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.

Robust Bonding of Tough Double Network Hydrogel to Bone

NASA Astrophysics Data System (ADS)

Nonoyama, Takayuki; Wada, Susumu; Kiyama, Ryuji; Kitamura, Nobuto; Kurokawa, Takayuki; Nakajima, Tasuku; Yasuda, Kazunori; Gong, Jian Ping

Tough Double Network (DN) hydrogels are one of candidates as next-generation artificial cartilage from the viewpoints of low friction, water storage capability and toughness. For practical use, the hydrogel must be strongly fixed at the joint. However, strong fixation of such hydrogel to other materials (tissues) has not been achieved yet because the surface property of hydrogel is almost equal to water due to its high water content. Therefore, robust adhesion for fixation and low friction for lithe motion are trade-off relation. Here, we report robust fixation of hydroxyapatite (HAp) mineralized DN hydrogel to the bone without any toxicity. HAp is main inorganic component of bone tissues and has osteoconductive capability. After 4 weeks implantation of HAp/DN gel into rabbit femoral groove, The robust fixation between bone and HAp/DN gel, more than strength of gel matrix, was achieved. The methodology is universal for new biomaterials, which should be fixed on bone, such as ligament and tendon systems.

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

Hematopoietic Stem Cells from Ts65Dn Mice Are Deficient in the Repair of DNA Double-Strand Breaks.

PubMed

Wang, Yingying; Chang, Jianhui; Shao, Lijian; Feng, Wei; Luo, Yi; Chow, Marie; Du, Wei; Meng, Aimin; Zhou, Daohong

2016-06-01

Down syndrome (DS) is a genetic disorder caused by the presence of an extra partial or whole copy of chromosome 21. In addition to musculoskeletal and neurodevelopmental abnormalities, children with DS exhibit various hematologic disorders and have an increased risk of developing acute lymphoblastic leukemia and acute megakaryocytic leukemia. Using the Ts65Dn mouse model, we investigated bone marrow defects caused by trisomy for 132 orthologs of the genes on human chromosome 21. The results showed that, although the total bone marrow cellularity as well as the frequency of hematopoietic progenitor cells (HPCs) was comparable between Ts65Dn mice and their age-matched euploid wild-type (WT) control littermates, human chromosome 21 trisomy led to a significant reduction in hematopoietic stem cell (HSC) numbers and clonogenic function in Ts65Dn mice. We also found that spontaneous DNA double-strand breaks (DSBs) were significantly increased in HSCs from the Ts65Dn mice, which was correlated with the significant reduction in HSC clonogenic activity compared to those from WT controls. Moreover, analysis of the repair kinetics of radiation-induced DSBs revealed that HSCs from Ts65Dn mice were less proficient in DSB repair than the cells from WT controls. This deficiency was associated with a higher sensitivity of Ts65Dn HSCs to radiation-induced suppression of HSC clonogenic activity than that of euploid HSCs. These findings suggest that an additional copy of genes on human chromosome 21 may selectively impair the ability of HSCs to repair DSBs, which may contribute to DS-associated hematological abnormalities and malignancies.

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

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

Highly Conductive Ionic-Liquid Gels Prepared with Orthogonal Double Networks of a Low-Molecular-Weight Gelator and Cross-Linked Polymer.

PubMed

Kataoka, Toshikazu; Ishioka, Yumi; Mizuhata, Minoru; Minami, Hideto; Maruyama, Tatsuo

2015-10-21

We prepared a heterogeneous double-network (DN) ionogel containing a low-molecular-weight gelator network and a polymer network that can exhibit high ionic conductivity and high mechanical strength. An imidazolium-based ionic liquid was first gelated by the molecular self-assembly of a low-molecular-weight gelator (benzenetricarboxamide derivative), and methyl methacrylate was polymerized with a cross-linker to form a cross-linked poly(methyl methacrylate) (PMMA) network within the ionogel. Microscopic observation and calorimetric measurement revealed that the fibrous network of the low-molecular-weight gelator was maintained in the DN ionogel. The PMMA network strengthened the ionogel of the low-molecular-weight gelator and allowed us to handle the ionogel using tweezers. The orthogonal DNs produced ionogels with a broad range of storage elastic moduli. DN ionogels with low PMMA concentrations exhibited high ionic conductivity that was comparable to that of a neat ionic liquid. The present study demonstrates that the ionic conductivities of the DN and single-network, low-molecular-weight gelator or polymer ionogels strongly depended on their storage elastic moduli.

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.

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.

Intra-articular administration of hyaluronic acid increases the volume of the hyaline cartilage regenerated in a large osteochondral defect by implantation of a double-network gel.

PubMed

Fukui, Takaaki; Kitamura, Nobuto; Kurokawa, Takayuki; Yokota, Masashi; Kondo, Eiji; Gong, Jian Ping; Yasuda, Kazunori

2014-04-01

Implantation of PAMPS/PDMAAm double-network (DN) gel can induce hyaline cartilage regeneration in the osteochondral defect. However, it is a problem that the volume of the regenerated cartilage tissue is gradually reduced at 12 weeks. This study investigated whether intra-articular administration of hyaluronic acid (HA) increases the volume of the cartilage regenerated with the DN gel at 12 weeks. A total of 48 rabbits were used in this study. A cylindrical osteochondral defect created in the bilateral femoral trochlea was treated with DN gel (Group DN) or left without any implantation (Group C). In both Groups, we injected 1.0 mL of HA in the left knee, and 1.0 mL of saline solution in the right knee. Quantitative histological evaluations were performed at 2, 4, and 12 weeks, and PCR analysis was performed at 2 and 4 weeks after surgery. In Group DN, the proteoglycan-rich area was significantly greater in the HA-injected knees than in the saline-injected knees at 12 weeks (P = 0.0247), and expression of type 2 collagen, aggrecan, and Sox9 mRNAs was significantly greater in the HA-injected knees than in the saline-injected knees at 2 weeks (P = 0.0475, P = 0.0257, P = 0.0222, respectively). The intra-articular administration of HA significantly enhanced these gene expression at 2 weeks and significantly increased the volume of the hyaline cartilage regenerated by implantation of a DN gel at 12 weeks. This information is important to develop an additional method to increase the volume of the hyaline cartilage tissue in a potential cartilage regeneration strategy using the DN gel.

Hematopoietic Stem Cells from Ts65Dn Mice Are Deficient in the Repair of DNA Double-Strand Breaks

PubMed Central

Wang, Yingying; Chang, Jianhui; Shao, Lijian; Feng, Wei; Luo, Yi; Chow, Marie; Du, Wei; Meng, Aimin; Zhou, Daohong

2016-01-01

Down syndrome (DS) is a genetic disorder caused by the presence of an extra partial or whole copy of chromosome 21. In addition to musculoskeletal and neurodevelopmental abnormalities, children with DS exhibit various hematologic disorders and have an increased risk of developing acute lymphoblastic leukemia and acute megakaryocytic leukemia. Using the Ts65Dn mouse model, we investigated bone marrow defects caused by trisomy for 132 orthologs of the genes on human chromosome 21. The results showed that, although the total bone marrow cellularity as well as the frequency of hematopoietic progenitor cells (HPCs) was comparable between Ts65Dn mice and their age-matched euploid wild-type (WT) control littermates, human chromosome 21 trisomy led to a significant reduction in hematopoietic stem cell (HSC) numbers and clonogenic function in Ts65Dn mice. We also found that spontaneous DNA double-strand breaks (DSBs) were significantly increased in HSCs from the Ts65Dn mice, which was correlated with the significant reduction in HSC clonogenic activity compared to those from WT controls. Moreover, analysis of the repair kinetics of radiation-induced DSBs revealed that HSCs from Ts65Dn mice were less proficient in DSB repair than the cells from WT controls. This deficiency was associated with a higher sensitivity of Ts65Dn HSCs to radiation-induced suppression of HSC clonogenic activity than that of euploid HSCs. These findings suggest that an additional copy of genes on human chromosome 21 may selectively impair the ability of HSCs to repair DSBs, which may contribute to DS-associated hematological abnormalities and malignancies. PMID:27243896

Induction of spontaneous hyaline cartilage regeneration using a double-network gel: efficacy of a novel therapeutic strategy for an articular cartilage defect.

PubMed

Kitamura, Nobuto; Yasuda, Kazunori; Ogawa, Munehiro; Arakaki, Kazunobu; Kai, Shuken; Onodera, Shin; Kurokawa, Takayuki; Gong, Jian Ping

2011-06-01

A double-network (DN) gel, which was composed of poly-(2-acrylamido-2-methylpropanesulfonic acid) and poly-(N,N'-dimetyl acrylamide) (PAMPS/PDMAAm), has the potential to induce chondrogenesis both in vitro and in vivo. To establish the efficacy of a therapeutic strategy for an articular cartilage defect using a DN gel. Controlled laboratory study. A 4.3-mm-diameter osteochondral defect was created in rabbit trochlea. A DN gel plug was implanted into the defect of the right knee so that a defect 2 mm in depth remained after surgery. An untreated defect of the left knee provided control data. The osteochondral defects created were examined by histological and immunohistochemical evaluations, surface assessment using confocal laser scanning microscopy, and real-time polymerase chain reaction (PCR) analysis at 4 and 12 weeks. Samples were quantitatively evaluated with 2 scoring systems reported by Wayne et al and O'Driscoll et al. The DN gel-implanted defect was filled with a sufficient volume of the hyaline cartilage tissue rich in proteoglycan and type 2 collagen. Quantitative evaluation using the grading scales revealed a significantly higher score in the DN gel-implanted defects compared with the untreated control at each period (P < .0001). The mean relative values of type 2 collagen mRNAs in the regenerated tissue were obviously higher in the DN gel-implanted defect than in the untreated control at each period. The mean surface roughness of the untreated control was significantly higher than the normal cartilage at 12 weeks (P = .0106), while there was no statistical difference between the DN gel-implanted and normal knees. This study using the mature rabbit femoral trochlea osteochondral defect model demonstrated that DN gel implantation is an effective treatment to induce cartilage regeneration in vivo without any cultured cells or mammalian-derived scaffolds. This study has prompted us to develop a potential innovative strategy to repair cartilage lesions in the field of joint surgery.

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.

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.

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.

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

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.

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.

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.

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.

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

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.

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.

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

A closer look at the relationship between the default network, mind wandering, negative mood, and depression.

PubMed

Konjedi, Shaghayegh; Maleeh, Reza

2017-08-01

By a systematic analysis of the current literature on the neural correlates of mind wandering, that is, the default network (DN), and by shedding light on some determinative factors and conditions which affect the relationship between mind wandering and negative mood, we show that (1) mind wandering per se does not necessarily have a positive correlation with negative mood and, on the higher levels, depression. We propose that negative mood as a consequence of mind wandering generally depends on two determinative conditions, that is, whether mind wandering is with or without meta-awareness and whether mind wandering occurs during high or low vigilance states; (2) increased activity of the DN is not necessarily followed by an increase in unhappiness and depression. We argue that while in some kinds of meditation practices we witness an increase in the structure and in the activity of the DN, no increase in unhappiness and depression is observed.

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.

Conditional deletion reveals a cell-autonomous requirement of SLP-76 for thymocyte selection.

PubMed

Maltzman, Jonathan S; Kovoor, Lisa; Clements, James L; Koretzky, Gary A

2005-10-03

The SH2 domain containing leukocyte phosphoprotein of 76 kD (SLP-76) is critical for pre-TCR-mediated maturation to the CD4+CD8+ double positive (DP) stage in the thymus. The absolute block in SLP-76null mice at the CD4-CD8-CD44-CD25+ (double-negative 3, DN3) stage has hindered our understanding of the role of this adaptor in alphabeta TCR-mediated signal transduction in primary thymocytes and peripheral T lymphocytes. To evaluate the requirements for SLP-76 in these events, we used a cre-loxP approach to generate mice that conditionally delete SLP-76 after the DN3 checkpoint. These mice develop DP thymocytes that express the alphabeta TCR on the surface, but lack SLP-76 at the genomic DNA and protein levels. The DP compartment has reduced cellularity in young mice and fails to undergo positive selection to CD4+ or CD8+ single positive (SP) cells in vivo or activation-induced cell death in vitro. A small number of CD4+SP thymocytes are generated, but these cells fail to flux calcium in response to an alphabeta TCR-generated signal. Peripheral T cells are reduced in number, lack SLP-76 protein, and have an abnormal surface phenotype. These studies show for the first time that SLP-76 is required for signal transduction through the mature alphabeta TCR in primary cells of the T lineage.

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

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

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

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.

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.

Metalinguistic Negation in English and Arabic

ERIC Educational Resources Information Center

Nedwick, Kelly M.

2014-01-01

Negation is a unique and fascinating property of human language which has been given extensive theoretical and typological treatment. One categorization divides negation use into metalinguistic negation and descriptive negation (Horn, 1985). Descriptive negation (DN) is the truth-functional semantic operator which has received the most attention…

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.

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.

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.

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

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

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.

AAV-dominant negative tumor necrosis factor (DN-TNF) gene transfer to the striatum does not rescue medium spiny neurons in the YAC128 mouse model of Huntington's disease.

PubMed

Alto, Laura Taylor; Chen, Xi; Ruhn, Kelly A; Treviño, Isaac; Tansey, Malú G

2014-01-01

CNS inflammation is a hallmark of neurodegenerative disease, and recent studies suggest that the inflammatory response may contribute to neuronal demise. In particular, increased tumor necrosis factor (TNF) signaling is implicated in the pathology of both Parkinson's disease (PD) and Alzheimer's disease (AD). We have previously shown that localized gene delivery of dominant negative TNF to the degenerating brain region can limit pathology in animal models of PD and AD. TNF is upregulated in Huntington's disease (HD), like in PD and AD, but it is unknown whether TNF signaling contributes to neuronal degeneration in HD. We used in vivo gene delivery to test whether selective reduction of soluble TNF signaling could attenuate medium spiny neuron (MSN) degeneration in the YAC128 transgenic (TG) mouse model of Huntington's disease (HD). AAV vectors encoding cDNA for dominant-negative tumor necrosis factor (DN-TNF) or GFP (control) were injected into the striatum of young adult wild type WT and YAC128 TG mice and achieved 30-50% target coverage. Expression of dominant negative TNF protein was confirmed immunohistologically and biochemically and was maintained as mice aged to one year, but declined significantly over time. However, the extent of striatal DN-TNF gene transfer achieved in our studies was not sufficient to achieve robust effects on neuroinflammation, rescue degenerating MSNs or improve motor function in treated mice. Our findings suggest that alternative drug delivery strategies should be explored to determine whether greater target coverage by DN-TNF protein might afford some level of neuroprotection against HD-like pathology and/or that soluble TNF signaling may not be the primary driver of striatal neuroinflammation and MSN loss in YAC128 TG mice.

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

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.

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

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

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

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).

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.

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.

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.

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

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.

Interleukin-7 negatively regulates the development of mature T cells in fetal thymus organ cultures.

PubMed

DeLuca, Dominick; Clark, Dawn R

2002-05-01

We added antibody specific for interleukin-7 (IL-7) to chimeric fetal thymus organ cultures (FTOC) to investigate the involvement of this cytokine at distinct stages of T cell development. We report that the neutralization of IL-7 early in fetal T cell development results in a decrease in the production of mature CD4 or CD8 ('single positive', SP) or CD4/8 negative ('double negative', DN) T cell phenotypes, as defined by their expression of CD3. This loss of T cell development was not complete, but it did include the development of gammadelta T cells. However, if IL-7 was neutralized at later stages of FTOC, the production of CD4/8 positive ('double positive', DP) T cells was increased, and if the addition of the antibody was delayed further, the production of mature SP T cells was increased. This last result could be extended to both alphabeta and gammadelta T cells. These data suggested that IL-7 played a negative regulatory role in the development of progressively mature T cells. Tissue sections of FTOC showed that IL-7 was expressed in the subcapsular region of the tissue where immature T cells reside. However, IL-7 was not detected in the medullary region where mature T cells are located. These data suggest that IL-7 not only supports the development of immature fetal T cells, but it may inhibit the development of mature T cells. The production of mature fetal T cells may, therefore, be delayed until their precursors enter the medullary microenvironment, where IL-7 production is low. In this way, T cells may be prevented from maturing until negative selection or anergy events eliminate or inactivate autoreactive clones.

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.

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.

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.

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

The DP-1 transcription factor is required for keratinocyte growth and epidermal stratification.

PubMed

Chang, Wing Y; Bryce, Dawn M; D'Souza, Sudhir J A; Dagnino, Lina

2004-12-03

The epidermis is a stratified epithelium constantly replenished through the ability of keratinocytes in its basal layer to proliferate and self-renew. The epidermis arises from a single-cell layer ectoderm during embryogenesis. Large proliferative capacity is central to ectodermal cell and basal keratinocyte function. DP-1, a heterodimeric partner of E2F transcription factors, is highly expressed in the ectoderm and all epidermal layers during embryogenesis. To investigate the role of DP-1 in epidermal morphogenesis, we inhibited DP-1 activity through exogenous expression of a dominant-negative mutant (dnDP-1). Expression of the dnDP-1 mutant interferes with binding of E2F/DP-1 heterodimers to DNA and inhibits DNA replication, as well as cyclin A mRNA and protein expression. Chromatin immunoprecipitation analysis demonstrated that the cyclin A promoter is predominantly bound in proliferating keratinocytes by complexes containing E2F-3 and E2F-4. Thus, the mechanisms of decreased expression of cyclin A in the presence of dnDP-1 seem to involve inactivation of DP-1 complexes containing E2F-3 and E2F-4. To assess the consequences on epidermal morphogenesis of inhibiting DP-1 activity, we expressed dnDP-1 in rat epithelial keratinocytes in organotypic culture and observed that DP-1 inhibition negatively affected stratification of these cells. Likewise, expression of dnDP-1 in embryonic ectoderm explants produced extensive disorganization of subsequently formed epidermal basal and suprabasal layers, interfering with normal epidermal formation. We conclude that DP-1 activity is required for normal epidermal morphogenesis and ectoderm-to-epidermis transition.

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.

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.

Dominant negative DISC1 mutant mice display specific social behaviour deficits and aberration in BDNF and cannabinoid receptor expression.

PubMed

Kaminitz, Ayelet; Barzilay, Ran; Segal, Hadar; Taler, Michal; Offen, Daniel; Gil-Ad, Irit; Mechoulam, Raphael; Weizman, Abraham

2014-01-01

OBJECTIVES. Disrupted in schizophrenia 1 (DISC1) is considered the most prominent candidate gene for schizophrenia. In this study, we aimed to characterize behavioural and brain biochemical traits in a mouse expressing a dominant negative DISC1mutant (DN-DISC1). DN-DISC1 mice underwent behavioural tests to evaluate object recognition, social preference and social novelty seeking. ELISA was conducted on brain tissue to evaluate BDNF levels. Western blot was employed to measure BDNF receptor (TrkB) and cannabinoid receptor CB1. The mutant DISC1 mice displayed deficits in preference to social novelty while both social preference and object recognition were intact. Biochemical analysis of prefrontal cortex and hippocampus revealed a modest reduction in cortical TrkB protein levels of male mice while no differences in BDNF levels were observed. We found sex dependent differences in the expression of cannabinoid-1 receptors. We describe novel behavioural and biochemical abnormalities in the DN-DISC1 mouse model of schizophrenia. The data shows for the first time a possible link between DISC1 mutation and the cannabinoid system.

A threshold level of NFATc1 activity facilitates thymocyte differentiation and opposes notch-driven leukaemia development

PubMed Central

Klein-Hessling, Stefan; Rudolf, Ronald; Muhammad, Khalid; Knobeloch, Klaus-Peter; Maqbool, Muhammad Ahmad; Cauchy, Pierre; Andrau, Jean-Christophe; Avots, Andris; Talora, Claudio; Ellenrieder, Volker; Screpanti, Isabella; Serfling, Edgar; Patra, Amiya Kumar

2016-01-01

NFATc1 plays a critical role in double-negative thymocyte survival and differentiation. However, the signals that regulate Nfatc1 expression are incompletely characterized. Here we show a developmental stage-specific differential expression pattern of Nfatc1 driven by the distal (P1) or proximal (P2) promoters in thymocytes. Whereas, preTCR-negative thymocytes exhibit only P2 promoter-derived Nfatc1β expression, preTCR-positive thymocytes express both Nfatc1β and P1 promoter-derived Nfatc1α transcripts. Inducing NFATc1α activity from P1 promoter in preTCR-negative thymocytes, in addition to the NFATc1β from P2 promoter impairs thymocyte development resulting in severe T-cell lymphopenia. In addition, we show that NFATc1 activity suppresses the B-lineage potential of immature thymocytes, and consolidates their differentiation to T cells. Further, in the pTCR-positive DN3 cells, a threshold level of NFATc1 activity is vital in facilitating T-cell differentiation and to prevent Notch3-induced T-acute lymphoblastic leukaemia. Altogether, our results show NFATc1 activity is crucial in determining the T-cell fate of thymocytes. PMID:27312418

Overexpression of microRNA-21 is associated with elevated pro-inflammatory cytokines in dominant-negative TGF-β receptor type II mouse.

PubMed

Ando, Yugo; Yang, Guo-Xiang; Kenny, Thomas P; Kawata, Kazuhito; Zhang, Weici; Huang, Wenting; Leung, Patrick S C; Lian, Zhe-Xiong; Okazaki, Kazuichi; Ansari, Aftab A; He, Xiao-Song; Invernizzi, Pietro; Ridgway, William M; Lu, Qianjin; Gershwin, M Eric

2013-03-01

Dominant-negative TGF-β receptor II (dnTGF-βRII) mice spontaneously develop an autoimmune cholangitis resembling human primary biliary cirrhosis (PBC). Interestingly, the dominant-negative TGF-β receptor is expressed by both CD4(+) and CD8(+) T cells and leads to greatly reduced (but not absent) TGF-β signaling resulting in T cell intrinsic cell mediated autoimmunity. However, the mechanisms of the T cell dysregulation remain unclear. Recently it has been shown that TGF-β signaling is intimately involved with miRNA biogenesis and control. Herein we show that lack of T cell TGF-β signaling leads to down regulation of T cell miRNAs but up-regulation of the key inflammatory miRNA 21. Furthermore, the expression of miR-21 from hepatic effector CD8(+) T cells is significantly higher than in the same subsets isolated from spleen and mesenteric lymph nodes of the dnTGF-βRII mice. Previous studies indicate that miR-21 increases the synthesis of IFN-γ and IL-17A by T cells and suppresses apoptosis via programmed cell death protein 4 (PDCD4). Data presented herein demonstrate that transfecting w.t. B6 T cell subsets with miR-21 resulted in up-regulation of the inflammatory cytokines TNF-α and IFN-γ, thus partly replicating the dnTGF-βRII T cell phenotype. In conclusion, these data suggest miR-21 plays a critical role in the production of pro-inflammatory cytokines in dnTGF-βRII mice, which could be a contributing factor for the development of the organ-specific autoimmune cholangitis and colitis in this murine model of human PBC. Copyright © 2013 Elsevier Ltd. All rights reserved.

Hypothalamic nutrient sensing activates a forebrain-hindbrain neuronal circuit to regulate glucose production in vivo.

PubMed

Lam, Carol K L; Chari, Madhu; Rutter, Guy A; Lam, Tony K T

2011-01-01

Hypothalamic nutrient sensing regulates glucose production, but the neuronal circuits involved remain largely unknown. Recent studies underscore the importance of N-methyl-d-aspartate (NMDA) receptors in the dorsal vagal complex in glucose regulation. These studies raise the possibility that hypothalamic nutrient sensing activates a forebrain-hindbrain NMDA-dependent circuit to regulate glucose production. We implanted bilateral catheters targeting the mediobasal hypothalamus (MBH) (forebrain) and dorsal vagal complex (DVC) (hindbrain) and performed intravenous catheterizations to the same rat for infusion and sampling purposes. This model enabled concurrent selective activation of MBH nutrient sensing by either MBH delivery of lactate or an adenovirus expressing the dominant negative form of AMPK (Ad-DN AMPK α2 [D¹⁵⁷A]) and inhibition of DVC NMDA receptors by either DVC delivery of NMDA receptor blocker MK-801 or an adenovirus expressing the shRNA of NR1 subunit of NMDA receptors (Ad-shRNA NR1). Tracer-dilution methodology and the pancreatic euglycemic clamp technique were performed to assess changes in glucose kinetics in the same conscious, unrestrained rat in vivo. MBH lactate or Ad-DN AMPK with DVC saline increased glucose infusion required to maintain euglycemia due to an inhibition of glucose production during the clamps. However, DVC MK-801 negated the ability of MBH lactate or Ad-DN AMPK to increase glucose infusion or lower glucose production. Molecular knockdown of DVC NR1 of NMDA receptor via Ad-shRNA NR1 injection also negated MBH Ad-DN AMPK to lower glucose production. Molecular and pharmacological inhibition of DVC NMDA receptors negated hypothalamic nutrient sensing mechanisms activated by lactate metabolism or AMPK inhibition to lower glucose production. Thus, DVC NMDA receptor is required for hypothalamic nutrient sensing to lower glucose production and that hypothalamic nutrient sensing activates a forebrain-hindbrain circuit to lower glucose production.

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.

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

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.

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.

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

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 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

Development of AIM-Based Fast Solver for Efficient Design and Synthesis of Negative Index Materials

DTIC Science & Technology

2007-12-06

N∑ n=1 Dn < fn/ε̂ > = N∑ n=1 Dn [ 1 ε̂+n ∫ T+m fn · fmdv + 1 ε̂−n ∫ T−m fn · fmdv ] (A.34) (Recall that fm, is zero outside of T±m These integrals...the centroid of Tm. The scalar potential term of (A.32) can be written as < ∇Φ,fm >= ∫ S Φfm · n̂ds− ∫ V Φ∇ · fmdv (A.37) where Sis the boundary of V

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

High Performance Double-null Plasma Operation Under Radiating Divertor Conditions

NASA Astrophysics Data System (ADS)

Petrie, T. W.; Osborne, T.; Leonard, A. W.; Luce, T. C.; Petty, C. C.; Fenstermacher, M. E.; Lasnier, C. J.; Turco, F.; Watkins, J. G.

2017-10-01

We report on heat flux reduction experiments in which deuterium/neon- or deuterium/argon-based radiating mantle/divertor approaches were applied to high performance double-null (DN) plasmas (H98 1.4-1.7,βN 4 , q 95 6) with a combined neutral beam and ECH power input PIN 15 MW. When the radial location of the ECH deposition is close to the magnetic axis (e.g., ρ <=0.20), the radial profiles of both injected and intrinsic impurities are flat to somewhat hollow. For deposition farther out (e.g., ρ=0.45), the impurity profiles are highly peaked on axis, which would make high performance DN operation with impurity injection more problematical. Comparison of neon with argon `seeding' with respect to core dilution, energy confinement, and heat flux reduction under these conditions favors argon. Conditions that lead to an improved τE as predicted previously from ELITE code analysis, i.e., very high PIN, proximity to magnetic balance, and higher q95, are largely consistent with this data. Work was supported by the US DOE under DE-FC02-04ER54698, DE-AC52-07NA27344, DE-FG02-04ER54761, and DE-AC04-94AL85000.

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.

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.

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.

β-Arrestins promote podocyte injury by inhibition of autophagy in diabetic nephropathy.

PubMed

Liu, J; Li, Q X; Wang, X J; Zhang, C; Duan, Y Q; Wang, Z Y; Zhang, Y; Yu, X; Li, N J; Sun, J P; Yi, F

2016-04-07

β-Arrestins are multifunctional proteins originally identified as negative adaptors of G protein-coupled receptors (GPCRs). Emerging evidence has also indicated that β-arrestins can activate signaling pathways independent of GPCR activation. This study was to elucidate the role of β-arrestins in diabetic nephropathy (DN) and hypothesized that β-arrestins contribute to diabetic renal injury by mediating podocyte autophagic process. We first found that both β-arrestin-1 and β-arrestin-2 were upregulated in the kidney from streptozotocin-induced diabetic mice, diabetic db/db mice and kidney biopsies from diabetic patients. We further revealed that either β-arrestin-1 or β-arrestin-2 deficiency (Arrb1(-/-) or Arrb2(-/-)) ameliorated renal injury in diabetic mice. In vitro, we observed that podocytes increased both β-arrestin-1 and β-arrestin-2 expression levels under hyperglycemia condition and further demonstrated that β-arrestin-1 and β-arrestin-2 shared common mechanisms to suppress podocyte autophagy by negative regulation of ATG12-ATG5 conjugation. Collectively, this study for the first time demonstrates that β-arrestin-1 and β-arrestin-2 mediate podocyte autophagic activity, indicating that β-arrestins are critical components of signal transduction pathways that link renal injury to reduce autophagy in DN. Modulation of these pathways may be an innovative therapeutic strategy for treating patients with DN.

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.

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

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

Progression of Mouse Skin Carcinogenesis Is Associated with Increased Erα Levels and Is Repressed by a Dominant Negative Form of Erα

PubMed Central

Michalopoulos, Ioannis; Sideridou, Maria; Tsimaratou, Katerina; Christodoulou, Ioannis; Pyrillou, Katerina; Gorgoulis, Vassilis; Vlahopoulos, Spiros; Zoumpourlis, Vassilis

2012-01-01

Estrogen receptors (ER), namely ERα and ERβ, are hormone-activated transcription factors with an important role in carcinogenesis. In the present study, we aimed at elucidating the implication of ERα in skin cancer, using chemically-induced mouse skin tumours, as well as cell lines representing distinct stages of mouse skin oncogenesis. First, using immunohistochemical staining we showed that ERα is markedly increased in aggressive mouse skin tumours in vivo as compared to the papilloma tumours, whereas ERβ levels are low and become even lower in the aggressive spindle tumours of carcinogen-treated mice. Then, using the multistage mouse skin carcinogenesis model, we showed that ERα gradually increases during promotion and progression stages of mouse skin carcinogenesis, peaking at the most aggressive stage, whereas ERβ levels only slightly change throughout skin carcinogenesis. Stable transfection of the aggressive, spindle CarB cells with a dominant negative form of ERα (dnERα) resulted in reduced ERα levels and reduced binding to estrogen responsive elements (ERE)-containing sequences. We characterized two highly conserved EREs on the mouse ERα promoter through which dnERα decreased endogenous ERα levels. The dnERα-transfected CarB cells presented altered protein levels of cytoskeletal and cell adhesion molecules, slower growth rate and impaired anchorage-independent growth in vitro, whereas they gave smaller tumours with extended latency period of tumour onset in vivo. Our findings suggest an implication of ERα in the aggressiveness of spindle mouse skin cancer cells, possibly through regulation of genes affecting cell shape and adhesion, and they also provide hints for the effective targeting of spindle cancer cells by dnERα. PMID:22870269

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

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

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

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.

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.

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.

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.

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.

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

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.

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.

Thermal Threshold: Research Study on Small Fiber Dysfunction in Distal Diabetic Polyneuropathy

PubMed Central

Jimenez-Cohl, Pedro; Grekin, Carlos; Leyton, Cristian; Vargas, Claudio; Villaseca, Roberto

2012-01-01

Objective The most commonly used technique for diagnosis of diabetic neuropathy (DN) is nervous conduction (NC). Our hypothesis is that the use of the thermal threshold (TT) technique to evaluate small fiber damage, which precedes large fiber damage, could enable earlier diagnosis and diminish false negatives. Research Design and Methods The study involved 70 asymptomatic patients with type 2 diabetes mellitus (T2DM) all being treated with oral hypoglycemic medication, and having negative metabolic control levels with glycosylated hemoglobin A1c greater than 7% and less than 8%. Diabetic neuropathy was their only evident complication. All other complications or other causes of neuropathy were discarded. Their time of evolution was 1 to 48 months since date of diagnosis of diabetes. Both thermal threshold and sensory and motor nervous conduction were determined in upper and lower limbs. Results Nervous conduction was found normal in 81% and altered in 19% of patients (large fiber neuropathy). Thermal threshold was normal in 57% and altered in 43% of patients (small fiber neuropathy). In those with normal TTs, no case with an altered NC was found (p < 0.001). Patients with altered TTs could have normal (57%) or altered NC (43%). Thus, NC showed a high frequency of false negatives for DN (57% of 30 cases). The frequency of small fiber neuropathy found with the TT test was higher than that of large fiber neuropathy found with the NC test (p < 0.001) and was found at an earlier age. Conclusions The TT test demonstrated a higher frequency of neuropathy than the NC test in clinically asymptomatic T2DM patients. We suggest that small fiber should be studied before large fiber function to diagnosis distal and symmetrical DN. PMID:22401337

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.

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

Tracing how normative messages may influence physical activity intention

USDA-ARS?s Scientific Manuscript database

Normative messages have been shown to increase intention to do physical activity (PA). We traced how 'positive' and 'negative' normative messages influenced PA intention by comparing constructs of the model of goal-directed behaviour with descriptive norms (MGDB+DN) across control and treatment grou...

Reconfiguration of Intrinsic Functional Coupling Patterns Following Circumscribed Network Lesions.

PubMed

Eldaief, Mark C; McMains, Stephanie; Hutchison, R Matthew; Halko, Mark A; Pascual-Leone, Alvaro

2017-05-01

Communication between cortical regions is necessary for optimal cognitive processing. Functional relationships between cortical regions can be inferred through measurements of temporal synchrony in spontaneous activity patterns. These relationships can be further elaborated by surveying effects of cortical lesions upon inter-regional connectivity. Lesions to cortical hubs and heteromodal association regions are expected to induce distributed connectivity changes and higher-order cognitive deficits, yet their functional consequences remain relatively unexplored. Here, we used resting-state fMRI to investigate intrinsic functional connectivity (FC) and graph theoretical metrics in 12 patients with circumscribed lesions of the medial prefrontal cortex (mPFC) portion of the Default Network (DN), and compared these metrics with those observed in healthy matched comparison participants and a sample of 1139 healthy individuals. Despite significant mPFC destruction, patients did not demonstrate weakened intrinsic FC among undamaged DN nodes. Instead, network-specific changes were manifested as weaker negative correlations between the DN and attentional and somatomotor networks. These findings conflict with the DN being a homogenous system functionally anchored at mPFC. Rather, they implicate a role for mPFC in mediating cross-network functional interactions. More broadly, our data suggest that lesions to association cortical hubs might induce clinical deficits by disrupting communication between interacting large-scale systems. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Role of ARF6 in internalization of metal-binding proteins, metallothionein and transferrin, and cadmium-metallothionein toxicity in kidney proximal tubule cells

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

Wolff, Natascha A.; Lee, Wing-Kee; Abouhamed, Marouan

2008-07-01

Filtered metal-protein complexes, such as cadmium-metallothionein-1 (CdMT-1) or transferrin (Tf) are apically endocytosed partly via megalin/cubilin by kidney proximal tubule (PT) cells where CdMT-1 internalization causes apoptosis. Small GTPase ARF (ADP-ribosylation factor) proteins regulate endocytosis and vesicular trafficking. We investigated roles of ARF6, which has been shown to be involved in internalization of ligands and endocytic trafficking in PT cells, following MT-1/CdMT-1 and Tf uptake by PT cells. WKPT-0293 Cl.2 cells derived from rat PT S1 segment were transfected with hemagglutinin-tagged wild-type (ARF6-WT) or dominant negative (ARF6-T27N) forms of ARF6. Using immunofluorescence, endogenous ARF6 was associated with the plasma membranemore » (PM) as well as juxtanuclear and co-localized with Rab5a and Rab11 involved in early and recycling endosomal trafficking. Immunofluorescence staining of megalin showed reduced surface labelling in ARF6 dominant negative (ARF6-DN) cells. Intracellular Alexa Fluor 546-conjugated MT-1 uptake was reduced in ARF6-DN cells and CdMT-1 (14.8 {mu}M for 24 h) toxicity was significantly attenuated from 27.3 {+-} 3.9% in ARF6-WT to 11.1 {+-} 4.0% in ARF6-DN cells (n = 6, P < 0.02). Moreover, reduced Alexa Fluor 546-conjugated Tf uptake was observed in ARF-DN cells (75.0 {+-} 4.6% versus 3.9 {+-} 3.9% of ARF6-WT cells, n = 3, P < 0.01) and/or remained near the PM (89.3 {+-} 5. 6% versus 45.2 {+-} 14.3% of ARF6-WT cells, n = 3, P < 0.05). In conclusion, the data support roles for ARF6 in receptor-mediated endocytosis and trafficking of MT-1/Tf to endosomes/lysosomes and CdMT-1 toxicity of PT cells.« less

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

Hashimoto, Muneaki, E-mail: muneaki@juntendo.ac.jp; Nara, Takeshi, E-mail: tnara@juntendo.ac.jp; Enomoto, Masahiro, E-mail: menomoto@uhnres.utoronto.ca

Inositol 1,4,5-trisphosphate receptor (IP{sub 3}R) is a key regulator of intracellular Ca{sup 2+} concentration that release Ca{sup 2+} from Ca{sup 2+} stores in response to various external stimuli. IP{sub 3}R also works as a signal hub which form a platform for interacting with various proteins involved in diverse cell signaling. Previously, we have identified an IP{sub 3}R homolog in the parasitic protist, Trypanosoma cruzi (TcIP{sub 3}R). Parasites expressing reduced or increased levels of TcIP{sub 3}R displayed defects in growth, transformation, and infectivity. In the present study, we established parasitic strains expressing a dominant negative form of TcIP{sub 3}R, named DN-TcIP{submore » 3}R, to further investigate the physiological role(s) of TcIP{sub 3}R. We found that the growth of epimastigotes expressing DN-TcIP{sub 3}R was significantly slower than that of parasites with TcIP{sub 3}R expression levels that were approximately 65% of wild-type levels. The expression of DN-TcIP{sub 3}R in epimastigotes induced metacyclogenesis even in the normal growth medium. Furthermore, these epimastigotes showed the presence of dense mitochondria under a transmission electron microscope. Our findings confirm that TcIP{sub 3}R is crucial for epimastigote growth, as previously reported. They also suggest that a strong inhibition of the IP{sub 3}R-mediated signaling induces metacyclogenesis and that mitochondrial integrity is closely associated with this signaling. - Highlights: • We established T. cruzi strains expressing a dominant negative form of the TcIP{sub 3}R. • DN-TcIP{sub 3}R expression inhibits epimastigote growth and induces metacyclogenesis. • Microscopic analysis indicated TcIP{sub 3}R role in maintaining mitochondrial integrity. • Growth, but not microbial density, was altered by mammalian IP{sub 3}R inhibitor (2-APB).« less

NF-κB Regulates Caspase-4 Expression and Sensitizes Neuroblastoma Cells to Fas-Induced Apoptosis

PubMed Central

Yang, Hai-Jie; Wang, Mian; Wang, Lei; Cheng, Bin-Feng; Lin, Xiao-Yu; Feng, Zhi-Wei

2015-01-01

Found in neurons and neuroblastoma cells, Fas-induced apoptosis and accompanied activation of NF-κB signaling were thought to be associated with neurodegenerative diseases. However, the detailed functions of NF-κB activation in Fas killing and the effect of NF-κB activation on its downstream events remain unclear. Here, we demonstrated that agonistic Fas antibody induces cell death in a dose-dependent way and NF-κB signaling is activated as well, in neuroblastoma cells SH-EP1. Unexpectedly, NF-κB activation was shown to be pro-apoptotic, as suggested by the reduction of Fas-induced cell death with either a dominant negative form of IκBα (DN-IκBα) or an IκB kinase-specific inhibitor. To our interest, when analyzing downstream events of NF-κB signaling, we found that DN-IκBα only suppressed the expression of caspase-4, but not other caspases. Vice versa, enhancement of NF-κB activity by p65 (RelA) overexpression increased the expression of caspase-4 at both mRNA and protein levels. More directly, results from dual luciferase reporter assay demonstrated the regulation of caspase-4 promoter activity by NF-κB. When caspase-4 activity was blocked by its dominant negative (DN) form, Fas-induced cell death was substantially reduced. Consistently, the cleavage of PARP and caspase-3 induced by Fas was also reduced. In contrast, the cleavage of caspase-8 remained unaffected in caspase-4 DN cells, although caspase-8 inhibitor could rescue Fas-induced cell death. Collectively, these data suggest that caspase-4 activity is required for Fas-induced cell apoptosis and caspase-4 may act upstream of PARP and caspase-3 and downstream of caspase-8. Overall, we demonstrate that NF-κB can mediate Fas-induced apoptosis through caspase-4 protease, indicating that caspase-4 is a new mediator of NF-κB pro-apoptotic pathway in neuroblastoma cells. PMID:25695505

Involvement of AMPK in regulating slow-twitch muscle atrophy during hindlimb unloading in mice.

PubMed

Egawa, Tatsuro; Goto, Ayumi; Ohno, Yoshitaka; Yokoyama, Shingo; Ikuta, Akihiro; Suzuki, Miho; Sugiura, Takao; Ohira, Yoshinobu; Yoshioka, Toshitada; Hayashi, Tatsuya; Goto, Katsumasa

2015-10-01

AMPK is considered to have a role in regulating skeletal muscle mass. However, there are no studies investigating the function of AMPK in modulating skeletal muscle mass during atrophic conditions. In the present study, we investigated the difference in unloading-associated muscle atrophy and molecular functions in response to 2-wk hindlimb suspension between transgenic mice overexpressing the dominant-negative mutant of AMPK (AMPK-DN) and their wild-type (WT) littermates. Male WT (n = 24) and AMPK-DN (n = 24) mice were randomly divided into two groups: an untreated preexperimental control group (n = 12 in each group) and an unloading (n = 12 in each group) group. The relative soleus muscle weight and fiber cross-sectional area to body weight were decreased by ∼30% in WT mice by hindlimb unloading and by ∼20% in AMPK-DN mice. There were no changes in puromycin-labeled protein or Akt/70-kDa ribosomal S6 kinase signaling, the indicators of protein synthesis. The expressions of ubiquitinated proteins and muscle RING finger 1 mRNA and protein, markers of the ubiquitin-proteasome system, were increased by hindlimb unloading in WT mice but not in AMPK-DN mice. The expressions of molecules related to the protein degradation system, phosphorylated forkhead box class O3a, inhibitor of κBα, microRNA (miR)-1, and miR-23a, were decreased only in WT mice in response to hindlimb unloading, and 72-kDa heat shock protein expression was higher in AMPK-DN mice than in WT mice. These results imply that AMPK partially regulates unloading-induced atrophy of slow-twitch muscle possibly through modulation of the protein degradation system, especially the ubiquitin-proteasome system. Copyright © 2015 the American Physiological Society.

AMPK-α2 is involved in exercise training-induced adaptations in insulin-stimulated metabolism in skeletal muscle following high-fat diet.

PubMed

Abbott, Marcia J; Turcotte, Lorraine P

2014-10-15

AMP-activated protein kinase (AMPK) has been studied extensively and postulated to be a target for the treatment and/or prevention of metabolic disorders such as insulin resistance. Exercise training has been deemed a beneficial treatment for obesity and insulin resistance. Furthermore, exercise is a feasible method to combat high-fat diet (HFD)-induced alterations in insulin sensitivity. The purpose of this study was to determine whether AMPK-α2 activity is required to gain beneficial effects of exercise training with high-fat feeding. Wild-type (WT) and AMPK-α2 dominant-negative (DN) male mice were fed standard diet (SD), underwent voluntary wheel running (TR), fed HFD, or trained with HFD (TR + HFD). By week 6, TR, irrespective of genotype, decreased blood glucose and increased citrate synthase activity in both diet groups and decreased insulin levels in HFD groups. Hindlimb perfusions were performed, and, in WT mice with SD, TR increased insulin-mediated palmitate uptake (76.7%) and oxidation (>2-fold). These training-induced changes were not observed in the DN mice. With HFD, TR decreased palmitate oxidation (61-64%) in both WT and DN and increased palmitate uptake (112%) in the WT with no effects on palmitate uptake in the DN. With SD, TR increased ERK1/2 and JNK1/2 phosphorylation, regardless of genotype. With HFD, TR reduced JNK1/2 phosphorylation, regardless of genotype, carnitine palmitoyltransferase 1 expression in WT, and CD36 expression in both DN and WT. These data suggest that low AMPK-α2 signaling disrupts, in part, the exercise training-induced adaptations in insulin-stimulated metabolism in skeletal muscle following HFD. Copyright © 2014 the American Physiological Society.

Signal transducer and activator of transcription 3 is the dominant mediator of the anti-inflammatory effects of IL-10 in human macrophages.

PubMed

Williams, Lynn; Bradley, Laura; Smith, Alexandra; Foxwell, Brian

2004-01-01

The signaling mechanism by which the anti-inflammatory cytokine IL-10 mediates suppression of proinflammatory cytokine synthesis remains largely unknown. Macrophage-specific STAT3-null mice have demonstrated that STAT3 plays a critical role in the suppression of LPS-induced TNF-alpha release, although the mechanism by which STAT3 mediates this inhibition is still not clear. Using an adenoviral system, we have expressed a dominant negative (DN) STAT3 in human macrophages to broaden the investigation to determine the role of STAT3 in IL-10-mediated anti-inflammatory signaling and gene expression. Overexpression of STAT3 DN completely inhibited IL-10-induced suppressor of cytokine signaling 3, tissue inhibitor of MMP-1, TNF receptor expression, and the recently identified IL-10-inducible genes, T cell protein tyrosine phosphatase and signaling lymphocyte activation molecule. STAT3 DN also blocked IL-10-mediated inhibition of MHC class II and COX2 expression. In agreement with the studies in STAT3-null mice, overexpression of the STAT3 DN completely reversed the ability of IL-10 to inhibit LPS-mediated TNF-alpha and IL-6 production. However, real-time PCR analysis showed that STAT3 DN expression did not affect immediate suppression of TNF-alpha mRNA, but did reverse the suppression observed at later time points, suggesting a biphasic regulation of TNF-alpha mRNA levels by IL-10. In conclusion, although STAT3 does appear to be the dominant mediator of the majority of IL-10 functions, there are elements of its anti-inflammatory activity that are STAT3 independent.

Rab11a differentially modulates epidermal growth factor-induced proliferation and motility in immortal breast cells.

PubMed

Palmieri, Diane; Bouadis, Amina; Ronchetti, Ruban; Merino, Maria J; Steeg, Patricia S

2006-11-01

The development of cancer prevention strategies depends on the elucidation of molecular pathways underlying oncogenesis. In a previous proteomic study of matched normal breast ducts and Ductal Carcinoma in Situ (DCIS), we identified overexpression of Rab11a in DCIS. Rab11a is not well studied in cancer, but is known to regulate the recycling of internalized cell surface proteins and receptors from the early endosome through the trans-Golgi network. Using immunohistochemistry, we confirmed our observation, noting increased Rab11a expression in 19 of 22 (86%) DCIS cases compared to matched normal breast epithelium. To study the function of Rab11a, immortal, nontumorigenic MCF10A breast cells were stimulated with ligands to the EGF receptor (EGFR) after transfection with empty vector (control), Rab11a, or a S25N dominant-negative (DN) Rab11a. Using an iodinated ligand:receptor recycling assay, transfection of Rab11a accelerated, while DN-Rab11a postponed EGFR recycling in vitro. The signaling and in vitro phenotypic consequences of Rab11a expression and function were studied. Transfection of DN-Rab11a increased Erk1/2 activation downstream of EGF, but exerted no effect on the Akt pathway. Expression of DN-Rab11a inhibited MCF10A proliferation by 50-60%, and also inhibited anchorage-dependent colonization. Notably, DN-Rab11a transfection increased motility toward EGFR ligands. The data provide a first demonstration that Rab11a modulates EGFR recycling, and promotes the proliferation but inhibits the motility of an immortal breast line, consistent with the DCIS phenotype.

Selective Erasure of Distinct Forms of Long-Term Synaptic Plasticity Underlying Different Forms of Memory in the Same Postsynaptic Neuron.

PubMed

Hu, Jiangyuan; Ferguson, Larissa; Adler, Kerry; Farah, Carole A; Hastings, Margaret H; Sossin, Wayne S; Schacher, Samuel

2017-07-10

Generalization of fear responses to non-threatening stimuli is a feature of anxiety disorders. It has been challenging to target maladaptive generalized memories without affecting adaptive memories. Synapse-specific long-term plasticity underlying memory involves the targeting of plasticity-related proteins (PRPs) to activated synapses. If distinct tags and PRPs are used for different forms of plasticity, one could selectively remove distinct forms of memory. Using a stimulation paradigm in which associative long-term facilitation (LTF) occurs at one input and non-associative LTF at another input to the same postsynaptic neuron in an Aplysia sensorimotor preparation, we found that each form of LTF is reversed by inhibiting distinct isoforms of protein kinase M (PKM), putative PRPs, in the postsynaptic neuron. A dominant-negative (dn) atypical PKM selectively reversed associative LTF, while a dn classical PKM selectively reversed non-associative LTF. Although both PKMs are formed from calpain-mediated cleavage of protein kinase C (PKC) isoforms, each form of LTF is sensitive to a distinct dn calpain expressed in the postsynaptic neuron. Associative LTF is blocked by dn classical calpain, whereas non-associative LTF is blocked by dn small optic lobe (SOL) calpain. Interfering with a putative synaptic tag, the adaptor protein KIBRA, which protects the atypical PKM from degradation, selectively erases associative LTF. Thus, the activity of distinct PRPs and tags in a postsynaptic neuron contribute to the maintenance of different forms of synaptic plasticity at separate inputs, allowing for selective reversal of synaptic plasticity and providing a cellular basis for developing therapeutic strategies for selectively reversing maladaptive memories. Copyright © 2017 Elsevier Ltd. All rights reserved.

Cryogenic Refractive Index and Coefficient of Thermal Expansion for the S-TIH1 Glass

NASA Technical Reports Server (NTRS)

Quijada, Manuel A.; Leviton, Douglas; Content, David

2013-01-01

Using the CHARMS facility at NASA GSFC, we have measured the cryogenic refractive index of the Ohara S-TIH1 glass from 0.40 to 2.53 micrometers and from 120 to 300 K. We have also examined the spectral dispersion and thermo-optic coefficients (dn/dT). We also derived temperature-dependent Sellmeier models from which refractive index may be calculated for any wavelength and temperature within the stated ranges of each model. The S-TIH1 glass we tested exhibited unusual behavior in the thermo-optic coefficient. We found that for delta < 0.5 micrometers, the index of refraction decrease with a decrease in temperature (positive dn/dT). However, the situation was reversed for delta larger than 0.63 micrometers, where the index will increase with a decrease in temperature (negative dn/dT). We also measured the coefficient of thermal expansion (CTE) for the similar batch of S-TIH1 glass in order to understand its thermal properties. The CTE showed a monotonic change with a decrease in temperature.

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.

OXIDATIVE STRESS AND TREG DEPLETION IN LUPUS PATIENTS WITH ANTI-PHOSPHOLIPID SYNDROME

PubMed Central

Lai, Zhi-wei; Marchena-Mendez, Ivan; Perl, Andras

2015-01-01

Anti-phospholipid antibodies (APLA) represent a diagnostic criterion of systemic lupus erythematosus (SLE) and cause morbidity, termed anti-phospholipid syndrome (APS). Activation of the mechanistic target of rapamycin (mTOR) has been recently associated with APS. mTOR is a sensor of oxidative stress. Therefore, we examined mitochondrial mass, superoxide production, mTOR and FoxP3 expression in 72 SLE patients, twelve of whom also had APS, and 54 healthy controls by flow cytometry. Mitochondrial mass was increased in CD4−CD8− double-negative (DN) T cells of SLE patients with APS (2.7-fold) in comparison to those without APS (1.7-fold; p=0.014). Superoxide production was increased in all lymphocyte subsets of APS patients. FoxP3+ cells were depleted within CD4+CD25+ Tregs in patients with APS (28.4%) relative to those without APS (46.3%, p=0.008). mTOR activity was similar between SLE patients with and without APS. Thus, oxidative stress and Treg depletion rather than mTOR activation underlie APS in patients with SLE. PMID:25862984

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

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.

Passive cavity surface-emitting lasers: option of temperature-insensitive lasing wavelength for uncooled dense wavelength division multiplexing systems

NASA Astrophysics Data System (ADS)

Shchukin, V. A.; Ledentsov, N. N.; Slight, T.; Meredith, W.; Gordeev, N. Y.; Nadtochy, A. M.; Payusov, A. S.; Maximov, M. V.; Blokhin, S. A.; Blokhin, A. A.; Zadiranov, Yu. M.; Maleev, N. A.; Ustinov, V. M.; Choquette, K. D.

2016-03-01

A concept of passive cavity surface-emitting laser is proposed aimed to control the temperature shift of the lasing wavelength. The device contains an all-semiconductor bottom distributed Bragg reflector (DBR), in which the active medium is placed, a dielectric resonant cavity and a dielectric top DBR, wherein at least one of the dielectric materials has a negative temperature coefficient of the refractive index, dn/dT < 0. This is shown to be the case for commonly used dielectric systems SiO2/TiO2 and SiO2/Ta2O5. Two SiO2/TiO2 resonant structures having a cavity either of SiO2 or TiO2 were deposited on a substrate, their optical power reflectance spectra were measured at various temperatures, and refractive index temperature coefficients were extracted, dn/dT = 0.0021 K-1 for SiO2 and dn/dT = -0.0092 K-1 for TiO2. Using such dielectric materials allows designing passive cavity surface-emitting lasers having on purpose either positive, or zero, or negative temperature shift of the lasing wavelength dλ/dT. A design for temperature-insensitive lasing wavelength (dλ/dT = 0) is proposed. Employing devices with temperature-insensitive lasing wavelength in wavelength division multiplexing systems may allow significant reducing of the spectral separation between transmission channels and an increase in number of channels for a defined spectral interval enabling low cost energy efficient uncooled devices.

47 CFR 73.128 - AM stereophonic broadcasting.

Code of Federal Regulations, 2014 CFR

2014-10-01

... magnitude of the nth term of the difference signal ωsn=the nth order angular velocity of the sum signal ωdn=the nth order angular velocity of the difference signal ωc=the angular velocity of the carrier... presence of envelope modulation. (5) Maximum angular modulation, which occurs on negative peaks of the left...

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.

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.

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.

Inhibition of N-type Ca2+ channels ameliorates an imbalance in cardiac autonomic nerve activity and prevents lethal arrhythmias in mice with heart failure.

PubMed

Yamada, Yuko; Kinoshita, Hideyuki; Kuwahara, Koichiro; Nakagawa, Yasuaki; Kuwabara, Yoshihiro; Minami, Takeya; Yamada, Chinatsu; Shibata, Junko; Nakao, Kazuhiro; Cho, Kosai; Arai, Yuji; Yasuno, Shinji; Nishikimi, Toshio; Ueshima, Kenji; Kamakura, Shiro; Nishida, Motohiro; Kiyonaka, Shigeki; Mori, Yasuo; Kimura, Takeshi; Kangawa, Kenji; Nakao, Kazuwa

2014-10-01

Dysregulation of autonomic nervous system activity can trigger ventricular arrhythmias and sudden death in patients with heart failure. N-type Ca(2+) channels (NCCs) play an important role in sympathetic nervous system activation by regulating the calcium entry that triggers release of neurotransmitters from peripheral sympathetic nerve terminals. We have investigated the ability of NCC blockade to prevent lethal arrhythmias associated with heart failure. We compared the effects of cilnidipine, a dual N- and L-type Ca(2+) channel blocker, with those of nitrendipine, a selective L-type Ca(2+) channel blocker, in transgenic mice expressing a cardiac-specific, dominant-negative form of neuron-restrictive silencer factor (dnNRSF-Tg). In this mouse model of dilated cardiomyopathy leading to sudden arrhythmic death, cardiac structure and function did not significantly differ among the control, cilnidipine, and nitrendipine groups. However, cilnidipine dramatically reduced arrhythmias in dnNRSF-Tg mice, significantly improving their survival rate and correcting the imbalance between cardiac sympathetic and parasympathetic nervous system activity. A β-blocker, bisoprolol, showed similar effects in these mice. Genetic titration of NCCs, achieved by crossing dnNRSF-Tg mice with mice lacking CACNA1B, which encodes the α1 subunit of NCCs, improved the survival rate. With restoration of cardiac autonomic balance, dnNRSF-Tg;CACNA1B(+/-) mice showed fewer malignant arrhythmias than dnNRSF-Tg;CACNA1B(+/+) mice. Both pharmacological blockade of NCCs and their genetic titration improved cardiac autonomic balance and prevented lethal arrhythmias in a mouse model of dilated cardiomyopathy and sudden arrhythmic death. Our findings suggest that NCC blockade is a potentially useful approach to preventing sudden death in patients with heart failure. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.

Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL)-Troglitazone-induced Apoptosis in Prostate Cancer Cells Involve AMP-activated Protein Kinase*

PubMed Central

Santha, Sreevidya; Viswakarma, Navin; Das, Subhasis; Rana, Ajay; Rana, Basabi

2015-01-01

Prostate cancer (PCa) is one of the most frequently diagnosed cancers in men with limited treatment options for the hormone-resistant forms. Development of novel therapeutic options is critically needed to target advanced forms. Here we demonstrate that combinatorial treatment with the thiazolidinedione troglitazone (TZD) and TNF-related apoptosis-inducing ligand (TRAIL) can induce significant apoptosis in various PCa cells independent of androgen receptor status. Because TZD is known to activate AMP-activated protein kinase (AMPK), we determined whether AMPK is a molecular target mediating this apoptotic cascade by utilizing PCa cell lines stably overexpressing AMPKα1 dominant negative (C4-2-DN) or empty vector (C4-2-EV). Our results indicated a significantly higher degree of apoptosis with TRAIL-TZD combination in C4-2-EV cells compared with C4-2-DN cells. Similarly, results from a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed a larger reduction of viability of C4-2-EV cells compared with C4-2-DN cells when treated with TRAIL-TZD, thus suggesting that C4-2-DN cells were more apoptosis-resistant. Additionally, siRNA-mediated knockdown of endogenous AMPKα1 expression showed a reduction of TRAIL-TZD-induced apoptosis, further confirming the participation of AMPK in mediating this apoptosis. Apoptosis induction by this combinatorial treatment was also associated with a cleavage of β-catenin that was inhibited in both C4-2-DN cells and those cells in which AMPKα1 was knocked down. In addition, time course studies showed an increase in pACCS79 (AMPK target) levels coinciding with the time of apoptosis. These studies indicate the involvement of AMPK in TRAIL-TZD-mediated apoptosis and β-catenin cleavage and suggest the possibility of utilizing AMPK as a therapeutic target in apoptosis-resistant prostate cancer. PMID:26198640

Involvement of Prolonged Ras Activation in Thrombopoietin-Induced Megakaryocytic Differentiation of a Human Factor-Dependent Hematopoietic Cell Line

PubMed Central

Matsumura, Itaru; Nakajima, Koichi; Wakao, Hiroshi; Hattori, Seisuke; Hashimoto, Koji; Sugahara, Hiroyuki; Kato, Takashi; Miyazaki, Hiroshi; Hirano, Toshio; Kanakura, Yuzuru

1998-01-01

Thrombopoietin (TPO) is a hematopoietic growth factor that plays fundamental roles is both megakaryopoiesis and thrombopoiesis through binding to its receptor, c-mpl. Although TPO has been shown to activate various types of intracellular signaling molecules, such as the Janus family of protein tyrosine kinases, signal transducers and activators of transcription (STATs), and ras, the precise mechanisms underlying TPO-induced proliferation and differentiation remain unknown. In an effort to clarify the mechanisms of TPO-induced proliferation and differentiation, c-mpl was introduced into F-36P, a human interleukin-3 (IL-3)-dependent erythroleukemia cell line, and the effects of TPO on the c-mpl-transfected F-36P (F-36P-mpl) cells were investigated. F-36P-mpl cells were found to proliferate and differentiate at a high rate into mature megakaryocytes in response to TPO. Dominant-negative (dn) forms of STAT1, STAT3, STAT5, and ras were inducibly expressed in F-36P-mpl cells, and their effects on TPO-induced proliferation and megakaryocytic differentiation were analyzed. Among these dn molecules, both dn ras and dn STAT5 reduced TPO- or IL-3-induced proliferation of F-36P-mpl cells by ∼30%, and only dn ras could inhibit TPO-induced megakaryocytic differentiation. In accord with this result, overexpression of activated ras (H-rasG12V) for 5 days led to megakaryocytic differentiation of F-36P-mpl cells. In a time course analysis on H-rasG12V-induced differentiation, activation of the ras pathway for 24 to 28 h was required and sufficient to induce megakaryocytic differentiation. Consistent with this result, the treatment of F-36P-mpl cells with TPO was able to induce prolonged activation of ras for more than 24 h, whereas IL-3 had only a transient effect. These results suggest that prolonged ras activation may be involved in TPO-induced megakaryocytic differentiation. PMID:9632812

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.

Age differences in default and reward networks during processing of personally relevant information.

PubMed

Grady, Cheryl L; Grigg, Omer; Ng, Charisa

2012-06-01

We recently found activity in default mode and reward-related regions during self-relevant tasks in young adults. Here we examine the effect of aging on engagement of the default network (DN) and reward network (RN) during these tasks. Previous studies have shown reduced engagement of the DN and reward areas in older adults, but the influence of age on these circuits during self-relevant tasks has not been examined. The tasks involved judging personality traits about one's self or a well known other person. There were no age differences in reaction time on the tasks but older adults had more positive Self and Other judgments, whereas younger adults had more negative judgments. Both groups had increased DN and RN activity during the self-relevant tasks, relative to non-self tasks, but this increase was reduced in older compared to young adults. Functional connectivity of both networks during the tasks was weaker in the older relative to younger adults. Intrinsic functional connectivity, measured at rest, also was weaker in the older adults in the DN, but not in the RN. These results suggest that, in younger adults, the processing of personally relevant information involves robust activation of and functional connectivity within these two networks, in line with current models that emphasize strong links between the self and reward. The finding that older adults had more positive judgments, but weaker engagement and less consistent functional connectivity in these networks, suggests potential brain mechanisms for the "positivity bias" with aging. Copyright © 2012 Elsevier Ltd. All rights reserved.

Age differences in default and reward networks during processing of personally relevant information

PubMed Central

Grady, Cheryl L.; Grigg, Omer; Ng, Charisa

2013-01-01

We recently found activity in default mode and reward-related regions during self-relevant tasks in young adults. Here we examine the effect of aging on engagement of the default network (DN) and reward network (RN) during these tasks. Previous studies have shown reduced engagement of the DN and reward areas in older adults, but the influence of age on these circuits during self-relevant tasks has not been examined. The tasks involved judging personality traits about one’s self or a well known other person. There were no age differences in reaction time on the tasks but older adults had more positive Self and Other judgments, whereas younger adults had more negative judgments. Both groups had increased DN and RN activity during the self-relevant tasks, relative to non-self tasks, but this increase was reduced in older compared to young adults. Functional connectivity of both networks during the tasks was weaker in the older relative to younger adults. Intrinsic functional connectivity, measured at rest, also was weaker in the older adults in the DN, but not in the RN. These results suggest that, in younger adults, the processing of personally relevant information involves robust activation of and functional connectivity within these two networks, in line with current models that emphasize strong links between the self and reward. The finding that older adults had more positive judgments, but weaker engagement and less consistent functional connectivity in these networks, suggests potential brain mechanisms for the “positivity bias” with aging. PMID:22484520

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.

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

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

Santilli’s detection of antimatter galaxies: An introduction and experimental confirmation

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

Bhujbal, P. M.

2015-03-10

Studies accompanied over the past few decades on the generalization of quantum mechanics known as hadronic mechanics, initiated in 1978 by the Italian-American physicist Ruggero Maria Santilli and its application for detection of light from antimatter galaxy is reported in this paper. The isodual (antimatter) light has negative energy E{sup d} =-E with negative unit, experiences a negative curvature tensor R{sup d}=-R (gravitational repulsion) when in a matter gravitational field, and possesses a negative index of refraction n{sup d}=-n when propagating within a transparent matter medium. Detection of antimatter galaxies is possible by the refractive telescope with concave lenses constructedmore » by Santilli which follow the concept of negative energy and negative index of refraction for antimatter.« less

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.

On the Deficiencies of the Ferricinium-Ferrocene Redox Couple for Estimating Transfer Energies of Single Ions.

DTIC Science & Technology

1980-08-15

breakdown of the "ferrocene assumption" for estimating the transfer thermodynamics of single ions. I 4 Experimental Most solvents were Aldrich " Gold ...solvent "donor number" DN1 6 (Table I). A similar finding has been noted previously for monoatomic cations. 1 5 The small negative value of - Sc+) in water

Dissection of neuronal gap junction circuits that regulate social behavior in Caenorhabditis elegans.

PubMed

Jang, Heeun; Levy, Sagi; Flavell, Steven W; Mende, Fanny; Latham, Richard; Zimmer, Manuel; Bargmann, Cornelia I

2017-02-14

A hub-and-spoke circuit of neurons connected by gap junctions controls aggregation behavior and related behavioral responses to oxygen, pheromones, and food in Caenorhabditis elegans The molecular composition of the gap junctions connecting RMG hub neurons with sensory spoke neurons is unknown. We show here that the innexin gene unc-9 is required in RMG hub neurons to drive aggregation and related behaviors, indicating that UNC-9-containing gap junctions mediate RMG signaling. To dissect the circuit in detail, we developed methods to inhibit unc-9 -based gap junctions with dominant-negative unc-1 transgenes. unc-1(dn) alters a stomatin-like protein that regulates unc-9 electrical signaling; its disruptive effects can be rescued by a constitutively active UNC-9::GFP protein, demonstrating specificity. Expression of unc-1(dn) in RMG hub neurons, ADL or ASK pheromone-sensing neurons, or URX oxygen-sensing neurons disrupts specific elements of aggregation-related behaviors. In ADL, unc-1(dn) has effects opposite to those of tetanus toxin light chain, separating the roles of ADL electrical and chemical synapses. These results reveal roles of gap junctions in a complex behavior at cellular resolution and provide a tool for similar exploration of other gap junction circuits.

Dissection of neuronal gap junction circuits that regulate social behavior in Caenorhabditis elegans

PubMed Central

Jang, Heeun; Levy, Sagi; Flavell, Steven W.; Mende, Fanny; Latham, Richard; Zimmer, Manuel; Bargmann, Cornelia I.

2017-01-01

A hub-and-spoke circuit of neurons connected by gap junctions controls aggregation behavior and related behavioral responses to oxygen, pheromones, and food in Caenorhabditis elegans. The molecular composition of the gap junctions connecting RMG hub neurons with sensory spoke neurons is unknown. We show here that the innexin gene unc-9 is required in RMG hub neurons to drive aggregation and related behaviors, indicating that UNC-9–containing gap junctions mediate RMG signaling. To dissect the circuit in detail, we developed methods to inhibit unc-9–based gap junctions with dominant-negative unc-1 transgenes. unc-1(dn) alters a stomatin-like protein that regulates unc-9 electrical signaling; its disruptive effects can be rescued by a constitutively active UNC-9::GFP protein, demonstrating specificity. Expression of unc-1(dn) in RMG hub neurons, ADL or ASK pheromone-sensing neurons, or URX oxygen-sensing neurons disrupts specific elements of aggregation-related behaviors. In ADL, unc-1(dn) has effects opposite to those of tetanus toxin light chain, separating the roles of ADL electrical and chemical synapses. These results reveal roles of gap junctions in a complex behavior at cellular resolution and provide a tool for similar exploration of other gap junction circuits. PMID:28143932

A prenatal interruption of DISC1 function in the brain exhibits a lasting impact on adult behaviors, brain metabolism, and interneuron development.

PubMed

Deng, Dazhi; Jian, Chongdong; Lei, Ling; Zhou, Yijing; McSweeney, Colleen; Dong, Fengping; Shen, Yilun; Zou, Donghua; Wang, Yonggang; Wu, Yuan; Zhang, Limin; Mao, Yingwei

2017-10-17

Mental illnesses like schizophrenia (SCZ) and major depression disorder (MDD) are devastating brain disorders. The SCZ risk gene, disrupted in schizophrenia 1 ( DISC1 ), has been associated with neuropsychiatric conditions. However, little is known regarding the long-lasting impacts on brain metabolism and behavioral outcomes from genetic insults on fetal NPCs during early life. We have established a new mouse model that specifically interrupts DISC1 functions in NPCs in vivo by a dominant-negative DISC1 (DN-DISC1) with a precise temporal and spatial regulation. Interestingly, prenatal interruption of mouse Disc1 function in NPCs leads to abnormal depression-like deficit in adult mice. Here we took a novel unbiased metabonomics approach to identify brain-specific metabolites that are significantly changed in DN-DISC1 mice. Surprisingly, the inhibitory neurotransmitter, GABA, is augmented. Consistently, parvalbumin (PV) interneurons are increased in the cingulate cortex, retrosplenial granular cortex, and motor cortex. Interestingly, somatostatin (SST) positive and neuropeptide Y (NPY) interneurons are decreased in some brain regions, suggesting that DN-DISC1 expression affects the localization of interneuron subtypes. To further explore the cellular mechanisms that cause this change, DN-DISC1 suppresses proliferation and promotes the cell cycle exit of progenitors in the medial ganglionic eminence (MGE), whereas it stimulates ectopic proliferation of neighboring cells through cell non-autonomous effect. Mechanistically, it modulates GSK3 activity and interrupts Dlx2 activity in the Wnt activation. In sum, our results provide evidence that specific genetic insults on NSCs at a short period of time could lead to prolonged changes of brain metabolism and development, eventually behavioral defects.

The expression of intermediate filament protein nestin and its association with cyclin-dependent kinase 5 in the glomeruli of rats with diabetic nephropathy.

PubMed

Liu, Wei; Zhang, Yue; Liu, Shuxia; Liu, Qingjuan; Hao, Jun; Shi, Yonghong; Zhao, Song; Duan, Huijun

2013-06-01

Podocyte injury plays a crucial role in the development of diabetic nephropathy (DN), but its underlying mechanism remains poorly understood. Emerging evidences suggest that the cytoskeleton disruption is related to podocyte injury. The aim of this study was to investigate whether nestin, a cytoskeleton-associated intermediate filament protein, is involved in the development of DN. Rat diabetes was induced by intraperitoneal injection of streptozotocin. The renal histological changes were investigated by light microscopy and transmission electron microscopy. The location of nestin and vimentin in renal tissues was observed by immunohistochemistry. The protein or messenger RNA levels of nestin and cyclin-dependent kinase 5 (Cdk5) were detected by Western blot and real-time polymerase chain reaction. The relationship between nestin and vimentin was detected by co-immunoprecipitation. Compared with controls, diabetic rats showed significant characteristics of renal damage. The expression of nestin and vimentin in the glomeruli was increased at the early stage of diabetes, which then gradually decreased. Co-immunoprecipitation assays demonstrated that nestin disassembled with vimentin in diabetic rats. The expression of Cdk5 was increased in a time-dependent manner in diabetic rats. The degree of albuminuria in diabetic rats was negatively correlated with nestin and positively correlated with Cdk5. Roscovitine, a Cdk5 inhibitor, reduced the degradation of nestin. Moreover, podocyte injuries were significantly ameliorated by treatment with roscovitine. The intermediate filament protein nestin is associated with development of DN. Blockage of Cdk5 increases the level of nestin and attenuates renal damage, which would provide a useful target for DN therapy.

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.

The mitochondrial uniporter controls fight or flight heart rate increases.

PubMed

Wu, Yuejin; Rasmussen, Tyler P; Koval, Olha M; Joiner, Mei-Ling A; Hall, Duane D; Chen, Biyi; Luczak, Elizabeth D; Wang, Qiongling; Rokita, Adam G; Wehrens, Xander H T; Song, Long-Sheng; Anderson, Mark E

2015-01-20

Heart rate increases are a fundamental adaptation to physiological stress, while inappropriate heart rate increases are resistant to current therapies. However, the metabolic mechanisms driving heart rate acceleration in cardiac pacemaker cells remain incompletely understood. The mitochondrial calcium uniporter (MCU) facilitates calcium entry into the mitochondrial matrix to stimulate metabolism. We developed mice with myocardial MCU inhibition by transgenic expression of a dominant-negative (DN) MCU. Here, we show that DN-MCU mice had normal resting heart rates but were incapable of physiological fight or flight heart rate acceleration. We found that MCU function was essential for rapidly increasing mitochondrial calcium in pacemaker cells and that MCU-enhanced oxidative phoshorylation was required to accelerate reloading of an intracellular calcium compartment before each heartbeat. Our findings show that MCU is necessary for complete physiological heart rate acceleration and suggest that MCU inhibition could reduce inappropriate heart rate increases without affecting resting heart rate.

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.

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.

EARTH, MOON, SUN, AND CV ACCRETION DISKS

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

Montgomery, M. M.

2009-11-01

Net tidal torque by the secondary on a misaligned accretion disk, like the net tidal torque by the Moon and the Sun on the equatorial bulge of the spinning and tilted Earth, is suggested by others to be a source to retrograde precession in non-magnetic, accreting cataclysmic variable (CV) dwarf novae (DN) systems that show negative superhumps in their light curves. We investigate this idea in this work. We generate a generic theoretical expression for retrograde precession in spinning disks that are misaligned with the orbital plane. Our generic theoretical expression matches that which describes the retrograde precession of Earths'more » equinoxes. By making appropriate assumptions, we reduce our generic theoretical expression to those generated by others, or to those used by others, to describe retrograde precession in protostellar, protoplanetary, X-ray binary, non-magnetic CV DN, quasar, and black hole systems. We find that spinning, tilted CV DN systems cannot be described by a precessing ring or by a precessing rigid disk. We find that differential rotation and effects on the disk by the accretion stream must be addressed. Our analysis indicates that the best description of a retrogradely precessing spinning, tilted, CV DN accretion disk is a differentially rotating, tilted disk with an attached rotating, tilted ring located near the innermost disk annuli. In agreement with the observations and numerical simulations by others, we find that our numerically simulated CV DN accretion disks retrogradely precess as a unit. Our final, reduced expression for retrograde precession agrees well with our numerical simulation results and with selective observational systems that seem to have main-sequence secondaries. Our results suggest that a major source to retrograde precession is tidal torques like that by the Moon and the Sun on the Earth. In addition, these tidal torques should be common to a variety of systems where one member is spinning and tilted, regardless if accretion disks are present or not. Our results suggest that the accretion disk's geometric shape directly affects the disk's precession rate.« less

Defense Facts of Life

DTIC Science & Technology

1980-12-05

planning process. Do the positive attributes of high complexity weapons outweigh their negative qualities’ What effect does our investment in...account for the future consequences of current decisions. We advocate increased budgets because we perceive a growing threat, yet at the same time we...Defense and therefore should not be construed as reflecting an official position of the Department. Thi3 dn .,ment has been opproved for public

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 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

A Co-Receptor Independent Transgenic Human TCR Mediates Anti-Tumor and Anti-Self Immunity in Mice

PubMed Central

Mehrotra, Shikhar; Al-Khami, Amir A.; Klarquist, Jared; Husain, Shahid; Naga, Osama; Eby, Jonathan M.; Murali, Anuradha K.; Lyons, Gretchen E.; Li, Mingli; Spivey, Natali D.; Norell, Håkan; Martins da Palma, Telma; Onicescu, Georgiana; Diaz-Montero, C. Marcela; Garrett-Mayer, Elizabeth; Cole, David J.; Le Poole, I. Caroline; Nishimura, Michael I.

2013-01-01

Recent advancements in T cell immunotherapy suggest that T cells engineered with high affinity T cell receptors (TCR) can offer better tumor regression. However, whether a high affinity TCR alone is sufficient to control tumor growth, or the T cell subset bearing the TCR is also important remains unclear. Using the human tyrosinase epitope reactive, CD8 independent, high affinity TCR isolated from MHC class-I restricted CD4+ T cells obtained from tumor infiltrating lymphocytes of a metastatic melanoma patient, we developed a novel TCR transgenic mouse with a C57BL/6 background. This HLA-A2 restricted TCR was positively selected on both CD4+ and CD8+ single-positive (SP) cells. However, when the TCR transgenic mouse was developed with an HLA-A2 background, the transgenic TCR was primarily expressed by CD3+CD4-CD8- double-negative (DN) T cells. TIL 1383I TCR transgenic CD4+, CD8+ and CD4-CD8- T cells were functional and retained the ability to control tumor growth without the need for vaccination or cytokine support in vivo. Furthermore, the HLA-A2+/human tyrosinase TCR double transgenic mice developed spontaneous hair depigmentation and had visual defects that progressed with age. Our data show that the expression of the high affinity TIL 1383I TCR alone in CD3+ T cells is sufficient to control the growth of murine and human melanoma and the presence or absence of CD4 and CD8 co-receptors had little effect on its functional capacity. PMID:22798675

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.

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 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.

Double Negative Materials (DNM), Phenomena and Applications

DTIC Science & Technology

2009-07-01

Nanoparticles Formed by Pairs Of Concentric Double-Negative (DNG), Single-Negative ( SNG ) and/or Double-Positive (DPS) Metamaterial Layers.” J. Appl...material RRL Rapid Research Letters SHG second-harmonic generation SNG single-negative SSR split-ring resonator A-1 Appendix A. October 2008...Pairs of Concentric Double-Negative (DNG), Single-Negative ( SNG ), and/or Double-Positive (DPS) Metamaterial Layers.” J. Appl. Phys. 97, no. 9 (May

Role of T Cell TGF-β Signaling in Intestinal Cytokine Responses and Helminthic Immune Modulation

PubMed Central

Ince, M. Nedim; Elliott, David E.; Setiawan, Tommy; Metwali, Ahmed; Blum, Arthur; Chen, Hung-lin; Urban, Joseph F.; Flavell, Richard A.; Weinstock, Joel V.

2010-01-01

Colonization with helminthic parasites induces mucosal regulatory cytokines, like IL-10 or TGF-β that are important in suppressing colitis. Helminths induce mucosal T cell IL-10 secretion and regulate lamina propria mononuclear cell Th1 cytokine generation in an IL-10 dependent manner in wild-type mice. Helminths also stimulate mucosal TGF-β release. As TGF-β exerts major regulatory effects on T lymphocytes, we investigated the role of T lymphocyte TGF-β signaling in helminthic modulation of intestinal immunity. T cell TGF-β signaling is interrupted in TGF-βRII DN mice by T cell-specific over-expression of a dominant negative TGF-β receptor II. We studied lamina propria mononuclear cell responses in wild-type and TGF-βRII DN mice that were uninfected or colonized with the nematode, Heligmosomoides polygyrus. Our results indicate an essential role of T cell TGF-β signaling in limiting mucosal Th1 and Th2 responses. Furthermore, we demonstrate that helminthic induction of intestinal T cell IL-10 secretion requires intact T cell TGF-β signaling pathway. Helminths fail to curtail robust, dysregulated intestinal Th1 cytokine production and chronic colitis in TGF-βRII DN mice. Thus, T cell TGF-β signaling is essential for helminthic stimulation of mucosal IL-10 production, helminthic modulation of intestinal interferon-γ generation and H. polygyrus-mediated suppression of chronic colitis. PMID:19544487

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

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

Chemosensitizing tumor cells by targeting the Fanconi anemia pathway with an adenovirus overexpressing dominant-negative FANCA.

PubMed

Ferrer, Miriam; de Winter, Johan P; Mastenbroek, D C Jeroen; Curiel, David T; Gerritsen, Winald R; Giaccone, Giuseppe; Kruyt, Frank A E

2004-08-01

Fanconi anemia (FA) is a rare genetic disorder characterized by bone-marrow failure and cellular hypersensitivity to crosslinking agents, including cisplatin. Here, we studied the use of the FA pathway as a possible target for cancer gene therapy with the aim to sensitize tumor cells for cisplatin by interfering with the FA pathway. As proof-of-principle, FA and non-FA lymphoblast-derived tumors were grown subcutaneously in scid mice and treated with two different concentrations of cisplatin. As predicted, the antitumor response was considerably improved in FA tumors. An adenoviral vector encoding a dominant-negative form of FANCA, FANCA600DN, was generated that interfered with endogenous FANCA-FANCG interaction resulting in the disruption of the FA pathway as illustrated by disturbed FANCD2 monoubiquitination. A panel of cell lines, including non-small-cell lung cancer cells, could be sensitized approximately two- to three-fold for cisplatin after Ad.CMV.FANCA600DN infection that may increase upon enhanced infection efficiency. In conclusion, targeting the FA pathway may provide a novel strategy for the sensitization of solid tumors for cisplatin and, in addition, provides a tool for examining the role of the FA pathway in determining chemoresistance in different tumor types.

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

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.

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

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.

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.

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.

One year monitoring of fire-induced effects on dissolved organic matter and nutrient dynamics under different land-use

NASA Astrophysics Data System (ADS)

Potthast, Karin; Meyer, Stefanie; Crecelius, Anna; Schubert, Ulrich; Michalzik, Beate

2016-04-01

It is supposed that the changing climate will promote extreme weather events that in turn will increase drought periods and the abundance of fire events in temperate climate regions such as Central Europe. The impact of fires on the nutrient budgets of ecosystems is highly diverse and seems to depend on the ecosystem type. For example, little is known about fire effects on water-bound organic matter (OM) and nutrient fluxes in temperate managed forest ecosystems. Fires can strongly alter the distribution (forest floor vs. mineral soil), binding forms (organic vs. inorganic) and availability (solubility by water) of OM and associated nutrients. To elucidate the effects and seasonality of low intensity fires on the mobilization of dissolved organic carbon and nutrients, an experimental ground fire was conducted in November 2014 in the Hainich region, Central Germany. In addition, differences in response patterns between two land-use types (pasture and beech forest) were investigated. Lysimeters (n=5 controls/ 5 fire-manipulated) with topsoil monoliths (0-4 cm), rainfall/throughfall samplers, littertraps as well as temperature and moisture sensors were installed on three sites of each land-use type. During the one year of monitoring (Sep14-Dec15) soil solution, rainfall, and throughfall samples were taken biweekly and analyzed for pH, dissolved and particulate organic carbon (DOC, POC) and nitrogen (DN, PN) as well as for nutrients (e.g. K, Ca, Mg, P, S). Compared to the control sites, the ground fire immediately induced a short-run release peak of DOC in both land-use types. Within two weeks these differences were muted in the post-fire period. The effect of fire was land-use specific with annual DOC fluxes of 82 and 45 kg/(ha*a) for forest and pasture sites, respectively. In contrast, nitrogen fluxes responded differently to the fire event. In the forest, a significant increase in DN concentrations was notable five months after the fire, at the beginning of the vegetation period and lasted until November with DN concentrations in June being 4 times higher compared to the control (82 vs. 18 mg DN/L) and being negatively correlated with pH-values (r=-0.51 p<0.001). Annual DN fluxes from fire manipulated forest plots were two times higher compared to control ones (62 vs. 29 kg DN/(ha*a)) whereas only low impact was found at the pasture with 45 and 38 kg DN/(ha*a) for fire-manipulated plots and control, respectively. In general, the results exhibit highly differing response patterns of elements to fire between the two land-use types and with season. Starting in spring higher DN fluxes following fire event at the forest site could be associated with accelerated activity of soil microbes mineralizing released organic substances from burned forest floor and/or from dead roots. This mineralization process resulted in a significant increase in acidity of the soil solution that may affect important ecosystem functions like nutrient cycling and primary production. Hence, high resolution monitoring following a low intensive fire indicated nutrient losses from the forest ecosystem that could be a hazard for managed forests on nutrient poor soils if fire frequency increases with climate change.

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.

A SERIES OF SUPPRESSIVE SIGNALS WITHIN THE DROSOPHILA CIRCADIAN NEURAL CIRCUIT GENERATES SEQUENTIAL DAILY OUTPUTS

PubMed Central

Liang, Xitong; Holy, Timothy E; Taghert, Paul H

2017-01-01

Summary We studied the Drosophila circadian neural circuit using whole brain imaging in vivo. Five major groups of pacemaker neurons display synchronized molecular clocks, yet each exhibits a distinct phase of daily Ca2+ activation. Light and neuropeptide PDF from morning cells (s-LNv) together delay the phase of the evening (LNd) group by ~12 h; PDF alone delays the phase of the DN3 group, by ~17 h. Neuropeptide sNPF, released from s-LNv and LNd pacemakers, produces latenight Ca2+ activation in the DN1 group. The circuit also features negative feedback by PDF to truncate the s-LNv Ca2+ wave and terminate PDF release. Both PDF and sNPF suppress basal Ca2+ levels in target pacemakers with long durations by cell autonomous actions. Thus, light and neuropeptides act dynamically at distinct hubs of the circuit to produce multiple suppressive events that create the proper tempo and sequence of circadian pacemaker neuronal activities. PMID:28552314

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

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/.

The Role of DN-GSK3b in Mammary Tumorigenesis

DTIC Science & Technology

2007-07-01

many human cancers, including breast cancer. β-catenin is a critical co-activator in this signaling pathway, and is regulated in a complex fashion...function in a dominant negative fashion by antagonizing the endogenous activity of GSK3β and promoting breast cancer development. Consistent with this...predisposition to breast cancer. 15. SUBJECT TERMS GSK3b, b-catenin, Wnt Signaling Pathway, Kinase, Transgenic mice, SiRNA, chemical carcinogens (DMBA

FOXO3a regulates BNIP3 and modulates mitochondrial calcium, dynamics, and function in cardiac stress

PubMed Central

Kohlbrenner, Erik; Gamb, Scott I.; Guenzel, Adam J.; Klaus, Katherine; Fayyaz, Ahmed U.; Nair, K. Sreekumaran; Hajjar, Roger J.

2016-01-01

The forkhead box O3a (FOXO3a) transcription factor has been shown to regulate glucose metabolism, muscle atrophy, and cell death in postmitotic cells. Its role in regulation of mitochondrial and myocardial function is not well studied. Based on previous work, we hypothesized that FOXO3a, through BCL2/adenovirus E1B 19-kDa protein-interacting protein 3 (BNIP3), modulates mitochondrial morphology and function in heart failure (HF). We modulated the FOXO3a-BNIP3 pathway in normal and phenylephrine (PE)-stressed adult cardiomyocytes (ACM) in vitro and developed a cardiotropic adeno-associated virus serotype 9 encoding dominant-negative FOXO3a (AAV9.dn-FX3a) for gene delivery in a rat model of HF with preserved ejection fraction (HFpEF). We found that FOXO3a upregulates BNIP3 expression in normal and PE-stressed ACM, with subsequent increases in mitochondrial Ca2+, leading to decreased mitochondrial membrane potential, mitochondrial fragmentation, and apoptosis. Whereas dn-FX3a attenuated the increase in BNIP3 expression and its consequences in PE-stressed ACM, AAV9.dn-FX3a delivery in an experimental model of HFpEF decreased BNIP3 expression, reversed adverse left ventricular remodeling, and improved left ventricular systolic and, particularly, diastolic function, with improvements in mitochondrial structure and function. Moreover, AAV9.dn-FX3a restored phospholamban phosphorylation at S16 and enhanced dynamin-related protein 1 phosphorylation at S637. Furthermore, FOXO3a upregulates maladaptive genes involved in mitochondrial apoptosis, autophagy, and cardiac atrophy. We conclude that FOXO3a activation in cardiac stress is maladaptive, in that it modulates Ca2+ cycling, Ca2+ homeostasis, and mitochondrial dynamics and function. Our results suggest an important role of FOXO3a in HF, making it an attractive potential therapeutic target. Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/role-of-foxo3a-in-heart-failure/. PMID:27694219

CLOCK expression identifies developing circadian oscillator neurons in the brains of Drosophila embryos.

PubMed

Houl, Jerry H; Ng, Fanny; Taylor, Pete; Hardin, Paul E

2008-12-18

The Drosophila circadian oscillator is composed of transcriptional feedback loops in which CLOCK-CYCLE (CLK-CYC) heterodimers activate their feedback regulators period (per) and timeless (tim) via E-box mediated transcription. These feedback loop oscillators are present in distinct clusters of dorsal and lateral neurons in the adult brain, but how this pattern of expression is established during development is not known. Since CLK is required to initiate feedback loop function, defining the pattern of CLK expression in embryos and larvae will shed light on oscillator neuron development. A novel CLK antiserum is used to show that CLK expression in the larval CNS and adult brain is limited to circadian oscillator cells. CLK is initially expressed in presumptive small ventral lateral neurons (s-LNvs), dorsal neurons 2 s (DN2s), and dorsal neuron 1 s (DN1s) at embryonic stage (ES) 16, and this CLK expression pattern persists through larval development. PER then accumulates in all CLK-expressing cells except presumptive DN2s during late ES 16 and ES 17, consistent with the delayed accumulation of PER in adult oscillator neurons and antiphase cycling of PER in larval DN2s. PER is also expressed in non-CLK-expressing cells in the embryonic CNS starting at ES 12. Although PER expression in CLK-negative cells continues in ClkJrk embryos, PER expression in cells that co-express PER and CLK is eliminated. These data demonstrate that brain oscillator neurons begin development during embryogenesis, that PER expression in non-oscillator cells is CLK-independent, and that oscillator phase is an intrinsic characteristic of brain oscillator neurons. These results define the temporal and spatial coordinates of factors that initiate Clk expression, imply that circadian photoreceptors are not activated until the end of embryogenesis, and suggest that PER functions in a different capacity before oscillator cell development is initiated.

LKB1, an upstream AMPK kinase, regulates glucose and lipid metabolism in cultured liver and muscle cells.

PubMed

Imai, Kenta; Inukai, Kouichi; Ikegami, Yuichi; Awata, Takuya; Katayama, Shigehiro

2006-12-22

LKB1 is a 50 kDa serine/threonine kinase that phosphorylates and activates the catalytic subunit of AMPK at its T-loop residue Thr 172. We prepared adenoviruses expressing the constitutive active (wild-type) form (CA) or dominant negative (kinase inactive, D194A mutant) form (DN) of LKB1 and overexpressed these proteins in cultured myotubes (C2C12 cells) and rat hepatoma cells (FAO cells). When analyzed by immunoblotting with the antibody against Thr172-phosphorylated AMPK, the phosphorylation of AMPK was increased (2.5-fold) and decreased (0.4-fold) in cells expressing CA and DN LKB1, respectively, as compared with Lac-Z expressing control cells. Immunoprecipitation experiments, using isoform-specific antibody, revealed these alterations of AMPK phosphorylation to be attributable to altered phosphorylation of AMPK alpha2, but not alpha1 catalytic subunits, strongly suggesting the alpha2 catalytic subunit to be the major substrate for LKB1 in mammalian cells. In addition, adiponectin or AICAR-stimulated AMPK phosphorylation was inhibited by overexpression of DN LKB1, while phenformin-stimulated phosphorylation was unaffected. These results may explain the difference in AMPK activation mechanisms between AMP and phenformin, and also indicate that AMPK phosphorylation by LKB1 is involved in AMP-stimulated AMPK activation. As a downstream target for AMPK, AICAR-induced glucose uptake and ACCbeta phosphorylation were found to be significantly reduced in DN LKB1 expressing C2C12 cells. The expression of key enzymes for gluconeogenesis, glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, was also dependent on LKB1 activities in FAO cells. These results demonstrate that LKB1 is a crucial regulator of AMPK activation in muscle and liver cells and, therefore, that LKB1 activity is potentially of importance to our understanding of glucose and lipid metabolism.

Notch Signaling Augments BMP9-Induced Bone Formation by Promoting the Osteogenesis-Angiogenesis Coupling Process in Mesenchymal Stem Cells (MSCs).

PubMed

Liao, Junyi; Wei, Qiang; Zou, Yulong; Fan, Jiaming; Song, Dongzhe; Cui, Jing; Zhang, Wenwen; Zhu, Yunxiao; Ma, Chao; Hu, Xue; Qu, Xiangyang; Chen, Liqun; Yu, Xinyi; Zhang, Zhicai; Wang, Claire; Zhao, Chen; Zeng, Zongyue; Zhang, Ruyi; Yan, Shujuan; Wu, Tingting; Wu, Xingye; Shu, Yi; Lei, Jiayan; Li, Yasha; Luu, Hue H; Lee, Michael J; Reid, Russell R; Ameer, Guillermo A; Wolf, Jennifer Moriatis; He, Tong-Chuan; Huang, Wei

2017-01-01

Mesenchymal stem cells (MSCs) are multipotent progenitors that can differentiate into several lineages including bone. Successful bone formation requires osteogenesis and angiogenesis coupling of MSCs. Here, we investigate if simultaneous activation of BMP9 and Notch signaling yields effective osteogenesis-angiogenesis coupling in MSCs. Recently-characterized immortalized mouse adipose-derived progenitors (iMADs) were used as MSC source. Transgenes BMP9, NICD and dnNotch1 were expressed by adenoviral vectors. Gene expression was determined by qPCR and immunohistochem¡stry. Osteogenic activity was assessed by in vitro assays and in vivo ectopic bone formation model. BMP9 upregulated expression of Notch receptors and ligands in iMADs. Constitutively-active form of Notch1 NICD1 enhanced BMP9-induced osteogenic differentiation both in vitro and in vivo, which was effectively inhibited by dominant-negative form of Notch1 dnNotch1. BMP9- and NICD1-transduced MSCs implanted with a biocompatible scaffold yielded highly mature bone with extensive vascularization. NICD1 enhanced BMP9-induced expression of key angiogenic regulators in iMADs and Vegfa in ectopic bone, which was blunted by dnNotch1. Notch signaling may play an important role in BMP9-induced osteogenesis and angiogenesis. It's conceivable that simultaneous activation of the BMP9 and Notch pathways should efficiently couple osteogenesis and angiogenesis of MSCs for successful bone tissue engineering. © 2017 The Author(s)Published by S. Karger AG, Basel.

Inhibition of FoxO transcriptional activity prevents muscle fiber atrophy during cachexia and induces hypertrophy

PubMed Central

Reed, Sarah A.; Sandesara, Pooja B.; Senf, Sarah M.; Judge, Andrew R.

2012-01-01

Cachexia is characterized by inexorable muscle wasting that significantly affects patient prognosis and increases mortality. Therefore, understanding the molecular basis of this muscle wasting is of significant importance. Recent work showed that components of the forkhead box O (FoxO) pathway are increased in skeletal muscle during cachexia. In the current study, we tested the physiological significance of FoxO activation in the progression of muscle atrophy associated with cachexia. FoxO-DNA binding dependent transcription was blocked in the muscles of mice through injection of a dominant negative (DN) FoxO expression plasmid prior to inoculation with Lewis lung carcinoma cells or the induction of sepsis. Expression of DN FoxO inhibited the increased mRNA levels of atrogin-1, MuRF1, cathepsin L, and/or Bnip3 and inhibited muscle fiber atrophy during cancer cachexia and sepsis. Interestingly, during control conditions, expression of DN FoxO decreased myostatin expression, increased MyoD expression and satellite cell proliferation, and induced fiber hypertrophy, which required de novo protein synthesis. Collectively, these data show that FoxO-DNA binding-dependent transcription is necessary for normal muscle fiber atrophy during cancer cachexia and sepsis, and further suggest that basal levels of FoxO play an important role during normal conditions to depress satellite cell activation and limit muscle growth.—Reed, S. A., Sandesara, P. B., Senf, S. F., Judge, A. R. Inhibition of FoxO transcriptional activity prevents muscle fiber atrophy during cachexia and induces hypertrophy. PMID:22102632

Arterial α2-Na+ pump expression influences blood pressure: lessons from novel, genetically engineered smooth muscle-specific α2 mice.

PubMed

Chen, Ling; Song, Hong; Wang, Youhua; Lee, Jane C; Kotlikoff, Michael I; Pritchard, Tracy J; Paul, Richard J; Zhang, Jin; Blaustein, Mordecai P

2015-09-01

Arterial myocytes express α1-catalytic subunit isoform Na(+) pumps (75-80% of total), which are ouabain resistant in rodents, and high ouabain affinity α2-Na(+) pumps. Mice with globally reduced α2-pumps (but not α1-pumps), mice with mutant ouabain-resistant α2-pumps, and mice with a smooth muscle (SM)-specific α2-transgene (α2 (SM-Tg)) that induces overexpression all have altered blood pressure (BP) phenotypes. We generated α2 (SM-DN) mice with SM-specific α2 (not α1) reduction (>50%) using nonfunctional dominant negative (DN) α2. We compared α2 (SM-DN) and α2 (SM-Tg) mice to controls to determine how arterial SM α2-pumps affect vasoconstriction and BP. α2 (SM-DN) mice had elevated basal mean BP (mean BP by telemetry: 117 ± 4 vs. 106 ± 1 mmHg, n = 7/7, P < 0.01) and enhanced BP responses to chronic ANG II infusion (240 ng·kg(-1)·min(-1)) and high (6%) NaCl. Several arterial Ca(2+) transporters, including Na(+)/Ca(2+) exchanger 1 (NCX1) and sarcoplasmic reticulum and plasma membrane Ca(2+) pumps [sarco(endo)plasmic reticulum Ca(2+)-ATPase 2 (SERCA2) and plasma membrane Ca(2+)-ATPase 1 (PMCA1)], were also reduced (>50%). α2 (SM-DN) mouse isolated small arteries had reduced myogenic reactivity, perhaps because of reduced Ca(2+) transporter expression. In contrast, α2 (SM-Tg) mouse aortas overexpressed α2 (>2-fold), NCX1, SERCA2, and PMCA1 (43). α2 (SM-Tg) mice had reduced basal mean BP (104 ± 1 vs. 109 ± 2 mmHg, n = 15/9, P < 0.02) and attenuated BP responses to chronic ANG II (300-400 ng·kg(-1)·min(-1)) with or without 2% NaCl but normal myogenic reactivity. NCX1 expression was inversely related to basal BP in SM-α2 engineered mice but was directly related in SM-NCX1 engineered mice. NCX1, which usually mediates arterial Ca(2+) entry, and α2-Na(+) pumps colocalize at plasma membrane-sarcoplasmic reticulum junctions and functionally couple via the local Na(+) gradient to help regulate cell Ca(2+). Altered Ca(2+) transporter expression in SM-α2 engineered mice apparently compensates to minimize Ca(2+) overload (α2 (SM-DN)) or depletion (α2 (SM-Tg)) and attenuate BP changes. In contrast, Ca(2+) transporter upregulation, observed in many rodent hypertension models, should enhance Ca(2+) entry and signaling and contribute significantly to BP elevation. Copyright © 2015 the American Physiological Society.

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.

NFATc1 regulation of the human β3 integrin promoter in osteoclast differentiation

PubMed Central

Crotti, Tania N.; Flannery, Merrilee; Walsh, Nicole C.; Fleming, Joseph D.; Goldring, Steven R.; McHugh, Kevin P.

2006-01-01

The transcription factor NFATc1 plays an essential role in transducing signals from RANKL in osteoclast differentiation. To date, however, the specific transcriptional targets of NFATc1 are unknown. Expression of the β3 integrin is required for normal osteoclast function. We therefore examined the role of NFATc1 in human β3 integrin expression in osteoclast differentiation. Analysis of the mouse and human β3 gene promoters revealed considerable sequence homology across a 1.3 kb region upstream of the transcription start site (TSS), with conserved NFAT binding elements present. The region −1242 to +29 (relative to the TSS) was cloned as a luciferase reporter construct (pB3-1.3) and a deletion construct removing to −997 (pB3-1) made. The deletion of 245 bp 5′ removed three conserved NFAT sites including a consensus NFAT:AP-1 site. The pB3-1.3 reporter construct was induced by treatment with RANKL in the range 2.5–40 ng/ml and dose-dependently induced by co-transfection with human NFATc1 in RAW264.7 cells. The pB3-1 deletion construct was minimally induced with RANKL treatment and unresponsive to co-transfected NFATc1. Direct NFAT binding to two of the consensus NFAT sites within this 245 bp 5′ region was demonstrated by EMSA and supershift with anti-NFAT antibodies. Mutation of two of the conserved NFAT sites in the −1242 to −997 fragment was required to prevent binding. The double NFAT mutant, in the context of the full-length promoter was unresponsive to RANKL treatment or co-transfected NFATc1. We generated cell-permeable TAT-dominant-negative (dn)NFATc1 fusion proteins to assess the effect of blockade of NFAT signaling. Transduction with dnNFAT inhibited RANKL induction of the human β3 integrin promoter. Involvement of the NFATc1-calcineurin pathway in regulating the human β3 integrin promoter was further confirmed using the calcineurin pathway inhibitory peptide 11R-VIVIT. Together these results establish the β3 gene as a direct target of NFATc1 in RANKL-dependent osteoclast formation. PMID:16513293

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

Beta Catenin in Prostate Cancer Apoptosis

DTIC Science & Technology

2014-04-01

indicate that, Glycogen Synthase Kinase 3β (GSK3β) might be a key player in mediating this. GSK3β, a multifunctional serine/ threonine kinase regulates...for TRAIL-TZD-induced apoptosis in prostate cancer cells. AMPK is a family of serine/ threonine protein kinase and is highly conserved from yeast to...metabolic syndrome and Type 2 diabetes . We used C42-DN (stably overexpressing AMPK α1-dominant negative) and C42-EV (empty vector) prostate cancer cell

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.

A DN-mda5 transgenic zebrafish model demonstrates that Mda5 plays an important role in snakehead rhabdovirus resistance.

PubMed

Gabor, K A; Charette, J R; Pietraszewski, M J; Wingfield, D J; Shim, J S; Millard, P J; Kim, C H

2015-08-01

Melanoma Differentiation-Associated protein 5 (MDA5) is a member of the retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) family, which is a cytosolic pattern recognition receptor that detects viral nucleic acids. Here we show an Mda5-dependent response to rhabdovirus infection in vivo using a dominant-negative mda5 transgenic zebrafish. Dominant-negative mda5 zebrafish embryos displayed an impaired antiviral immune response compared to wild-type counterparts that can be rescued by recombinant full-length Mda5. To our knowledge, we have generated the first dominant-negative mda5 transgenic zebrafish and demonstrated a critical role for Mda5 in the antiviral response to rhabdovirus. Copyright © 2015 Elsevier Ltd. All rights reserved.

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.

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.

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.

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

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.

Elucidation of the Molecular Mechanisms Underlying Lymph Node Metastasis in Prostate Cancer

DTIC Science & Technology

2005-10-01

overexpressed (Figure 8B). This result is significant for two reasons. First, it provides a mechanistic explanation for how FOXO-1, activated by SIRT1 ...transcription (Figure 4c). This result was confirmed when we used the dominant-negative form of SIRT1 to inhibit its activity (Figure 4d). SIRT-1DN protein... activated by SIRT1 , can act to Figure 3 (a) Androgen increases the IGF-IR protein level in LNCaP. LNCaP cells were grown in the charcoal–dextran

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

Targeted Sos1 deletion reveals its critical role in early T-cell development

PubMed Central

Kortum, Robert L.; Sommers, Connie L.; Alexander, Clayton P.; Pinski, John M.; Li, Wenmei; Grinberg, Alex; Lee, Jan; Love, Paul E.; Samelson, Lawrence E.

2011-01-01

Activation of the small G protein Ras is required for thymocyte differentiation. In thymocytes, Ras is activated by the Ras guanine exchange factors (RasGEFs) Sos1, Sos2, and RasGRP1. We report the development of a floxed allele of sos1 to assess the role of Sos1 during thymocyte development. Sos1 was required for pre–T-cell receptor (pre-TCR)– but not TCR-stimulated developmental signals. Sos1 deletion led to a partial block at the DN-to-DP transition. Sos1-deficient thymocytes showed reduced pre-TCR–stimulated proliferation, differentiation, and ERK phosphorylation. In contrast, TCR-stimulated positive selection, and negative selection under strong stimulatory conditions, remained intact in Sos1-deficient mice. Comparison of RasGEF expression at different developmental stages showed that relative to Sos2 and RasGRP1, Sos1 is most abundant in DN thymocytes, but least abundant in DP thymocytes. These data reveal that Sos1 is uniquely positioned to affect signal transduction early in thymocyte development. PMID:21746917

Inhibition of endogenous MTF-1 signaling in zebrafish embryos identifies novel roles for MTF-1 in development.

PubMed

O'Shields, Britton; McArthur, Andrew G; Holowiecki, Andrew; Kamper, Martin; Tapley, Jeffrey; Jenny, Matthew J

2014-09-01

The metal responsive element-binding transcription factor-1 (MTF-1) responds to changes in cellular zinc levels caused by zinc exposure or disruption of endogenous zinc homeostasis by heavy metals or oxygen-related stress. Here we report the functional characterization of a complete zebrafish MTF-1 in comparison with the previously identified isoform lacking the highly conserved cysteine-rich motif (Cys-X-Cys-Cys-X-Cys) found in all other vertebrate MTF-1 orthologs. In an effort to develop novel molecular tools, a constitutively nuclear dominant-negative MTF-1 (dnMTF-1) was generated as tool for inhibiting endogenous MTF-1 signaling. The in vivo efficacy of the dnMTF-1 was determined by microinjecting in vitro transcribed dnMTF-1 mRNA into zebrafish embryos (1-2 cell stage) followed by transcriptomic profiling using an Agilent 4x44K array on 28- and 36-hpf embryos. A total of 594 and 560 probes were identified as differentially expressed at 28hpf and 36hpf, respectively, with interesting overlaps between timepoints. The main categories of genes affected by the inhibition of MTF-1 signaling were: nuclear receptors and genes involved in stress signaling, neurogenesis, muscle development and contraction, eye development, and metal homeostasis, including novel observations in iron and heme homeostasis. Finally, we investigate both the transcriptional activator and transcriptional repressor role of MTF-1 in potential novel target genes identified by transcriptomic profiling during early zebrafish development. Copyright © 2014 Elsevier B.V. All rights reserved.

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.

Integrity of the Linker of Nucleoskeleton and Cytoskeleton Is Required for Efficient Herpesvirus Nuclear Egress.

PubMed

Klupp, Barbara G; Hellberg, Teresa; Granzow, Harald; Franzke, Kati; Dominguez Gonzalez, Beatriz; Goodchild, Rose E; Mettenleiter, Thomas C

2017-10-01

Herpesvirus capsids assemble in the nucleus, while final virion maturation proceeds in the cytoplasm. This requires that newly formed nucleocapsids cross the nuclear envelope (NE), which occurs by budding at the inner nuclear membrane (INM), release of the primary enveloped virion into the perinuclear space (PNS), and subsequent rapid fusion with the outer nuclear membrane (ONM). During this process, the NE remains intact, even at late stages of infection. In addition, the spacing between the INM and ONM is maintained, as is that between the primary virion envelope and nuclear membranes. The linker of nucleoskeleton and cytoskeleton (LINC) complex consists of INM proteins with a luminal SUN (Sad1/UNC-84 homology) domain connected to ONM proteins with a KASH (Klarsicht, ANC-1, SYNE homology) domain and is thought to be responsible for spacing the nuclear membranes. To investigate the role of the LINC complex during herpesvirus infection, we generated cell lines constitutively expressing dominant negative (dn) forms of SUN1 and SUN2. Ultrastructural analyses revealed a significant expansion of the PNS and the contiguous intracytoplasmic lumen, most likely representing endoplasmic reticulum (ER), especially in cells expressing dn-SUN2. After infection, primary virions accumulated in these expanded luminal regions, also very distant from the nucleus. The importance of the LINC complex was also confirmed by reduced progeny virus titers in cells expressing dn-SUN2. These data show that the intact LINC complex is required for efficient nuclear egress of herpesviruses, likely acting to promote fusion of primary enveloped virions with the ONM. IMPORTANCE While the viral factors for primary envelopment of nucleocapsids at the inner nuclear membrane are known to the point of high-resolution structures, the roles of cellular components and regulators remain enigmatic. Furthermore, the machinery responsible for fusion with the outer nuclear membrane is unsolved. We show here that dominant negative SUN2 interferes with efficient herpesvirus nuclear egress, apparently by interfering with fusion between the primary virion envelope and outer nuclear membrane. This identifies a new cellular component important for viral egress and implicates LINC complex integrity in nonconventional nuclear membrane trafficking. Copyright © 2017 American Society for Microbiology.

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.

Insulin Activates RSK (p90 Ribosomal S6 Kinase) to Trigger a New Negative Feedback Loop That Regulates Insulin Signaling for Glucose Metabolism*

PubMed Central

Smadja-Lamère, Nicolas; Shum, Michael; Déléris, Paul; Roux, Philippe P.; Abe, Jun-Ichi; Marette, André

2013-01-01

We previously demonstrated that the mTORC1/S6K1 pathway is activated by insulin and nutrient overload (e.g. amino acids (AA)), which leads to the inhibition of the PI3K/Akt pathway via the inhibitory serine phosphorylation of IRS-1, notably on serine 1101 (Ser-1101). However, even in the absence of AA, insulin can still promote IRS-1 Ser-1101 phosphorylation by other kinases that remain to be fully characterized. Here, we describe a new negative regulator of IRS-1, the p90 ribosomal S6 kinase (RSK). Computational analyses revealed that Ser-1101 within IRS-1 falls into the consensus motif of RSK. Moreover, recombinant RSK phosphorylated IRS-1 C-terminal fragment on Ser-1101, which was prevented by mutations of this site or when a kinase-inactive mutant of RSK was used. Using antibodies directed toward the phosphorylation sites located in the activation segment of RSK (Ser-221 or Ser-380), we found that insulin activates RSK in L6 myocytes in the absence of AA overload. Inhibition of RSK using either the pharmacological inhibitor BI-D1870 or after adenoviral expression of a dominant negative RSK1 mutant (RSK1-DN) showed that RSK selectively phosphorylates IRS-1 on Ser-1101. Accordingly, expression of the RSK1-DN mutant in L6 myocytes and FAO hepatic cells improved insulin action on glucose uptake and glucose production, respectively. Furthermore, RSK1 inhibition prevented insulin resistance in L6 myocytes chronically exposed to high glucose and high insulin. These results show that RSK is a novel regulator of insulin signaling and glucose metabolism and a potential mediator of insulin resistance, notably through the negative phosphorylation of IRS-1 on Ser-1101. PMID:24036112

Hepatic p38α regulates gluconeogenesis by suppressing AMPK.

PubMed

Jing, Yanyan; Liu, Wei; Cao, Hongchao; Zhang, Duo; Yao, Xuan; Zhang, Shengjie; Xia, Hongfeng; Li, Dan; Wang, Yu-cheng; Yan, Jun; Hui, Lijian; Ying, Hao

2015-06-01

It is proposed that p38 is involved in gluconeogenesis, however, the genetic evidence is lacking and precise mechanisms remain poorly understood. We sought to delineate the role of hepatic p38α in gluconeogenesis during fasting by applying a loss-of-function genetic approach. We examined fasting glucose levels, performed pyruvate tolerance test, imaged G6Pase promoter activity, as well as determined the expression of gluconeogenic genes in mice with a targeted deletion of p38α in liver. Results were confirmed both in vivo and in vitro by using an adenoviral dominant-negative form of p38α (p38α-AF) and the constitutively active mitogen-activated protein kinase 6, respectively. Adenoviral dominant-negative form of AMP-activated protein kinase α (DN-AMPKα) was employed to test our proposed model. Mice lacking hepatic p38α exhibited reduced fasting glucose level and impaired gluconeogenesis. Interestingly, hepatic deficiency of p38α did not result in an alteration in CREB phosphorylation, but led to an increase in AMPKα phosphorylation. Adenoviral DN-AMPKα could abolish the effect of p38α-AF on gluconeogenesis. Knockdown of up-steam transforming growth factor β-activated kinase 1 decreased the AMPKα phosphorylation induced by p38α-AF, suggesting a negative feedback loop. Consistently, inverse correlations between p38 and AMPKα phosphorylation were observed during fasting and in diabetic mouse models. Importantly, adenoviral p38α-AF treatment ameliorated hyperglycemia in diabetic mice. Our study provides evidence that hepatic p38α functions as a negative regulator of AMPK signaling in maintaining gluconeogenesis, dysregulation of this regulatory network contributes to unrestrained gluconeogenesis in diabetes, and hepatic p38α could be a drug target for hyperglycemia. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

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

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.

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

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

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.

Osmosensation in TRPV2 dominant negative expressing skeletal muscle fibres

PubMed Central

Zanou, Nadège; Mondin, Ludivine; Fuster, Clarisse; Seghers, François; Dufour, Inès; de Clippele, Marie; Schakman, Olivier; Tajeddine, Nicolas; Iwata, Yuko; Wakabayashi, Shigeo; Voets, Thomas; Allard, Bruno; Gailly, Philippe

2015-01-01

Abstract Increased plasma osmolarity induces intracellular water depletion and cell shrinkage followed by activation of a regulatory volume increase (RVI). In skeletal muscle, this is accompanied by transverse tubule (TT) dilatation and by a membrane depolarization responsible for a release of Ca2+ from intracellular pools. We observed that both hyperosmotic shock-induced Ca2+ transients and RVI were inhibited by Gd3+, ruthenium red and GsMTx4 toxin, three inhibitors of mechanosensitive ion channels. The response was also completely absent in muscle fibres overexpressing a non-permeant, dominant negative (DN) mutant of the transient receptor potential, V2 isoform (TRPV2) ion channel, suggesting the involvement of TRPV2 or of a TRP isoform susceptible to heterotetramerization with TRPV2. The release of Ca2+ induced by hyperosmotic shock was increased by cannabidiol, an activator of TRPV2, and decreased by tranilast, an inhibitor of TRPV2, suggesting a role for the TRPV2 channel itself. Hyperosmotic shock-induced membrane depolarization was impaired in TRPV2-DN fibres, suggesting that TRPV2 activation triggers the release of Ca2+ from the sarcoplasmic reticulum by depolarizing TTs. RVI requires the sequential activation of STE20/SPS1-related proline/alanine-rich kinase (SPAK) and NKCC1, a Na+–K+–Cl− cotransporter, allowing ion entry and driving osmotic water flow. In fibres overexpressing TRPV2-DN as well as in fibres in which Ca2+ transients were abolished by the Ca2+ chelator BAPTA, the level of P-SPAKSer373 in response to hyperosmotic shock was reduced, suggesting a modulation of SPAK phosphorylation by intracellular Ca2+. We conclude that TRPV2 is involved in osmosensation in skeletal muscle fibres, acting in concert with P-SPAK-activated NKCC1. Key points Increased plasma osmolarity induces intracellular water depletion and cell shrinkage (CS) followed by activation of a regulatory volume increase (RVI). In skeletal muscle, the hyperosmotic shock-induced CS is accompanied by a small membrane depolarization responsible for a release of Ca2+ from intracellular pools. Hyperosmotic shock also induces phosphorylation of STE20/SPS1-related proline/alanine-rich kinase (SPAK). TRPV2 dominant negative expressing fibres challenged with hyperosmotic shock present a slower membrane depolarization, a diminished Ca2+ response, a smaller RVI response, a decrease in SPAK phosphorylation and defective muscle function. We suggest that hyperosmotic shock induces TRPV2 activation, which accelerates muscle cell depolarization and allows the subsequent Ca2+ release from the sarcoplasmic reticulum, activation of the Na+–K+–Cl− cotransporter by SPAK, and the RVI response. PMID:26108786

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.

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

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.

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

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.

Distinct Functional Connectivities Predict Clinical Response with Emotion Regulation Therapy

PubMed Central

Fresco, David M.; Roy, Amy K.; Adelsberg, Samantha; Seeley, Saren; García-Lesy, Emmanuel; Liston, Conor; Mennin, Douglas S.

2017-01-01

Despite the success of available medical and psychosocial treatments, a sizable subgroup of individuals with commonly co-occurring disorders, generalized anxiety disorder (GAD) and major depressive disorder (MDD), fail to make sufficient treatment gains thereby prolonging their deficits in life functioning and satisfaction. Clinically, these patients often display temperamental features reflecting heightened sensitivity to underlying motivational systems related to threat/safety and reward/loss (e.g., somatic anxiety) as well as inordinate negative self-referential processing (e.g., worry, rumination). This profile may reflect disruption in two important neural networks associated with emotional/motivational salience (e.g., salience network) and self-referentiality (e.g., default network, DN). Emotion Regulation Therapy (ERT) was developed to target this hypothesized profile and its neurobehavioral markers. In the present study, 22 GAD patients (with and without MDD) completed resting state MRI scans before receiving 16 sessions of ERT. To test study these hypotheses, we examined the associations between baseline patterns of intrinsic functional connectivity (iFC) of the insula and of hubs within the DN (anterior and dorsal medial prefrontal cortex [MPFC] and posterior cingulate cortex [PCC]) and treatment-related changes in worry, somatic anxiety symptoms and decentering. Results suggest that greater treatment linked reductions in worry were associated with iFC clusters in both the insular and parietal cortices. Greater treatment linked gains in decentering, a metacognitive process that involves the capacity to observe items that arise in the mind with healthy psychological distance that is targeted by ERT, was associated with iFC clusters in the anterior and posterior DN. The current study adds to the growing body of research implicating disruptions in the default and salience networks as promising targets of treatment for GAD with and without co-occurring MDD. PMID:28316567

BDNF overexpression prevents cognitive deficit elicited by adolescent cannabis exposure and host susceptibility interaction.

PubMed

Segal-Gavish, Hadar; Gazit, Neta; Barhum, Yael; Ben-Zur, Tali; Taler, Michal; Hornfeld, Shay Henry; Gil-Ad, Irit; Weizman, Abraham; Slutsky, Inna; Niwa, Minae; Kamiya, Atsushi; Sawa, Akira; Offen, Daniel; Barzilay, Ran

2017-07-01

Cannabis abuse in adolescence is associated with increased risk of psychotic disorders. Δ-9-tetrahydrocannabinol (THC) is the primary psychoactive component of cannabis. Disrupted-In-Schizophrenia-1 (DISC1) protein is a driver for major mental illness by influencing neurodevelopmental processes. Here, utilizing a unique mouse model based on host (DISC1) X environment (THC administration) interaction, we aimed at studying the pathobiological basis through which THC exposure elicits psychiatric manifestations. Wild-Type and dominant-negative-DISC1 (DN-DISC1) mice were injected with THC (10 mg/kg) or vehicle for 10 days during mid-adolescence-equivalent period. Behavioral tests were conducted to assess exploratory activity (open field test, light-dark box test) and cognitive function (novel object recognition test). Electrophysiological effect of THC was evaluated using acute hippocampal slices, and hippocampal cannabinoid receptor type 1 and brain-derived neurotrophic factor (BDNF) protein levels were measured. Our results indicate that THC exposure elicits deficits in exploratory activity and recognition memory, together with reduced short-term synaptic facilitation and loss of BDNF surge in the hippocampus of DN-DISC mice, but not in wild-type mice. Over-expression of BDNF in the hippocampus of THC-treated DN-DISC1 mice prevented the impairment in recognition memory. The results of this study imply that induction of BDNF following adolescence THC exposure may serve as a homeostatic response geared to maintain proper cognitive function against exogenous insult. The BDNF surge in response to THC is perturbed in the presence of mutant DISC1, suggesting DISC1 may be a useful probe to identify biological cascades involved in the neurochemical, electrophysiological, and behavioral effects of cannabis related psychiatric manifestations. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Hypothalamic AMP-activated protein kinase mediates counter-regulatory responses to hypoglycaemia in rats.

PubMed

Han, S-M; Namkoong, C; Jang, P G; Park, I S; Hong, S W; Katakami, H; Chun, S; Kim, S W; Park, J-Y; Lee, K-U; Kim, M-S

2005-10-01

Appropriate counter-regulatory hormonal responses are essential for recovery from hypoglycaemia. Although the hypothalamus is known to be involved in these responses, the molecular mechanisms have not been fully elucidated. AMP-activated protein kinase (AMPK) functions as a cellular energy sensor, being activated during energy depletion. As AMPK is expressed in the hypothalamus, an important site of neuroendocrine regulation, the present study was undertaken to determine whether hypothalamic AMPK mediates counter-regulatory responses to hypoglycaemia. Hypoglycaemia was induced by i.p. injection of regular insulin (6 U/kg) in Sprague-Dawley rats. Hypothalamic AMPK phosphorylation and activities were determined 1 h after i.p. insulin injection. To investigate the role of hypothalamic AMPK activation in mediating counter-regulatory responses, an AMPK inhibitor, compound C, was pre-administered intracerebroventricularly (i.c.v.) or dominant-negative (DN)-AMPK was overexpressed in the hypothalamus before induction of hypoglycaemia. Insulin-induced hypoglycaemia increased hypothalamic AMPK phosphorylation and alpha2-AMPK activities in rats. The change was significant in the arcuate nucleus/ventromedial hypothalamus (ARC/VMH) and paraventricular nuclei (PVN). Prior i.c.v. administration of compound C attenuated hypoglycaemia-induced increases in plasma concentrations of corticosterone, glucagon and catecholamines, resulting in severe and prolonged hypoglycaemia. ARC/VMH DN-AMPK overexpression impaired early counter-regulation, as evidenced by reduced glucagon and catecholamine responses. In contrast, PVN DN-AMPK overexpression attenuated late counter-regulation and corticosterone responses. Systemic hypoglycaemia causes hypothalamic AMPK activation, which is important for counter-regulatory hormonal responses. Our data indicate that hypothalamic AMPK acts as a fuel gauge, sensing the whole-body energy state and regulating not only energy homeostasis but also neuroendocrine functions.

Combined TRAF6 Targeting and Proteasome Blockade Has Anti-myeloma and Anti-Bone Resorptive Effects.

PubMed

Chen, Haiming; Li, Mingjie; Sanchez, Eric; Wang, Cathy S; Lee, Tiffany; Soof, Camilia M; Casas, Christian E; Cao, Jasmin; Xie, Colin; Udd, Kyle A; DeCorso, Kevin; Tang, George Y; Spektor, Tanya M; Berenson, James R

2017-05-01

TNF receptor-associated factor 6 (TRAF6) has been implicated in polyubiquitin-mediated IL1R/TLR signaling through activation of IκB kinase (IKK) to regulate the NF-κB and JNK signaling pathways. Here, TRAF6 protein was determined to be overexpressed in bone marrow mononuclear cells (BMMC) from patients with multiple myeloma. TRAF6 expression in BMMCs from patients with progressive disease is significantly elevated as compared with individuals in complete remission, with monoclonal gammopathy of undetermined significance, or healthy subjects. Furthermore, TRAF6 dominant-negative (TRAF6dn) peptides were constructed which specifically reduced TRAF6 signaling and activation of IKK. TRAF6 not only reduced cellular growth but also increased the apoptosis of multiple myeloma tumor cells in a concentration-dependent fashion. Because TRAF6 activates IKK through polyubiquitination, independent of its proteasome activity, a TRAF6dn peptide was combined with the proteasome inhibitors bortezomib or carfilzomib to treat multiple myeloma. Importantly, targeting of TRAF6 in the presence of proteasome inhibition enhanced anti-multiple myeloma effects and also decreased TLR/TRAF6/NF-κB-related signaling. Finally, TRAF6dn dose dependently inhibited osteoclast cell formation from CD14 + monocytes, induced with RANKL and mCSF , and markedly reduced bone resorption in dentin pits. In all, these data demonstrate that blocking TRAF6 signaling has anti-multiple myeloma effects and reduces bone loss. Implications: The ability to target TRAF6 signaling and associated pathways in multiple myeloma suggests a promising new therapeutic approach. Mol Cancer Res; 15(5); 598-609. ©2017 AACR . ©2017 American Association for Cancer Research.

RoMo: An efficient strategy for functional mosaic analysis via stochastic Cre recombination and gene targeting in the ROSA26 locus.

PubMed

Movahedi, Kiavash; Wiegmann, Robert; De Vlaminck, Karen; Van Ginderachter, Jo A; Nikolaev, Viacheslav O

2018-07-01

Functional mosaic analysis allows for the direct comparison of mutant cells with differentially marked control cells in the same organism. While this offers a powerful approach for elucidating the role of specific genes or signalling pathways in cell populations of interest, genetic strategies for generating functional mosaicism remain challenging. We describe a novel and streamlined approach for functional mosaic analysis, which combines stochastic Cre/lox recombination with gene targeting in the ROSA26 locus. With the RoMo strategy a cell population of interest is randomly split into a cyan fluorescent and red fluorescent subset, of which the latter overexpresses a chosen transgene. To integrate this approach into high-throughput gene targeting initiatives, we developed a procedure that utilizes Gateway cloning for the generation of new targeting vectors. RoMo can be used for gain-of-function experiments or for altering signaling pathways in a mosaic fashion. To demonstrate this, we developed RoMo-dnGs mice, in which Cre-recombined red fluorescent cells co-express a dominant-negative Gs protein. RoMo-dnGs mice allowed us to inhibit G protein-coupled receptor activation in a fraction of cells, which could then be directly compared to differentially marked control cells in the same animal. We demonstrate how RoMo-dnGs mice can be used to obtain mosaicism in the brain and in peripheral organs for various cell types. RoMo offers an efficient new approach for functional mosaic analysis that extends the current toolbox and may reveal important new insights into in vivo gene function. © 2018 Wiley Periodicals, Inc.

Tumor p38MAPK signaling enhances breast carcinoma vascularization and growth by promoting expression and deposition of pro-tumorigenic factors.

PubMed

Limoge, Michelle; Safina, Alfiya; Truskinovsky, Alexander M; Aljahdali, Ieman; Zonneville, Justin; Gruevski, Aleksandar; Arteaga, Carlos L; Bakin, Andrei V

2017-09-22

The breast carcinoma microenvironment strikingly influences cancer progression and response to therapy. Various cell types in the carcinoma microenvironment show significant activity of p38 mitogen-activated protein kinase (MAPK), although the role of p38MAPK in breast cancer progression is still poorly understood. The present study examined the contribution of tumor p38MAPK to breast carcinoma microenvironment and metastatic capacity. Inactivation of p38MAPK signaling in metastatic breast carcinoma cells was achieved by forced expression of the kinase-inactive mutant of p38/MAPK14 (a dominant-negative p38, dn-p38). Disruption of tumor p38MAPK signaling reduced growth and metastases of breast carcinoma xenografts. Importantly, dn-p38 markedly decreased tumor blood-vessel density and lumen sizes. Mechanistic studies revealed that p38 controls expression of pro-angiogenic extracellular factors such as matrix protein Fibronectin and cytokines VEGFA, IL8, and HBEGF. Tumor-associated fibroblasts enhanced tumor growth and vasculature as well as increased expression of the pro-angiogenic factors. These effects were blunted by dn-p38. Metadata analysis showed elevated expression of p38 target genes in breast cancers and this was an unfavorable marker of disease recurrence and poor-outcome. Thus, our study demonstrates that tumor p38MAPK signaling promotes breast carcinoma growth, invasive and metastatic capacities. Importantly, p38 enhances carcinoma vascularization by facilitating expression and deposition of pro-angiogenic factors. These results argue that p38MAPK is a valuable target for anticancer therapy affecting tumor vasculature. Anti-p38 drugs may provide new therapeutic strategies against breast cancer, including metastatic disease.

Tumor p38MAPK signaling enhances breast carcinoma vascularization and growth by promoting expression and deposition of pro-tumorigenic factors

PubMed Central

Limoge, Michelle; Safina, Alfiya; Truskinovsky, Alexander M.; Aljahdali, Ieman; Zonneville, Justin; Gruevski, Aleksandar; Arteaga, Carlos L.; Bakin, Andrei V.

2017-01-01

The breast carcinoma microenvironment strikingly influences cancer progression and response to therapy. Various cell types in the carcinoma microenvironment show significant activity of p38 mitogen-activated protein kinase (MAPK), although the role of p38MAPK in breast cancer progression is still poorly understood. The present study examined the contribution of tumor p38MAPK to breast carcinoma microenvironment and metastatic capacity. Inactivation of p38MAPK signaling in metastatic breast carcinoma cells was achieved by forced expression of the kinase-inactive mutant of p38/MAPK14 (a dominant-negative p38, dn-p38). Disruption of tumor p38MAPK signaling reduced growth and metastases of breast carcinoma xenografts. Importantly, dn-p38 markedly decreased tumor blood-vessel density and lumen sizes. Mechanistic studies revealed that p38 controls expression of pro-angiogenic extracellular factors such as matrix protein Fibronectin and cytokines VEGFA, IL8, and HBEGF. Tumor-associated fibroblasts enhanced tumor growth and vasculature as well as increased expression of the pro-angiogenic factors. These effects were blunted by dn-p38. Metadata analysis showed elevated expression of p38 target genes in breast cancers and this was an unfavorable marker of disease recurrence and poor-outcome. Thus, our study demonstrates that tumor p38MAPK signaling promotes breast carcinoma growth, invasive and metastatic capacities. Importantly, p38 enhances carcinoma vascularization by facilitating expression and deposition of pro-angiogenic factors. These results argue that p38MAPK is a valuable target for anticancer therapy affecting tumor vasculature. Anti-p38 drugs may provide new therapeutic strategies against breast cancer, including metastatic disease. PMID:28977919

DSM-IV-TR “pain disorder associated with psychological factors” as a nonhysterical form of somatization

PubMed Central

Aragona, Massimiliano; Tarsitani, Lorenzo; De Nitto, Serena; Inghilleri, Maurizio

2008-01-01

BACKGROUND: Elevated Minnesota Multiphasic Personality Inventory (MMPI) scores on the hysteria (Hy) scale are reported in several forms of pain. Previous results were possibly biased by diagnostic heterogeneity (psychogenic, somatic and mixed pain syndromes included in the same index sample) or Hy heterogeneity (failure to differentiate Hy scores into clinically meaningful sub-scales, such as admission of symptoms [Ad] and denial of symptoms [Dn]). METHODS: To overcome this drawback, 48 patients diagnosed as having a Diagnostic and Statistical Manual of Mental Disorders, 4th edn, Text Revision (DSM-IV-TR) diagnosis of “pain disorder associated with psychological factors” were compared with 48 patients experiencing somatic pain excluding psychological factors, and 42 somatic controls without pain. RESULTS: MMPI Hy and hypochondriasis (Hs) scores were significantly higher in the pain disorder group than in control groups, who scored similarly. MMPI correction (K) scores and Dn scores were similar in the three groups, whereas Ad was significantly higher in the pain disorder group and lower and similar in the two control groups, respectively. In the pain disorder group, Ad and Dn were negatively correlated, whereas in control groups they were unrelated. CONCLUSIONS: These findings suggest that whereas a pattern of high Hs and Hy scores together with a normal K score might characterize patients with a pain disorder associated with psychological factors, elevated Hy scores per se do not indicate hysterical traits. In the pain disorder group, elevated Hy scores reflected the Ad subscale alone, indicating a strikingly high frequency of distressing somatic symptoms. They tend not to repress or deny the emotional malaise linked to symptoms, as the hysterical construct expects. The pain disorder designation should be considered a nonhysterical form of somatization. PMID:18301811

DSM-IV-TR "pain disorder associated with psychological factors" as a nonhysterical form of somatization.

PubMed

Aragona, Massimiliano; Tarsitani, Lorenzo; De Nitto, Serena; Inghilleri, Maurizio

2008-01-01

Elevated Minnesota Multiphasic Personality Inventory (MMPI) scores on the hysteria (Hy) scale are reported in several forms of pain. Previous results were possibly biased by diagnostic heterogeneity (psychogenic, somatic and mixed pain syndromes included in the same index sample) or Hy heterogeneity (failure to differentiate Hy scores into clinically meaningful subscales, such as admission of symptoms [Ad] and denial of symptoms [Dn]). To overcome this drawback, 48 patients diagnosed as having a Diagnostic and Statistical Manual of Mental Disorders, 4th edn, Text Revision (DSM-IV-TR) diagnosis of "pain disorder associated with psychological factors" were compared with 48 patients experiencing somatic pain excluding psychological factors, and 42 somatic controls without pain. MMPI Hy and hypochondriasis (Hs) scores were significantly higher in the pain disorder group than in control groups, who scored similarly. MMPI correction (K) scores and Dn scores were similar in the three groups, whereas Ad was significantly higher in the pain disorder group and lower and similar in the two control groups, respectively. In the pain disorder group, Ad and Dn were negatively correlated, whereas in control groups they were unrelated. These findings suggest that whereas a pattern of high Hs and Hy scores together with a normal K score might characterize patients with a pain disorder associated with psychological factors, elevated Hy scores per se do not indicate hysterical traits. In the pain disorder group, elevated Hy scores reflected the Ad subscale alone, indicating a strikingly high frequency of distressing somatic symptoms. They tend not to repress or deny the emotional malaise linked to symptoms, as the hysterical construct expects. The pain disorder designation should be considered a nonhysterical form of somatization.

Nicotine-specific and non-specific effects of cigarette smoking on endogenous opioid mechanisms.

PubMed

Nuechterlein, Emily B; Ni, Lisong; Domino, Edward F; Zubieta, Jon-Kar

2016-08-01

This study investigates differences in μ-opioid receptor mediated neurotransmission in healthy controls and overnight-abstinent smokers, and potential effects of the OPRM1 A118G genotype. It also examines the effects of smoking denicotinized (DN) and average nicotine (N) cigarettes on the μ-opioid system. Positron emission tomography with (11)C-carfentanil was used to determine regional brain μ-opioid receptor (MOR) availability (non-displaceable binding potential, BPND) in a sample of 19 male smokers and 22 nonsmoking control subjects. Nonsmokers showed greater MOR BPND than overnight abstinent smokers in the basal ganglia and thalamus. BPND in the basal ganglia was negatively correlated with baseline craving levels and Fagerström scores. Interactions between group and genotype were seen in the nucleus accumbens bilaterally and the amygdala, with G-allele carriers demonstrating lower BPND in these regions, but only among smokers. After smoking the DN cigarette, smokers showed evidence of MOR activation in the thalamus and nucleus accumbens. No additional activation was observed after the N cigarette, with a mean effect of increases in MOR BPND (i.e., deactivation) with respect to the DN cigarette effects in the thalamus and left amygdala. Changes in MOR BPND were related to both Fagerström scores and changes in craving. This study showed that overnight-abstinent smokers have lower concentrations of available MORs than controls, an effect that was related to both craving and the severity of addiction. It also suggests that nicotine non-specific elements of the smoking experience have an important role in regulating MOR-mediated neurotransmission, and in turn modulating withdrawal-induced craving ratings. Copyright © 2016 Elsevier Inc. All rights reserved.

The role of chicken ovalbumin upstream promoter transcription factor II in the regulation of hepatic fatty acid oxidation and gluconeogenesis in newborn mice.

PubMed

Planchais, Julien; Boutant, Marie; Fauveau, Véronique; Qing, Lou Dan; Sabra-Makke, Lina; Bossard, Pascale; Vasseur-Cognet, Mireille; Pégorier, Jean-Paul

2015-05-15

Chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) is an orphan nuclear receptor involved in the control of numerous functions in various organs (organogenesis, differentiation, metabolic homeostasis, etc.). The aim of the present work was to characterize the regulation and contribution of COUP-TFII in the control of hepatic fatty acid and glucose metabolisms in newborn mice. Our data show that postnatal increase in COUP-TFII mRNA levels is enhanced by glucagon (via cAMP) and PPARα. To characterize COUP-TFII function in the liver of suckling mice, we used a functional (dominant negative form; COUP-TFII-DN) and a genetic (shRNA) approach. Adenoviral COUP-TFII-DN injection induces a profound hypoglycemia due to the inhibition of gluconeogenesis and fatty acid oxidation secondarily to reduced PEPCK, Gl-6-Pase, CPT I, and mHMG-CoA synthase gene expression. Using the crossover plot technique, we show that gluconeogenesis is inhibited at two different levels: 1) pyruvate carboxylation and 2) trioses phosphate synthesis. This could result from a decreased availability in fatty acid oxidation arising cofactors such as acetyl-CoA and reduced equivalents. Similar results are observed using the shRNA approach. Indeed, when fatty acid oxidation is rescued in response to Wy-14643-induced PPARα target genes (CPT I and mHMG-CoA synthase), blood glucose is normalized in COUP-TFII-DN mice. In conclusion, this work demonstrates that postnatal increase in hepatic COUP-TFII gene expression is involved in the regulation of liver fatty acid oxidation, which in turn sustains an active hepatic gluconeogenesis that is essential to maintain an appropriate blood glucose level required for newborn mice survival. Copyright © 2015 the American Physiological Society.

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.

Validity and reliability of the Spanish version of the DN4 (Douleur Neuropathique 4 questions) questionnaire for differential diagnosis of pain syndromes associated to a neuropathic or somatic component

PubMed Central

Perez, Concepcion; Galvez, Rafael; Huelbes, Silvia; Insausti, Joaquin; Bouhassira, Didier; Diaz, Silvia; Rejas, Javier

2007-01-01

Background This study assesses the validity and reliability of the Spanish version of DN4 questionnaire as a tool for differential diagnosis of pain syndromes associated to a neuropathic (NP) or somatic component (non-neuropathic pain, NNP). Methods A study was conducted consisting of two phases: cultural adaptation into the Spanish language by means of conceptual equivalence, including forward and backward translations in duplicate and cognitive debriefing, and testing of psychometric properties in patients with NP (peripheral, central and mixed) and NNP. The analysis of psychometric properties included reliability (internal consistency, inter-rater agreement and test-retest reliability) and validity (ROC curve analysis, agreement with the reference diagnosis and determination of sensitivity, specificity, and positive and negative predictive values in different subsamples according to type of NP). Results A sample of 164 subjects (99 women, 60.4%; age: 60.4 ± 16.0 years), 94 (57.3%) with NP (36 with peripheral, 32 with central, and 26 with mixed pain) and 70 with NNP was enrolled. The questionnaire was reliable [Cronbach's alpha coefficient: 0.71, inter-rater agreement coefficient: 0.80 (0.71–0.89), and test-retest intra-class correlation coefficient: 0.95 (0.92–0.97)] and valid for a cut-off value ≥ 4 points, which was the best value to discriminate between NP and NNP subjects. Discussion This study, representing the first validation of the DN4 questionnaire into another language different than the original, not only supported its high discriminatory value for identification of neuropathic pain, but also provided supplemental psychometric validation (i.e. test-retest reliability, influence of educational level and pain intensity) and showed its validity in mixed pain syndromes. PMID:18053212

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

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.

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.

SH2 domain-containing inositol 5-phosphatase (SHIP2) regulates de-novo lipogenesis and secretion of apoB100 containing lipoproteins in HepG2 cells.

PubMed

Gorgani-Firuzjaee, Sattar; Khatami, Shohreh; Adeli, Khosrow; Meshkani, Reza

2015-09-04

Hepatic de-novo lipogenesis and production of triglyceride rich VLDL are regulated via the phosphoinositide 3-kinase cascade, however, the role of a negative regulator of this pathway, the SH2 domain-containing inositol 5-phosphatase (SHIP2) in this process, remains unknown. In the present study, we investigated the molecular link between SHIP2 expression and metabolic dyslipidemia using overexpression or suppression of SHIP2 gene in HepG2 cells. The results showed that overexpression of the wild type SHIP2 gene (SHIP2-WT) led to a higher total lipid content (28%) compared to control, whereas overexpression of the dominant negative SHIP2 gene (SHIP2-DN) reduced total lipid content in oleate treated cells by 40%. Overexpression of SHIP2-WT also led to a significant increase in both secretion of apoB100 containing lipoproteins and de-novo lipogenesis, as demonstrated by an enhancement in secreted apoB100 and MTP expression, increased intra and extracellular triglyceride levels and enhanced expression of lipogenic genes such as SREBP1c, FAS and ACC. On the other hand, overexpression of the SHIP2-DN gene prevented oleate-induced de-novo lipogenesis and secretion of apoB100 containing lipoproteins in HepG2 cells. Collectively, these findings suggest that SHIP2 expression level is a key determinant of hepatic lipogenesis and lipoprotein secretion, and its inhibition could be considered as a potential target for treatment of dyslipidemia. Copyright © 2015 Elsevier Inc. All rights reserved.

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.

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.

Double exposure using 193nm negative tone photoresist

NASA Astrophysics Data System (ADS)

Kim, Ryoung-han; Wallow, Tom; Kye, Jongwook; Levinson, Harry J.; White, Dave

2007-03-01

Double exposure is one of the promising methods for extending lithographic patterning into the low k I regime. In this paper, we demonstrate double patterning of k 1-effective=0.25 with improved process window using a negative resist. Negative resist (TOK N- series) in combination with a bright field mask is proven to provide a large process window in generating 1:3 = trench:line resist features. By incorporating two etch transfer steps into the hard mask material, frequency doubled patterns could be obtained.

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.

Families’ Experiences of Doubling Up After Homelessness

PubMed Central

Bush, Hannah; Shinn, Marybeth

2017-01-01

This study examined experiences of doubling up among families after episodes of homelessness. Doubling up refers to two or more adults or families residing in the same housing unit, which has been an increasing trend in the United States in recent decades. Within the past 14 years, the number of households containing more than one family, related or unrelated, has more than tripled. Although doubling up is increasingly common among families at all income levels, this study seeks to understand the experiences of doubling up among families who have been homeless. Through qualitative interviews with caregivers of 29 families, we analyzed advantages and disadvantages of doubling up with the caregiver’s parent, other family, and nonfamily. Experiences were rated on a four-point scale—(1) mostly negative, (2) negative mixed, (3) positive mixed, and (4) mostly positive—and coded for various positive and negative themes. Overall, we found that doubling up was a generally negative experience for families in our sample, regardless of their relationship to their hosts. Common themes included negative effects on children, undesirable environments, interpersonal tension, and feelings of impermanence and instability. For formerly sheltered families in this study, doubling up after shelter did not resolve their period of housing instability and may be only another stop in an ongoing cycle of homelessness. PMID:29326758

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

β-arrestins negatively control human adrenomedullin type 1-receptor internalization.

PubMed

Kuwasako, Kenji; Kitamura, Kazuo; Nagata, Sayaka; Sekiguchi, Toshio; Danfeng, Jiang; Murakami, Manabu; Hattori, Yuichi; Kato, Johji

2017-05-27

Adrenomedullin (AM) is a potent hypotensive peptide that exerts a powerful variety of protective effects against multiorgan damage through the AM type 1 receptor (AM 1 receptor), which consists of the calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 2 (RAMP2). Two β-arrestin (β-arr) isoforms, β-arr-1 and β-arr-2, play a central role in the agonist-induced internalization of many receptors for receptor resensitization. Notably, β-arr-biased agonists are now being tested in phase II clinical trials, targeting acute pain and acute heart failure. Here, we examined the effects of β-arr-1 and β-arr-2 on human AM 1 receptor internalization. We constructed a V5-tagged chimera in which the cytoplasmic C-terminal tail (C-tail) of CLR was replaced with that of the β 2 -adrenergic receptor (β 2 -AR), and it was transiently transfected into HEK-293 cells that stably expressed RAMP2. The cell-surface expression and internalization of the wild-type or chimeric receptor were quantified by flow cytometric analysis. The [ 125 I]AM binding and the AM-induced cAMP production of these receptors were also determined. Surprisingly, the coexpression of β-arr-1 or -2 resulted in significant decreases in AM 1 receptor internalization without affecting AM binding and signaling prior to receptor internalization. Dominant-negative (DN) β-arr-1 or -2 also significantly decreased AM-induced AM 1 receptor internalization. In contrast, the AM-induced internalization of the chimeric AM 1 receptor was markedly augmented by the cotransfection of β-arr-1 or -2 and significantly reduced by the coexpression of DN-β-arr-1 or -2. These results were consistent with those seen for β 2 -AR. Thus, both β-arrs negatively control AM 1 receptor internalization, which depends on the C-tail of CLR. Copyright © 2017 Elsevier Inc. 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

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

Osmosensation in TRPV2 dominant negative expressing skeletal muscle fibres.

PubMed

Zanou, Nadège; Mondin, Ludivine; Fuster, Clarisse; Seghers, François; Dufour, Inès; de Clippele, Marie; Schakman, Olivier; Tajeddine, Nicolas; Iwata, Yuko; Wakabayashi, Shigeo; Voets, Thomas; Allard, Bruno; Gailly, Philippe

2015-09-01

Increased plasma osmolarity induces intracellular water depletion and cell shrinkage (CS) followed by activation of a regulatory volume increase (RVI). In skeletal muscle, the hyperosmotic shock-induced CS is accompanied by a small membrane depolarization responsible for a release of Ca(2+) from intracellular pools. Hyperosmotic shock also induces phosphorylation of STE20/SPS1-related proline/alanine-rich kinase (SPAK). TRPV2 dominant negative expressing fibres challenged with hyperosmotic shock present a slower membrane depolarization, a diminished Ca(2+) response, a smaller RVI response, a decrease in SPAK phosphorylation and defective muscle function. We suggest that hyperosmotic shock induces TRPV2 activation, which accelerates muscle cell depolarization and allows the subsequent Ca(2+) release from the sarcoplasmic reticulum, activation of the Na(+) -K(+) -Cl(-) cotransporter by SPAK, and the RVI response. Increased plasma osmolarity induces intracellular water depletion and cell shrinkage followed by activation of a regulatory volume increase (RVI). In skeletal muscle, this is accompanied by transverse tubule (TT) dilatation and by a membrane depolarization responsible for a release of Ca(2+) from intracellular pools. We observed that both hyperosmotic shock-induced Ca(2+) transients and RVI were inhibited by Gd(3+) , ruthenium red and GsMTx4 toxin, three inhibitors of mechanosensitive ion channels. The response was also completely absent in muscle fibres overexpressing a non-permeant, dominant negative (DN) mutant of the transient receptor potential, V2 isoform (TRPV2) ion channel, suggesting the involvement of TRPV2 or of a TRP isoform susceptible to heterotetramerization with TRPV2. The release of Ca(2+) induced by hyperosmotic shock was increased by cannabidiol, an activator of TRPV2, and decreased by tranilast, an inhibitor of TRPV2, suggesting a role for the TRPV2 channel itself. Hyperosmotic shock-induced membrane depolarization was impaired in TRPV2-DN fibres, suggesting that TRPV2 activation triggers the release of Ca(2+) from the sarcoplasmic reticulum by depolarizing TTs. RVI requires the sequential activation of STE20/SPS1-related proline/alanine-rich kinase (SPAK) and NKCC1, a Na(+) -K(+) -Cl(-) cotransporter, allowing ion entry and driving osmotic water flow. In fibres overexpressing TRPV2-DN as well as in fibres in which Ca(2+) transients were abolished by the Ca(2+) chelator BAPTA, the level of P-SPAK(Ser373) in response to hyperosmotic shock was reduced, suggesting a modulation of SPAK phosphorylation by intracellular Ca(2+) . We conclude that TRPV2 is involved in osmosensation in skeletal muscle fibres, acting in concert with P-SPAK-activated NKCC1. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

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.

Properties and Applications of Lossy Metamaterials

DTIC Science & Technology

2011-12-01

Ring ENG Epsilon-Negative MNG Mu-Negative SNG Single-Negative NRI Negative Refractive Index FIT Finite Integration Technique xiv THIS PAGE...r r r rB ε µ ε µ′ ′′ ′′ ′= + parameters. A classification of double positive (DPS), double negative (DNG) and single negative ( SNG ) materials with...negative, and when 0B > the phase constant and the refractive index are both positive. The parameter A is negative in SNG materials but can be positive or

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.

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.

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

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.

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

Cell Attachment to the Extracellular Matrix Induces Proteasomal Degradation of p21CIP1 via Cdc42/Rac1 Signaling

PubMed Central

Bao, Wenjie; Thullberg, Minna; Zhang, Hongquan; Onischenko, Anatoli; Strömblad, Staffan

2002-01-01

The cyclin-dependent kinase 2 (Cdk2) inhibitors p21CIP1 and p27KIP1 are negatively regulated by anchorage during cell proliferation, but it is unclear how integrin signaling may affect these Cdk2 inhibitors. Here, we demonstrate that integrin ligation led to rapid reduction of p21CIP1 and p27KIP1 protein levels in three distinct cell types upon attachment to various extracellular matrix (ECM) proteins, including fibronectin (FN), or to immobilized agonistic anti-integrin monoclonal antibodies. Cell attachment to FN did not rapidly influence p21CIP1 mRNA levels, while the protein stability of p21CIP1 was decreased. Importantly, the down-regulation of p21CIP1 and p27KIP1 was completely blocked by three distinct proteasome inhibitors, demonstrating that integrin ligation induced proteasomal degradation of these Cdk2 inhibitors. Interestingly, ECM-induced proteasomal proteolysis of a ubiquitination-deficient p21CIP1 mutant (p21K6R) also occurred, showing that the proteasomal degradation of p21CIP1 was ubiquitin independent. Concomitant with our finding that the small GTPases Cdc42 and Rac1 were activated by attachment to FN, constitutively active (ca) Cdc42 and ca Rac1 promoted down-regulation of p21CIP1. However, dominant negative (dn) Cdc42 and dn Rac1 mutants blocked the anchorage-induced degradation of p21CIP1, suggesting that an integrin-induced Cdc42/Rac1 signaling pathway activates proteasomal degradation of p21CIP1. Our results indicate that integrin-regulated proteasomal proteolysis might contribute to anchorage-dependent cell cycle control. PMID:12052868

Unsteady laminar flow with convective heat transfer through a rotating curved square duct with small curvature

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

Mondal, Rabindra Nath, E-mail: rnmondal71@yahoo.com; Shaha, Poly Rani; Roy, Titob

Unsteady laminar flow with convective heat transfer through a curved square duct rotating at a constant angular velocity about the center of curvature is investigated numerically by using a spectral method, and covering a wide range of the Taylor number −300≤Tr≤1000 for the Dean number Dn = 1000. A temperature difference is applied across the vertical sidewalls for the Grashof number Gr = 100, where the outer wall is heated and the inner wall cooled, the top and bottom walls being adiabatic. Flow characteristics are investigated with the effects of rotational parameter, Tr, and the pressure-driven parameter, Dn, for themore » constant curvature 0.001. Time evolution calculations as well as their phase spaces show that the unsteady flow undergoes through various flow instabilities in the scenario ‘multi-periodic → chaotic → steady-state → periodic → multi-periodic → chaotic’, if Tr is increased in the positive direction. For negative rotation, however, time evolution calculations show that the flow undergoes in the scenario ‘multi-periodic → periodic → steady-state’, if Tr is increased in the negative direction. Typical contours of secondary flow patterns and temperature profiles are obtained at several values of Tr, and it is found that the unsteady flow consists of two- to six-vortex solutions if the duct rotation is involved. External heating is shown to generate a significant temperature gradient at the outer wall of the duct. This study also shows that there is a strong interaction between the heating-induced buoyancy force and the centrifugal-Coriolis instability in the curved channel that stimulates fluid mixing and consequently enhances heat transfer in the fluid.« less

Endogenous interleukin-22 protects against inflammatory bowel disease but not autoimmune cholangitis in dominant negative form of transforming growth factor beta receptor type II mice.

PubMed

Yang, G-X; Sun, Y; Tsuneyama, K; Zhang, W; Leung, P S C; He, X-S; Ansari, A A; Bowlus, C; Ridgway, W M; Gershwin, M E

2016-08-01

During chronic inflammation, interleukin (IL)-22 expression is up-regulated in both CD4 and CD8 T cells, exerting a protective role in infections. However, in autoimmunity, IL-22 appears to have either a protective or a pathogenic role in a variety of murine models of autoimmunity and, by extrapolation, in humans. It is not clear whether IL-22 itself mediates inflammation or is a by-product of inflammation. We have taken advantage of the dominant negative form of transforming growth factor beta receptor type II (dnTGF-βRII) mice that develop both inflammatory bowel disease and autoimmune cholangitis and studied the role and the biological function of IL-22 by generating IL-22(-/-) dnTGF-βRII mice. Our data suggest that the influence of IL-22 on autoimmunity is determined in part by the local microenvironment. In particular, IL-22 deficiency exacerbates tissue injury in inflammatory bowel disease, but has no influence on either the hepatocytes or cholangiocytes in the same model. These data take on particular significance in the previously defined effects of IL-17A, IL-12p40 and IL-23p19 deficiency and emphasize that, in colitis, there is a dominant role of IL-23/T helper type 17 (Th17) signalling. Furthermore, the levels of IL-22 are IL-23-dependent. The use of cytokine therapy in patients with autoimmune disease has significant potential, but must take into account the overlapping and often promiscuous effects that can theoretically exacerbate inflammation. © 2016 British Society for Immunology.

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

Activins and inhibins: Novel regulators of thymocyte development

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

Licona-Limon, Paula; Aleman-Muench, German; Chimal-Monroy, Jesus

2009-04-03

Activins and inhibins are members of the transforming growth factor-{beta} superfamily that act on different cell types and regulate a broad range of cellular processes including proliferation, differentiation, and apoptosis. Here, we provide the first evidence that activins and inhibins regulate specific checkpoints during thymocyte development. We demonstrate that both activin A and inhibin A promote the DN3-DN4 transition in vitro, although they differentially control the transition to the DP stage. Whereas activin A induces the accumulation of a CD8{sup +}CD24{sup hi}TCR{beta}{sup lo} intermediate subpopulation, inhibin A promotes the differentiation of DN4 to DP. In addition, both activin A andmore » inhibin A appear to promote CD8{sup +}SP differentiation. Moreover, inhibin {alpha} null mice have delayed in vitro T cell development, showing both a decrease in the DN-DP transition and reduced thymocyte numbers, further supporting a role for inhibins in the control of developmental signals taking place during T cell differentiation in vivo.« less

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.

Coactosin accelerates cell dynamism by promoting actin polymerization.

PubMed

Hou, Xubin; Katahira, Tatsuya; Ohashi, Kazumasa; Mizuno, Kensaku; Sugiyama, Sayaka; Nakamura, Harukazu

2013-07-01

During development, cells dynamically move or extend their processes, which are achieved by actin dynamics. In the present study, we paid attention to Coactosin, an actin binding protein, and studied its role in actin dynamics. Coactosin was associated with actin and Capping protein in neural crest cells and N1E-115 neuroblastoma cells. Accumulation of Coactosin to cellular processes and its association with actin filaments prompted us to reveal the effect of Coactosin on cell migration. Coactosin overexpression induced cellular processes in cultured neural crest cells. In contrast, knock-down of Coactosin resulted in disruption of actin polymerization and of neural crest cell migration. Importantly, Coactosin was recruited to lamellipodia and filopodia in response to Rac signaling, and mutated Coactosin that cannot bind to F-actin did not react to Rac signaling, nor support neural crest cell migration. It was also shown that deprivation of Rac signaling from neural crest cells by dominant negative Rac1 (DN-Rac1) interfered with neural crest cell migration, and that co-transfection of DN-Rac1 and Coactosin restored neural crest cell migration. From these results we have concluded that Coactosin functions downstream of Rac signaling and that it is involved in neurite extension and neural crest cell migration by actively participating in actin polymerization. Copyright © 2013 Elsevier Inc. All rights reserved.

Increased functional connectivity within memory networks following memory rehabilitation in multiple sclerosis.

PubMed

Leavitt, Victoria M; Wylie, Glenn R; Girgis, Peter A; DeLuca, John; Chiaravalloti, Nancy D

2014-09-01

Identifying effective behavioral treatments to improve memory in persons with learning and memory impairment is a primary goal for neurorehabilitation researchers. Memory deficits are the most common cognitive symptom in multiple sclerosis (MS), and hold negative professional and personal consequences for people who are often in the prime of their lives when diagnosed. A 10-session behavioral treatment, the modified Story Memory Technique (mSMT), was studied in a randomized, placebo-controlled clinical trial. Behavioral improvements and increased fMRI activation were shown after treatment. Here, connectivity within the neural networks underlying memory function was examined with resting-state functional connectivity (RSFC) in a subset of participants from the clinical trial. We hypothesized that the treatment would result in increased integrity of connections within two primary memory networks of the brain, the hippocampal memory network, and the default network (DN). Seeds were placed in left and right hippocampus, and the posterior cingulate cortex. Increased connectivity was found between left hippocampus and cortical regions specifically involved in memory for visual imagery, as well as among critical hubs of the DN. These results represent the first evidence for efficacy of a behavioral intervention to impact the integrity of neural networks subserving memory functions in persons with MS.

PDK1-dependent activation of atypical PKC leads to degradation of the p21 tumour modifier protein

PubMed Central

Scott, Mary T.; Ingram, Angela; Ball, Kathryn L.

2002-01-01

p21WAF1/CIP1 contributes to positive and negative growth control on multiple levels. We previously mapped phosphorylation sites within the C-terminal domain of p21 that regulate proliferating cell nucear antigen binding. In the current study, a kinase has been fractionated from mammalian cells that stoichiometrically phosphorylates p21 at the Ser146 site, and the enzyme has been identified as an insulin-responsive atypical protein kinase C (aPKC). Expression of PKCζ or activation of the endogenous kinase by 3-phosphoinositide dependent protein kinase-1 (PDK1) decreased the half-life of p21. Conversely, dnPKCζ or dnPDK1 increased p21 protein half-life, and a PDK1-dependent increase in the rate of p21 degradation was mediated by aPKC. Insulin stimulation gave a biphasic response with a rapid transient decrease in p21 protein levels during the initial signalling phase that was dependent on phosphatidylinositol 3- kinase, PKC and proteasome activity. Thus, aPKC provides a physiological signal for the degradation of p21. The rapid degradation of p21 protein during the signalling phase of insulin stimulation identifies a novel link between energy metabolism and a key modulator of cell cycle progression. PMID:12485998

Regulation of HTLV-1 Gag budding by Vps4A, Vps4B, and AIP1/Alix

PubMed Central

Urata, Shuzo; Yokosawa, Hideyoshi; Yasuda, Jiro

2007-01-01

Background HTLV-1 Gag protein is a matrix protein that contains the PTAP and PPPY sequences as L-domain motifs and which can be released from mammalian cells in the form of virus-like particles (VLPs). The cellular factors Tsg101 and Nedd4.1 interact with PTAP and PPPY, respectively, within the HTLV-1 Gag polyprotein. Tsg101 forms a complex with Vps28 and Vps37 (ESCRT-I complex) and plays an important role in the class E Vps pathway, which mediates protein sorting and invagination of vesicles into multivesicular bodies. Nedd4.1 is an E3 ubiquitin ligase that binds to the PPPY motif through its WW motif, but its function is still unknown. In the present study, to investigate the mechanism of HTLV-1 budding in detail, we analyzed HTLV-1 budding using dominant negative (DN) forms of the class E proteins. Results Here, we report that DN forms of Vps4A, Vps4B, and AIP1 inhibit HTLV-1 budding. Conclusion These findings suggest that HTLV-1 budding utilizes the MVB pathway and that these class E proteins may be targets for prevention of mother-to-infant vertical transmission of the virus. PMID:17601348

Reduced endothelin converting enzyme-1 and endothelin-3 mRNA in the developing bowel of male mice may increase expressivity and penetrance of Hirschsprung disease-like distal intestinal aganglionosis.

PubMed

Vohra, Bhupinder P S; Planer, William; Armon, Jennifer; Fu, Ming; Jain, Sanjay; Heuckeroth, Robert O

2007-01-01

Hirschsprung disease (distal intestinal aganglionosis, HSCR) is a multigenic disorder with incomplete penetrance, variable expressivity, and a strong male gender bias. Recent studies demonstrated that these genetic patterns arise because gene interactions determine whether enteric nervous system (ENS) precursors successfully proliferate and migrate into the distal bowel. We now demonstrate that male gender bias in the extent of distal intestinal aganglionosis occurs in mice with Ret dominant-negative mutations (RetDN) that mimic human HSCR. We hypothesized that male gender bias could result from reduced expression of a gene already known to be essential for ENS development. Using quantitative real-time polymerase chain reaction (PCR) we demonstrated reduced levels of endothelin converting enzyme-1 and endothelin-3 mRNA in the male mouse bowel at the time that ENS precursors migrate into the colon. Other HSCR-associated genes are expressed at comparable levels in male and female mice. Testosterone and Mullerian inhibiting substance had no deleterious effect on ENS precursor development, but adding EDN3 peptide to E11.5 male RetDN heterozygous mouse gut explants in organ culture significantly increased the rate of ENS precursor migration through the bowel.

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.

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.

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

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.

PI3K/Akt is involved in brown adipogenesis mediated by growth differentiation factor-5 in association with activation of the Smad pathway

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

Hinoi, Eiichi; Iezaki, Takashi; Fujita, Hiroyuki

2014-07-18

Highlights: • Akt is preferentially phosphorylated in BAT and sWAT of aP2-GDF5 mice. • PI3K/Akt signaling is involved in GDF5-induced brown adipogenesis. • PI3K/Akt signaling regulates GDF5-induced Smad5 phosphorylation. - Abstract: We have previously demonstrated promotion by growth differentiation factor-5 (GDF5) of brown adipogenesis for systemic energy expenditure through a mechanism relevant to activating the bone morphological protein (BMP) receptor/mothers against decapentaplegic homolog (Smad)/peroxisome proliferator-activated receptor gamma co-activator 1α (PGC-1α) pathway. Here, we show the involvement of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in brown adipogenesis mediated by GDF5. Overexpression of GDF5 in cells expressing adipocyte protein-2 markedly accelerated the phosphorylationmore » of Smad1/5/8 and Akt in white and brown adipose tissues. In brown adipose tissue from heterozygous GDF5{sup Rgsc451} mutant mice expressing a dominant-negative (DN) GDF5 under obesogenic conditions, the basal phosphorylation of Smad1/5/8 and Akt was significantly attenuated. Exposure to GDF5 not only promoted the phosphorylation of both Smad1/5/8 and Akt in cultured brown pre-adipocytes, but also up-regulated Pgc1a and uncoupling protein-1 expression in a manner sensitive to the PI3K/Akt inhibitor Ly294002 as well as retroviral infection with DN-Akt. GDF5 drastically promoted BMP-responsive luciferase reporter activity in a Ly294002-sensitive fashion. Both Ly294002 and DN-Akt markedly inhibited phosphorylation of Smad5 in the nuclei of brown pre-adipocytes. These results suggest that PI3K/Akt signals play a role in the GDF5-mediated brown adipogenesis through a mechanism related to activation of the Smad pathway.« less

GPER activates Notch signaling in breast cancer cells and cancer-associated fibroblasts (CAFs).

PubMed

Pupo, Marco; Pisano, Assunta; Abonante, Sergio; Maggiolini, Marcello; Musti, Anna Maria

2014-01-01

The G protein-coupled receptor GPR30/GPER has been shown to mediate rapid effects of 17β-estradiol (E2) in diverse types of cancer cells. Here, we provide evidence for a novel crosstalk between GPER and the Notch signaling pathway in breast cancer cells and cancer-associated fibroblasts (CAFs). We show that E2 and the GPER selective ligand G-1 induce both the γ-secretase-dependent activation of Notch-1 and the expression of the Notch target gene Hes-1. These inductions are prevented by knocking down GPER or by using a dominant-negative mutant of the Notch transcriptional co-activator Master-mind like-1 (DN-MAML-1), hence suggesting the involvement of GPER in the Notch-dependent transcription. By performing chromatin-immunoprecipitation experiments and luciferase assays, we also demonstrate that E2 and G-1 induce the recruitment of the intracellular domain of Notch-1 (N1ICD) to the Hes-1 promoter and the transactivation of a Hes-1-reporter gene, respectively. Functionally, the E2 and G-1-induced migration of breast cancer cells and CAFs is abolished in presence of the γ-secretase inhibitor GSI or DN-MAML-1, which both inhibit the Notch signaling pathway. In addition, we demonstrate that E2 and G-1 prevent the expression of VE-Cadherin, while both compounds induce the expression of Snail, a Notch target gene acting as a repressor of cadherins expression. Notably, both GSI and DN-MAML-1 abolish the up-regulation of Snail-1 by E2 and G-1, whereas the use of GSI rescues VE-Cadherin expression. Taken together, our results prove the involvement of the Notch signaling pathway in mediating the effects of estrogenic GPER signaling in breast cancer cells and CAFs. Copyright © 2013 Elsevier Ltd. All rights reserved.

Therapeutic targeting of oxidative stress with coenzyme Q10 counteracts exaggerated diabetic cardiomyopathy in a mouse model of diabetes with diminished PI3K(p110α) signaling.

PubMed

De Blasio, Miles J; Huynh, Karina; Qin, Chengxue; Rosli, Sarah; Kiriazis, Helen; Ayer, Anita; Cemerlang, Nelly; Stocker, Roland; Du, Xiao-Jun; McMullen, Julie R; Ritchie, Rebecca H

2015-10-01

Diabetes-induced cardiac complications include left ventricular (LV) dysfunction and heart failure. We previously demonstrated that LV phosphoinositide 3-kinase p110α (PI3K) protects the heart against diabetic cardiomyopathy, associated with reduced NADPH oxidase expression and activity. Conversely, in dominant negative PI3K(p110α) transgenic mice (dnPI3K), reduced cardiac PI3K signaling exaggerated diabetes-induced cardiomyopathy, associated with upregulated NADPH oxidase. The goal was to examine whether chronic supplementation with the antioxidant coenzyme Q(10) (CoQ(10)) could attenuate LV superoxide and diabetic cardiomyopathy in a setting of impaired PI3K signaling. Diabetes was induced in 6-week-old nontransgenic and dnPI3K male mice via streptozotocin. After 4 weeks of diabetes, CoQ(10) supplementation commenced (10 mg/kg ip, 3 times/week, 8 weeks). At study end (12 weeks of diabetes), markers of LV function, cardiomyocyte hypertrophy, collagen deposition, NADPH oxidase, oxidative stress (3-nitrotyrosine), and concentrations of CoQ(9) and CoQ(10) were determined. LV NADPH oxidase (Nox2 gene expression and activity, and lucigenin-enhanced chemiluminescence), as well as oxidative stress, were increased by diabetes, exaggerated in diabetic dnPI3K mice, and attenuated by CoQ(10). Diabetes-induced LV diastolic dysfunction (prolonged deceleration time, elevated end-diastolic pressure, impaired E/A ratio), cardiomyocyte hypertrophy and fibrosis, expression of atrial natriuretic peptide, connective tissue growth factor, and β-myosin heavy chain were all attenuated by CoQ(10). Chronic CoQ(10) supplementation attenuates aspects of diabetic cardiomyopathy, even in a setting of reduced cardiac PI3K protective signaling. Given that CoQ(10) supplementation has been suggested to have positive outcomes in heart failure patients, chronic CoQ(10) supplementation may be an attractive adjunct therapy for diabetic heart failure. Copyright © 2015 Elsevier Inc. All rights reserved.

Influence of LTB4 on CD4-, CD8- thymocytes. Evidence that LTB4 plus IL-2 generate CD8+ suppressor thymocytes involved in tolerance to self. Effect of LTB4 and IL-2 on double negative thymocytes.

PubMed

Gualde, N; Cogny van Weydevelt, F; Buffière, F; Jauberteau, M O; Daculsi, R; Vaillier, D

1991-09-01

Leukotriene B4 (LTB4) is produced by a large variety of cells involved in immune response and it has been demonstrated that this arachidonic acid metabolite acts as an immunomodulator. Because LTB4 and IL-2 both influence the physiology of immature cells we studied the effects of the leukotriene on double negative thymocytes. For that purpose C57 Bl/6 double negative thymocytes were treated by LTB4 plus IL-2 in the presence of either autologous or allogenic red blood cells (RBC). Then, preincubated CD4- CD8- thymocytes were cocultured with red blood cells stimulated fresh splenocytes. We observed that fresh splenocytes responding to autologous RBC were CD4+ cells and that the proliferative response of spleen lymphocytes driven by RBC was inhibited by preincubated double negative thymocytes. On the other hand a majority of double negative thymocytes overnight preincubated in vitro in the presence of both IL-2 and LTB4 give rise to CD8+ CD4- cells. Therefore we speculate that LTB4 plus IL-2 generate CD8+ suppressor thymocytes among double negative thymocytes and that these suppressive T cells are involved in tolerance to self.

Overexpression of p35 in Min6 pancreatic beta cells induces a stressed neuron-like apoptosis.

PubMed

Zheng, Ya-Li; Hu, Ya-Fang; Zhang, Aiping; Wang, Wei; Li, Bo; Amin, Niranjana; Grant, Philip; Pant, Harish C

2010-12-15

Cdk5 activity has been implicated in brain development and the regulation of many neuronal processes. Recently, the expression of p35 and Cdk5 activity has been reported in pancreatic beta cells. Decreased Cdk5 activity enhanced glucose-stimulated insulin secretion. This suggests that Cdk5 may play an important role in the regulation of insulin secretion. To further understand how Cdk5 regulates insulin secretion in glucose-stimulated pancreatic β cells, we first confirmed the presence of a low level of p35 in pancreatic Min6 cells. Next, in a time-course experiment in high glucose (25 mM) we showed that endogenous p35 increased gradually accompanied by a 3-fold increase in Cdk5 activity by 16 h. Insulin secretion, however, doubled after 2 h followed by progressive downregulation, negatively correlated with Cdk5 activity. On the other hand, overexpression of p35 in these cells resulted in more than a three-fold increase in Cdk5 activity within 2 h coupled to a 50% reduction in insulin secretion in both high and low (3 mM) glucose. Most significantly, cells overexpressing p35, treated with high glucose for 4 h, showed induction of p25, the p35-derived truncated fragment which hyperactivates Cdk5 in neurons. As a result, insulin secretion was inhibited and cells became apoptotic. Roscovitine or co-infection of dominant negative Cdk5 (dnCdk5) with p35 increased insulin secretion and inhibited apoptosis. These results suggest that the model for deregulation and hyperactivation of Cdk5 in neurodegeneration may apply to the pathology seen in type 2 diabetes (T2DM). It is consistent with the view that Alzheimer's disease and T2DM are linked metabolically and pathologically by Cdk5 in a number of ways. Copyright © 2010. Published by Elsevier B.V.

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

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.

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.

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

Chromatin remodeling enzyme Brg1 is required for mouse lens fiber cell terminal differentiation and its denucleation

PubMed Central

2010-01-01

Background Brahma-related gene 1 (Brg1, also known as Smarca4 and Snf2β) encodes an adenosine-5'-triphosphate (ATP)-dependent catalytical subunit of the (switch/sucrose nonfermentable) (SWI/SNF) chromatin remodeling complexes. SWI/SNF complexes are recruited to chromatin through multiple mechanisms, including specific DNA-binding factors (for example, heat shock transcription factor 4 (Hsf4) and paired box gene 6 (Pax6)), chromatin structural proteins (for example, high-mobility group A1 (HMGA1)) and/or acetylated core histones. Previous studies have shown that a single amino acid substitution (K798R) in the Brg1 ATPase domain acts via a dominant-negative (dn) mechanism. Genetic studies have demonstrated that Brg1 is an essential gene for early (that is, prior implantation) mouse embryonic development. Brg1 also controls neural stem cell maintenance, terminal differentiation of multiple cell lineages and organs including the T-cells, glial cells and limbs. Results To examine the roles of Brg1 in mouse lens development, a dnBrg1 transgenic construct was expressed using the lens-specific αA-crystallin promoter in postmitotic lens fiber cells. Morphological studies revealed abnormal lens fiber cell differentiation in transgenic lenses resulting in cataract. Electron microscopic studies showed abnormal lens suture formation and incomplete karyolysis (that is, denucleation) of lens fiber cells. To identify genes regulated by Brg1, RNA expression profiling was performed in embryonic day 15.5 (E15.5) wild-type and dnBrg1 transgenic lenses. In addition, comparisons between differentially expressed genes in dnBrg1 transgenic, Pax6 heterozygous and Hsf4 homozygous lenses identified multiple genes coregulated by Brg1, Hsf4 and Pax6. DNase IIβ, a key enzyme required for lens fiber cell denucleation, was found to be downregulated in each of the Pax6, Brg1 and Hsf4 model systems. Lens-specific deletion of Brg1 using conditional gene targeting demonstrated that Brg1 was required for lens fiber cell differentiation, for expression of DNase IIβ, for lens fiber cell denucleation and indirectly for retinal development. Conclusions These studies demonstrate a cell-autonomous role for Brg1 in lens fiber cell terminal differentiation and identified DNase IIβ as a potential direct target of SWI/SNF complexes. Brg1 is directly or indirectly involved in processes that degrade lens fiber cell chromatin. The presence of nuclei and other organelles generates scattered light incompatible with the optical requirements for the lens. PMID:21118511

Bilayer synergetic coupling double negative acoustic metasurface and cloak.

PubMed

Ma, Fuyin; Huang, Meng; Xu, Yicai; Wu, Jiu Hui

2018-04-12

In this paper, we propose a bilayer plate-type lightweight double negative metasurface based on a new synergetic coupling design concept, by which the perfect absorption, double negative bands, free manipulation of phase shifts with a 2π span and acoustic cloak can be successively realized. Firstly, the synergetic behavior between resonant and anti-resonant plates is presented to construct a bilayer unit in which each component respectively provides a pre-defined function in realizing the perfect absorption. Based on this bilayer structure, a double negative band with simultaneously negative effective mass density and bulk modulus is obtained, which, as a metasurface, can obtain continuous phase shifts almost completely covering a 2π range, thus facilitating the design of a three-dimensional (3D) acoustic cloak. In addition, based on this strong sound absorption concept, a two-dimensional (2D) omnidirectional broadband acoustical dark skin, covering between 800 to 6000 Hz, is also demonstrated through the proposed bilayer plate-type structure form. The proposed design concepts and metasurfaces have widespread potential application values in strong sound attenuation, filtering, superlens, imaging, cloak, and extraordinary wave steering, in which the attributes of strong absorption, double negative parameters or continuous phase shifts with full 2π span are required to realize the expected extraordinary physical features.

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.

Metallothionein plays a prominent role in the prevention of diabetic nephropathy by sulforaphane via up-regulation of Nrf2

PubMed Central

Wu, Hao; Kong, Lili; Cheng, Yanli; Zhang, Zhiguo; Wang, Yangwei; Lou, Manyu; Tan, Yi; Chen, Xiangmei; Miao, Lining; Cai, Lu

2015-01-01

Sulforaphane (SFN) prevents diabetic nephropathy (DN) in type 1 diabetes via up-regulation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2). However, it has not been addressed whether SFN also prevents DN from type 2 diabetes or which Nrf2 downstream gene(s) play(s) the key role in SFN renal protection. Here we investigated whether Nrf2 is required for SFN protection against type 2 diabetes-induced DN and whether metallothionein (MT) is an Nrf2 downstream antioxidant using Nrf2 knockout (Nrf2-null) mice. In addition, MT knockout mice were used to further verify if MT is indispensable for SFN protection against DN. Diabetes-increased albuminuria, renal fibrosis, and inflammation were significantly prevented by SFN, and Nrf2 and MT expression was increased. However, SFN renal protection was completely lost in Nrf2-null diabetic mice, confirming the pivotal role of Nrf2 in SFN protection from type 2 diabetes-induced DN. Moreover, SFN failed to up-regulate MT in the absence of Nrf2, suggesting that MT is an Nrf2 downstream antioxidant. MT deletion resulted in a partial, but significant attenuation of SFN renal protection from type 2 diabetes, demonstrating a partial requirement for MT for SFN renal protection. Therefore, the present study demonstrates for the first time that as an Nrf2 downstream antioxidant, MT plays an important, though partial, role in mediating SFN renal protection from type 2 diabetes. PMID:26415026

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

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.

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.

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.

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

A Novel Mechanism for the Pathogenesis of Nonmelanoma Skin Cancer Resulting from Early Exposure to Ultraviolet Light

DTIC Science & Technology

2014-09-01

hybrid mice show a large population of cells that fluoresce with Tomato Red and few cells that fluoresce with GFP only or GFP/ Tomato Red double positive...percent of total cells Double Negative GFP Tomato Red Double Positive 15 Figure 3. Fluorescent activated cell sorting (FACS) shows slight...Negative Tomato Red Double Positive 17 Figure 5. Fluorescent activated cell sorting (FACS) shows no K14-GFP expressing cells and slight expression of

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)−

A tunable acoustic metamaterial with double-negativity driven by electromagnets

PubMed Central

Chen, Zhe; Xue, Cheng; Fan, Li; Zhang, Shu-yi; Li, Xiao-juan; Zhang, Hui; Ding, Jin

2016-01-01

With the advance of the research on acoustic metamaterials, the limits of passive metamaterials have been observed, which prompts the studies concerning actively tunable metamaterials with adjustable characteristic frequency bands. In this work, we present a tunable acoustic metamaterial with double-negativity composed of periodical membranes and side holes, in which the double-negativity pass band can be controlled by an external direct-current voltage. The tension and stiffness of the periodically arranged membranes are actively controlled by electromagnets producing additional stresses, and thus, the transmission and phase velocity of the metamaterial can be adjusted by the driving voltage of the electromagnets. It is demonstrated that a tiny direct-current voltage of 6V can arise a shift of double-negativity pass band by 40% bandwidth, which exhibits that it is an easily controlled and highly tunable acoustic metamaterial, and furthermore, the metamaterial marginally causes electromagnetic interference to the surroundings. PMID:27443196

c-Myc-Induced Survivin Is Essential for Promoting the Notch-Dependent T Cell Differentiation from Hematopoietic Stem Cells

PubMed Central

Haque, Rizwanul; Song, Jianyong; Haque, Mohammad; Lei, Fengyang; Sandhu, Praneet; Ni, Bing; Zheng, Songguo; Fang, Deyu; Yang, Jin-Ming; Song, Jianxun

2017-01-01

Notch is indispensable for T cell lineage commitment, and is needed for thymocyte differentiation at early phases. During early stages of T cell development, active Notch prevents other lineage potentials including B cell lineage and myeloid cell (e.g., dendritic cell) lineage. Nevertheless, the precise intracellular signaling pathways by which Notch promotes T cell differentiation remain unclear. Here we report that the transcription factor c-Myc is a key mediator of the Notch signaling–regulated T cell differentiation. In a well-established in vitro differentiation model of T lymphocytes from hematopoietic stem cells, we showed that Notch1 and 4 directly promoted c-Myc expression; dominant-negative (DN) c-Myc inhibited early T cell differentiation. Moreover, the c-Myc expression activated by Notch signaling increased the expression of survivin, an inhibitor of apoptosis (IAP) protein. We further demonstrated that over-expression of c-Myc increased the abundance of survivin and the T cell differentiation thereof, whereas dn c-Myc reduced survivin levels and concomitantly retarded the differentiation. The c-Myc–dependent survivin induction is functionally germane, because Notch-dependent T cell differentiation was canceled by the depletion of survivin. These results identify both c-Myc and survivin as important mediators of the Notch signaling–regulated differentiation of T lymphocytes from hematopoietic stem cells. PMID:28272325

Hippo Cascade Controls Lineage Commitment of Liver Tumors in Mice and Humans.

PubMed

Zhang, Shanshan; Wang, Jingxiao; Wang, Haichuan; Fan, Lingling; Fan, Biao; Zeng, Billy; Tao, Junyan; Li, Xiaolei; Che, Li; Cigliano, Antonio; Ribback, Silvia; Dombrowski, Frank; Chen, Bin; Cong, Wenming; Wei, Lixin; Calvisi, Diego F; Chen, Xin

2018-04-01

Primary liver cancer consists mainly of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). A subset of human HCCs expresses a ICC-like gene signature and is classified as ICC-like HCC. The Hippo pathway is a critical regulator of normal and malignant liver development. However, the precise function(s) of the Hippo cascade along liver carcinogenesis remain to be fully delineated. The role of the Hippo pathway in a murine mixed HCC/ICC model induced by activated forms of AKT and Ras oncogenes (AKT/Ras) was investigated. The authors demonstrated the inactivation of Hippo in AKT/Ras liver tumors leading to nuclear localization of Yap and TAZ. Coexpression of AKT/Ras with Lats2, which activates Hippo, or the dominant negative form of TEAD2 (dnTEAD2), which blocks Yap/TAZ activity, resulted in delayed hepatocarcinogenesis and elimination of ICC-like lesions in the liver. Mechanistically, Notch2 expression was found to be down-regulated by the Hippo pathway in liver tumors. Overexpression of Lats2 or dnTEAD2 in human HCC cell lines inhibited their growth and led to the decreased expression of ICC-like markers, as well as Notch2 expression. Altogether, this study supports the key role of the Hippo cascade in regulating the differentiation status of liver tumors. Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Modeling coexistence of oscillation and Delta/Notch-mediated lateral inhibition in pancreas development and neurogenesis.

PubMed

Tiedemann, Hendrik B; Schneltzer, Elida; Beckers, Johannes; Przemeck, Gerhard K H; Hrabě de Angelis, Martin

2017-10-07

During pancreas development, Neurog3 positive endocrine progenitors are specified by Delta/Notch (D/N) mediated lateral inhibition in the growing ducts. During neurogenesis, genes that determine the transition from the proneural state to neuronal or glial lineages are oscillating before their expression is sustained. Although the basic gene regulatory network is very similar, cycling gene expression in pancreatic development was not investigated yet, and previous simulations of lateral inhibition in pancreas development excluded by design the possibility of oscillations. To explore this possibility, we developed a dynamic model of a growing duct that results in an oscillatory phase before the determination of endocrine progenitors by lateral inhibition. The basic network (D/N + Hes1 + Neurog3) shows scattered, stable Neurog3 expression after displaying transient expression. Furthermore, we included the Hes1 negative feedback as previously discussed in neurogenesis and show the consequences for Neurog3 expression in pancreatic duct development. Interestingly, a weakened HES1 action on the Hes1 promoter allows the coexistence of stable patterning and oscillations. In conclusion, cycling gene expression and lateral inhibition are not mutually exclusive. In this way, we argue for a unified mode of D/N mediated lateral inhibition in neurogenic and pancreatic progenitor specification. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Targeted adenovirus mediated inhibition of NF-κB-dependent inflammatory gene expression in endothelial cells in vitro and in vivo.

PubMed

Kułdo, J M; Ásgeirsdóttir, S A; Zwiers, P J; Bellu, A R; Rots, M G; Schalk, J A C; Ogawara, K I; Trautwein, C; Banas, B; Haisma, H J; Molema, G; Kamps, J A A M

2013-02-28

In chronic inflammatory diseases the endothelium expresses mediators responsible for harmful leukocyte infiltration. We investigated whether targeted delivery of a therapeutic transgene that inhibits nuclear factor κB signal transduction could silence the proinflammatory activation status of endothelial cells. For this, an adenovirus encoding dominant-negative IκB (dnIκB) as a therapeutic transgene was employed. Selectivity for the endothelial cells was achieved by introduction of antibodies specific for inflammatory endothelial adhesion molecules E-selectin or VCAM-1 chemically linked to the virus via polyethylene glycol. In vitro, the retargeted adenoviruses selectively infected cytokine-activated endothelial cells to express functional transgene. The comparison of transductional capacity of both retargeted viruses revealed that E-selectin based transgene delivery exerted superior pharmacological effects. Targeted delivery mediated dnIκB transgene expression in endothelial cells inhibited the induced expression of several inflammatory genes, including adhesion molecules, cytokines, and chemokines. In vivo, in mice suffering from glomerulonephritis, E-selectin-retargeted adenovirus selectively homed in the kidney to microvascular glomerular endothelium. Subsequent downregulation of endothelial adhesion molecule expression 2 days after induction of inflammation demonstrated the pharmacological potential of this gene therapy approach. The data justify further studies towards therapeutic virus design and optimization of treatment schedules to investigate their capacity to interfere with inflammatory disease progression. Copyright © 2012 Elsevier B.V. All rights reserved.

SDSS-IV MaNGA: properties of galaxies with kinematically decoupled stellar and gaseous components

NASA Astrophysics Data System (ADS)

Jin, Yifei; Chen, Yanmei; Shi, Yong; Tremonti, C. A.; Bershady, M. A.; Merrifield, M.; Emsellem, E.; Fu, Hai; Wake, D.; Bundy, K.; Lin, Lihwai; Argudo-Fernandez, M.; Huang, Song; Stark, D. V.; Storchi-Bergmann, T.; Bizyaev, D.; Brownstein, J.; Chisholm, J.; Guo, Qi; Hao, Lei; Hu, Jian; Li, Cheng; Li, Ran; Masters, K. L.; Malanushenko, E.; Pan, Kaike; Riffel, R. A.; Roman-Lopes, A.; Simmons, A.; Thomas, D.; Wang, Lan; Westfall, K.; Yan, Renbin

2016-11-01

We study the properties of 66 galaxies with kinematically misaligned gas and stars from MaNGA survey. The fraction of kinematically misaligned galaxies varies with galaxy physical parameters, I.e. M*, SFR and sSFR. According to their sSFR, we further classify these 66 galaxies into three categories, 10 star-forming, 26 `Green Valley' and 30 quiescent ones. The properties of different types of kinematically misaligned galaxies are different in that the star-forming ones have positive gradient in Dn4000 and higher gas-phase metallicity, while the green valley/quiescent ones have negative Dn4000 gradients and lower gas-phase metallicity on average. There is evidence that all types of the kinematically misaligned galaxies tend to live in more isolated environment. Based on all these observational results, we propose a scenario for the formation of star-forming galaxies with kinematically misaligned gas and stars - the progenitor accretes misaligned gas from a gas-rich dwarf or cosmic web, the cancellation of angular momentum from gas-gas collisions between the pre-existing gas and the accreted gas largely accelerates gas inflow, leading to fast centrally concentrated star formation. The higher metallicity is due to enrichment from this star formation. For the kinematically misaligned green valley and quiescent galaxies, they might be formed through gas-poor progenitors accreting kinematically misaligned gas from satellites which are smaller in mass.

Double layer of platinum electrodes: Non-monotonic surface charging phenomena and negative double layer capacitance

NASA Astrophysics Data System (ADS)

Huang, Jun; Zhou, Tao; Zhang, Jianbo; Eikerling, Michael

2018-01-01

In this study, a refined double layer model of platinum electrodes accounting for chemisorbed oxygen species, oriented interfacial water molecules, and ion size effects in solution is presented. It results in a non-monotonic surface charging relation and a peculiar capacitance vs. potential curve with a maximum and possibly negative values in the potential regime of oxide-formation.

Nonlinear Modeling of Radial Stellar Pulsations

NASA Astrophysics Data System (ADS)

Smolec, R.

2009-09-01

In this thesis, I present the results of my work concerning the nonlinear modeling of radial stellar pulsations. I will focus on classical Cepheids, particularly on the double-mode phenomenon. History of nonlinear modeling of radial stellar pulsations begins in the sixties of the previous century. At the beginning convection was disregarded in model equations. Qualitatively, almost all features of the radial pulsators were successfully modeled with purely radiative hydrocodes. Among problems that remained, the most disturbing was modeling of the double-mode phenomenon. This long-standing problem seemed to be finally solved with the inclusion of turbulent convection into the model equations (Kollath et al. 1998, Feuchtinger 1998). Although dynamical aspects of the double-mode behaviour were extensively studied, its origin, particularly the specific role played by convection, remained obscure. To study this and other problems of radial stellar pulsations, I implemented the convection into pulsation hydrocodes. The codes adopt the Kuhfuss (1986) convection model. In other codes, particularly in the Florida-Budapest hydrocode (e.g. Kollath et al. 2002), used in comput! ation of most of the published double-mode models, different approximations concerning e.g. eddy-viscous terms or treatment of convectively stable regions are adopted. Particularly the neglect of negative buoyancy effects in the Florida-Budapest code and its consequences, were never discussed in the literature. These consequences are severe. Concerning the single-mode pulsators, neglect of negative buoyancy leads to smaller pulsation amplitudes, in comparison to amplitudes computed with code including these effects. Particularly, neglect of negative buoyancy reduces the amplitude of the fundamental mode very strong. This property of the Florida-Budapest models is crucial in bringing up the stable non-resonant double-mode Cepheid pulsation involving fundamental and first overtone modes (F/1O). Such pulsation is not observed in models computed including negative buoyancy. As the neglect of negative buoyancy is physically not correct, so are the double-mode Cepheid models computed with the Florida-Budapest hydrocode. Extensive search for F/1O double-mode Cepheid pulsation with the codes including negative buoyancy effects yielded null result. Some resonant double-mode F/1O Cepheid models were found, but their occurrence was restricted to a very narrow domain in the Hertzsprung-Russel diagram. Model computations intended to model the double-overtone (1O/2O) Cepheids in the Large Magellanic Cloud, also revealed some stable double-mode pulsations, however, restricted to a narrow period range. Resonances are most likely conductive in bringing up the double-mode behaviour observed in these models. However, majority of the double-overtone LMC Cepheids cannot be reproduced with our codes. Hence, the modeling of double-overtone Cepheids with convective hydrocodes is not satisfactory, either. Double-mode pulsation still lacks satisfactory explanation, and problem of its modeling remains open.

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

Metallothionein plays a prominent role in the prevention of diabetic nephropathy by sulforaphane via up-regulation of Nrf2.

PubMed

Wu, Hao; Kong, Lili; Cheng, Yanli; Zhang, Zhiguo; Wang, Yangwei; Luo, Manyu; Tan, Yi; Chen, Xiangmei; Miao, Lining; Cai, Lu

2015-12-01

Sulforaphane (SFN) prevents diabetic nephropathy (DN) in type 1 diabetes via up-regulation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2). However, it has not been addressed whether SFN also prevents DN from type 2 diabetes or which Nrf2 downstream gene(s) play(s) the key role in SFN renal protection. Here we investigated whether Nrf2 is required for SFN protection against type 2 diabetes-induced DN and whether metallothionein (MT) is an Nrf2 downstream antioxidant using Nrf2 knockout (Nrf2-null) mice. In addition, MT knockout mice were used to further verify if MT is indispensable for SFN protection against DN. Diabetes-increased albuminuria, renal fibrosis, and inflammation were significantly prevented by SFN, and Nrf2 and MT expression was increased. However, SFN renal protection was completely lost in Nrf2-null diabetic mice, confirming the pivotal role of Nrf2 in SFN protection from type 2 diabetes-induced DN. Moreover, SFN failed to up-regulate MT in the absence of Nrf2, suggesting that MT is an Nrf2 downstream antioxidant. MT deletion resulted in a partial, but significant attenuation of SFN renal protection from type 2 diabetes, demonstrating a partial requirement for MT for SFN renal protection. Therefore, the present study demonstrates for the first time that as an Nrf2 downstream antioxidant, MT plays an important, though partial, role in mediating SFN renal protection from type 2 diabetes. Copyright © 2015 Elsevier Inc. All rights reserved.

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