45–60 days after treatment cessation. Untreated Ts65Dn mice had a hypotrophyc mossy fiber bundle, fewer synaptic contacts, fewer glutamatergic contacts, and fewer dendritic spines in the stratum lucidum of CA3, the terminal field of the granule cell projections. Electrophysiological recordings from CA3 pyramidal neurons showed that in Ts65Dn mice the frequency of both mEPSCs and mIPSCs was reduced, indicating an overall impairment of excitatory and inhibitory inputs to CA3 pyramidal neurons. In treated Ts65Dn mice all these aberrant features were fully normalized, indicating that fluoxetine can rescue functional connectivity between the DG and CA3. The positive effects of fluoxetine on the DG-CA3 system suggest that early treatment with this drug could be a suitable therapy, possibly usable in humans, to restore the physiology of the hippocampal networks and, hence, memory functions. PMID:23620781

Involvement of Potassium and Cation Channels in Hippocampal Abnormalities of Embryonic Ts65Dn and Tc1 Trisomic Mice

PubMed Central

Stern, Shani; Segal, Menahem; Moses, Elisha

2015-01-01

Down syndrome (DS) mouse models exhibit cognitive deficits, and are used for studying the neuronal basis of DS pathology. To understand the differences in the physiology of DS model neurons, we used dissociated neuronal cultures from the hippocampi of Ts65Dn and Tc1 DS mice. Imaging of [Ca2+]i and whole cell patch clamp recordings were used to analyze network activity and single neuron properties, respectively. We found a decrease of ~ 30% in both fast (A-type) and slow (delayed rectifier) outward potassium currents. Depolarization of Ts65Dn and Tc1 cells produced fewer spikes than diploid cells. Their network bursts were smaller and slower than diploids, displaying a 40% reduction in Δf / f0 of the calcium signals, and a 30% reduction in propagation velocity. Additionally, Ts65Dn and Tc1 neurons exhibited changes in the action potential shape compared to diploid neurons, with an increase in the amplitude of the action potential, a lower threshold for spiking, and a sharp decrease of about 65% in the after-hyperpolarization amplitude. Numerical simulations reproduced the DS measured phenotype by variations in the conductance of the delayed rectifier and A-type, but necessitated also changes in inward rectifying and M-type potassium channels and in the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. We therefore conducted whole cell patch clamp measurements of M-type potassium currents, which showed a ~ 90% decrease in Ts65Dn neurons, while HCN measurements displayed an increase of ~ 65% in Ts65Dn cells. Quantitative real-time PCR analysis indicates overexpression of 40% of KCNJ15, an inward rectifying potassium channel, contributing to the increased inhibition. We thus find that changes in several types of potassium channels dominate the observed DS model phenotype. PMID:26501103

Passive Localization of Underwater Acoustic Beacons

DTIC Science & Technology

1993-09-01

maxtime) TickCounto; aborto ; FSRead(gASerRefln,&numCharln,&addressBuf); TalkSail(’O); iistart the PTR’s data collecticn DrawString(w\\p: H) I display a...34); aborto ; EventLoopO; II main execution loop RAMSDClose(sPortA); HI must close the RAM Drivers before shutdown 193 free(gw); //must release the...kNumExp+l),sizeof(double)); if(wtrue ==NULL) DrawString("\\pCan’t allocate memory for data collection!!! ); aborto ; Nvmeas = calloc(3L*(kStep~kNumExp+l

Activity-Dependent Excitability Changes Suggest Na[superscript +]/K[superscript +] Pump Dysfunction in Diabetic Neuropathy

ERIC Educational Resources Information Center

Krishnan, Arun V.; Lin, Cindy S.-Y.; Kiernan, Matthew C.

2008-01-01

The present study was undertaken to evaluate the role of Na[superscript +]/K[superscript +] pump dysfunction in the development of diabetic neuropathy (DN). Nerve excitability techniques, which provide information about membrane potential and axonal ion channel function, were undertaken in 15 patients with established DN and in 10 patients with…

Adhoc Wireless Network Control: Energy Efficiency and Hidden Terminal Considerations

DTIC Science & Technology

2009-12-01

Pnl (t) +Bn(t), Emax ) , (57) Ynl(t+ 1) = [Ynl(t)−Rnl,in(t)] + + γnl(t), (58) Dn(t+ 1) = [Dn(t...1− δ)Bn(t)] + + ∑ l∈On Pnl (t), (59) subject to constraints Rnl,in(t) ≤ Vnl(t) +Anl(t) ∀n, l, t, P (t) ∈ PS(t), ∑ l∈On Pnl (t) ≤ min ( En(t), P̂ ) ∀n...γnl(t)] ∣ ∣ ∣ ∣ ∣ ∣ X(t)   − 2E   ∑ n,l [Unl(t)µnl (S(t),P (t))−Dn(t) Pnl (t)] ∣ ∣ ∣ ∣ ∣ ∣ X(t)  − 2E   ∑ n,l [ηYnl(t)−

Multiple-labelling immunoEM using different sizes of colloidal gold: alternative approaches to test for differential distribution and colocalization in subcellular structures.

PubMed

Mayhew, Terry M; Lucocq, John M

2011-03-01

Various methods for quantifying cellular immunogold labelling on transmission electron microscope thin sections are currently available. All rely on sound random sampling principles and are applicable to single immunolabelling across compartments within a given cell type or between different experimental groups of cells. Although methods are also available to test for colocalization in double/triple immunogold labelling studies, so far, these have relied on making multiple measurements of gold particle densities in defined areas or of inter-particle nearest neighbour distances. Here, we present alternative two-step approaches to codistribution and colocalization assessment that merely require raw counts of gold particles in distinct cellular compartments. For assessing codistribution over aggregate compartments, initial statistical evaluation involves combining contingency table and chi-squared analyses to provide predicted gold particle distributions. The observed and predicted distributions allow testing of the appropriate null hypothesis, namely, that there is no difference in the distribution patterns of proteins labelled by different sizes of gold particle. In short, the null hypothesis is that of colocalization. The approach for assessing colabelling recognises that, on thin sections, a compartment is made up of a set of sectional images (profiles) of cognate structures. The approach involves identifying two groups of compartmental profiles that are unlabelled and labelled for one gold marker size. The proportions in each group that are also labelled for the second gold marker size are then compared. Statistical analysis now uses a 2 × 2 contingency table combined with the Fisher exact probability test. Having identified double labelling, the profiles can be analysed further in order to identify characteristic features that might account for the double labelling. In each case, the approach is illustrated using synthetic and/or experimental datasets and can be refined to correct observed labelling patterns to specific labelling patterns. These simple and efficient approaches should be of more immediate utility to those interested in codistribution and colocalization in multiple immunogold labelling investigations.

The inability of Bacillus licheniformis perR mutant to grow is mainly due to the lack of PerR-mediated fur repression.

PubMed

Kim, Jung-Hoon; Yang, Yoon-Mo; Ji, Chang-Jun; Ryu, Su-Hyun; Won, Young-Bin; Ju, Shin-Yeong; Kwon, Yumi; Lee, Yeh-Eun; Youn, Hwan; Lee, Jin-Won

2017-06-01

PerR, a member of Fur family protein, is a metal-dependent H 2 O 2 sensing transcription factor that regulates genes involved in peroxide stress response. Industrially important bacterium Bacillus licheniformis contains three PerR-like proteins (PerR BL , PerR2, and PerR3) compared to its close relative Bacillus subtilis. Interestingly, unlike other bacteria including B. subtilis, no authentic perR BL null mutant could be established for B. licheniformis. Thus, we constructed a conditional perR BL mutant using a xylose-inducible promoter, and investigated the genes under the control of PerR BL . PerR BL regulon genes include katA, mrgA, ahpC, pfeT, hemA, fur, and perR as observed for PerR BS . However, there is some variation in the expression levels of fur and hemA genes between B. subtilis and B. licheniformis in the derepressed state. Furthermore, katA, mrgA, and ahpC are strongly induced, whereas the others are only weakly or not induced by H 2 O 2 treatment. In contrast to the B. subtilis perR null mutant which frequently gives rise to large colony phenotype mainly due to the loss of katA, the suppressors of B. licheniformis perR mutant, which can form colonies on LB agar, were all catalase-positive. Instead, many of the suppressors showed increased levels of siderophore production, suggesting that the suppressor mutation is linked to the fur gene. Consistent with this, perR fur double mutant could grow on LB agar without Fe supplementation, whereas perR katA double mutant could only grow on LB agar with Fe supplementation. Taken together, our data suggest that in B. licheniformis, despite the similarity in PerR BL and PerR BS regulon genes, perR is an essential gene required for growth and that the inability of perR null mutant to grow is mainly due to elevated expression of Fur.

Neural circuit architecture defects in a Drosophila model of Fragile X syndrome are alleviated by minocycline treatment and genetic removal of matrix metalloproteinase

PubMed Central

Siller, Saul S.; Broadie, Kendal

2011-01-01

SUMMARY Fragile X syndrome (FXS), caused by loss of the fragile X mental retardation 1 (FMR1) product (FMRP), is the most common cause of inherited intellectual disability and autism spectrum disorders. FXS patients suffer multiple behavioral symptoms, including hyperactivity, disrupted circadian cycles, and learning and memory deficits. Recently, a study in the mouse FXS model showed that the tetracycline derivative minocycline effectively remediates the disease state via a proposed matrix metalloproteinase (MMP) inhibition mechanism. Here, we use the well-characterized Drosophila FXS model to assess the effects of minocycline treatment on multiple neural circuit morphological defects and to investigate the MMP hypothesis. We first treat Drosophila Fmr1 (dfmr1) null animals with minocycline to assay the effects on mutant synaptic architecture in three disparate locations: the neuromuscular junction (NMJ), clock neurons in the circadian activity circuit and Kenyon cells in the mushroom body learning and memory center. We find that minocycline effectively restores normal synaptic structure in all three circuits, promising therapeutic potential for FXS treatment. We next tested the MMP hypothesis by assaying the effects of overexpressing the sole Drosophila tissue inhibitor of MMP (TIMP) in dfmr1 null mutants. We find that TIMP overexpression effectively prevents defects in the NMJ synaptic architecture in dfmr1 mutants. Moreover, co-removal of dfmr1 similarly rescues TIMP overexpression phenotypes, including cellular tracheal defects and lethality. To further test the MMP hypothesis, we generated dfmr1;mmp1 double null mutants. Null mmp1 mutants are 100% lethal and display cellular tracheal defects, but co-removal of dfmr1 allows adult viability and prevents tracheal defects. Conversely, co-removal of mmp1 ameliorates the NMJ synaptic architecture defects in dfmr1 null mutants, despite the lack of detectable difference in MMP1 expression or gelatinase activity between the single dfmr1 mutants and controls. These results support minocycline as a promising potential FXS treatment and suggest that it might act via MMP inhibition. We conclude that FMRP and TIMP pathways interact in a reciprocal, bidirectional manner. PMID:21669931

Leaching of DOC, DN, and inorganic constituents from scrap tires.

PubMed

Selbes, Meric; Yilmaz, Ozge; Khan, Abdul A; Karanfil, Tanju

2015-11-01

One concern for recycle and reuse of scrap tires is the leaching of tire constituents (organic and inorganic) with time, and their subsequent potential harmful impacts in environment. The main objective of this study was to examine the leaching of dissolved organic carbon (DOC), dissolved nitrogen (DN), and selected inorganic constituents from scrap tires. Different sizes of tire chips and crumb rubber were exposed to leaching solutions with pH's ranging from 3.0 to 10.0 for 28days. The leaching of DOC and DN were found to be higher for smaller size tire chips; however, the leaching of inorganic constituents was independent of the size. In general, basic pH conditions increased the leaching of DOC and DN, whereas acidic pH conditions led to elevated concentrations of metals. Leaching was minimal around the neutral pH values for all the monitored parameters. Analysis of the leaching rates showed that components associated with the rubbery portion of the tires (DOC, DN, zinc, calcium, magnesium, etc.) exhibited an initial rapid followed by a slow release. On the other hand, a constant rate of leaching was observed for iron and manganese, which are attributed to the metal wires present inside the tires. Although the total amounts that leached varied, the observed leaching rates were similar for all tire chip sizes and leaching solutions. Operation under neutral pH conditions, use of larger size tire chips, prewashing of tires, and removal of metal wires prior to application will reduce the impact of tire recycle and reuse. Copyright © 2015 Elsevier Ltd. All rights reserved.

Effective Delivery of Endogenous Antioxidants Ameliorates Diabetic Nephropathy

PubMed Central

Park, Yongsoo; Kim, Hyunok; Park, Leejin; Min, Dongsoo; Park, Jinseu; Choi, Sooyoung; Park, Moon Hyang

2015-01-01

Background Diabetic nephropathy (DN) is thought to be partially due to the injury of renal cells and the renal micro-environment by free radicals. Free radial scavenging agents that inhibit free radical damage may well prevent the development of underlying conditions such as mesangial expansion (by inhibiting extracellular matrix expression) in these patients. Methods Using techniques for intra-cellular delivery of peptides, we made metallothionein (MT) and superoxide dismutase (SOD), potent endogenous antioxidants, readily transducible into cell membrane and tested their protective effect against the development of DN in OLETF rats. Herein, we study antioxidant peptides for their ability to prevent oxidative damage to primary rat mesangial cells (MCs), which are important constituents of renal glomeruli. Results Intraperitoneal administration of these antioxidants resulted in delivery to the kidney and decreased ROS and the expression of downstream signals in renal cells and postponed the usual progression to DN. In in vitro experiments, MT and SOD were efficiently transferred to MCs, and the increased removal of ROS by MT and SOD was proportional to the degree of scavenging enzymes delivered. MT and SOD decreased three major oxidative injuries (hyperglycemia, AGE and ROS exposure) and also injuries directly mediated by angiotensin II in MCs while changing downstream signal transduction. Conclusions The protective effects of MT and SOD for the progression of DN in experimental animals may be associated with the scavenging of ROS by MT and SOD and correlated changes in signal transduction downstream. Concomitant administration of these antioxidant peptides may prove to be a new approach for the prevention and therapy of DN. PMID:26114547

Re-evaluating the concept of "dominant/index tumor nodule" in multifocal prostate cancer.

PubMed

Huang, Cheng Cheng; Deng, Fang-Ming; Kong, Max X; Ren, Qinhu; Melamed, Jonathan; Zhou, Ming

2014-05-01

Prostate cancer (PCa) often presents as a multifocal disease with heterogeneity in Gleason score (GS) and genetic alterations. Dominant/index tumor nodule (DN), the largest nodule in a multifocal disease, is presumed to harbor the most aggressive biological behavior and therefore dictate the overall clinical behavior of PCa. In this study, we examined the pathological features of DN and re-evaluated the validity of the "DN" concept in multifocal PCa. A total of 201 consecutive radical prostatectomy specimens were totally submitted and examined. All independent cancer foci were recorded with prognostically important pathological parameters. Unifocal and multifocal disease was present in 25 (12.4 %) and 176 (87.6 %) cases, respectively. In 20 (11.3 %) multifocal cases, the highest GS, the largest tumor volume (TV), and extraprostatic extension (EPE) did not concur in the same tumor nodules. Non-DNs had a higher GS and EPE in 13 cases each and had both the highest GS and EPE in 5 cases. In the majority of multifocal prostate cancer (88.7 %), DNs have the highest GS and EPE. In these cases, DN is still a valid concept and can be used for assigning overall GS and procuring tissue for research. However, in a significant number of cases (11.3 %), the largest TV, the highest GS, and EPE did not concur in the same tumor nodules. In these cases, pathologists should de-emphasize the concept of DN. Instead, they should place the emphasis on the multifocal nature of the disease and document the pathological features of all independent tumor foci that have the largest TV, the highest GS, and EPE.

Maternal choline supplementation improves spatial mapping and increases basal forebrain cholinergic neuron number and size in aged Ts65Dn mice.

PubMed

Ash, Jessica A; Velazquez, Ramon; Kelley, Christy M; Powers, Brian E; Ginsberg, Stephen D; Mufson, Elliott J; Strupp, Barbara J

2014-10-01

Down syndrome (DS) is marked by intellectual disability (ID) and early-onset of Alzheimer's disease (AD) neuropathology, including basal forebrain cholinergic neuron (BFCN) degeneration. The present study tested the hypothesis that maternal choline supplementation (MCS) improves spatial mapping and protects against BFCN degeneration in the Ts65Dn mouse model of DS and AD. During pregnancy and lactation, dams were assigned to either a choline sufficient (1.1g/kg choline chloride) or choline supplemented (5.0g/kg choline chloride) diet. Between 13 and 17months of age, offspring were tested in the radial arm water maze (RAWM) to examine spatial mapping followed by unbiased quantitative morphometry of BFCNs. Spatial mapping was significantly impaired in unsupplemented Ts65Dn mice relative to normal disomic (2N) littermates. Additionally, a significantly lower number and density of medial septum (MS) hippocampal projection BFCNs was also found in unsupplemented Ts65Dn mice. Notably, MCS significantly improved spatial mapping and increased number, density, and size of MS BFCNs in Ts65Dn offspring. Moreover, the density and number of MS BFCNs correlated significantly with spatial memory proficiency, providing support for a functional relationship between these behavioral and morphometric effects of MCS for trisomic offspring. Thus, increasing maternal choline intake during pregnancy may represent a safe and effective treatment approach for expectant mothers carrying a DS fetus, as well as a possible means of BFCN neuroprotection during aging for the population at large. Copyright © 2014 Elsevier Inc. All rights reserved.

Using exposure prediction tools to link exposure and ...

EPA Pesticide Factsheets

A few different exposure prediction tools were evaluated for use in the new in vitro-based safety assessment paradigm using di-2-ethylhexyl phthalate (DEHP) and dibutyl phthalate (DnBP) as case compounds. Daily intake of each phthalate was estimated using both high-throughput (HT) prediction models such as the HT Stochastic Human Exposure and Dose Simulation model (SHEDS-HT) and the ExpoCast heuristic model and non-HT approaches based on chemical specific exposure estimations in the environment in conjunction with human exposure factors. Reverse dosimetry was performed using a published physiologically based pharmacokinetic (PBPK) model for phthalates and their metabolites to provide a comparison point. Daily intakes of DEHP and DnBP were estimated based on the urinary concentrations of their respective monoesters, mono-2-ethylhexyl phthalate (MEHP) and monobutyl phthalate (MnBP), reported in NHANES (2011–2012). The PBPK-reverse dosimetry estimated daily intakes at the 50th and 95th percentiles were 0.68 and 9.58 μg/kg/d and 0.089 and 0.68 μg/kg/d for DEHP and DnBP, respectively. For DEHP, the estimated median from PBPK-reverse dosimetry was about 3.6-fold higher than the ExpoCast estimate (0.68 and 0.18 μg/kg/d, respectively). For DnBP, the estimated median was similar to that predicted by ExpoCast (0.089 and 0.094 μg/kg/d, respectively). The SHEDS-HT prediction of DnBP intake from consumer product pathways alone was higher at 0.67 μg/kg/d. The PBPK-reve

Two-Dimensional Lead Halide Perovskites Templated by a Conjugated Asymmetric Diammonium.

PubMed

Hautzinger, Matthew P; Dai, Jun; Ji, Yujin; Fu, Yongping; Chen, Jie; Guzei, Ilia A; Wright, John C; Li, Youyong; Jin, Song

2017-12-18

We report novel two-dimensional lead halide perovskite structures templated by a unique conjugated aromatic dication, N,N-dimethylphenylene-p-diammonium (DPDA). The asymmetrically substituted primary and tertiary ammoniums in DPDA facilitate the formation of two-dimensional network (2DN) perovskite structures incorporating a conjugated dication between the PbX 4 2- (X = Br, I) layers. These 2DN structures of (DPDA)PbI 4 and (DPDA)PbBr 4 were characterized by single-crystal X-ray diffraction, showing uniquely low distortions in the Pb-X-Pb bond angle for 2D perovskites. The Pb-I-Pb bond angle is very close to ideal (180°) for a 2DN lead iodide perovskite, which can be attributed to the ability of the rigid diammonium DPDA to insert into the PbX 6 2- octahedral pockets. Optical characterization of (DPDA)PbI 4 shows an excitonic absorption peak at 2.29 eV (541 nm), which is red-shifted in comparison to similar 2DN lead iodide structures. Temperature-dependent photoluminescence of both compounds reveals both a self-trapped exciton and free exciton emission feature. The reduced exciton absorption energy and emission properties are attributed to the dication-induced structural order of the inorganic PbX 4 2- layers. DFT calculation results suggest mixing of the conjugated organic orbital component in the valence band of these 2DN perovskites. These results demonstrate a rational new strategy to incorporate conjugated organic dications into hybrid perovskites and will spur spectroscopic investigations of these compounds as well as optoelectronic applications.

Treatment with the matricellular protein CCN3 blocks and/or reverses fibrosis development in obesity with diabetic nephropathy.

PubMed

Riser, Bruce L; Najmabadi, Feridoon; Garchow, Kendra; Barnes, Jeffrey L; Peterson, Darryl R; Sukowski, Ernest J

2014-11-01

Fibrosis is at the core of the high morbidity and mortality rates associated with the complications of diabetes and obesity, including diabetic nephropathy (DN), without any US Food and Drug Administration-approved drugs with this specific target. We recently provided the first evidence that the matricellular protein CCN3 (official symbol NOV) functions in a reciprocal manner, acting on the profibrotic family member CCN2 to inhibit fibrosis in a mesangial cell model of DN. Herein, we used the BT/BR ob/ob mouse as a best model of human obesity and DN progression to determine whether recombinant human CCN3 could be used therapeutically, and the mechanisms involved. Eight weeks of thrice-weekly i.p. injections (0.604 and 6.04 μg/kg of recombinant human CCN3) beginning in early-stage DN completely blocked and/or reversed the up-regulation of mRNA expression of kidney cortex fibrosis genes (CCN2, Col1a2, TGF-β1, and PAI-1) seen in placebo-treated diabetic mice. The treatment completely blocked glomerular fibrosis, as determined by altered mesangial expansion and deposition of laminin. Furthermore, it protected against, or reversed, podocyte loss and kidney function reduction (rise in plasma creatinine concentration); albuminuria was also greatly reduced. This study demonstrates the potential efficacy of recombinant human CCN3 treatment in DN and points to mechanisms operating at multiple levels or pathways, upstream (eg, protecting against cell injury) and downstream (eg, regulating CCN2 activity and extracellular matrix metabolism).

Improving the reversibility of thermal denaturation and catalytic efficiency of Bacillus licheniformis α-amylase through stabilizing a long loop in domain B.

PubMed

Li, Zhu; Duan, Xuguo; Chen, Sheng; Wu, Jing

2017-01-01

The reversibility of thermal denaturation and catalytic efficiency of Bacillus licheniformis α-amylase were improved through site-directed mutagenesis. By using multiple sequence alignment and PoPMuSiC algorithm, Ser187 and Asn188, which located within a long loop in Domain B of Bacillus licheniformis α-amylase, were selected for mutation. In addition, Ala269, which is adjacent to Ser187 and Asn188, was also investigated. Seven mutants carrying the mutations S187D, N188T, N188S, A269K, A269K/S187D, S187D/N188T, and A269K/S187D/N188T were generated and characterized. The most thermostable mutant, A269K/S187D/N188T, exhibited a 9-fold improvement in half-life at 95°C and pH 5.5, compared with that of the wild-type enzyme. Mutant A269K/S187D/N188T also exhibited improved catalytic efficiency. The catalytic efficiency of mutant A269K/S187D/N188T reached 5.87×103±0.17 g·L-1·s-1 at pH 5.5, which is 1.84-fold larger than the corresponding value determined for the wild-type enzyme. Furthermore, the structure analysis showed that immobilization of the loop containing Ser187 and Asn188 plays a significant role in developing the properties of Bacillus licheniformis α-amylase.

Improving the reversibility of thermal denaturation and catalytic efficiency of Bacillus licheniformis α-amylase through stabilizing a long loop in domain B

PubMed Central

Li, Zhu; Duan, Xuguo; Chen, Sheng; Wu, Jing

2017-01-01

The reversibility of thermal denaturation and catalytic efficiency of Bacillus licheniformis α-amylase were improved through site-directed mutagenesis. By using multiple sequence alignment and PoPMuSiC algorithm, Ser187 and Asn188, which located within a long loop in Domain B of Bacillus licheniformis α-amylase, were selected for mutation. In addition, Ala269, which is adjacent to Ser187 and Asn188, was also investigated. Seven mutants carrying the mutations S187D, N188T, N188S, A269K, A269K/S187D, S187D/N188T, and A269K/S187D/N188T were generated and characterized. The most thermostable mutant, A269K/S187D/N188T, exhibited a 9-fold improvement in half-life at 95°C and pH 5.5, compared with that of the wild-type enzyme. Mutant A269K/S187D/N188T also exhibited improved catalytic efficiency. The catalytic efficiency of mutant A269K/S187D/N188T reached 5.87×103±0.17 g·L-1·s-1 at pH 5.5, which is 1.84-fold larger than the corresponding value determined for the wild-type enzyme. Furthermore, the structure analysis showed that immobilization of the loop containing Ser187 and Asn188 plays a significant role in developing the properties of Bacillus licheniformis α-amylase. PMID:28253342

Fasudil and DETA NONOate, Loaded in a Peptide-Modified Liposomal Carrier, Slow PAH Progression upon Pulmonary Delivery.

PubMed

Rashid, Jahidur; Nahar, Kamrun; Raut, Snehal; Keshavarz, Ali; Ahsan, Fakhrul

2018-05-07

We investigated the feasibility of a combination therapy comprising fasudil, a Rho-kinase inhibitor, and DETA NONOate (diethylenetriamine NONOate, DN), a long-acting nitric oxide donor, both loaded in liposomes modified with a homing peptide, CAR (CARSKNKDC), in the treatment of pulmonary arterial hypertension (PAH). We first prepared and characterized unmodified and CAR-modified liposomes of fasudil and DN. Using individual drugs alone or a mixture of fasudil and DN as controls, we studied the efficacy of the two liposomal preparations in reducing mean pulmonary arterial pressure (mPAP) in monocrotaline (MCT) and SUGEN-hypoxia-induced PAH rats. We also conducted morphometric studies (degree of muscularization, arterial medial wall thickness, and collagen deposition) after treating the PAH rats with test and control formulations. When the rats were treated acutely and chronically, the reduction in mPAP was more pronounced in the liposomal formulation-treated rats than in plain drug-treated rats. CAR-modified liposomes were more selective in reducing mPAP than unmodified liposomes of the drugs. Both drugs, formulated in CAR-modified liposomes, reduced the degree of muscularization, medial arterial wall thickness, and collagen deposition more than the combination of plain drugs did. As seen with the in vivo data, CAR-modified liposomes of fasudil or DN increased the levels of the vasodilatory signaling molecule, cGMP, in the smooth muscle cells of PAH-afflicted human pulmonary arteries. Overall, fasudil and DN, formulated in liposomes, could be used as a combination therapy for a better management of PAH.

Maternal choline supplementation improves spatial mapping and increases basal forebrain cholinergic neuron number and size in aged Ts65Dn mice

PubMed Central

Ash, Jessica A.; Velazquez, Ramon; Kelley, Christy M.; Powers, Brian E.; Ginsberg, Stephen D.; Mufson, Elliott J.; Strupp, Barbara J.

2014-01-01

Down syndrome (DS) is marked by intellectual disability (ID) and early-onset of Alzheimer’s disease (AD) neuropathology, including basal forebrain cholinergic neuron (BFCN) degeneration. The present study tested the hypothesis that maternal choline supplementation (MCS) lessens hippocampal dysfunction and protects against BFCN degeneration in the Ts65Dn mouse model of DS and AD. During pregnancy and lactation, dams were assigned to either a choline sufficient (1.1 g/kg choline chloride) or choline supplemented (5.0 g/kg choline chloride) diet. Between 13 and 17 months of age, offspring were tested in the radial arm water maze (RAWM) to examine spatial learning and memory followed by unbiased quantitative morphometry of BFCNs. Spatial mapping was significantly impaired in unsupplemented Ts65Dn mice relative to normal disomic (2N) littermates. Additionally, a significantly lower number and density of medial septum (MS) hippocampal projection BFCNs was also found in unsupplemented Ts65Dn mice. Notably, MCS significantly improved spatial mapping and increased number, density, and size of MS BFCNs in Ts65Dn offspring. Moreover, the density and number of MS BFCNs correlated significantly with spatial memory proficiency, providing powerful support for a functional relationship between these behavioral and morphometric effects of MCS for the trisomic offspring. Thus, increasing maternal choline intake during pregnancy may represent a safe and effective treatment approach for expectant mothers carrying a DS fetus, as well as a possible means of BFCN neuroprotection during aging for the population at large. PMID:24932939

75 FR 50856 - Airworthiness Directives; Airbus Model A380-800 Series Airplanes

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-18

... been found on the Droop Nose (DN) 1 master sidestay bracket on the inboard leading edge of an Airbus A380 flight test aeroplane. In case of failure of the master bracket, the sub-master bracket would be... been found on the Droop Nose (DN) 1 master sidestay bracket on the inboard leading edge of an Airbus...

76 FR 13696 - Admiralty Holding Co., American Consolidated Management Group, Inc., DnC Multimedia Corp., Dorsey...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-14

... Management Group, Inc., DnC Multimedia Corp., Dorsey Trailers, Inc. (n/k/a DT Liquidation, Inc.), and ElectraCapital, Inc. (a/k/a Electra Capital, Inc.); Order of Suspension of Trading March 10, 2011. It appears to.... (n/k/a DT Liquidation, Inc.) because it has not filed any periodic reports since the period ended...

How Should Fifth-Grade Mathematics Teachers Start the School Year?: Relations between Teacher-Student Interactions and Mathematics Instruction over One Year

ERIC Educational Resources Information Center

Banse, Holland W.; Curby, Timothy W.; Palacios, Natalia A.; Rimm-Kaufman, Sara E.

2018-01-01

Background: Teaching is comprised of interconnected practices. Some practices are domain neutral (DN), or independent of a content area. Examples of DN practices include emotional and instructional support and classroom organization. Others are domain specific (DS), or content dependent. Within a mathematics context, examples of DS practices…

Early environmental therapy rescues brain development in a mouse model of Down syndrome.

PubMed

Begenisic, Tatjana; Sansevero, Gabriele; Baroncelli, Laura; Cioni, Giovanni; Sale, Alessandro

2015-10-01

Down syndrome (DS), the most common genetic disorder associated with intellectual disabilities, is an untreatable condition characterized by a number of developmental defects and permanent deficits in the adulthood. Ts65Dn mice, the major animal model for DS, display severe cognitive and synaptic plasticity defects closely resembling the human phenotype. Here, we employed a multidisciplinary approach to investigate, for the first time in developing Ts65Dn mice, the effects elicited by early environmental enrichment (EE) on brain maturation and function. We report that exposure to EE resulted in a robust increase in maternal care levels displayed by Ts65Dn mothers and led to a normalization of declarative memory abilities and hippocampal plasticity in trisomic offspring. The positive effects of EE on Ts65Dn phenotype were not limited to the cognitive domain, but also included a rescue of visual system maturation. The beneficial EE effects were accompanied by increased BDNF and correction of over-expression of the GABA vesicular transporter vGAT. These findings highlight the beneficial impact of early environmental stimuli and their potential for application in the treatment of major functional deficits in children with DS. Copyright © 2015 Elsevier Inc. All rights reserved.

Cholinergic degeneration and memory loss delayed by vitamin E in a Down syndrome mouse model

PubMed Central

Lockrow, Jason; Prakasam, Annamalai; Huang, Peng; Bimonte-Nelson, Heather; Sambamurti, Kumar; Granholm, Ann-Charlotte

2009-01-01

Down syndrome (DS) individuals develop several neuropathological hallmarks seen in Alzheimer's disease, including cognitive decline and the early loss of cholinergic markers in the basal forebrain. These deficits are replicated in the Ts65Dn mouse, which contains a partial trisomy of murine chromosome 16, the orthologous genetic segment to human chromosome 21. Oxidative stress levels are elevated early in DS, and may contribute to the neurodegeneration seen in these individuals. We evaluated oxidative stress in Ts65Dn mice, and assessed the efficacy of long-term antioxidant supplementation on memory and basal forebrain pathology. We report that oxidative stress was elevated in the adult Ts65Dn brain, and that supplementation with the antioxidant vitamin E effectively reduced these markers. Also, Ts65Dn mice receiving vitamin E exhibited improved performance on a spatial working memory task and showed an attenuation of cholinergic neuron pathology in the basal forebrain. This study provides evidence that vitamin E delays onset of cognitive and morphological abnormalities in a mouse model of DS, and may represent a safe and effective treatment early in the progression of DS neuropathology. PMID:19135442

Development of the (d,n) Proton-transfer Reaction in Inverse Kinematics for Structure Studies

NASA Astrophysics Data System (ADS)

Jones, K. L.; Thornsberry, C.; Allen, J.; Atencio, A.; Bardayan, D. W.; Blankstein, D.; Burcher, S.; Carter, A. B.; Chipps, K. A.; Cizewski, J. A.; Cox, I.; Elledge, Z.; Febbraro, M.; Fijałkowska, A.; Grzywacz, R.; Hall, M. R.; King, T. T.; Lepailleur, A.; Madurga, M.; Marley, S. T.; O'Malley, P. D.; Paulauskas, S. V.; Pain, S. D.; Peters, W. A.; Reingold, C.; Smith, K.; Taylor, S.; Tan, W.; Vostinar, M.; Walter, D.

Transfer reactions have provided exciting opportunities to study the structure of exotic nuclei and are often used to inform studies relating to nucleosynthesis and applications. In order to benefit from these reactions and their application to rare ion beams (RIBs) it is necessary to develop the tools and techniques to perform and analyze the data from reactions performed in inverse kinematics, that is with targets of light nuclei and heavier beams. We are continuing to expand the transfer reaction toolbox in preparation for the next generation of facilities, such as the Facility for Rare Ion Beams (FRIB), which is scheduled for completion in 2022. An important step in this process is to perform the (d,n) reaction in inverse kinematics, with analyses that include Q-value spectra and differential cross sections. In this way, proton-transfer reactions can be placed on the same level as the more commonly used neutron-transfer reactions, such as (d,p), (9Be,8Be), and (13C,12C). Here we present an overview of the techniques used in (d,p) and (d,n), and some recent data from (d,n) reactions in inverse kinematics using stable beams of 12C and 16O.

Cell survival under nutrient stress is dependent on metabolic conditions regulated by Akt and not by autophagic vacuoles.

PubMed

Bruno, P; Calastretti, A; Priulla, M; Asnaghi, L; Scarlatti, F; Nicolin, A; Canti, G

2007-10-01

Akt activation assists tumor cell survival and promotes resistance to chemotherapy. Here we show that constitutively active Akt (CA-Akt) cells are highly sensitized to cell death induced by nutrient and growth factor deprivation, whereas dominant-negative Akt (DN-Akt) cells have a high rate of survival. The content of autophagosomes in starved CA-Akt cells was high, while DN-Akt cells expressed autophagic vacuoles constitutively, independently of nutrition conditions. Thus Akt down-regulation and downstream events can induce autophagosomes which were not directly determinants of cell death. Biochemical analysis in Akt-mutated cells show that (i) Akt and mTOR proteins were degraded more rapidly than the housekeeping proteins, (ii) mTOR phosphorylation at position Thr(2446) was relatively high in DN-Akt and low in CA-Akt cells, induced by starvation in mock cells only, which suggests reduced autoregulation of these pathways in Akt-mutated cells, (iii) both protein synthesis and protein degradation were significantly higher in starved CA-Akt cells than in starved DN-Akt cells or mock cells. In conclusion, constitutively active Akt, unable to control synthesis and wasting of proteins, accelerates the death of starved cells.

Agreement Between the Douleur Neuropathique in 4 Questions and Leeds Assessment of Neuropathic Symptoms and Signs Questionnaires to Classify Neuropathic Pain Among Patients with Leprosy.

PubMed

Santana, Jamilly C V; Santos, Victor S; Gurgel, Ricardo Q; Santana, Julianne C V; Reis, Francisco P; Cuevas, Luis E; Feitosa, Vera L C

2016-10-05

Neuropathic pain (NP) often occurs during the course of leprosy, and screening tools to differentiate NP from non-NP are often used. However, their performance varies in different settings. The most frequently used scales are the Douleur Neuropathique in 4 questions (DN4) and the Leeds assessment of neuropathic symptoms and signs (LANSS) questionnaires. Thus, we conducted a study to evaluate the agreement between DN4 and LANSS questionnaires to classify NP in 195 leprosy patients attending two reference centers in Sergipe, Brazil. The DN4 and LANSS classified 166 and 110 patients, respectively, as having NP. One hundred and seven (54.8%) were classified as NP by both questionnaires; 59 (30.2%) solely by the DN4 questionnaire and three (1.5%) solely by the LANSS. The agreement of the questionnaires was 66.2% (weak agreement, Kappa = 0.30). Although both questionnaires identified a high proportion of NP, the development of more robust instruments is necessary to ensure the accuracy of diagnosis of leprosy patients classified as having NP. © The American Society of Tropical Medicine and Hygiene.

Deleterious Effects of Chronic Folate Deficiency in the Ts65Dn Mouse Model of Down Syndrome

PubMed Central

Helm, Susan; Blayney, Morgan; Whited, Taylor; Noroozi, Mahjabin; Lin, Sen; Kern, Semira; Green, David; Salehi, Ahmad

2017-01-01

Folate is an important B vitamin naturally found in the human diet and plays a critical role in methylation of nucleic acids. Indeed, abnormalities in this major epigenetic mechanism play a pivotal role in the pathogenesis of cognitive deficit and intellectual disability in humans. The most common cause of cognitive dysfunction in children is Down syndrome (DS). Since folate deficiency is very common among the pediatric population, we questioned whether chronic folate deficiency (CFD) exacerbates cognitive dysfunction in a mouse model of DS. To test this, adult Ts65Dn mice and their disomic littermates were chronically fed a diet free of folic acid while preventing endogenous production of folate in the digestive tract for a period of 8 weeks. Our results show that the Ts65Dn mouse model of DS was significantly more vulnerable to CFD in terms of plasma homocysteine and N5-methyltetrahydrofolate (5-MTHF) levels. Importantly, these changes were linked to degenerative alterations in hippocampal dendritic morphology and impaired nest building behavior in Ts65Dn mice. Based on our results, a rigorous examination of folate intake and its metabolism in individuals with DS is warranted. PMID:28649192

HSYMDOCK: a docking web server for predicting the structure of protein homo-oligomers with Cn or Dn symmetry.

PubMed

Yan, Yumeng; Tao, Huanyu; Huang, Sheng-You

2018-05-26

A major subclass of protein-protein interactions is formed by homo-oligomers with certain symmetry. Therefore, computational modeling of the symmetric protein complexes is important for understanding the molecular mechanism of related biological processes. Although several symmetric docking algorithms have been developed for Cn symmetry, few docking servers have been proposed for Dn symmetry. Here, we present HSYMDOCK, a web server of our hierarchical symmetric docking algorithm that supports both Cn and Dn symmetry. The HSYMDOCK server was extensively evaluated on three benchmarks of symmetric protein complexes, including the 20 CASP11-CAPRI30 homo-oligomer targets, the symmetric docking benchmark of 213 Cn targets and 35 Dn targets, and a nonredundant test set of 55 transmembrane proteins. It was shown that HSYMDOCK obtained a significantly better performance than other similar docking algorithms. The server supports both sequence and structure inputs for the monomer/subunit. Users have an option to provide the symmetry type of the complex, or the server can predict the symmetry type automatically. The docking process is fast and on average consumes 10∼20 min for a docking job. The HSYMDOCK web server is available at http://huanglab.phys.hust.edu.cn/hsymdock/.

Double muscling in cattle due to mutations in the myostatin gene

PubMed Central

McPherron, Alexandra C.; Lee, Se-Jin

1997-01-01

Myostatin (GDF-8) is a member of the transforming growth factor β superfamily of secreted growth and differentiation factors that is essential for proper regulation of skeletal muscle mass in mice. Here we report the myostatin sequences of nine other vertebrate species and the identification of mutations in the coding sequence of bovine myostatin in two breeds of double-muscled cattle, Belgian Blue and Piedmontese, which are known to have an increase in muscle mass relative to conventional cattle. The Belgian Blue myostatin sequence contains an 11-nucleotide deletion in the third exon which causes a frameshift that eliminates virtually all of the mature, active region of the molecule. The Piedmontese myostatin sequence contains a missense mutation in exon 3, resulting in a substitution of tyrosine for an invariant cysteine in the mature region of the protein. The similarity in phenotypes of double-muscled cattle and myostatin null mice suggests that myostatin performs the same biological function in these two species and is a potentially useful target for genetic manipulation in other farm animals. PMID:9356471

Origami Arrays as Substrates for the Determination of Reaction Kinetics Using High-Speed Atomic Force Microscopy.

PubMed

Rahman, Masudur; Day, B Scott; Neff, David; Norton, Michael L

2017-08-01

DNA nanostructures (DN) are powerful platforms for the programmable assembly of nanomaterials. As applications for DN both as a structural material and as a support for functional biomolecular sensing systems develop, methods enabling the determination of reaction kinetics in real time become increasingly important. In this report, we present a study of the kinetics of streptavidin binding onto biotinylated DN constructs enabled by these planar structures. High-speed AFM was employed at a 2.5 frame/s rate to evaluate the kinetics and indicates that the binding fully saturates in less than 60 s. When the the data was fitted with an adsorption-limited kinetic model, a forward rate constant of 5.03 × 10 5 s -1 was found.

Annealing of Complementary DNA Sequences During Double-Strand Break Repair in Drosophila Is Mediated by the Ortholog of SMARCAL1.

PubMed

Holsclaw, Julie Korda; Sekelsky, Jeff

2017-05-01

DNA double-strand breaks (DSBs) pose a serious threat to genomic integrity. If unrepaired, they can lead to chromosome fragmentation and cell death. If repaired incorrectly, they can cause mutations and chromosome rearrangements. DSBs are repaired using end-joining or homology-directed repair strategies, with the predominant form of homology-directed repair being synthesis-dependent strand annealing (SDSA). SDSA is the first defense against genomic rearrangements and information loss during DSB repair, making it a vital component of cell health and an attractive target for chemotherapeutic development. SDSA has also been proposed to be the primary mechanism for integration of large insertions during genome editing with CRISPR/Cas9. Despite the central role for SDSA in genome stability, little is known about the defining step: annealing. We hypothesized that annealing during SDSA is performed by the annealing helicase SMARCAL1, which can anneal RPA-coated single DNA strands during replication-associated DNA damage repair. We used unique genetic tools in Drosophila melanogaster to test whether the fly ortholog of SMARCAL1, Marcal1, mediates annealing during SDSA. Repair that requires annealing is significantly reduced in Marcal1 null mutants in both synthesis-dependent and synthesis-independent (single-strand annealing) assays. Elimination of the ATP-binding activity of Marcal1 also reduced annealing-dependent repair, suggesting that the annealing activity requires translocation along DNA. Unlike the null mutant, however, the ATP-binding defect mutant showed reduced end joining, shedding light on the interaction between SDSA and end-joining pathways. Copyright © 2017 by the Genetics Society of America.

Immunohistochemical null-phenotype for mismatch repair proteins in colonic carcinoma associated with concurrent MLH1 hypermethylation and MSH2 somatic mutations.

PubMed

Wang, Tao; Stadler, Zsofia K; Zhang, Liying; Weiser, Martin R; Basturk, Olca; Hechtman, Jaclyn F; Vakiani, Efsevia; Saltz, Lenard B; Klimstra, David S; Shia, Jinru

2018-04-01

Microsatellite instability, a well-established driver pathway in colorectal carcinogenesis, can develop in both sporadic and hereditary conditions via different molecular alterations in the DNA mismatch repair (MMR) genes. MMR protein immunohistochemistry (IHC) is currently widely used for the detection of MMR deficiency in solid tumors. The IHC test, however, can show varied staining patterns, posing challenges in the interpretation of the staining results in some cases. Here we report a case of an 80-year-old female with a colonic adenocarcinoma that exhibited an unusual "null" IHC staining pattern with complete loss of all four MMR proteins (MLH1, MSH2, MSH6, and PMS2). This led to subsequent MLH1 methylation testing and next generation sequencing which demonstrated that the loss of all MMR proteins was associated with concurrent promoter hypermethylation of MLH1 and double somatic truncating mutations in MSH2. These molecular findings, in conjunction with the patient's age being 80 years and the fact that the patient had no personal or family cancer history, indicated that the MMR deficiency was highly likely sporadic in nature. Thus, the stringent Lynch syndrome type surveillance programs were not recommended to the patient and her family members. This case illustrates a rare but important scenario where a null IHC phenotype signifies complex underlying molecular alternations that bear clinical management implications, highlighting the need for recognition and awareness of such unusual IHC staining patterns.

The Aspergillus fumigatus SchASCH9 kinase modulates SakAHOG1 MAP kinase activity and it is essential for virulence

PubMed Central

Alves de Castro, Patrícia; dos Reis, Thaila Fernanda; Dolan, Stephen K.; Manfiolli, Adriana Oliveira; Brown, Neil Andrew; Jones, Gary W.; Doyle, Sean; Riaño-Pachón, Diego M.; Squina, Fábio Márcio; Caldana, Camila; Singh, Ashutosh; Del Poeta, Maurizio; Hagiwara, Daisuke; Silva-Rocha, Rafael; Goldman, Gustavo H.

2016-01-01

Summary The serine-threonine kinase TOR, the Target of Rapamycin, is an important regulator of nutrient, energy and stress signaling in eukaryotes. Sch9, a Ser/Thr kinase of AGC family (the cAMP-dependent PKA, cGMP- dependent protein kinase G and phospholipid-dependent protein kinase C family), is a substrate of TOR. Here, we characterized the fungal opportunistic pathogen Aspergillus fumigatus Sch9 homologue (SchA). The schA null mutant was sensitive to rapamycin, high concentrations of calcium, hyperosmotic stress and SchA was involved in iron metabolism. The ΔschA null mutant showed increased phosphorylation of SakA, the A. fumigatus Hog1 homologue. The schA null mutant has increased and decreased trehalose and glycerol accumulation, respectively, suggesting SchA performs different roles for glycerol and trehalose accumulation during osmotic stress. The schA was transcriptionally regulated by osmotic stress and this response was dependent on SakA and MpkC. The double ΔschA ΔsakA and ΔschA ΔmpkC mutants were more sensitive to osmotic stress than the corresponding parental strains. Transcriptomics and proteomics identified direct and indirect targets of SchA post-exposure to hyperosmotic stress. Finally, ΔschA was avirulent in a low dose murine infection model. Our results suggest there is a complex network of interactions amongst the A. fumigatus TOR, SakA and SchA pathways. PMID:27538790

The Aspergillus fumigatus SchASCH9 kinase modulates SakAHOG1 MAP kinase activity and it is essential for virulence.

PubMed

Alves de Castro, Patrícia; Dos Reis, Thaila Fernanda; Dolan, Stephen K; Oliveira Manfiolli, Adriana; Brown, Neil Andrew; Jones, Gary W; Doyle, Sean; Riaño-Pachón, Diego M; Squina, Fábio Márcio; Caldana, Camila; Singh, Ashutosh; Del Poeta, Maurizio; Hagiwara, Daisuke; Silva-Rocha, Rafael; Goldman, Gustavo H

2016-11-01

The serine-threonine kinase TOR, the Target of Rapamycin, is an important regulator of nutrient, energy and stress signaling in eukaryotes. Sch9, a Ser/Thr kinase of AGC family (the cAMP-dependent PKA, cGMP- dependent protein kinase G and phospholipid-dependent protein kinase C family), is a substrate of TOR. Here, we characterized the fungal opportunistic pathogen Aspergillus fumigatus Sch9 homologue (SchA). The schA null mutant was sensitive to rapamycin, high concentrations of calcium, hyperosmotic stress and SchA was involved in iron metabolism. The ΔschA null mutant showed increased phosphorylation of SakA, the A. fumigatus Hog1 homologue. The schA null mutant has increased and decreased trehalose and glycerol accumulation, respectively, suggesting SchA performs different roles for glycerol and trehalose accumulation during osmotic stress. The schA was transcriptionally regulated by osmotic stress and this response was dependent on SakA and MpkC. The double ΔschA ΔsakA and ΔschA ΔmpkC mutants were more sensitive to osmotic stress than the corresponding parental strains. Transcriptomics and proteomics identified direct and indirect targets of SchA post-exposure to hyperosmotic stress. Finally, ΔschA was avirulent in a low dose murine infection model. Our results suggest there is a complex network of interactions amongst the A. fumigatus TOR, SakA and SchA pathways. © 2016 John Wiley & Sons Ltd.

Treatment of acute, non-traumatic pain using a combination of diclofenac-cholestyramine, uridine triphosphate, cytidine monophosphate, and hydroxycobalamin.

PubMed

Mibielli, Marco Antonio; Nunes, Carlos Pereira; Cohen, José Carlos; Scussel, Ari Boulanger; Higashi, Rafael; Bendavit, Gabriel Gherman; Oliveira, Lisa; Geller, Mauro

2010-01-01

This randomized, controlled, double-blind clinical study in parallel groups evaluated the safety and efficacy of an oral combination diclofenac-cholestyramine, nucleotides (uridine and cytidine) and vitamin B12 versus the oral combination of nucleotides and vitamin B12 in the treatment of acute, non-traumatic pain. Subjects received twice-daily, 10-day oral administration of diclofenac-cholestyramine + uridine + cytidine + vitamin B12 (Group DN, n=40) or uridine + cytidine + vitamin B12 (Group NB, n=41). The primary study endpoint was the number of subjects with VAS reduction of >30mm after 10 days of treatment. Secondary endpoints included the number of patients with improvement >5 points in the Patient Functionality Questionnaire after 10 days of treatment, and the number of subjects presenting adverse events. Treatment with the combination of diclofenac-cholestyramine, nucleotides and Vitamin B12 resulted in a higher number of subjects with VAS score reductions >30mm after 10 days of treatment (87.5% subjects) than in the control group administered nucleotides and Vitamin B12 (51.23% of subjects), (p>0.0006). A significantly higher number of subjects in the DN group (80%) had a score reduction of >5 points in the Patient Functionality Questionnaire at after 10 days of treatment compared to Group NB (29.3%), (p<0.001). The number of subjects presenting AEs did not vary significantly between treatment groups (p=0.587). The combination of diclofenac-cholestyramine with uridine, cytidine and vitamin B12 was well-tolerated over a 10-day treatment period. The combination reduced pain and improved functionality among subjects presenting acute, non-traumatic pain in the lower back, hips, and neck.

Pain and recovery after total knee arthroplasty: a 12-month follow-up after a prospective randomized study evaluating Nefopam and Ketamine for early rehabilitation.

PubMed

Aveline, Christophe; Roux, Alain Le; Hetet, Hubert Le; Gautier, Jean F; Vautier, Pierre; Cognet, Fabrice; Bonnet, Francis

2014-09-01

Ketamine and nefopam has been documented to decrease pain intensity and improve rehabilitation after total knee arthroplasty (TKA). We conducted a follow-up study of a previously randomized clinical trial to determine the prevalence and risk factors of chronic pain 1 year after TKA and to assess the role of perioperative administration of ketamine and nefopam. The original randomized, double-blind trial evaluated postoperative pain in 75 patients scheduled for TKA who received either a 48-hour infusion of ketamine or nefopam compared with placebo. The current study has evaluated patients at 6 and 12 months for the presence of chronic pain defined as a visual analogue scale ≥40 mm during a stair-climbing test. Other outcomes were incidence of neuropathic pain evaluated (DN4 score), active flexion of the knee, and functional outcome (KOOS-PS score). A total of 69 patients completed the trial. The prevalence of chronic pain at 12 months was 17.4% (95% confidence interval [CI], 10.2%-27.9%) without difference between the ketamine (12.5%), nefopam (13.7%), and placebo groups (26.1%). Prevalence of neuropathic pain was 10.2% (95% CI, 3%-17.3%). Ketamine reduced DN4 scores (P=0.02), increased knee flexion (P=0.0007), and KOOS-PS scores (P<0.0001) compared with placebo. A visual analogue scale score ≥60 mm in the postoperative period was the only risk factor associated with the occurrence of chronic pain (odds ratio 4.54; 95% CI, 1.17-17.67). After TKA, the intensity of postoperative pain is a risk factor of chronic pain on movement. Intraoperative ketamine seems to improve long-term results of rehabilitation in this setting.

Prenatal cadmium exposure dysregulates sonic hedgehog and Wnt/beta-catenin signaling in the thymus resulting in altered thymocyte development

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hanson, Miranda L.; Brundage, Kathleen M.; Schafer, Rosana

2010-01-15

Cadmium (Cd) is both an environmental pollutant and a component of cigarette smoke. Although evidence demonstrates that adult exposure to Cd causes changes in the immune system, there are limited reports in the literature of immunomodulatory effects of prenatal exposure to Cd. The sonic hedgehog (Shh) and Wnt/beta-catenin pathways are required for thymocyte maturation. Several studies have demonstrated that Cd exposure affects these pathways in different organ systems. This study was designed to investigate the effect of prenatal Cd exposure on thymocyte development, and to determine if these effects were linked to dysregulation of Shh and Wnt/beta-catenin pathways. Pregnant C57Bl/6more » mice were exposed to an environmentally relevant dose (10 ppm) of Cd throughout pregnancy and effects on the thymus were assessed on the day of birth. Thymocyte phenotype was determined by flow cytometry. A Gli:luciferase reporter cell line was used to measure Shh signaling. Transcription of target genes and translation of key components of both signaling pathways were assessed using real-time RT-PCR and western blot, respectively. Prenatal Cd exposure increased the number of CD4{sup +} cells and a subpopulation of double-negative cells (DN; CD4{sup -}CD8{sup -}), DN4 (CD44{sup -}CD25{sup -}). Shh and Wnt/beta-catenin signaling were both decreased in the thymus. Target genes of Shh (Patched1 and Gli1) and Wnt/beta-catenin (c-fos, and c-myc) were affected differentially among thymocyte subpopulations. These findings suggest that prenatal exposure to Cd dysregulates two signaling pathways in the thymus, resulting in altered thymocyte development.« less

Activation of mTOR (mechanistic target of rapamycin) in rheumatic diseases.

PubMed

Perl, Andras

2016-03-01

Mechanistic target of rapamycin (mTOR, also known as mammalian target of rapamycin) is a ubiquitous serine/threonine kinase that regulates cell growth, proliferation and survival. These effects are cell-type-specific, and are elicited in response to stimulation by growth factors, hormones and cytokines, as well as to internal and external metabolic cues. Rapamycin was initially developed as an inhibitor of T-cell proliferation and allograft rejection in the organ transplant setting. Subsequently, its molecular target (mTOR) was identified as a component of two interacting complexes, mTORC1 and mTORC2, that regulate T-cell lineage specification and macrophage differentiation. mTORC1 drives the proinflammatory expansion of T helper (TH) type 1, TH17, and CD4(-)CD8(-) (double-negative, DN) T cells. Both mTORC1 and mTORC2 inhibit the development of CD4(+)CD25(+)FoxP3(+) T regulatory (TREG) cells and, indirectly, mTORC2 favours the expansion of T follicular helper (TFH) cells which, similarly to DN T cells, promote B-cell activation and autoantibody production. In contrast to this proinflammatory effect of mTORC2, mTORC1 favours, to some extent, an anti-inflammatory macrophage polarization that is protective against infections and tissue inflammation. Outside the immune system, mTORC1 controls fibroblast proliferation and chondrocyte survival, with implications for tissue fibrosis and osteoarthritis, respectively. Rapamycin (which primarily inhibits mTORC1), ATP-competitive, dual mTORC1/mTORC2 inhibitors and upstream regulators of the mTOR pathway are being developed to treat autoimmune, hyperproliferative and degenerative diseases. In this regard, mTOR blockade promises to increase life expectancy through treatment and prevention of rheumatic diseases.

The ultraviolet variations of iota Cas

NASA Technical Reports Server (NTRS)

Molnar, M. R.; Mallama, A. D.; Soskey, D. G.; Holm, A. V.

1976-01-01

The Ap variable star iota Cas was observed with the photometers on OAO-2 covering the spectral range 1430-4250 A. The ultraviolet light curves show a double wave with primary minimum and maximum at phase ? 0.00 and 0.35, respectively. Secondary minimum light is at phase ? 0.65 with secondary maximum at phase ? 0.85. The light curves longward of 3150 A vary in opposition to those shortward of this 'null region'. Ground-based coude spectra show that the Fe II and Cr II line strengths have a double-wave variation such that maximum strength occurs at minimum ultraviolet light. We suggest that the strong ultraviolet opacities due to photoionization and line blanketing by these metals may cause the observed photometric variations. We have also constructed an oblique-rotator model which shows iron and chromium lying in a great circle band rather than in circular spots.

Inhibition of Akt/mTOR/p70S6K Signaling Activity With Huangkui Capsule Alleviates the Early Glomerular Pathological Changes in Diabetic Nephropathy.

PubMed

Wu, Wei; Hu, Wei; Han, Wen-Bei; Liu, Ying-Lu; Tu, Yue; Yang, Hai-Ming; Fang, Qi-Jun; Zhou, Mo-Yi; Wan, Zi-Yue; Tang, Ren-Mao; Tang, Hai-Tao; Wan, Yi-Gang

2018-01-01

Huangkui capsule (HKC), a Chinese modern patent medicine extracted from Abelmoschus manihot (L.) medic, has been widely applied to clinical therapy in the early diabetic nephropathy (DN) patients. However, it remains elusive whether HKC can ameliorate the inchoate glomerular injuries in hyperglycemia. Recently the activation of phosphatidylinositol-3-kinase (PI3K)/serine-threonine kinase (Akt)/mammalian target of rapamycin (mTOR) signaling and its downstream regulator, 70-kDa ribosomal protein S6 kinase (p70S6K), play important roles in the early glomerular pathological changes of DN including glomerular hypertrophy, glomerular basement membrane (GBM) thickening and mild mesangial expansion. This study thereby aimed to clarify therapeutic effects of HKC during the initial phase of DN and its underlying mechanisms. Fifteen rats were randomly divided into 3 groups: the normal group, the model group and the HKC group. The early DN model rats were induced by unilateral nephrectomy combined with intraperitoneal injection of streptozotocin, and administered with either HKC suspension or vehicle after modeling and for a period of 4 weeks. Changes in the incipient glomerular lesions-related parameters in urine and blood were analyzed. Kidneys were isolated for histomorphometry, immunohistochemistry, immunofluorescence and Western blotting (WB) at sacrifice. In vitro , murine mesangial cells (MCs) were used to investigate inhibitory actions of hyperoside (HYP), a bioactive component of HKC, on cellular hypertrophy-associated signaling pathway by WB, compared with rapamycin (RAP). For the early DN model rats, HKC ameliorated micro-urinary albumin, body weight and serum albumin, but had no significant effects on renal function and liver enzymes; HKC improved renal shape, kidney weight and kidney hypertrophy index; HKC attenuated glomerular hypertrophy, GBM thickening and mild mesangial expansion; HKC inhibited the phosphorylation of Akt, mTOR and p70S6K, and the protein over-expression of transforming growth factor-β1 in kidneys. In vitro , the phosphorylation of PI3K, Akt, mTOR and p70S6K in MCs induced by high-glucose was abrogated by treatment of HYP or RAP. On the whole, this study further demonstrated HKC safely and efficiently alleviates the early glomerular pathological changes of DN, likely by inhibiting Akt/mTOR/p70S6K signaling activity in vivo and in vitro , and provided the first evidence that HKC directly contributes to the prevention of the early DN.

Effect of Dry Needling on Thigh Muscle Strength and Hip Flexion in Elite Soccer Players.

PubMed

Haser, Christian; Stöggl, Thomas; Kriner, Monika; Mikoleit, Jörg; Wolfahrt, Bernd; Scherr, Johannes; Halle, Martin; Pfab, Florian

2017-02-01

Increase in muscle force, endurance, and flexibility is desired in elite athletes to improve performance and to avoid injuries, but it is often hindered by the occurrence of myofascial trigger points. Dry needling (DN) has been shown effective in eliminating myofascial trigger points. This randomized controlled study in 30 elite youth soccer players of a professional soccer Bundesliga Club investigated the effects of four weekly sessions of DN plus water pressure massage on thigh muscle force and range of motion of hip flexion. A group receiving placebo laser plus water pressure massage and a group with no intervention served as controls. Data were collected at baseline (M1), treatment end (M2), and 4 wk follow-up (M3). Furthermore, a 5-month muscle injury follow-up was performed. DN showed significant improvement of muscular endurance of knee extensors at M2 (P = 0.039) and M3 (P = 0.008) compared with M1 (M1:294.6 ± 15.4 N·m·s, M2:311 ± 25 N·m·s; M3:316.0 ± 28.6 N·m·s) and knee flexors at M2 compared with M1 (M1:163.5 ± 10.9 N·m·s, M2:188.5 ± 16.3 N·m·s) as well as hip flexion (M1: 81.5° ± 3.3°, M2:89.8° ± 2.8°; M3:91.8° ± 3.8°). Compared with placebo (3.8° ± 3.8°) and control (1.4° ± 2.9°), DN (10.3° ± 3.5°) showed a significant (P = 0.01 and P = 0.0002) effect at M3 compared with M1 on hip flexion; compared with nontreatment control (-10 ± 11.9 N·m), DN (5.2 ± 10.2 N·m) also significantly (P = 0.049) improved maximum force of knee extensors at M3 compared with M1. During the rest of the season, muscle injuries were less frequent in the DN group compared with the control group. DN showed a significant effect on muscular endurance and hip flexion range of motion that persisted 4 wk posttreatment. Compared with placebo, it showed a significant effect on hip flexion that persisted 4 wk posttreatment, and compared with nonintervention control, it showed a significant effect on maximum force of knee extensors 4 wk posttreatment in elite soccer players.

Time Demand and Radiation Dose in 3D-Fluoroscopy-based Navigation-assisted 3D-Fluoroscopy-controlled Pedicle Screw Instrumentations.

PubMed

Balling, Horst

2018-05-01

Prospective single-center cohort study to record additional time requirements and radiation dose in navigation-assisted O-arm-controlled pedicle screw (PS) instrumentations. The aim of this study was to evaluate amount of extra-time and radiation dose for navigation-assisted PS instrumentations of the thoracolumbosacral spine using O-arm 3D-real-time-navigation (O3DN) compared to non-navigated spinal procedures (NNSPs) with a single C-arm and postoperative computed tomography (CT) scan for controlling PS positions. 3D-navigation is reported to enhance PS insertion accuracy. But time-consuming navigational steps and considerable additional radiation doses seem to limit this modern technique's attraction. A detailed analysis of additional time demand and extra-radiation dose in 3D-navigated spine surgery is not provided in literature, yet. From February 2011 through July 2015, 306 consecutive posterior instrumentations were performed in vertebral levels T10-S1 using O3DN for PS insertion. The duration of procedure-specific navigational steps of the overall collective (I) and the last cohort of 50 consecutive O3DN-surgeries (II) was compared to the average duration of analogous surgical steps in 100 consecutive NNSP using a single C-arm. 3D-radiation dose (dose-length-product, DLP) of navigational and postinstrumentation O-arm scans in group I and II was compared to the average DLP of 100 diagnostic lumbar CT scans. The average presurgical time from patient positioning on the operating table to skin incision was 46.2 ± 10.1 minutes (O3DN, I) and 40.6 ± 9.8 minutes (O3DN, II) versus 30.6 ± 8.3 minutes (NNSP) (P < 0.001, each). Intraoperative interruptions for scanning and data processing took 3.0 ± 0.6 minutes. DLPs averaged 865.1 ± 360.8 mGycm (O3DN, I) and 562.1 ± 352.6 mGycm (O3DN, II) compared to 575.5 ± 316.5 mGycm in diagnostic lumbar CT scans (P < 0.001 (I), P ≈ 0.81 [II]). After procedural experience, navigated surgeries can be performed with an additional time demand of 13.0 minutes compared to NNSP, and with a total DLP below that of a diagnostic lumbar CT scan (P ≈ 0.81). 4.

Numerical investigation of disruption characteristics for the snowflake divertor configuration in HL-2M

NASA Astrophysics Data System (ADS)

Xue, L.; Duan, X. R.; Zheng, G. Y.; Liu, Y. Q.; Pan, Y. D.; Yan, S. L.; Dokuka, V. N.; Lukash, V. E.; Khayrutdinov, R. R.

2016-05-01

Cold and hot vertical displacement events (VDEs) are frequently related to the disruption of vertically-elongated tokamaks. The weak poloidal magnetic field around the null-points of a snowflake divertor configuration may influence the vertical displacement process. In this paper, the major disruption with a cold VDE and the vertical disruption in the HL-2M tokamak are investigated by the DINA code. In order to better illustrate the effect from the weak poloidal field, a double-null snowflake configuration is compared with the standard divertor (SD) configuration under the same plasma parameters. Computational results show that the weak poloidal magnetic field can be partly beneficial for mitigating the vertical instability of the plasma under small perturbations. For major disruption, the peak poloidal halo current fraction is almost the same between the snowflake and the SD configurations. However, this fraction becomes much larger for the snowflake in the event of a hot VDE. Furthermore, during the disruption for a snowflake configuration, the distribution of electromagnetic force on a vacuum vessel gets more non-uniform during the current quench.

Thymic Stromal-Cell Abnormalities and Dysregulated T-Cell Development in IL-2-Deficient Mice

PubMed Central

Reya, Tannishtha; Bassiri, Hamid; Biancaniello, Renée

1998-01-01

The role that interleukin-2 (IL-2) plays in T-cell development is not known. To address this issue, we have investigated the nature of the abnormal thymic development and autoimmune disorders that occurs in IL-2-deficient (IL-2–/–) mice. After 4 to 5 weeks of birth, IL-2–/– mice progressively develop a thymic disorder resulting in the disruption of thymocyte maturation. This disorder is characterized by a dramatic reduction in cellularity, the selective loss of immature CD4-8- (double negative; DN) and CD4+8+ (double positive; DP) thymocytes and defects in the thymic stromal-cell compartment. Immunohistochemical staining of sections of thymuses from specific pathogen-free and germ-free IL-2–/– mice of various ages showed a progressive ,loss of cortical epithelial cells, MHC class II-expressing cells, monocytes, and macrophages. Reduced numbers of macrophages were apparent as early as week after birth. Since IL-2–/– thymocyte progenitor populations could mature normally on transfer into a normal thymus, the thymic defect in IL-2–/– mice appears to be due to abnormalities among thymic stromal cells. These results underscore the role of IL-2 in maintaining functional microenvironments that are necessary to support thymocyte growth, development, and selection. PMID:9814585

Targeting CD147 for T to NK Lineage Reprogramming and Tumor Therapy.

PubMed

Geng, Jie-Jie; Tang, Juan; Yang, Xiang-Min; Chen, Ruo; Zhang, Yang; Zhang, Kui; Miao, Jin-Lin; Chen, Zhi-Nan; Zhu, Ping

2017-06-01

CD147 is highly expressed on the surface of numerous tumor cells to promote invasion and metastasis. Targeting these cells with CD147-specific antibodies has been validated as an effective approach for lung and liver cancer therapy. In the immune system, CD147 is recognized as a co-stimulatory receptor and impacts the outcome of thymic selection. Using T cell-specific deletion, we showed here that in thymus CD147 is indispensable for the stable αβ T cell lineage commitment: loss of CD147 biases both multipotent DN (double negative) and fully committed DP (double positive) cells into innate NK-like lineages. Mechanistically, CD147 deficiency results in impaired Wnt signaling and expression of BCL11b, a master transcription factor in determining T cell identity. In addition, functional blocking of CD147 by antibody phenocopies genetic deletion to enrich NK-like cells in the periphery. Furthermore, using a melanoma model and orthotopic liver cancer transplants, we showed that the augmentation of NK-like cells strongly associates with resistance against tumor growth upon CD147 suppression. Therefore, besides its original function in tumorigenesis, CD147 is also an effective surface target for immune modulation in tumor therapy. Copyright © 2017. Published by Elsevier B.V.

T-cell-specific deletion of Mof blocks their differentiation and results in genomic instability in mice

PubMed Central

Pandita, Tej K.

2013-01-01

Ataxia telangiectasia patients develop lymphoid malignancies of both B- and T-cell origin. Similarly, ataxia telangiectasia mutated (Atm)-deficient mice exhibit severe defects in T-cell maturation and eventually develop thymomas. The function of ATM is known to be influenced by the mammalian orthologue of the Drosophila MOF (males absent on the first) gene. Here, we report the effect of T-cell-specific ablation of the mouse Mof (Mof) gene on leucocyte trafficking and survival. Conditional Mof Flox/Flox (Mof F/F) mice expressing Cre recombinase under control of the T-cell-specific Lck proximal promoter (Mof F/F/Lck-Cre +) display a marked reduction in thymus size compared with Mof F/F/Lck-Cre – mice. In contrast, the spleen size of Mof F/F/Lck-Cre + mice was increased compared with control Mof F/F/Lck-Cre – mice. The thymus of Mof F/F/Lck-Cre + mice contained significantly reduced T cells, whereas thymic B cells were elevated. Within the T-cell population, CD4+CD8+ double-positive T-cell levels were reduced, whereas the immature CD4–CD8– double-negative (DN) population was elevated. Defective T-cell differentiation is also evident as an increased DN3 (CD44–CD25+) population, the cell stage during which T-cell receptor rearrangement takes place. The differentiation defect in T cells and reduced thymus size were not rescued in a p53-deficient background. Splenic B-cell distributions were similar between Mof F/F/Lck-Cre + and Mof F/F/Lck-Cre – mice except for an elevation of the κ light-chain population, suggestive of an abnormal clonal expansion. T cells from Mof F/F/Lck-Cre + mice did not respond to phytohaemagglutinin (PHA) stimulation, whereas LPS-stimulated B cells from Mof F/F/Lck-Cre + mice demonstrated spontaneous genomic instability. Mice with T-cell-specific loss of MOF had shorter lifespans and decreased survival following irradiation than did Mof F/F/Lck-Cre – mice. These observations suggest that Mof plays a critical role in T-cell differentiation and that depletion of Mof in T cells reduces T-cell numbers and, by an undefined mechanism, induces genomic instability in B cells through bystander mechanism. As a result, these mice have a shorter lifespan and reduced survival after irradiation. PMID:23386701

T-cell-specific deletion of Mof blocks their differentiation and results in genomic instability in mice.

PubMed

Gupta, Arun; Hunt, Clayton R; Pandita, Raj K; Pae, Juhee; Komal, K; Singh, Mayank; Shay, Jerry W; Kumar, Rakesh; Ariizumi, Kiyoshi; Horikoshi, Nobuo; Hittelman, Walter N; Guha, Chandan; Ludwig, Thomas; Pandita, Tej K

2013-05-01

Ataxia telangiectasia patients develop lymphoid malignancies of both B- and T-cell origin. Similarly, ataxia telangiectasia mutated (Atm)-deficient mice exhibit severe defects in T-cell maturation and eventually develop thymomas. The function of ATM is known to be influenced by the mammalian orthologue of the Drosophila MOF (males absent on the first) gene. Here, we report the effect of T-cell-specific ablation of the mouse Mof (Mof) gene on leucocyte trafficking and survival. Conditional Mof(Flox/Flox) (Mof (F/F)) mice expressing Cre recombinase under control of the T-cell-specific Lck proximal promoter (Mof(F/F)/Lck-Cre(+)) display a marked reduction in thymus size compared with Mof(F/F)/Lck-Cre(-) mice. In contrast, the spleen size of Mof(F/F)/Lck-Cre(+) mice was increased compared with control Mof(F/F)/Lck-Cre(-) mice. The thymus of Mof(F/F)/Lck-Cre(+) mice contained significantly reduced T cells, whereas thymic B cells were elevated. Within the T-cell population, CD4(+)CD8(+) double-positive T-cell levels were reduced, whereas the immature CD4(-)CD8(-) double-negative (DN) population was elevated. Defective T-cell differentiation is also evident as an increased DN3 (CD44(-)CD25(+)) population, the cell stage during which T-cell receptor rearrangement takes place. The differentiation defect in T cells and reduced thymus size were not rescued in a p53-deficient background. Splenic B-cell distributions were similar between Mof(F/F)/Lck-Cre(+) and Mof(F/F)/Lck-Cre(-) mice except for an elevation of the κ light-chain population, suggestive of an abnormal clonal expansion. T cells from Mof(F/F)/Lck-Cre(+) mice did not respond to phytohaemagglutinin (PHA) stimulation, whereas LPS-stimulated B cells from Mof(F/F)/Lck-Cre(+) mice demonstrated spontaneous genomic instability. Mice with T-cell-specific loss of MOF had shorter lifespans and decreased survival following irradiation than did Mof(F/F)/Lck-Cre(-) mice. These observations suggest that Mof plays a critical role in T-cell differentiation and that depletion of Mof in T cells reduces T-cell numbers and, by an undefined mechanism, induces genomic instability in B cells through bystander mechanism. As a result, these mice have a shorter lifespan and reduced survival after irradiation.

77 FR 43063 - Affirmation of Vertical Datum for Surveying and Mapping Activities for the Territory of Puerto Rico

Federal Register 2010, 2011, 2012, 2013, 2014

2012-07-23

... National Water Level Observation Network (NWLON) for bench marks designated 975 5371 A TIDAL (PID TV1513) (1.334 meters), located at La Puntilla, San Juan Puerto Rico, 975 2235 D (PID DN8624) (0.973 meters), located on Culebra Island, 975 2695 A (PID DN8535) (1.962 meters), located at Esperanza, Vieques Island...

Latent Factor Structure of the Das-Naglieri Cognitive Assessment System: A Confirmatory Factor Analysis in a Chinese Setting

ERIC Educational Resources Information Center

Deng, Ci-ping; Liu, Ming; Wei, Wei; Chan, Raymond C. K.; Das, J. P.

2011-01-01

This study aims to measure the psychometric properties of the Das-Naglieri Cognitive Assessment System (D-N CAS) and to determine its clinical utility in a Chinese context. Confirmatory factor analysis (CFA) was conducted to examine the construct validity of the Chinese version of the D-N CAS among a group of 567, normally developed children.…

Changes in Signal Intensity of the Dentate Nucleus and Globus Pallidus in Pediatric Patients: Impact of Brain Irradiation and Presence of Primary Brain Tumors Independent of Linear Gadolinium-based Contrast Agent Administration.

PubMed

Tamrazi, Benita; Nguyen, Binh; Liu, Chia-Shang J; Azen, Colleen G; Nelson, Mary B; Dhall, Girish; Nelson, Marvin D

2018-05-01

Purpose To determine whether whole-brain irradiation, chemotherapy, and primary brain pathologic conditions affect magnetic resonance (MR) imaging signal changes in pediatric patients independent of the administration of gadolinium-based contrast agents (GBCAs). Materials and Methods This institutional review board-approved, HIPAA-compliant study included 144 pediatric patients who underwent intravenous GBCA-enhanced MR imaging examinations (55 patients with primary brain tumors and whole-brain irradiation, 19 with primary brain tumors and chemotherapy only, 52 with primary brain tumors without any treatment, and 18 with neuroblastoma without brain metastatic disease). The signal intensities (SIs) in the globus pallidus (GP), thalamus (T), dentate nucleus (DN), and pons (P) were measured on unenhanced T1-weighted images. GP:T and DN:P SI ratios were compared between groups by using the analysis of variance and were analyzed relative to group, total cumulative number of doses of GBCA, age, and sex by using multivariable linear models. Results DN:P ratio for the radiation therapy group was greater than that for the other groups except for the group of brain tumors treated with chemotherapy (P < .05). The number of GBCA doses was correlated with the DN:P ratio for the nontreated brain tumor group (P < .0001). The radiation therapy-treated brain tumor group demonstrated higher DN:P ratios than the nontreated brain tumor group for number of doses less than or equal to 10 (P < .0001), whereas ratios in the nontreated brain tumor group were higher than those in the radiation therapy-treated brain tumor group for doses greater than 20 (P = .05). The GP:T ratios for the brain tumor groups were greater than that for the neuroblastoma group (P = .01). Conclusion Changes in SI of the DN and GP that are independent of the administration of GBCA occur in patients with brain tumors undergoing brain irradiation, as well as in patients with untreated primary brain tumors. © RSNA, 2017.

INS-1 Cells Undergoing Caspase-Dependent Apoptosis Enhance the Regenerative Capacity of Neighboring Cells

PubMed Central

Bonner, Caroline; Bacon, Siobhán; Concannon, Caoimhín G.; Rizvi, Syed R.; Baquié, Mathurin; Farrelly, Angela M.; Kilbride, Seán M.; Dussmann, Heiko; Ward, Manus W.; Boulanger, Chantal M.; Wollheim, Claes B.; Graf, Rolf; Byrne, Maria M.; Prehn, Jochen H.M.

2010-01-01

OBJECTIVE In diabetes, β-cell mass is not static but in a constant process of cell death and renewal. Inactivating mutations in transcription factor 1 (tcf-1)/hepatocyte nuclear factor1a (hnf1a) result in decreased β-cell mass and HNF1A–maturity onset diabetes of the young (HNF1A-MODY). Here, we investigated the effect of a dominant-negative HNF1A mutant (DN-HNF1A) induced apoptosis on the regenerative capacity of INS-1 cells. RESEARCH DESIGN AND METHODS DN-HNF1A was expressed in INS-1 cells using a reverse tetracycline-dependent transactivator system. Gene(s)/protein(s) involved in β-cell regeneration were investigated by real-time quantitative RT-PCR, Western blotting, and immunohistochemistry. Pancreatic stone protein/regenerating protein (PSP/reg) serum levels in human subjects were detected by enzyme-linked immunosorbent assay. RESULTS We detected a prominent induction of PSP/reg at the gene and protein level during DN-HNF1A–induced apoptosis. Elevated PSP/reg levels were also detected in islets of transgenic HNF1A-MODY mice and in the serum of HNF1A-MODY patients. The induction of PSP/reg was glucose dependent and mediated by caspase activation during apoptosis. Interestingly, the supernatant from DN-HNF1A–expressing cells, but not DN-HNF1A–expressing cells treated with zVAD.fmk, was sufficient to induce PSP/reg gene expression and increase cell proliferation in naïve, untreated INS-1 cells. Further experiments demonstrated that annexin-V–positive microparticles originating from apoptosing INS-1 cells mediated the induction of PSP/reg. Treatment with recombinant PSP/reg reversed the phenotype of DN-HNF1A–induced cells by stimulating cell proliferation and increasing insulin gene expression. CONCLUSIONS Our results suggest that apoptosing INS-1 cells shed microparticles that may stimulate PSP/reg induction in neighboring cells, a mechanism that may facilitate the recovery of β-cell mass in HNF1A-MODY. PMID:20682686

Effectiveness of dry needling of rectus abdominis trigger points for the treatment of primary dysmenorrhoea: a randomised parallel-group trial.

PubMed

Gaubeca-Gilarranz, Alberto; Fernández-de-Las-Peñas, César; Medina-Torres, José Raúl; Seoane-Ruiz, José M; Company-Palonés, Aurelio; Cleland, Joshua A; Arias-Buría, Jose L

2018-05-02

To compare the effectiveness of trigger point dry needling (TrP-DN) versus placebo needling, relative to an untreated control group, on pain and quality of life in primary dysmenorrhoea. In this randomised, single blind, parallel-group trial, 56 females with primary dysmenorrhoea were randomly allocated to TrP-DN (n=19), placebo needling (n=18) or no treatment (n=19). Patients in both groups were asked to undertake a stretching exercise of the rectus abdominis daily. The needling group received a single session of TrP-DN to trigger points (TrPs) in the rectus abdominis, and the placebo group received placebo needling. The primary outcome was pain intensity (visual analogue scale). Secondary outcomes were quality of life, use of non-steroidal anti-inflammatory drugs, the number of days with pain, and self-perceived improvement, measured using a Global Rate of Change. Outcomes were assessed at baseline, and 1 and 2 months after the treatment. Females receiving TrP-DN exhibited greater decreases (P<0.001) in pain than those receiving placebo (1 month: Δ-19.8 mm, 25.9 to -13.7; 2 months: Δ-26.0 mm, -33.1 to -18.9) or assigned to the untreated control group (1 month: Δ-26.0mm, -32.5 to -19.5; 2 months: Δ-20.1 mm, -26.4 to -13.8). Females in the TrP-DN group also exhibited a greater decrease in the amount of medications (P<0.001). No differences in the number of days with pain or quality of life were found (all P>0.1). This trial suggests that a single session of TrP-DN of the rectus abdominis combined with stretching was more effective than placebo needling and stretching alone at reducing pain and the amount of medication used in primary dysmenorrhoea. ACTRN12616000170426. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Rab5 and Rab11 Are Required for Clathrin-Dependent Endocytosis of Japanese Encephalitis Virus in BHK-21 Cells.

PubMed

Liu, Chun-Chun; Zhang, Yun-Na; Li, Zhao-Yao; Hou, Jin-Xiu; Zhou, Jing; Kan, Lin; Zhou, Bin; Chen, Pu-Yan

2017-10-01

During infection Japanese encephalitis virus (JEV) generally enters host cells via receptor-mediated clathrin-dependent endocytosis. The trafficking of JEV within endosomes is controlled by Rab GTPases, but which Rab proteins are involved in JEV entry into BHK-21 cells is unknown. In this study, entry and postinternalization of JEV were analyzed using biochemical inhibitors, RNA interference, and dominant negative (DN) mutants. Our data demonstrate that JEV entry into BHK-21 cells depends on clathrin, dynamin, and cholesterol but not on caveolae or macropinocytosis. The effect on JEV infection of dominant negative (DN) mutants of four Rab proteins that regulate endosomal trafficking was examined. Expression of DN Rab5 and DN Rab11, but not DN Rab7 and DN Rab9, significantly inhibited JEV replication. These results were further tested by silencing Rab5 or Rab11 expression before viral infection. Confocal microscopy showed that virus particles colocalized with Rab5 or Rab11 within 15 min after virus entry, suggesting that after internalization JEV moves to early and recycling endosomes before the release of the viral genome. Our findings demonstrate the roles of Rab5 and Rab11 on JEV infection of BHK-21 cells through the endocytic pathway, providing new insights into the life cycle of flaviviruses. IMPORTANCE Although Japanese encephalitis virus (JEV) utilizes different endocytic pathways depending on the cell type being infected, the detailed mechanism of its entry into BHK-21 cells is unknown. Understanding the process of JEV endocytosis and postinternalization will advance our knowledge of JEV infection and pathogenesis as well as provide potential novel drug targets for antiviral intervention. With this objective, we used systematic approaches to dissect this process. The results show that entry of JEV into BHK-21 cells requires a low-pH environment and that the process occurs through dynamin-, actin-, and cholesterol-dependent clathrin-mediated endocytosis that requires Rab5 and Rab11. Our work provides a detailed picture of the entry of JEV into BHK-21 cells and the cellular events that follow. Copyright © 2017 American Society for Microbiology.

A distinct class of dominant negative Ras mutants: cytosolic GTP-bound Ras effector domain mutants that inhibit Ras signaling and transformation and enhance cell adhesion.

PubMed

Fiordalisi, James J; Holly, Stephen P; Johnson, Ronald L; Parise, Leslie V; Cox, Adrienne D

2002-03-29

Cytosolic GTP-bound Ras has been shown to act as a dominant negative (DN) inhibitor of Ras by sequestering Raf in non-productive cytosolic complexes. Nevertheless, this distinct class of DN mutants has been neither well characterized nor extensively used to analyze Ras signaling. In contrast, DN Ras17N, which functions by blocking Ras guanine nucleotide exchange factors, has been well characterized and is widely used. Cytosolic GTP-bound Ras mutants could be used to inhibit particular Ras effectors by introducing additional mutations (T35S, E37G or Y40C) that permit them to associate selectively with and inhibit Raf, RalGDS, or phosphoinositide 3-kinase, respectively. When the wild-type Ras effector binding region is used, cytosolic Ras should associate with all Ras effectors, even those that are not yet identified, making these DN Ras mutants effective inhibitors of multiple Ras functions. We generated cytosolic GTP-bound H-, N-, and K-Ras, and we assessed their ability to inhibit Ras-induced phenotypes. In fibroblasts, cytosolic H-, N-, and K-Ras inhibited Ras-induced Elk-1 activation and focus formation, induced a flattened cell morphology, and increased adhesion to fibronectin through modulation of a beta(1)-subunit-containing integrin, thereby demonstrating that DN activity is not limited to a subset of Ras isoforms. We also generated cytosolic GTP-bound Ras effector domain mutants (EDMs), each of which reduced the ability of cytosolic GTP-bound Ras proteins to inhibit Elk-1 activation and to induce cell flattening, implicating multiple pathways in these phenotypes. In contrast, Ras-induced focus formation, platelet-derived growth factor (PDGF)-, or Ras-induced phospho-Akt levels and cell adhesion to fibronectin were affected by T35S and Y40C EDMs, whereas PDGF- or Ras-induced phospho-Erk levels were affected only by the T35S EDM, implying that a more limited set of Ras-mediated pathways participate in these phenotypes. These data constitute the first extensive characterization of this functionally distinct class of DN Ras inhibitor proteins.

In vitro evaluation of acaricidal activity of novel green silver nanoparticles against deltamethrin resistance Rhipicephalus (Boophilus) microplus.

PubMed

Avinash, B; Venu, R; Alpha Raj, M; Srinivasa Rao, K; Srilatha, Ch; Prasad, T N V K V

2017-04-15

An investigation was undertaken to study, for the first time, in vitro acaricidal activity of green silver nanoparticles on deltamethrin resistance Rhipicephalus (Boophilus) microplus. The compounds tested were neem coated silver nanoparticles (N-Ag NPs), deltamethrin neem coated silver nanoparticles (DN-Ag NPs), 2, 3 dehydrosalannol (2,3 DHS), 2, 3 DHS coated silver nanoparticles (2, 3-DHS-Ag NPs), Quercetin dihydrate (QDH) and QDH coated silver nanoparticles (QDH-Ag NPs). Also included in this study, for the purpose of comparison, were neem leaf extract (NLE), silver nitrate (AgNO 3 ) and deltamethrin (D). Acaricidal activity on larvae and adults of R. (B.) microplus was tested by larval packet test (LPT) and adult immersion test (AIT) respectively. In the LPT, 100% mortality was obtained at concentrations (ppm) of 360, 6000, 260, 200, 50, 300, 85, 600 and 200 for the compounds, D, NLE, Ag NO 3 , N-Ag NPs, DN-Ag NPs, 2, 3 DHS, 2, 3 DHS-Ag NPs, QDH, QDH-Ag NPs respectively. In AIT, the proportions of mortality and oviposition inhibition were proportionate but the reproductive index was inversely proportional to the concentration of the compounds used. The effect of DN-Ag NPs on mortality was the highest (93.33%) at 50ppm concentration. The mean reproductive index (0.01) and oviposition inhibition (99.16%) values were statistically significant when compared to control group. DN-Ag NPs showed significantly (P<0.05) lower LC 50 (3.87ppm; 21.95ppm) and LC 99 (53.05ppm; 90.06ppm) values against both the larvae and adults of R. (B.) microplus. The oviposition inhibiting ability of various compounds was determined to assess the reproductive performance of adult female ticks. The DN-Ag NPs had potent oviposition inhibitory activity with significantly lower IC 50 and IC 99 values compared to the rest of the treatments at 0.034 and 51.07ppm respectively. These results showed that the DN-Ag NPs had significant acaricidal activity against R. (B.) microplus. Copyright © 2017 Elsevier B.V. All rights reserved.