Vitamin D Binding Protein-Macrophage Activating Factor Directly Inhibits Proliferation, Migration, and uPAR Expression of Prostate Cancer Cells

PubMed Central

Bielenberg, Diane R.; Dridi, Sami; Wu, Jason; Jiang, Weihua; Huang, Bin; Pirie-Shepherd, Steven; Fannon, Michael

2010-01-01

Background Vitamin D binding protein-macrophage activating factor (DBP-maf) is a potent inhibitor of tumor growth. Its activity, however, has been attributed to indirect mechanisms such as boosting the immune response by activating macrophages and inhibiting the blood vessel growth necessary for the growth of tumors. Methods and Findings In this study we show for the first time that DBP-maf exhibits a direct and potent effect on prostate tumor cells in the absence of macrophages. DBP-maf demonstrated inhibitory activity in proliferation studies of both LNCaP and PC3 prostate cancer cell lines as well as metastatic clones of these cells. Flow cytometry studies with annexin V and propidium iodide showed that this inhibitory activity is not due to apoptosis or cell death. DBP-maf also had the ability to inhibit migration of prostate cancer cells in vitro. Finally, DBP-maf was shown to cause a reduction in urokinase plasminogen activator receptor (uPAR) expression in prostate tumor cells. There is evidence that activation of this receptor correlates with tumor metastasis. Conclusions These studies show strong inhibitory activity of DBP-maf on prostate tumor cells independent of its macrophage activation. PMID:20976141

GC protein-derived macrophage-activating factor decreases α-N-acetylgalactosaminidase levels in advanced cancer patients.

PubMed

Thyer, Lynda; Ward, Emma; Smith, Rodney; Branca, Jacopo Jv; Morucci, Gabriele; Gulisano, Massimo; Noakes, David; Eslinger, Robert; Pacini, Stefania

2013-08-01

α- N -acetylgalactosaminidase (nagalase) accumulates in the serum of cancer patients and its activity correlates with tumor burden, aggressiveness and clinical disease progression. The administration of GC protein-derived macrophage-activating factor (GcMAF) to cancer patients with elevated levels of nagalase has been associated with a decrease of serum nagalase activity and with significant clinical benefits. Here, we report the results of the administration of GcMAF to a heterogeneous cohort of patients with histologically diverse, advanced neoplasms, generally considered as "incurable" diseases. In most cases, GcMAF therapy was initiated at late stages of tumor progression. As this is an open-label, non-controlled, retrospective analysis, caution must be employed when establishing cause-effect relationships between the administration GcMAF and disease outcome. However, the response to GcMAF was generally robust and some trends emerged. All patients (n = 20) presented with elevated serum nagalase activity, well above normal values. All patients but one showed a significant decrease of serum nagalase activity upon weekly GcMAF injections. Decreased nagalase activity was associated with improved clinical conditions and no adverse side effects were reported. The observations reported here confirm and extend previous results and pave the way to further studies aimed at assessing the precise role and indications for GcMAF-based anticancer immunotherapy.

Deglycosylation of serum vitamin D3-binding protein leads to immunosuppression in cancer patients.

PubMed

Yamamoto, N; Naraparaju, V R; Asbell, S O

1996-06-15

Serum vitamin D3-binding protein (Gc protein) can be converted by beta-galactosidase of B cells and sialidase of T cells to a potent macrophage activating factor, a protein with N-acetylgalactosamine as the remaining sugar moiety. Thus, Gc protein is the precursor of the macrophage activating factor (MAF). Treatment of Gc protein with immobilized beta-galactosidase and sialidase generates an extremely high titered MAF, Gc-MAF. When peripheral blood monocytes/macrophages of 52 patients bearing various types of cancer were incubated with 100 pg/ml of GcMAF, the monocytes/macrophages of all patients were efficiently activated. However, the MAF precursor activity of patient plasma Gc protein was found to be severely reduced in about 25% of this patient population. About 45% of the patients had moderately reduced MAF precursor activities. Loss of the precursor activity was found to be due to deglycosylation of plasma Gc protein by alpha-N-acetylgalactosaminidase detected in the patient's bloodstream. The source of the enzyme appeared to be cancerous cells. Radiation therapy decreased plasma alpha-N-acetylgalactosaminidase activity with concomitant increase of precursor activity. This implies that radiation therapy decreases the number of cancerous cells capable of secreting alpha-N-acetylgalactosaminidase. Both alpha-N-acetylgalactosaminidase activity and MAF precursor activity of Gc protein in patient bloodstream can serve as diagnostic and prognostic indices.

Gc protein-derived macrophage-activating factor (GcMAF) stimulates cAMP formation in human mononuclear cells and inhibits angiogenesis in chick embryo chorionallantoic membrane assay.

PubMed

Pacini, Stefania; Morucci, Gabriele; Punzi, Tiziana; Gulisano, Massimo; Ruggiero, Marco

2011-04-01

The effects of Gc protein-derived macrophage-activating factor (GcMAF) have been studied in cancer and other conditions where angiogenesis is deregulated. In this study, we demonstrate for the first time that the mitogenic response of human peripheral blood mononuclear cells (PBMCs) to GcMAF was associated with 3'-5'-cyclic adenosine monophosphate (cAMP) formation. The effect was dose dependent, and maximal stimulation was achieved using 0.1 ng/ml. Heparin inhibited the stimulatory effect of GcMAF on PBMCs. In addition, we demonstrate that GcMAF (1 ng/ml) inhibited prostaglandin E(1)- and human breast cancer cell-stimulated angiogenesis in chick embryo chorionallantoic membrane (CAM) assay. Finally, we tested different GcMAF preparations on CAM, and the assay proved to be a reliable, reproducible and inexpensive method to determine the relative potencies of different preparations and their stability; we observed that storage at room temperature for 15 days decreased GcMAF potency by about 50%. These data could prove useful for upcoming clinical trials on GcMAF.

β-Galactosidase treatment is a common first-stage modification of the three major subtypes of Gc protein to GcMAF.

PubMed

Uto, Yoshihiro; Yamamoto, Syota; Mukai, Hirotaka; Ishiyama, Noriko; Takeuchi, Ryota; Nakagawa, Yoshinori; Hirota, Keiji; Terada, Hiroshi; Onizuka, Shinya; Hori, Hitoshi

2012-06-01

The 1f1f subtype of the group-specific component (Gc) protein is converted into Gc protein-derived macrophage-activating factor (GcMAF) by enzymatic processing with β-galactosidase and sialidase. We previously demonstrated that preGc(1f1f)MAF, a full Gc(1f1f) protein otherwise lacking a galactosyl moiety, can be converted to GcMAF by treatment with mouse peritoneal fluid. Here, we investigated the effects of the β-galactosidase-treated 1s1s and 22 subtypes of Gc protein (preGc(1s1s)MAF and preGc₂₂MAF) on the phagocytic activation of mouse peritoneal macrophages. We demonstrated the presence of Gal-GalNAc disaccharide sugar structures in the Gc(1s1s) protein by western blotting using peanut agglutinin and Helix pomatia agglutinin lectin. We also found that preGc(1s1s)MAF and preGc₂₂MAF significantly enhanced the phagocytic activity of mouse peritoneal macrophages in the presence and absence of mouse peritoneal fluid. We demonstrate that preGc(1s1s)MAF and preGc₂₂MAF proteins can be used as effective macrophage activators.

Integration and diversity of the regulatory network composed of Maf and CNC families of transcription factors.

PubMed

Motohashi, Hozumi; O'Connor, Tania; Katsuoka, Fumiki; Engel, James Douglas; Yamamoto, Masayuki

2002-07-10

Recent progress in the analysis of transcriptional regulation has revealed the presence of an exquisite functional network comprising the Maf and Cap 'n' collar (CNC) families of regulatory proteins, many of which have been isolated. Among Maf factors, large Maf proteins are important in the regulation of embryonic development and cell differentiation, whereas small Maf proteins serve as obligatory heterodimeric partner molecules for members of the CNC family. Both Maf homodimers and CNC-small Maf heterodimers bind to the Maf recognition element (MARE). Since the MARE contains a consensus TRE sequence recognized by AP-1, Jun and Fos family members may act to compete or interfere with the function of CNC-small Maf heterodimers. Overall then, the quantitative balance of transcription factors interacting with the MARE determines its transcriptional activity. Many putative MARE-dependent target genes such as those induced by antioxidants and oxidative stress are under concerted regulation by the CNC family member Nrf2, as clearly proven by mouse germline mutagenesis. Since these genes represent a vital aspect of the cellular defense mechanism against oxidative stress, Nrf2-null mutant mice are highly sensitive to xenobiotic and oxidative insults. Deciphering the molecular basis of the regulatory network composed of Maf and CNC families of transcription factors will undoubtedly lead to a new paradigm for the cooperative function of transcription factors.

GC protein-derived macrophage-activating factor decreases α-N-acetylgalactosaminidase levels in advanced cancer patients

PubMed Central

Thyer, Lynda; Ward, Emma; Smith, Rodney; Branca, Jacopo JV; Morucci, Gabriele; Gulisano, Massimo; Noakes, David; Eslinger, Robert; Pacini, Stefania

2013-01-01

α-N-acetylgalactosaminidase (nagalase) accumulates in the serum of cancer patients and its activity correlates with tumor burden, aggressiveness and clinical disease progression. The administration of GC protein-derived macrophage-activating factor (GcMAF) to cancer patients with elevated levels of nagalase has been associated with a decrease of serum nagalase activity and with significant clinical benefits. Here, we report the results of the administration of GcMAF to a heterogeneous cohort of patients with histologically diverse, advanced neoplasms, generally considered as “incurable” diseases. In most cases, GcMAF therapy was initiated at late stages of tumor progression. As this is an open-label, non-controlled, retrospective analysis, caution must be employed when establishing cause-effect relationships between the administration GcMAF and disease outcome. However, the response to GcMAF was generally robust and some trends emerged. All patients (n = 20) presented with elevated serum nagalase activity, well above normal values. All patients but one showed a significant decrease of serum nagalase activity upon weekly GcMAF injections. Decreased nagalase activity was associated with improved clinical conditions and no adverse side effects were reported. The observations reported here confirm and extend previous results and pave the way to further studies aimed at assessing the precise role and indications for GcMAF-based anticancer immunotherapy. PMID:24179708

Case Report: GcMAF Treatment in a Patient with Multiple Sclerosis.

PubMed

Inui, Toshio; Katsuura, Goro; Kubo, Kentaro; Kuchiike, Daisuke; Chenery, Leslye; Uto, Yoshihiro; Nishikata, Takahito; Mette, Martin

2016-07-01

Gc protein-derived macrophage-activating factor (GcMAF) has various functions as an immune modulator, such as macrophage activation, anti-angiogenic activity and anti-tumor activity. Clinical trials of second-generation GcMAF demonstrated remarkable clinical effects in several types of cancers. Thus, GcMAF-based immunotherapy has a wide application for use in the treatment of many diseases via macrophage activation that can be used as a supportive therapy. Multiple sclerosis (MS) is considered to be an autoimmune disorder that affects the myelinated axons in the central nervous system (CNS). This study was undertaken to examine the effects of second-generation GcMAF in a patient with MS. This case study demonstrated that treatments of GcMAF in a patient with MS have potent therapeutic actions with early beneficial responses, especially improvement of motor dysfunction. GcMAF shows therapeutic potency in the treatment of MS. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Mitogen-activated protein kinase pathway mediates DBP-maf-induced apoptosis in RAW 264.7 macrophages.

PubMed

Gumireddy, Kiranmai; Reddy, C Damodar; Swamy, Narasimha

2003-09-01

Vitamin D-binding protein-macrophage-activating factor (DBP-maf) is derived from serum vitamin D binding protein (DBP) by selective deglycosylation during inflammation. In the present study, we investigated the effect of DBP-maf on RAW 264.7 macrophages and the underlying intracellular signal transduction pathways. DBP-maf increased proapoptotic caspase-3, -8, and -9 activities and induced apoptosis in RAW 264.7 cells. However, DBP, the precursor to DBP-maf did not induce apoptosis in these cells. Cell cycle analysis of DBP-maf-treated RAW 264.7 cells revealed growth arrest with accumulation of cells in sub-G(0)/G(1) phase. We also investigated the role of mitogen-activated protein kinase (MAPK) pathways in the DBP-maf-induced apoptosis of RAW264.7 cells. DBP-maf increased the phosphorylation of p38 and JNK1/2, while it decreased the ERK1/2 phosphorylation. Treatment with the p38 MAPK inhibitor, SB202190, attenuated DBP-maf-induced apoptosis. PD98059, a MEK specific inhibitor, did not show a significant inhibition of apoptosis induced by DBP-maf. Taken together, these results suggest that the p38 MAPK pathway plays a crucial role in DBP-maf-mediated apoptosis of macrophages. Our studies indicate that, during inflammation DBP-maf may function positively by causing death of the macrophages when activated macrophages are no longer needed at the site of inflammation. In summary, we report for the first time that DBP-maf induces apoptosis in macrophages via p38 and JNK1/2 pathway. Copyright 2003 Wiley-Liss, Inc.

Effects of vitamin D-binding protein-derived macrophage-activating factor on human breast cancer cells.

PubMed

Pacini, Stefania; Punzi, Tiziana; Morucci, Gabriele; Gulisano, Massimo; Ruggiero, Marco

2012-01-01

Searching for additional therapeutic tools to fight breast cancer, we investigated the effects of vitamin D-binding protein-derived macrophage activating factor (DBP-MAF, also known as GcMAF) on a human breast cancer cell line (MCF-7). The effects of DBP-MAF on proliferation, morphology, vimentin expression and angiogenesis were studied by cell proliferation assay, phase-contrast microscopy, immunohistochemistry and western blotting, and chorioallantoic membrane (CAM) assay. DBP-MAF inhibited human breast cancer cell proliferation and cancer cell-stimulated angiogenesis. MCF-7 cells treated with DBP-MAF predominantly grew in monolayer and appeared to be well adherent to each other and to the well surface. Exposure to DBP-MAF significantly reduced vimentin expression, indicating a reversal of the epithelial/mesenchymal transition, a hallmark of human breast cancer progression. These results are consistent with the hypothesis that the known anticancer efficacy of DBP-MAF can be ascribed to different biological properties of the molecule that include inhibition of tumour-induced angiogenesis and direct inhibition of cancer cell proliferation, migration and metastatic potential.

The toothless osteopetrotic rat has a normal vitamin D-binding protein-macrophage activating factor (DBP-MAF) cascade and chondrodysplasia resistant to treatments with colony stimulating factor-1 (CSF-1) and/or DBP-MAF.

PubMed

Odgren, P R; Popoff, S N; Safadi, F F; MacKay, C A; Mason-Savas, A; Seifert, M F; Marks, S C

1999-08-01

The osteopetrotic rat mutation toothless (tl) is characterized by little or no bone resorption, few osteoclasts and macrophages, and chondrodysplasia at the growth plates. Short-term treatment of tl rats with colony-stimulating factor-1 (CSF-1) has been shown to increase the number of osteoclasts and macrophages, producing dramatic resolution of skeletal sclerosis at some, but not all, sites. Defects in production of vitamin D-binding protein-macrophage activating factor (DBP-MAF) have been identified in two other independent osteopetrotic mutations of the rat (op and ia), and two in the mouse (op and mi), in which macrophages and osteoclasts can be activated by the administration of exogenous DBP-MAF. The present studies were undertaken to examine the histology and residual growth defects in tl rats following longer CSF-1 treatments, to investigate the possibility that exogenous DBP-MAF might act synergistically with CSF-1 to improve the tl phenotype, and to assess the integrity of the endogenous DBP-MAF pathway in this mutation. CSF-1 treatment-with or without DBP-MAF-induced resorption of metaphyseal bone to the growth plate on the marrow side, improved slightly but did not normalize long bone growth, and caused no improvement in the abnormal histology of the growth plate. Injections of lysophosphatidylcholine (lyso-Pc) to prime macrophage activation via the DBP-MAF pathway raised superoxide production to similar levels in peritoneal macrophages from both normal and mutant animals, indicating no defect in the DBP-MAF pathway in tl rats. Interestingly, pretreatments with CSF-1 alone also increased superoxide production, although the mechanism for this remains unknown. In summary, we find that, unlike other osteopetrotic mutations investigated to date, the DBP-MAF pathway does not appear to be defective in the tl rat; that additional DBP-MAF does not augment the beneficial skeletal effects seen with CSF-1 alone; and that the growth plate chondrodystrophy seen in this mutation is unaffected by either molecule. Thus, the tl mutation intercepts the function of a gene required for both normal endochondral ossification and bone resorption, thereby uncoupling the coordination of skeletal metabolism required for normal long bone growth.

The MafA Transcription Factor Becomes Essential to Islet β-Cells Soon After Birth

PubMed Central

Hang, Yan; Yamamoto, Tsunehiko; Benninger, Richard K.P.; Brissova, Marcela; Guo, Min; Bush, Will; Piston, David W.; Powers, Alvin C.; Magnuson, Mark; Thurmond, Debbie C.; Stein, Roland

2014-01-01

The large Maf transcription factors, MafA and MafB, are expressed with distinct spatial–temporal patterns in rodent islet cells. Analysis of Mafa−/− and pancreas-specific Mafa∆panc deletion mutant mice demonstrated a primary role for MafA in adult β-cell activity, different from the embryonic importance of MafB. Our interests here were to precisely define when MafA became functionally significant to β-cells, to determine how this was affected by the brief period of postnatal MafB production, and to identify genes regulated by MafA during this period. We found that islet cell organization, β-cell mass, and β-cell function were influenced by 3 weeks of age in MafaΔpanc mice and compromised earlier in MafaΔpanc;Mafb+/− mice. A combination of genome-wide microarray profiling, electron microscopy, and metabolic assays were used to reveal mechanisms of MafA control. For example, β-cell replication was produced by actions on cyclin D2 regulation, while effects on granule docking affected first-phase insulin secretion. Moreover, notable differences in the genes regulated by embryonic MafB and postnatal MafA gene expression were found. These results not only clearly define why MafA is an essential transcriptional regulator of islet β-cells, but also why cell maturation involves coordinated actions with MafB. PMID:24520122

Structurally well-defined macrophage activating factor derived from vitamin D3-binding protein has a potent adjuvant activity for immunization.

PubMed

Yamamoto, N; Naraparaju, V R

1998-06-01

Freund's adjuvant produced severe inflammation that augments development of antibodies. Thus, mixed administration of antigens with adjuvant was not required as long as inflammation was induced in the hosts. Since macrophage activation for phagocytosis and antigen processing is the first step of antibody development, inflammation-primed macrophage activation plays a major role in immune development. Therefore, macrophage activating factor should act as an adjuvant for immunization. The inflammation-primed macrophage activation process is the major macrophage activating cascade that requires participation of serum vitamin D3-binding protein (DBP; human DBP is known as Gc protein) and glycosidases of B and T lymphocytes. Stepwise incubation of Gc protein with immobilized beta-galactosidase and sialidase efficiently generated the most potent macrophage activating factor (designated GcMAF) we have ever encountered. Administration of GcMAF (20 or 100 pg/mouse) resulted in stimulation of the progenitor cells for extensive mitogenesis and activation of macrophages. Administration of GcMAF (100 pg/mouse) along with immunization of mice with sheep red blood cells (SRBC) produced a large number of anti-SRBC antibody secreting splenic cells in 2-4 days. Thus, GcMAF has a potent adjuvant activity for immunization. Although malignant tumours are poorly immunogenic, 4 days after GcMAF-primed immunization of mice with heat-killed Ehrlich ascites tumour cells, the ascites tumour was no longer transplantable in these mice.

Immunotherapy of HIV-infected patients with Gc protein-derived macrophage activating factor (GcMAF).

PubMed

Yamamoto, Nobuto; Ushijima, Naofumi; Koga, Yoshihiko

2009-01-01

Serum Gc protein (known as vitamin D3-binding protein) is the precursor for the principal macrophage activating factor (MAF). The MAF precursor activity of serum Gc protein of HIV-infected patients was lost or reduced because Gc protein is deglycosylated by alpha-N-acetylgalactosaminidase (Nagalase) secreted from HIV-infected cells. Therefore, macrophages of HIV-infected patients having deglycosylated Gc protein cannot be activated, leading to immunosuppression. Since Nagalase is the intrinsic component of the envelope protein gp120, serum Nagalase activity is the sum of enzyme activities carried by both HIV virions and envelope proteins. These Nagalase carriers were already complexed with anti-HIV immunoglobulin G (IgG) but retained Nagalase activity that is required for infectivity. Stepwise treatment of purified Gc protein with immobilized beta-galactosidase and sialidase generated the most potent macrophage activating factor (termed GcMAF), which produces no side effects in humans. Macrophages activated by administration of 100 ng GcMAF develop a large amount of Fc-receptors as well as an enormous variation of receptors that recognize IgG-bound and unbound HIV virions. Since latently HIV-infected cells are unstable and constantly release HIV virions, the activated macrophages rapidly intercept the released HIV virions to prevent reinfection resulting in exhaustion of infected cells. After less than 18 weekly administrations of 100 ng GcMAF for nonanemic patients, they exhibited low serum Nagalase activities equivalent to healthy controls, indicating eradication of HIV-infection, which was also confirmed by no infectious center formation by provirus inducing agent-treated patient PBMCs. No recurrence occurred and their healthy CD + cell counts were maintained for 7 years.

Case report: A breast cancer patient treated with GcMAF, sonodynamic therapy and hormone therapy.

PubMed

Inui, Toshio; Makita, Kaori; Miura, Hirona; Matsuda, Akiko; Kuchiike, Daisuke; Kubo, Kentaro; Mette, Martin; Uto, Yoshihiro; Nishikata, Takahito; Hori, Hitoshi; Sakamoto, Norihiro

2014-08-01

Gc protein-derived macrophage-activating factor (GcMAF) occurs naturally in the human body. It has various functions, such as macrophage activation and antitumor activities. Recently, immunotherapy has become an attractive new strategy in the treatment of cancer. GcMAF-based immunotherapy can be combined with many other therapies. Sonodynamic therapy (SDT) using low-intensity ultrasound is a novel therapeutic modality. Ultrasound has been demonstrated to activate a number of sonosensitive agents allowing for the possibility of non-invasive targeted treatment for both superficial and deep-seated tumors. The current case study demonstrates that GcMAF and SDT can be used in combination with conventional therapies in patients with metastatic cancer, especially where treatment options are limited due to factors such as toxicity. This case study also suggests a new concept of cancer treatment using local destruction of cancer tissue, in this case conducted with SDT, to be used in combination with GcMAF immunotherapy as a systemic treatment. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Effect of salivary gland adenocarcinoma cell-derived alpha-N-acetylgalactosaminidase on the bioactivity of macrophage activating factor.

PubMed

Matsuura, Takashi; Uematsu, Takashi; Yamaoka, Minoru; Furusawa, Kiyofumi

2004-03-01

The aim of this study was to clarify the effects of alpha-N-acetylgalactosaminidase (alpha-NaGalase) produced by human salivary gland adenocarcinoma (SGA) cells on the bioactivity of macrophage-activating factor (GcMAF). High exo-alpha-NaGalase activity was detected in the SGA cell line HSG. HSG alpha-NaGalase had both exo- and endo-enzyme activities, cleaving the Gal-GalNAc and GalNAc residues linked to Thr/Ser but not releasing the [NeuAc2-6]GalNac residue. Furthermore, GcMAF enzymatically prepared from the Gc protein enhanced the superoxide-generation capacity and phagocytic activity of monocytes/macrophages. However, GcMAF treated with purified alpha-NaGalase did not exhibit these effects. Thus, HSG possesses the capacity to produce larger quantities of alpha-NaGalase, which inactivates GcMAF produced from Gc protein, resulting in reduced phagocytic activity and superoxide-generation capacity of monocytes/macrophages. The present data strongly suggest that HSG alpha-NaGalase acts as an immunodeficiency factor in cancer patients.

Gc-protein-derived macrophage activating factor counteracts the neuronal damage induced by oxaliplatin.

PubMed

Morucci, Gabriele; Branca, Jacopo J V; Gulisano, Massimo; Ruggiero, Marco; Paternostro, Ferdinando; Pacini, Alessandra; Di Cesare Mannelli, Lorenzo; Pacini, Stefania

2015-02-01

Oxaliplatin-based regimens are effective in metastasized advanced cancers. However, a major limitation to their widespread use is represented by neurotoxicity that leads to peripheral neuropathy. In this study we evaluated the roles of a proven immunotherapeutic agent [Gc-protein-derived macrophage activating factor (GcMAF)] in preventing or decreasing oxaliplatin-induced neuronal damage and in modulating microglia activation following oxaliplatin-induced damage. The effects of oxaliplatin and of a commercially available formula of GcMAF [oleic acid-GcMAF (OA-GcMAF)] were studied in human neurons (SH-SY5Y cells) and in human microglial cells (C13NJ). Cell density, morphology and viability, as well as production of cAMP and expression of vascular endothelial growth factor (VEGF), markers of neuron regeneration [neuromodulin or growth associated protein-43 (Gap-43)] and markers of microglia activation [ionized calcium binding adaptor molecule 1 (Iba1) and B7-2], were determined. OA-GcMAF reverted the damage inflicted by oxaliplatin on human neurons and preserved their viability. The neuroprotective effect was accompanied by increased intracellular cAMP production, as well as by increased expression of VEGF and neuromodulin. OA-GcMAF did not revert the effects of oxaliplatin on microglial cell viability. However, it increased microglial activation following oxaliplatin-induced damage, resulting in an increased expression of the markers Iba1 and B7-2 without any concomitant increase in cell number. When neurons and microglial cells were co-cultured, the presence of OA-GcMAF significantly counteracted the toxic effects of oxaliplatin. Our results demonstrate that OA-GcMAF, already used in the immunotherapy of advanced cancers, may significantly contribute to neutralizing the neurotoxicity induced by oxaliplatin, at the same time possibly concurring to an integrated anticancer effect. The association between these two powerful anticancer molecules would probably produce the dual effect of reduction of oxaliplatin-induced neurotoxicity, together with possible synergism in the overall anticancer effect.

Association of the macrophage activating factor (MAF) precursor activity with polymorphism in vitamin D-binding protein.

PubMed

Nagasawa, Hideko; Sasaki, Hideyuki; Uto, Yoshihiro; Kubo, Shinichi; Hori, Hitoshi

2004-01-01

Serum vitamin D-binding protein (Gc protein or DBP) is a highly expressed polymorphic protein, which is a precursor of the inflammation-primed macrophage activating factor, GcMAF, by a cascade of carbohydrate processing reactions. In order to elucidate the relationship between Gc polymorphism and GcMAF precursor activity, we estimated the phagocytic ability of three homotypes of Gc protein, Gc1F-1F, Gc1S-1S and Gc2-2, through processing of their carbohydrate moiety. We performed Gc typing of human serum samples by isoelectric focusing (IEF). Gc protein from human serum was purified by affinity chromatography with 25-hydroxyvitamin D3-sepharose. A phagocytosis assay of Gc proteins, modified using beta-glycosidase and sialidase, was carried out. The Gc1F-1F phenotype was revealed to possess Galbeta1-4GalNAc linkage by the analysis of GcMAF precursor activity using beta1-4 linkage-specific galactosidase from jack bean. The GcMAF precursor activity of the Gc1F-1F phenotype was highest among three Gc homotypes. The Gc polymorphism and carbohydrate diversity of Gc protein are significant for its pleiotropic effects.

Immunotherapy of BALB/c mice bearing Ehrlich ascites tumor with vitamin D-binding protein-derived macrophage activating factor.

PubMed

Yamamoto, N; Naraparaju, V R

1997-06-01

Vitamin D3-binding protein (DBP; human DBP is known as Gc protein) is the precursor of macrophage activating factor (MAF). Treatment of mouse DBP with immobilized beta-galactosidase or treatment of human Gc protein with immobilized beta-galactosidase and sialidase generated a remarkably potent MAF, termed DBPMAF or GcMAF, respectively. The domain of Gc protein responsible for macrophage activation was cloned and enzymatically converted to the cloned MAF, designated CdMAF. In Ehrlich ascites tumor-bearing mice, tumor-specific serum alpha-N-acetylgalactosaminidase (NaGalase) activity increased linearly with time as the transplanted tumor cells grew in the peritoneal cavity. Therapeutic effects of DBPMAF, GcMAF, and CdMAF on mice bearing Ehrlich ascites tumor were assessed by survival time, the total tumor cell count in the peritoneal cavity, and serum NaGalase activity. Mice that received a single administration of DBPMAF or GcMAF (100 pg/mouse) on the same day after transplantation of tumor (1 x 10(5) cells) showed a mean survival time of 35 +/- 4 days, whereas tumor-bearing controls had a mean survival time of 16 +/- 2 days. When mice received the second DBPMAF or GcMAF administration at day 4, they survived more than 50 days. Mice that received two DBPMAF administrations, at days 4 and 8 after transplantation of 1 x 10(5) tumor cells, survived up to 32 +/- 4 days. At day 4 posttransplantation, the total tumor cell count in the peritoneal cavity was approximately 5 x 10(5) cells. Mice that received two DBPMAF administrations, at days 0 and 4 after transplantation of 5 x 10(5) tumor cells, also survived up to 32 +/- 4 days, while control mice that received the 5 x 10(5) ascites tumor cells only survived for 14 +/- 2 days. Four DBPMAF, GcMAF, or CdMAF administrations to mice transplanted with 5 x 10(5) Ehrlich ascites tumor cells with 4-day intervals showed an extended survival of at least 90 days and an insignificantly low serum NaGalase level between days 30 and 90.

A defect in the inflammation-primed macrophage-activation cascade in osteopetrotic rats.

PubMed

Yamamoto, N; Lindsay, D D; Naraparaju, V R; Ireland, R A; Popoff, S N

1994-05-15

Macrophages were activated by administration of lysophosphatidylcholine (lyso-Pc) or dodecylglycerol (DDG) to wild-type rats but not in osteopetrotic (op) mutant rats. In vitro treatment of wild-type rat peritoneal cells with lyso-Pc or DDG efficiently activated macrophages whereas treatment of op mutant rat peritoneal cells with lyso-Pc or DDG did not activate macrophages. The inflammation-primed macrophage activation cascade in rats requires participation of B lymphocytes and vitamin D binding protein (DBP). Lyso-Pc-inducible beta-galactosidase of wild-type rat B lymphocytes can convert DBP to the macrophage-activating factor (MAF), whereas B lymphocytes of the op mutant rats were shown to be deficient in lyso-Pc-inducible beta-galactosidase. DBP is conserved among mammalian species. Treatment of human DBP (Gc1 protein) with commercial glycosidases yields an extremely high titrated MAF as assayed on mouse and rat macrophages. Because the enzymatically generated MAF (GcMAF) bypasses the role of lymphocytes in macrophage activation, the op mutant rat macrophages were efficiently activated by administration of a small quantity (100 pg/rat) of GcMAF. Likewise, in vitro treatment of op rat peritoneal cells with as little as 40 pg GcMAF/ml activated macrophages.

c-Maf controls immune responses by regulating disease-specific gene networks and repressing IL-2 in CD4+ T cells.

PubMed

Gabryšová, Leona; Alvarez-Martinez, Marisol; Luisier, Raphaëlle; Cox, Luke S; Sodenkamp, Jan; Hosking, Caroline; Pérez-Mazliah, Damián; Whicher, Charlotte; Kannan, Yashaswini; Potempa, Krzysztof; Wu, Xuemei; Bhaw, Leena; Wende, Hagen; Sieweke, Michael H; Elgar, Greg; Wilson, Mark; Briscoe, James; Metzis, Vicki; Langhorne, Jean; Luscombe, Nicholas M; O'Garra, Anne

2018-05-01

The transcription factor c-Maf induces the anti-inflammatory cytokine IL-10 in CD4 + T cells in vitro. However, the global effects of c-Maf on diverse immune responses in vivo are unknown. Here we found that c-Maf regulated IL-10 production in CD4 + T cells in disease models involving the T H 1 subset of helper T cells (malaria), T H 2 cells (allergy) and T H 17 cells (autoimmunity) in vivo. Although mice with c-Maf deficiency targeted to T cells showed greater pathology in T H 1 and T H 2 responses, T H 17 cell-mediated pathology was reduced in this context, with an accompanying decrease in T H 17 cells and increase in Foxp3 + regulatory T cells. Bivariate genomic footprinting elucidated the c-Maf transcription-factor network, including enhanced activity of NFAT; this led to the identification and validation of c-Maf as a negative regulator of IL-2. The decreased expression of the gene encoding the transcription factor RORγt (Rorc) that resulted from c-Maf deficiency was dependent on IL-2, which explained the in vivo observations. Thus, c-Maf is a positive and negative regulator of the expression of cytokine-encoding genes, with context-specific effects that allow each immune response to occur in a controlled yet effective manner.

Case Report: A Non-small Cell Lung Cancer Patient Treated with GcMAF, Sonodynamic Therapy and Tumor Treating Fields.

PubMed

Inui, Toshio; Amitani, Haruka; Kubo, Kentaro; Kuchiike, Daisuke; Uto, Yoshihiro; Nishikata, Takahito; Mette, Martin

2016-07-01

Macrophage activating factor (MAF)-based immunotherapy has a wide application for use in treating many diseases via macrophage activation. Sonodynamic therapy (SDT) using low-intensity ultrasound and tumor treating field (TTF) therapy are novel therapeutic modalities. SDT is usually combined with ozone therapy to improve local hypoxia within the tumor environment. We treated a 77-year-old male diagnosed with non-small cell lung cancer ((NSCLC) stage 3B) using second-generation serum GcMAF and oral colostrum MAF-based immunotherapy combined with SDT, TTF and ozone therapies. This case report demonstrates that GcMAF, oral colostrum MAF, SDT, TTF and ozone therapy can be used for NSCLC without adverse effects. This case report suggests a new concept of cancer treatment using local destruction of cancer tissue, in this case conducted with SDT and TTF therapy, to be used in combination with serum GcMAF and colostrum MAF immunotherapy as a systemic treatment. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Is chondroitin sulfate responsible for the biological effects attributed to the GC protein-derived Macrophage Activating Factor (GcMAF)?

PubMed

Ruggiero, Marco; Reinwald, Heinz; Pacini, Stefania

2016-09-01

We hypothesize that a plasma glycosaminoglycan, chondroitin sulfate, may be responsible for the biological and clinical effects attributed to the Gc protein-derived Macrophage Activating Factor (GcMAF), a protein that is extracted from human blood. Thus, Gc protein binds chondroitin sulfate on the cell surface and such an interaction may occur also in blood, colostrum and milk. This interpretation would solve the inconsistencies encountered in explaining the effects of GcMAF in vitro and in vivo. According to our model, the Gc protein or the GcMAF bind to chondroitin sulfate both on the cell surface and in bodily fluids, and the resulting multimolecular complexes, under the form of oligomers trigger a transmembrane signal or, alternatively, are internalized and convey the signal directly to the nucleus thus eliciting the diverse biological effects observed for both GcMAF and chondroitin sulfate. Copyright © 2016 Elsevier Ltd. All rights reserved.

Effects of oxaliplatin and oleic acid Gc-protein-derived macrophage-activating factor on murine and human microglia.

PubMed

Branca, Jacopo J V; Morucci, Gabriele; Malentacchi, Francesca; Gelmini, Stefania; Ruggiero, Marco; Pacini, Stefania

2015-09-01

The biological properties and characteristics of microglia in rodents have been widely described, but little is known about these features in human microglia. Several murine microglial cell lines are used to investigate neurodegenerative and neuroinflammatory conditions; however, the extrapolation of the results to human conditions is frequently met with criticism because of the possibility of species-specific differences. This study compares the effects of oxaliplatin and of oleic acid Gc-protein-derived macrophage-activating factor (OA-GcMAF) on two microglial cell lines, murine BV-2 cells and human C13NJ cells. Cell viability, cAMP levels, microglial activation, and vascular endothelial growth factor (VEGF) expression were evaluated. Our data demonstrate that oxaliplatin induced a significant decrease in cell viability in BV-2 and in C13NJ cells and that this effect was not reversed with OA-GcMAF treatment. The signal transduction pathway involving cAMP/VEGF was activated after treatment with oxaliplatin and/or OA-GcMAF in both cell lines. OA-GcMAF induced a significant increase in microglia activation, as evidenced by the expression of the B7-2 protein, in BV-2 as well as in C13NJ cells that was not associated with a concomitant increase in cell number. Furthermore, the effects of oxaliplatin and OA-GcMAF on coculture morphology and apoptosis were evaluated. Oxaliplatin-induced cell damage and apoptosis were nearly completely reversed by OA-GcMAF treatment in both BV-2/SH-SY5Y and C13NJ/SH-SY5Y cocultures. Our data show that murine and human microglia share common signal transduction pathways and activation mechanisms, suggesting that the murine BV-2 cell line may represent an excellent model for studying human microglia. © 2015 Wiley Periodicals, Inc.

MafB antagonizes phenotypic alteration induced by GM-CSF in microglia

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

Koshida, Ryusuke, E-mail: rkoshida-myz@umin.ac.jp; Oishi, Hisashi, E-mail: hoishi@md.tsukuba.ac.jp; Hamada, Michito

2015-07-17

Microglia are tissue-resident macrophages which are distributed throughout the central nervous system (CNS). Recent studies suggest that microglia are a unique myeloid population distinct from peripheral macrophages in terms of origin and gene expression signature. Granulocyte-macrophage colony-stimulating factor (GM-CSF), a pleiotropic cytokine regulating myeloid development, has been shown to stimulate proliferation and alter phenotype of microglia in vitro. However, how its signaling is modulated in microglia is poorly characterized. MafB, a bZip transcriptional factor, is highly expressed in monocyte-macrophage lineage cells including microglia, although its role in microglia is largely unknown. We investigated the crosstalk between GM-CSF signaling and MafB bymore » analyzing primary microglia. We found that Mafb-deficient microglia grew more rapidly than wild-type microglia in response to GM-CSF. Moreover, the expression of genes associated with microglial differentiation was more downregulated in Mafb-deficient microglia cultured with GM-CSF. Notably, such differences between the genotypes were not observed in the presence of M-CSF. In addition, we found that Mafb-deficient microglia cultured with GM-CSF barely extended their membrane protrusions, probably due to abnormal activation of RhoA, a key regulator of cytoskeletal remodeling. Altogether, our study reveals that MafB is a negative regulator of GM-CSF signaling in microglia. These findings could provide new insight into the modulation of cytokine signaling by transcription factors in microglia. - Highlights: • GM-CSF alters the phenotype of microglia in vitro more potently than M-CSF. • Transcription factor MafB antagonizes the effect of GM-CSF on microglia in vitro. • MafB deficiency leads to RhoA activation in microglia in response to GM-CSF. • We show for the first time the function of MafB in microglia.« less

A novel role for a major component of the vitamin D axis: vitamin D binding protein-derived macrophage activating factor induces human breast cancer cell apoptosis through stimulation of macrophages.

PubMed

Thyer, Lynda; Ward, Emma; Smith, Rodney; Fiore, Maria Giulia; Magherini, Stefano; Branca, Jacopo J V; Morucci, Gabriele; Gulisano, Massimo; Ruggiero, Marco; Pacini, Stefania

2013-07-08

The role of vitamin D in maintaining health appears greater than originally thought, and the concept of the vitamin D axis underlines the complexity of the biological events controlled by biologically active vitamin D (1,25(OH)(2)D3), its two binding proteins that are the vitamin D receptor (VDR) and the vitamin D-binding protein-derived macrophage activating factor (GcMAF). In this study we demonstrate that GcMAF stimulates macrophages, which in turn attack human breast cancer cells, induce their apoptosis and eventually phagocytize them. These results are consistent with the observation that macrophages infiltrated implanted tumors in mice after GcMAF injections. In addition, we hypothesize that the last 23 hydrophobic amino acids of VDR, located at the inner part of the plasma membrane, interact with the first 23 hydrophobic amino acids of the GcMAF located at the external part of the plasma membrane. This allows 1,25(OH)(2)D3 and oleic acid to become sandwiched between the two vitamin D-binding proteins, thus postulating a novel molecular mode of interaction between GcMAF and VDR. Taken together, these results support and reinforce the hypothesis that GcMAF has multiple biological activities that could be responsible for its anti-cancer effects, possibly through molecular interaction with the VDR that in turn is responsible for a multitude of non-genomic as well as genomic effects.

The effects of vitamin D binding protein-macrophage activating factor and colony-stimulating factor-1 on hematopoietic cells in normal and osteopetrotic rats.

PubMed

Benis, K A; Schneider, G B

1996-10-15

Osteopetrosis is a heterogeneous group of bone disorders characterized by the failure of osteoclasts to resorb bone and by several immunological defects including macrophage dysfunction. Two compounds, colony-stimulating factor-1 (CSF-1) and vitamin D-binding protein-macrophage activating factor (DBP-MAF) were used in the present study to evaluate their effects on the peritoneal population of cells and on cells within the bone marrow microenvironment in normal and incisors absent (ia) osteopetrotic rats. Previous studies in this laboratory have demonstrated that administration of DBP-MAF to newborn ia animals results in a substantial increase in bone marrow cavity size due to upregulated osteoclast function. To study the effects of these compounds on the macrophage/osteoclast precursors, DBP-MAF, CSF-1, and the combination of these compounds were given to newborn ia and normal littermate animals. Both the normal and mutant phenotypes responded similarly when treated with these compounds. Rats exhibited a profound shift toward the macrophage lineage from the neutrophil lineage when compared with vehicle-treated control animals after treatment with these compounds. In the in vivo peritoneal lavage study, animals received injections of CSF-1, DBP-MAF or DBP-MAF/CSF-1 over a 4-week period. The various types of cells in the peritoneal cavity were then enumerated. The in vitro study consisted of cells isolated from the bone marrow microenvironment and cultured on feeder layers of CSF-1, DBP-MAF, or DBP-MAF/CSF-1 for colony enumeration. The increase in macrophage numbers at the expense of neutrophil numbers could be seen in both the in vivo and in vitro experiments. The macrophage/osteoclast and neutrophil lineages have a common precursor, the granulocyte/macrophage colony-forming cell (GM-CFC). With the addition of CSF-1, the GM-CFC precursor may be induced into the macrophage/osteoclast lineage rather than the granulocyte lineage. This increased pool of cells in the macrophage/osteoclast lineage can be functionally upregulated with the subsequent addition of DBP-MAF to perform the activities of phagocytosis and bone resorption. The in vitro data also showed that DBP-MAF did not support colony development as in CSF-1 or the combination treatment. The recruitment and activation of cells into the macrophage/ osteoclast lineage may help to correct the bone and immune defects found in diseases demonstrating a significant lack of myeloid cells, as well as neutrophilia disorders and the disease, osteopetrosis.

Structural definition of a potent macrophage activating factor derived from vitamin D3-binding protein with adjuvant activity for antibody production.

PubMed

Yamamoto, N

1996-10-01

Incubation of human vitamin D3-binding protein (Gc protein), with a mixture of immobilized beta-galactosidase and sialidase, efficiently generated a potent macrophage activating factor, a protein with N-acetylgalactosamine as the remaining sugar. Stepwise incubation of Gc protein with immobilized beta-galactosidase and sialidase, and isolation of the intermediates with immobilized lectins, revealed that either sequence of hydrolysis of Gc glycoprotein by these glycosidases yields the macrophage-activating factor, implying that Gc protein carries a trisaccharide composed of N-acetylgalactosamine and dibranched galactose and sialic acid termini. A 3 hr incubation of mouse peritoneal macrophages with picomolar amounts of the enzymatically generated macrophage-activating factor (GcMAF) resulted in a greatly enhanced phagocytic activity. Administration of a minute amount (10-50 pg/mouse) of GcMAF resulted in a seven- to nine-fold enhanced phagocytic activity of macrophages. Injection of sheep red blood cells (SRBC) along with GcMAF into mice produced a large number of anti-SRBC antibody secreting splenic cells in 2-4 days.

Inhibitory effect of vitamin D-binding protein-derived macrophage activating factor on DMBA-induced hamster cheek pouch carcinogenesis and its derived carcinoma cell line.

PubMed

Toyohara, Yukiyo; Hashitani, Susumu; Kishimoto, Hiromitsu; Noguchi, Kazuma; Yamamoto, Nobuto; Urade, Masahiro

2011-07-01

This study investigated the inhibitory effect of vitamin D-binding protein-derived macrophage-activating factor (GcMAF) on carcinogenesis and tumor growth, using a 9,10-dimethyl-1,2-benzanthracene (DMBA)-induced hamster cheek pouch carcinogenesis model, as well as the cytocidal effect of activated macrophages against HCPC-1, a cell line established from DMBA-induced cheek pouch carcinoma. DMBA application induced squamous cell carcinoma in all 15 hamsters of the control group at approximately 10 weeks, and all 15 hamsters died of tumor burden within 20 weeks. By contrast, 2 out of the 14 hamsters with GcMAF administration did not develop tumors and the remaining 12 hamsters showed a significant delay of tumor development for approximately 3.5 weeks. The growth of tumors formed was significantly suppressed and none of the hamsters died within the 20 weeks during which they were observed. When GcMAF administration was stopped at the 13th week of the experiment in 4 out of the 14 hamsters in the GcMAF-treated group, tumor growth was promoted, but none of the mice died within the 20-week period. On the other hand, when GcMAF administration was commenced after the 13th week in 5 out of the 15 hamsters in the control group, tumor growth was slightly suppressed and all 15 hamsters died of tumor burden. However, the mean survival time was significantly extended. GcMAF treatment activated peritoneal macrophages in vitro and in vivo, and these activated macrophages exhibited a marked cytocidal effect on HCPC-1 cells. Furthermore, the cytocidal effect of activated macrophages was enhanced by the addition of tumor-bearing hamster serum. These findings indicated that GcMAF possesses an inhibitory effect on tumor development and growth in a DMBA-induced hamster cheek pouch carcinogenesis model.

Inhibitory effect of vitamin D-binding protein-derived macrophage activating factor on DMBA-induced hamster cheek pouch carcinogenesis and its derived carcinoma cell line

PubMed Central

TOYOHARA, YUKIYO; HASHITANI, SUSUMU; KISHIMOTO, HIROMITSU; NOGUCHI, KAZUMA; YAMAMOTO, NOBUTO; URADE, MASAHIRO

2011-01-01

This study investigated the inhibitory effect of vitamin D-binding protein-derived macrophage-activating factor (GcMAF) on carcinogenesis and tumor growth, using a 9,10-dimethyl-1,2-benzanthracene (DMBA)-induced hamster cheek pouch carcinogenesis model, as well as the cytocidal effect of activated macrophages against HCPC-1, a cell line established from DMBA-induced cheek pouch carcinoma. DMBA application induced squamous cell carcinoma in all 15 hamsters of the control group at approximately 10 weeks, and all 15 hamsters died of tumor burden within 20 weeks. By contrast, 2 out of the 14 hamsters with GcMAF administration did not develop tumors and the remaining 12 hamsters showed a significant delay of tumor development for approximately 3.5 weeks. The growth of tumors formed was significantly suppressed and none of the hamsters died within the 20 weeks during which they were observed. When GcMAF administration was stopped at the 13th week of the experiment in 4 out of the 14 hamsters in the GcMAF-treated group, tumor growth was promoted, but none of the mice died within the 20-week period. On the other hand, when GcMAF administration was commenced after the 13th week in 5 out of the 15 hamsters in the control group, tumor growth was slightly suppressed and all 15 hamsters died of tumor burden. However, the mean survival time was significantly extended. GcMAF treatment activated peritoneal macrophages in vitro and in vivo, and these activated macrophages exhibited a marked cytocidal effect on HCPC-1 cells. Furthermore, the cytocidal effect of activated macrophages was enhanced by the addition of tumor-bearing hamster serum. These findings indicated that GcMAF possesses an inhibitory effect on tumor development and growth in a DMBA-induced hamster cheek pouch carcinogenesis model. PMID:22848250

Vitamin D binding protein-macrophage activating factor (DBP-maf) inhibits angiogenesis and tumor growth in mice.

PubMed

Kisker, Oliver; Onizuka, Shinya; Becker, Christian M; Fannon, Michael; Flynn, Evelyn; D'Amato, Robert; Zetter, Bruce; Folkman, Judah; Ray, Rahul; Swamy, Narasimha; Pirie-Shepherd, Steven

2003-01-01

We have isolated a selectively deglycosylated form of vitamin D binding protein (DBP-maf) generated from systemically available DBP by a human pancreatic cancer cell line. DBP-maf is antiproliferative for endothelial cells and antiangiogenic in the chorioallantoic membrane assay. DBP-maf administered daily was able to potently inhibit the growth of human pancreatic cancer in immune compromised mice (T/C=0.09). At higher doses, DBP-maf caused tumor regression. Histological examination revealed that treated tumors had a higher number of infiltrating macrophages as well as reduced microvessel density, and increased levels of apoptosis relative to untreated tumors. Taken together, these data suggest that DBP-maf is an antiangiogenic molecule that can act directly on endothelium as well as stimulate macrophages to attack both the endothelial and tumor cell compartment of a growing malignancy.

A Novel Role for a Major Component of the Vitamin D Axis: Vitamin D Binding Protein-Derived Macrophage Activating Factor Induces Human Breast Cancer Cell Apoptosis through Stimulation of Macrophages

PubMed Central

Thyer, Lynda; Ward, Emma; Smith, Rodney; Fiore, Maria Giulia; Magherini, Stefano; Branca, Jacopo J. V.; Morucci, Gabriele; Gulisano, Massimo; Ruggiero, Marco; Pacini, Stefania

2013-01-01

The role of vitamin D in maintaining health appears greater than originally thought, and the concept of the vitamin D axis underlines the complexity of the biological events controlled by biologically active vitamin D (1,25(OH)(2)D3), its two binding proteins that are the vitamin D receptor (VDR) and the vitamin D-binding protein-derived macrophage activating factor (GcMAF). In this study we demonstrate that GcMAF stimulates macrophages, which in turn attack human breast cancer cells, induce their apoptosis and eventually phagocytize them. These results are consistent with the observation that macrophages infiltrated implanted tumors in mice after GcMAF injections. In addition, we hypothesize that the last 23 hydrophobic amino acids of VDR, located at the inner part of the plasma membrane, interact with the first 23 hydrophobic amino acids of the GcMAF located at the external part of the plasma membrane. This al1ows 1,25(OH)(2)D3 and oleic acid to become sandwiched between the two vitamin D-binding proteins, thus postulating a novel molecular mode of interaction between GcMAF and VDR. Taken together, these results support and reinforce the hypothesis that GcMAF has multiple biological activities that could be responsible for its anti-cancer effects, possibly through molecular interaction with the VDR that in turn is responsible for a multitude of non-genomic as well as genomic effects. PMID:23857228

Antitumor effect of degalactosylated gc-globulin on orthotopic grafted lung cancer in mice.

PubMed

Hirota, Keiji; Nakagawa, Yoshinori; Takeuchi, Ryota; Uto, Yoshihiro; Hori, Hitoshi; Onizuka, Shinya; Terada, Hiroshi

2013-07-01

Group-specific component (Gc)-globulin-derived macrophage-activating factor (GcMAF) generated by a cascade of catalytic reactions with deglycosidase enzymes exerts antitumor activity. We hypothesized that degalactosyl Gc-globulin (DG3), a precursor of GcMAF, also plays a role in recovery from cancer as well as GcMAF due to progression of deglycosylation by generally resident sialidases and mannosidases. We prepared the subtypes of DG3, such as 1f1f and 1s1s and its 22 homodimers, by using vitamin D3-binding Sepharose CL-6B and examined their antitumor activity in mice bearing Lewis lung carcinoma cells, by counting the number of nodules formed in their lungs. Antitumor activity of DG3 was observed regardless of its subtype, being equivalent to that of GcMAF. The injection route of DG3 affected its antitumor activity, with subcutaneous and intramuscular administration being more favorable than the intraperitoneal or intravenous route. In order to obtain significant antitumor activity, more than 160 ng/kg of DG3 were required. DG3 proved to be promising as an antitumor agent, similarly to GcMAF.

Development of a cell-based high throughput luciferase enzyme fragment complementation assay to identify nuclear-factor-e2-related transcription factor 2 activators.

PubMed

Xie, Wensheng; Pao, Christina; Graham, Taylor; Dul, Ed; Lu, Quinn; Sweitzer, Thomas D; Ames, Robert S; Li, Hu

2012-12-01

Nuclear-factor-E2-related transcription factor 2 (Nrf2) regulates a large panel of Phase II genes and plays an important role in cell survival. Nrf2 activation has been shown as preventing cigarette smoke-induced alveolar enlargement in mice. Therefore, activation of the Nrf2 protein by small-molecule activators represents an attractive therapeutic strategy that is used for chronic obstructive pulmonary disease. In this article, we describe a cell-based luciferase enzyme fragment complementation assay that identifies Nrf2 activators. This assay is based on the interaction of Nrf2 with its nuclear partner MafK or runt-related transcription factor 2 (RunX2) and is dependent on the reconstitution of a "split" luciferase. Firefly luciferase is split into two fragments, which are genetically fused to Nrf2 and MafK or RunX2, respectively. BacMam technology was used to deliver the fusion constructs into cells for expression of the tagged proteins. When the BacMam-transduced cells were treated with Nrf2 activators, the Nrf2 protein was stabilized and translocated into the nucleus where it interacted with MafK or RunX2. The interaction of Nrf2 and MafK or RunX2 brought together the two luciferase fragments that form an active luciferase. The assay was developed in a 384-well format and was optimized by titrating the BacMam concentration, transduction time, cell density, and fetal bovine serum concentration. It was further validated with known Nrf2 activators. Our data show that this assay is robust, sensitive, and amenable to high throughput screening of a large compound collection for the identification of novel Nrf2 activators.

Black tea high-molecular-weight polyphenol stimulates exercise training-induced improvement of endurance capacity in mouse via the link between AMPK and GLUT4.

PubMed

Eguchi, Tomoaki; Kumagai, Chiaki; Fujihara, Takashi; Takemasa, Thoru; Ozawa, Tetsuo; Numata, Osamu

2013-01-01

Aerobic exercise can promote "fast-to-slow transition" in skeletal muscles, i.e. an increase in oxidative fibers, mitochondria, and myoglobin and improvement in glucose and lipid metabolism. Here, we found that mice administered Mitochondria Activation Factor (MAF) combined with exercise training could run longer distances and for a longer time compared with the exercise only group; MAF is a high-molecular-weight polyphenol purified from black tea. Furthermore, MAF intake combined with exercise training increased phosphorylation of AMPK and mRNA level of glucose transporter 4 (GLUT4). Thus, our data demonstrate for the first time that MAF activates exercise training-induced intracellular signaling pathways that involve AMPK, and improves endurance capacity.

Vitamin D Binding Protein-Macrophage Activating Factor (DBP-maf) Inhibits Angiogenesis and Tumor Growth in Mice1

PubMed Central

Kisker, Oliver; Onizuka, Shinya; Becker, Christian M; Fannon, Michael; Flynn, Evelyn; D'Amato, Robert; Zetter, Bruce; Folkman, Judah; Ray, Rahul; Swamy, Narasimha; Pirie-Shepherd, Steven

2003-01-01

Abstract We have isolated a selectively deglycosylated form of vitamin D binding protein (DBP-maf) generated from systemically available DBP by a human pancreatic cancer cell line. DBP-maf is antiproliferative for endothelial cells and antiangiogenic in the chorioallantoic membrane assay. DBP-maf administered daily was able to potently inhibit the growth of human pancreatic cancer in immune compromised mice (T/C=0.09). At higher doses, DBP-maf caused tumor regression. Histological examination revealed that treated tumors had a higher number of infiltrating macrophages as well as reduced microvessel density, and increased levels of apoptosis relative to untreated tumors. Taken together, these data suggest that DBP-maf is an antiangiogenic molecule that can act directly on endothelium as well as stimulate macrophages to attack both the endothelial and tumor cell compartment of a growing malignancy. PMID:12659668

Promising role for Gc-MAF in cancer immunotherapy: from bench to bedside

PubMed Central

Saburi, Ehsan; Saburi, Amin; Ghanei, Mostafa

2017-01-01

Immunotherapy has been used for years in many types of cancer therapy. Recently, cancer immunotherapy has focused on mechanisms which can enhance the development of cell-mediated immunity. Anticancer medications are administered to inhibit immunosuppressive factors such as nagalase enzyme, which is produced by neoplastic cells and destroys macrophage activating factor (Gc-MAF). Anti-neoplastics medications can also enhance immune-cell activity against tumors. Such medications show great potential in cancer immunotherapy using natural human mechanisms against neoplasms. PMID:29201312

MafA is a Key Molecule in Glucose and Energy Balance in the Central Nervous System and Peripheral Organs

PubMed Central

Tsuchiya, Mariko; Tsuchiya, Ken; Yasuda, Kazuki; Fujita, Mikiko; Takinishi, Akira; Furukawa, Maiko; Nitta, Kosaku; Maeda, Atsushi

2011-01-01

MafA is a strong transactivator of insulin in pancreatic β cells. Elucidating the profile of MafA action in organs other than the pancreas is essential. We established an mRNA interference technique that modifies the level of target mRNAs in mice in vivo. After rapidly injecting MafA-siRNA, the resulting changes in the gene profile were analyzed using a microarray system. Significant suppression of the MafA mRNA levels was observed in the pancreas, liver, adipose tissue, and brain of siRNA-injected mice. As we reported previously, the down-regulation of insulin mRNA and adipocytokines was observed in the pancreas, and MafA siRNA caused alterations in the expressions of genes related to lipid metabolism and cell growth in the liver, and the attenuation of cell differentiation in cultured adipocytes. In addition to the effects on these organs, MafA expression was immunohistochemically detected in the brain in our preliminary data, and the expression level in siRNA-treated mice was significantly suppressed. The expressions of the affected genes were distinct, including growth hormone, vasopressin, hypocretin, and pro-melanin-concentrating hormone, were almost completely down-regulated (to ~1/100). These results suggested that MafA is likely involved in the regulation of hormonal systems related to glucose metabolism, and MafA is likely positioned near the beginning of the cascade or may influence the expressions of the above-mentioned genes in coordination with other factors in brain tissue. Taken together, the findings in this study suggested that MafA functions as a transcription factor with distinct activities in each organ and is cross-linked in several organs. PMID:23675216

Macrophage Activation Mechanisms in Human Monocytic Cell Line-derived Macrophages.

PubMed

Sumiya, Yu; Ishikawa, Mami; Inoue, Takahiro; Inui, Toshio; Kuchiike, Daisuke; Kubo, Kentaro; Uto, Yoshihiro; Nishikata, Takahito

2015-08-01

Although the mechanisms of macrophage activation are important for cancer immunotherapy, they are poorly understood. Recently, easy and robust assay systems for assessing the macrophage-activating factor (MAF) using monocytic cell line-derived macrophages were established. Gene-expression profiles of U937- and THP-1-derived macrophages were compared using gene expression microarray analysis and their responses against several MAFs were examined by in vitro experiments. Activated states of these macrophages could not be assigned to a specific sub-type but showed, however, different unique characteristics. The unique of monocytic cell line-derived macrophages could provide clues to understand the activation mechanism of macrophages and, therefore, help to develop effective cancer immunotherapy with MAFs. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

The in vitro GcMAF effects on endocannabinoid system transcriptionomics, receptor formation, and cell activity of autism-derived macrophages.

PubMed

Siniscalco, Dario; Bradstreet, James Jeffrey; Cirillo, Alessandra; Antonucci, Nicola

2014-04-17

Immune system dysregulation is well-recognized in autism and thought to be part of the etiology of this disorder. The endocannabinoid system is a key regulator of the immune system via the cannabinoid receptor type 2 (CB2R) which is highly expressed on macrophages and microglial cells. We have previously published significant differences in peripheral blood mononuclear cell CB2R gene expression in the autism population. The use of the Gc protein-derived Macrophage Activating Factor (GcMAF), an endogenous glycosylated vitamin D binding protein responsible for macrophage cell activation has demonstrated positive effects in the treatment of autistic children. In this current study, we investigated the in vitro effects of GcMAF treatment on the endocannabinoid system gene expression, as well as cellular activation in blood monocyte-derived macrophages (BMDMs) from autistic patients compared to age-matched healthy developing controls. To achieve these goals, we used biomolecular, biochemical and immunocytochemical methods. GcMAF treatment was able to normalize the observed differences in dysregulated gene expression of the endocannabinoid system of the autism group. GcMAF also down-regulated the over-activation of BMDMs from autistic children. This study presents the first observations of GcMAF effects on the transcriptionomics of the endocannabinoid system and expression of CB2R protein. These data point to a potential nexus between endocannabinoids, vitamin D and its transporter proteins, and the immune dysregulations observed with autism.

The in vitro GcMAF effects on endocannabinoid system transcriptionomics, receptor formation, and cell activity of autism-derived macrophages

PubMed Central

2014-01-01

Background Immune system dysregulation is well-recognized in autism and thought to be part of the etiology of this disorder. The endocannabinoid system is a key regulator of the immune system via the cannabinoid receptor type 2 (CB2R) which is highly expressed on macrophages and microglial cells. We have previously published significant differences in peripheral blood mononuclear cell CB2R gene expression in the autism population. The use of the Gc protein-derived Macrophage Activating Factor (GcMAF), an endogenous glycosylated vitamin D binding protein responsible for macrophage cell activation has demonstrated positive effects in the treatment of autistic children. In this current study, we investigated the in vitro effects of GcMAF treatment on the endocannabinoid system gene expression, as well as cellular activation in blood monocyte-derived macrophages (BMDMs) from autistic patients compared to age-matched healthy developing controls. Methods To achieve these goals, we used biomolecular, biochemical and immunocytochemical methods. Results GcMAF treatment was able to normalize the observed differences in dysregulated gene expression of the endocannabinoid system of the autism group. GcMAF also down-regulated the over-activation of BMDMs from autistic children. Conclusions This study presents the first observations of GcMAF effects on the transcriptionomics of the endocannabinoid system and expression of CB2R protein. These data point to a potential nexus between endocannabinoids, vitamin D and its transporter proteins, and the immune dysregulations observed with autism. PMID:24739187

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.

The glycosylation and characterization of the candidate Gc macrophage activating factor.

PubMed

Ravnsborg, Tina; Olsen, Dorthe T; Thysen, Anna Hammerich; Christiansen, Maja; Houen, Gunnar; Højrup, Peter

2010-04-01

The vitamin D binding protein, Gc globulin, has in recent years received some attention for its role as precursor for the extremely potent macrophage activating factor (GcMAF). An O-linked trisaccharide has been allocated to the threonine residue at position 420 in two of the three most common isoforms of Gc globulin (Gc1s and Gc1f). A substitution for a lysine residue at position 420 in Gc2 prevents this isoform from being glycosylated at that position. It has been suggested that Gc globulin subjected sequentially to sialidase and galactosidase treatment generates GcMAF in the form of Gc globulin with only a single GalNAc attached to T420. In this study we confirm the location of a linear trisaccharide on T420. Furthermore, we provide the first structural evidence of the generation of the proposed GcMAF by use of glycosidase treatment and mass spectrometry. Additionally the generated GcMAF candidate was tested for its effect on cytokine release from macrophages in human whole blood. Copyright 2010 Elsevier B.V. All rights reserved.

Effects of vitamin D binding protein-macrophage activating factor (DBP-MAF) infusion on bone resorption in two osteopetrotic mutations.

PubMed

Schneider, G B; Benis, K A; Flay, N W; Ireland, R A; Popoff, S N

1995-06-01

Osteopetrosis is a heterogeneous group of bone diseases characterized by an excess accumulation of bone and a variety of immune defects. Osteopetrosis (op) and incisors absent (ia) are two nonallelic mutations in the rat which demonstrated these skeletal defects as a result of reduced bone resorption. Osteopetrotic (op) rats have severe sclerosis as a result of reduced numbers of osteoclasts which are structurally abnormal. The sclerosis in ia rats is not as severe as in op mutants; they have elevated numbers of osteoclasts, but they are also morphologically abnormal, lacking a ruffled border. Both of these mutations have defects in the inflammation-primed activation of macrophages. They demonstrate independent defects in the cascade involved in the conversion of vitamin D binding protein (DBP) to a potent macrophage activating factor (DBP-MAF). Because this factor may also play a role in the pathogenesis of osteoclastic dysfunction, the effects of ex vivo-generated DBP-MAF were evaluated on the skeletal system of these two mutations. Newborn ia and op rats and normal littermate controls were injected with DBP-MAF or vehicle once every 4 days from birth until 2 weeks of age, at which time bone samples were collected to evaluate a number of skeletal parameters. DBP-MAF treated op rats had an increased number of osteoclasts and the majority of them exhibited normal structure. There was also reduced bone volume in the treated op animals and an associated increased cellularity of the marrow spaces. The skeletal sclerosis was also corrected in the ia rats; the bone marrow cavity size was significantly enlarged and the majority of the osteoclasts appeared normal with extensive ruffled borders.

The recombinant expression and activity detection of MAF-1 fusion protein.

PubMed

Fu, Ping; Wu, Jianwei; Gao, Song; Guo, Guo; Zhang, Yong; Liu, Jian

2015-10-01

This study establishes the recombinant expression system of MAF-1 (Musca domestica antifungal peptide-1) and demonstrates the antifungal activity of the expression product and shows the relationship between biological activity and structure. The gene segments on mature peptide part of MAF-1 were cloned, based on the primers designed according to the cDNA sequence of MAF-1. We constructed the recombinant prokaryotic expression plasmid using prokaryotic expression vector (pET-28a(+)) and converted it to the competent cell of BL21(DE3) to gain recombinant MAF-1 fusion protein with His tag sequence through purifying affinity chromatographic column of Ni-NTA. To conduct the Western Blotting test, recombinant MAF-1 fusion protein was used to produce the polyclonal antibody of rat. The antifungal activity of the expression product was detected using Candida albicans (ATCC10231) as the indicator. The MAF-1 recombinant fusion protein was purified to exhibit obvious antifungal activity, which lays the foundation for the further study of MAF-1 biological activity, the relationship between structure and function, as well as control of gene expression.

Lineage-specific enhancers activate self-renewal genes in macrophages and embryonic stem cells

PubMed Central

Soucie, Erinn L.; Weng, Ziming; Geirsdóttir, Laufey; Molawi, Kaaweh; Maurizio, Julien; Fenouil, Romain; Mossadegh-Keller, Noushine; Gimenez, Gregory; VanHille, Laurent; Beniazza, Meryam; Favret, Jeremy; Berruyer, Carole; Perrin, Pierre; Hacohen, Nir; Andrau, J.-C.; Ferrier, Pierre; Dubreuil, Patrice; Sidow, Arend; Sieweke, Michael H.

2016-01-01

Differentiated macrophages can self-renew in tissues and expand long-term in culture, but the gene regulatory mechanisms that accomplish self-renewal in the differentiated state have remained unknown. Here we show that in mice, the transcription factors MafB and c-Maf repress a macrophage-specific enhancer repertoire associated with a gene network controlling self-renewal. Single cell analysis revealed that, in vivo, proliferating resident macrophages can access this network by transient down-regulation of Maf transcription factors. The network also controls embryonic stem cell self-renewal but is associated with distinct embryonic stem cell-specific enhancers. This indicates that distinct lineage-specific enhancer platforms regulate a shared network of genes that control self-renewal potential in both stem and mature cells. PMID:26797145

Oleic Acid, deglycosylated vitamin D-binding protein, nitric oxide: a molecular triad made lethal to cancer.

PubMed

Ruggiero, Marco; Ward, Emma; Smith, Rodney; Branca, Jacopo J V; Noakes, David; Morucci, Gabriele; Taubmann, Margit; Thyer, Lynda; Pacini, Stefania

2014-07-01

Oleic Acid (OA) has been shown to have anticancer properties mediated by interaction with proteins such as α-lactalbumin and lactoferrins. Therefore, we synthesized complexes of OA and Gc protein-derived macrophage activating factor (GcMAF) that inhibits per se cancer cell proliferation and metastatic potential. We hypothesised that OA-GcMAF complexes could exploit the anticancer properties of both OA and GcMAF in a synergistic manner. We postulated that the stimulating effects of GcMAF on macrophages might lead to release of nitric oxide (NO). Patients with advanced cancer were treated at the Immuno Biotech Treatment Centre with OA-GcMAF-based integrative immunotherapy in combination with a low-carbohydrate, high-protein diet, fermented milk products containing naturally-produced GcMAF, Vitamin D3, omega-3 fatty acids and low-dose acetylsalicylic acid. Measuring the tumour by ultrasonographic techniques, we observed a decrease of tumour volume of about 25%. These observations demonstrate that OA, GcMAF and NO can be properly combined and specifically delivered to advanced cancer patients with significant effects on immune system stimulation and tumour volume reduction avoiding harmful side-effects. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Cutting Edge: c-Maf Is Required for Regulatory T Cells To Adopt RORγt+ and Follicular Phenotypes.

PubMed

Wheaton, Joshua D; Yeh, Chen-Hao; Ciofani, Maria

2017-12-15

Regulatory T cells (Tregs) adopt specialized phenotypes defined by coexpression of lineage-defining transcription factors, such as RORγt, Bcl-6, or PPARγ, alongside Foxp3. These Treg subsets have unique tissue distributions and diverse roles in maintaining organismal homeostasis. However, despite extensive functional characterization, the factors driving Treg specialization are largely unknown. In this article, we show that c-Maf is a critical transcription factor regulating this process in mice, essential for generation of both RORγt + Tregs and T follicular regulatory cells, but not for adipose-resident Tregs. c-Maf appears to function primarily in Treg specialization, because IL-10 production, expression of other effector molecules, and general immune homeostasis are not c-Maf dependent. As in other T cells, c-Maf is induced in Tregs by IL-6 and TGF-β, suggesting that a combination of inflammatory and tolerogenic signals promote c-Maf expression. Therefore, c-Maf is a novel regulator of Treg specialization, which may integrate disparate signals to facilitate environmental adaptation. Copyright © 2017 by The American Association of Immunologists, Inc.

β-Cell-Specific Mafk Overexpression Impairs Pancreatic Endocrine Cell Development

PubMed Central

Abdellatif, Ahmed M.; Oishi, Hisashi; Itagaki, Takahiro; Jung, Yunshin; Shawki, Hossam H.; Okita, Yukari; Hasegawa, Yoshikazu; Suzuki, Hiroyuki; El-Morsy, Salah E.; El-Sayed, Mesbah A.; Shoaib, Mahmoud B.; Sugiyama, Fumihiro; Takahashi, Satoru

2016-01-01

The MAF family transcription factors are homologs of v-Maf, the oncogenic component of the avian retrovirus AS42. They are subdivided into 2 groups, small and large MAF proteins, according to their structure, function, and molecular size. MAFK is a member of the small MAF family and acts as a dominant negative form of large MAFs. In previous research we generated transgenic mice that overexpress MAFK in order to suppress the function of large MAF proteins in pancreatic β-cells. These mice developed hyperglycemia in adulthood due to impairment of glucose-stimulated insulin secretion. The aim of the current study is to examine the effects of β-cell-specific Mafk overexpression in endocrine cell development. The developing islets of Mafk-transgenic embryos appeared to be disorganized with an inversion of total numbers of insulin+ and glucagon+ cells due to reduced β-cell proliferation. Gene expression analysis by quantitative RT-PCR revealed decreased levels of β-cell-related genes whose expressions are known to be controlled by large MAF proteins. Additionally, these changes were accompanied with a significant increase in key β-cell transcription factors likely due to compensatory mechanisms that might have been activated in response to the β-cell loss. Finally, microarray comparison of gene expression profiles between wild-type and transgenic pancreata revealed alteration of some uncharacterized genes including Pcbd1, Fam132a, Cryba2, and Npy, which might play important roles during pancreatic endocrine development. Taken together, these results suggest that Mafk overexpression impairs endocrine development through a regulation of numerous β-cell-related genes. The microarray analysis provided a unique data set of differentially expressed genes that might contribute to a better understanding of the molecular basis that governs the development and function of endocrine pancreas. PMID:26901059

Lineage-specific enhancers activate self-renewal genes in macrophages and embryonic stem cells.

PubMed

Soucie, Erinn L; Weng, Ziming; Geirsdóttir, Laufey; Molawi, Kaaweh; Maurizio, Julien; Fenouil, Romain; Mossadegh-Keller, Noushine; Gimenez, Gregory; VanHille, Laurent; Beniazza, Meryam; Favret, Jeremy; Berruyer, Carole; Perrin, Pierre; Hacohen, Nir; Andrau, J-C; Ferrier, Pierre; Dubreuil, Patrice; Sidow, Arend; Sieweke, Michael H

2016-02-12

Differentiated macrophages can self-renew in tissues and expand long term in culture, but the gene regulatory mechanisms that accomplish self-renewal in the differentiated state have remained unknown. Here we show that in mice, the transcription factors MafB and c-Maf repress a macrophage-specific enhancer repertoire associated with a gene network that controls self-renewal. Single-cell analysis revealed that, in vivo, proliferating resident macrophages can access this network by transient down-regulation of Maf transcription factors. The network also controls embryonic stem cell self-renewal but is associated with distinct embryonic stem cell-specific enhancers. This indicates that distinct lineage-specific enhancer platforms regulate a shared network of genes that control self-renewal potential in both stem and mature cells. Copyright © 2016, American Association for the Advancement of Science.

Cajanus cajan Linn. (Leguminosae) prevents alcohol-induced rat liver damage and augments cytoprotective function.

PubMed

Kundu, Rakesh; Dasgupta, Suman; Biswas, Anindita; Bhattacharya, Anirban; Pal, Bikas C; Bandyopadhyay, Debashis; Bhattacharya, Shelley; Bhattacharya, Samir

2008-08-13

Cajanus cajan Linn. (Leguminosae) is a nontoxic edible herb, widely used in Indian folk medicine for the prevention of various liver disorders. In the present study we have demonstrated that methanol-aqueous fraction (MAF2) of Cajanus cajan leaf extract could prevent the chronically treated alcohol induced rat liver damage. Chronic doses of alcohol (3.7 g/ kg) orally administered to rats for 28 days and liver function marker enzymes such as GPT, GOT, ALP and anti-oxidant enzyme activities were determined. Effect of MAF2 at a dose of 50mg/kg body weight on alcohol treated rats was noted. Alcohol effected significant increase in liver marker enzyme activities and reduced the activities of anti-oxidant enzymes. Co-administration of MAF2 reversed the liver damage due to alcohol; it decreased the activities of liver marker enzymes and augmented antioxidant enzyme activities. We also demonstrate significant decrease of the phase II detoxifying enzyme, UDP-glucuronosyl transferase (UGT) activity along with a three- and two-fold decrease of UGT2B gene and protein expression respectively. MAF2 co-administration normalized UGT activity and revived the expression of UGT2B with a concomitant expression and nuclear translocation of Nrf2, a transcription factor that regulates the expression of many cytoprotective genes. Cajanus cajan extract therefore shows a promise in therapeutic use in alcohol induced liver dysfunction.

Evidence for differential activation of arachidonic acid metabolism in formylpeptide- and macrophage-activation-factor-stimulated guinea-pig macrophages.

PubMed Central

Homma, Y; Hashimoto, T; Nagai, Y; Takenawa, T

1985-01-01

Alterations of phospholipid and arachidonic acid metabolism were studied by treatment of guinea-pig peritoneal-exudate macrophages with chemotactic peptide, formylmethionyl-leucylphenylalanine (fMet-Leu-Phe) and macrophage activation factor (MAF). The chemotactic peptide caused a rapid rearrangement in inositol phospholipids, including a breakdown of polyphosphoinositides within 30s, followed by a resultant formation of phosphatidylinositol (PI), diacylglycerol, phosphatidic acid and non-esterified arachidonic acid within 5 min. In addition to these sequential alterations, arachidonic acid was released mainly from PI. On the other hand, MAF induced a slow liberation of arachidonic acid, mainly from phosphatidylethanolamine (PE) and phosphatidylcholine (PC) by phospholipase A2 after the incubation period of 30 min, but not any rapid changes in phospholipids. Treatment of macrophages for 15 min with fMet-Leu-Phe produced the leukotrienes (LTs) B4, C4 and D4, prostaglandins (PG) E2 and F2 alpha and thromboxane (TX) B2. In contrast, MAF could not stimulate the production of arachidonic acid metabolites during the incubation period of 15 min, but could enhance that of PGE2, PGF2 alpha, TXB2 and hydroxyeicosatetraenoic acids at 6 h. However, the stimulated formation of LTs was not detected at any time. These results indicate that the effects of fMet-Leu-Phe on both phospholipid and arachidonic acid metabolism are very different from those mediated by MAF. PMID:3931627

Dimeric combinations of MafB, cFos and cJun control the apoptosis-survival balance in limb morphogenesis.

PubMed

Suda, Natsuno; Itoh, Takehiko; Nakato, Ryuichiro; Shirakawa, Daisuke; Bando, Masashige; Katou, Yuki; Kataoka, Kohsuke; Shirahige, Katsuhiko; Tickle, Cheryll; Tanaka, Mikiko

2014-07-01

Apoptosis is an important mechanism for sculpting morphology. However, the molecular cascades that control apoptosis in developing limb buds remain largely unclear. Here, we show that MafB was specifically expressed in apoptotic regions of chick limb buds, and MafB/cFos heterodimers repressed apoptosis, whereas MafB/cJun heterodimers promoted apoptosis for sculpting the shape of the limbs. Chromatin immunoprecipitation sequencing in chick limb buds identified potential target genes and regulatory elements controlled by Maf and Jun. Functional analyses revealed that expression of p63 and p73, key components known to arrest the cell cycle, was directly activated by MafB and cJun. Our data suggest that dimeric combinations of MafB, cFos and cJun in developing chick limb buds control the number of apoptotic cells, and that MafB/cJun heterodimers lead to apoptosis via activation of p63 and p73. © 2014. Published by The Company of Biologists Ltd.

Tumor cell alpha-N-acetylgalactosaminidase activity and its involvement in GcMAF-related macrophage activation.

PubMed

Mohamad, Saharuddin B; Nagasawa, Hideko; Uto, Yoshihiro; Hori, Hitoshi

2002-05-01

Alpha-N-acetyl galactosaminidase (alpha-NaGalase) has been reported to accumulate in serum of cancer patients and be responsible for deglycosylation of Gc protein, which is a precursor of GcMAF-mediated macrophage activation cascade, finally leading to immunosuppression in advanced cancer patients. We studied the biochemical characterization of alpha-NaGalase from several human tumor cell lines. We also examined its effect on the potency of GcMAF to activate mouse peritoneal macrophage to produce superoxide in GcMAF-mediated macrophage activation cascade. The specific activity of alpha-NaGalases from human colon tumor cell line HCT116, human hepatoma cell line HepG2, and normal human liver cells (Chang liver cell line) were evaluated using two types of substrates; GalNAc-alpha-PNP (exo-type substrate) and Gal-beta-GalNAc-alpha-PNP (endo-type substrate). Tumor-derived alpha-NaGalase having higher activity than normal alpha-NaGalase, had higher substrate specificity to the exo-type substrate than to the endo-type substrate, and still maintained its activity at pH 7. GcMAF enhance superoxide production in mouse macrophage, and pre-treatment of GcMAF with tumor cell lysate reduce the activity. We conclude that tumor-derived alpha-NaGalase is different in biochemical characterization compared to normal alpha-NaGalase from normal Chang liver cells. In addition, tumor cell-derived alpha-NaGalase decreases the potency of GcMAF on macrophage activation.

MafK/NF-E2 p18 is required for beta-globin genes activation by mediating the proximity of LCR and active beta-globin genes in MEL cell line.

PubMed

Du, Mei-Jun; Lv, Xiang; Hao, De-Long; Zhao, Guo-Wei; Wu, Xue-Song; Wu, Feng; Liu, De-Pei; Liang, Chih-Chuan

2008-01-01

Evidences indicate that locus control region (LCR) of beta-globin spatially closes to the downstream active gene promoter to mediate the transcriptional activation by looping. DNA binding proteins may play an important role in the looping formation. NF-E2 is one of the key transcription factors in beta-globin gene transcriptional activation. To shed light on whether NF-E2 is involved in this process, DS19MafKsiRNA cell pools were established by specifically knocked down the expression of MafK/NF-E2 p18, one subunit of NF-E2 heterodimer. In the above cell pools, it was observed that the occupancy efficiency of NF-E2 on beta-globin gene locus and the expression level of beta-globin genes were decreased. H3 acetylation, H3-K4 methylation and the deposition of RNA polymerase II, but not the recruitment of GATA-1, were also found reduced at the beta-globin gene cluster. Chromosome Conformation Capture (3C) assay showed that the cross-linking frequency between the main NF-E2 binding site HS2 and downstream structural genes was reduced compared to the normal cell. This result demonstrated that MafK/NF-E2 p18 recruitment was involved in the physical proximity of LCR and active beta-globin genes upon beta-globin gene transcriptional activation.

Identification of a novel missense mutation of MAF in a Japanese family with congenital cataract by whole exome sequencing: a clinical report and review of literature.

PubMed

Narumi, Yoko; Nishina, Sachiko; Tokimitsu, Motoharu; Aoki, Yoko; Kosaki, Rika; Wakui, Keiko; Azuma, Noriyuki; Murata, Toshinori; Takada, Fumio; Fukushima, Yoshimitsu; Kosho, Tomoki

2014-05-01

Congenital cataracts are the most important cause of severe visual impairment in infants. Genetic factors contribute to the disease development and 29 genes are known to cause congenital cataracts. Identifying the genetic cause of congenital cataracts can be difficult because of genetic heterogeneity. V-maf avian musculoaponeurotic fibrosarcoma oncogene homolog (MAF) encodes a basic region/leucine zipper transcription factor that plays a key role as a regulator of embryonic lens fiber cell development. MAF mutations have been reported to cause juvenile-onset pulverulent cataract, microcornea, iris coloboma, and other anterior segment dysgenesis. We report on six patients in a family who have congenital cataracts were identified MAF mutation by whole exome sequencing (WES). The heterozygous MAF mutation Q303L detected in the present family occurs in a well conserved glutamine residue at the basic region of the DNA-binding domain. All affected members showed congenital cataracts. Three of the six members showed microcornea and one showed iris coloboma. Congenital cataracts with MAF mutation exhibited phenotypically variable cataracts within the family. Review of the patients with MAF mutations supports the notion that congenital cataracts caused by MAF mutations could be accompanied by microcornea and/or iris coloboma. WES is a useful tool for detecting disease-causing mutations in patients with genetically heterogeneous conditions. © 2014 Wiley Periodicals, Inc.

Evidence for a gamma-interferon receptor that regulates macrophage tumoricidal activity

PubMed Central

1984-01-01

Gamma-interferon (IFN-gamma) is the macrophage-activating factor (MAF) produced by normal murine splenic cells and the murine T cell hybridoma 24/G1 that induces nonspecific tumoricidal activity in macrophages. Incubation of 24/G1 supernatants diluted to 8.3 IRU IFN-gamma/ml with 6 X 10(6) elicited peritoneal macrophages or bone marrow-derived macrophages for 4 h at 37 degrees C, resulted in removal of 80% of the MAF activity from the lymphokine preparation. Loss of activity appeared to result from absorption and not consumption because (a) 40% of the activity was removed after exposure to macrophage for 30 min at 4 degrees C, (b) no reduction of MAF activity was detected when the 24/G1 supernatant was incubated with macrophage culture supernatants, and (c) macrophage-treated supernatants showed a selective loss of MAF activity but not interleukin 2 (IL-2) activity. Absorption was dependent on the input of either IFN-gamma or macrophages and was time dependent at 37 degrees C but not at 4 degrees C. With four rodent species tested, absorption of murine IFN-gamma displayed species specificity. However, cultured human peripheral blood monocytes and the human histiocytic lymphoma cell line U937 were able to absorb the murine lymphokine. Although the majority of murine cell lines tested absorbed 24/G1 MAF activity, two murine macrophage cell lines, P388D1 and J774, were identified which absorbed significantly reduced amounts of natural IFN- gamma. Purified murine recombinant IFN-gamma was absorbed by elicited macrophages but not by P388D1. Normal macrophages but not P388D1 bound fluoresceinated microspheres coated with recombinant IFN-gamma and binding was inhibited by pretreatment of the normal cells with 24/G1 supernatants. Scatchard plot analysis showed that 12,000 molecules of soluble 125I-recombinant IFN-gamma bound per bone marrow macrophage with a Ka of 0.9 X 10(8) M-1. Binding was quantitatively inhibitable by natural IFN-gamma but not by murine IFN alpha. IFN-beta competed only weakly. Monoclonal antibodies against IFN-gamma either inhibited or enhanced MAF activity by blocking or increasing IFN-gamma binding to macrophages, respectively. These results indicate that IFN-gamma reacts with a receptor on macrophage in a specific and saturable manner and this interaction initiates macrophage activation. PMID:6330272

A mammary cell-specific enhancer in mouse mammary tumor virus DNA is composed of multiple regulatory elements including binding sites for CTF/NFI and a novel transcription factor, mammary cell-activating factor.

PubMed Central

Mink, S; Härtig, E; Jennewein, P; Doppler, W; Cato, A C

1992-01-01

Mouse mammary tumor virus (MMTV) is a milk-transmitted retrovirus involved in the neoplastic transformation of mouse mammary gland cells. The expression of this virus is regulated by mammary cell type-specific factors, steroid hormones, and polypeptide growth factors. Sequences for mammary cell-specific expression are located in an enhancer element in the extreme 5' end of the long terminal repeat region of this virus. This enhancer, when cloned in front of the herpes simplex thymidine kinase promoter, endows the promoter with mammary cell-specific response. Using functional and DNA-protein-binding studies with constructs mutated in the MMTV long terminal repeat enhancer, we have identified two main regulatory elements necessary for the mammary cell-specific response. These elements consist of binding sites for a transcription factor in the family of CTF/NFI proteins and the transcription factor mammary cell-activating factor (MAF) that recognizes the sequence G Pu Pu G C/G A A G G/T. Combinations of CTF/NFI- and MAF-binding sites or multiple copies of either one of these binding sites but not solitary binding sites mediate mammary cell-specific expression. The functional activities of these two regulatory elements are enhanced by another factor that binds to the core sequence ACAAAG. Interdigitated binding sites for CTF/NFI, MAF, and/or the ACAAAG factor are also found in the 5' upstream regions of genes encoding whey milk proteins from different species. These findings suggest that mammary cell-specific regulation is achieved by a concerted action of factors binding to multiple regulatory sites. Images PMID:1328867

Gc protein (vitamin D-binding protein): Gc genotyping and GcMAF precursor activity.

PubMed

Nagasawa, Hideko; Uto, Yoshihiro; Sasaki, Hideyuki; Okamura, Natsuko; Murakami, Aya; Kubo, Shinichi; Kirk, Kenneth L; Hori, Hitoshi

2005-01-01

The Gc protein (human group-specific component (Gc), a vitamin D-binding protein or Gc globulin), has important physiological functions that include involvement in vitamin D transport and storage, scavenging of extracellular G-actin, enhancement of the chemotactic activity of C5a for neutrophils in inflammation and macrophage activation (mediated by a GalNAc-modified Gc protein (GcMAF)). In this review, the structure and function of the Gc protein is focused on especially with regard to Gc genotyping and GcMAF precursor activity. A discussion of the research strategy "GcMAF as a target for drug discovery" is included, based on our own research.

A Novel DNA Binding Mechanism for maf Basic Region-Leucine Zipper Factors Inferred from a MafA-DNA Complex Structure and Binding Specificities

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

Lu, Xun; Guanga, Gerald P; Wan, Cheng

2012-11-13

MafA is a proto-oncoprotein and is critical for insulin gene expression in pancreatic β-cells. Maf proteins belong to the AP1 superfamily of basic region-leucine zipper (bZIP) transcription factors. Residues in the basic helix and an ancillary N-terminal domain, the Extended Homology Region (EHR), endow maf proteins with unique DNA binding properties: binding a 13 bp consensus site consisting of a core AP1 site (TGACTCA) flanked by TGC sequences and binding DNA stably as monomers. To further characterize maf DNA binding, we determined the structure of a MafA–DNA complex. MafA forms base-specific hydrogen bonds with the flanking G –5C –4 andmore » central C 0/G 0 bases, but not with the core-TGA bases. However, in vitro binding studies utilizing a pulse–chase electrophoretic mobility shift assay protocol revealed that mutating either the core-TGA or flanking-TGC bases dramatically increases the binding off rate. Comparing the known maf structures, we propose that DNA binding specificity results from positioning the basic helix through unique phosphate contacts. The EHR does not contact DNA directly but stabilizes DNA binding by contacting the basic helix. Collectively, these results suggest a novel multistep DNA binding process involving a conformational change from contacting the core-TGA to contacting the flanking-TGC bases.« less

The transcription factor Lc-Maf participates in Col27a1 regulation during chondrocyte maturation

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

Mayo, Jaime L.; Holden, Devin N.; Barrow, Jeffery R.

2009-08-01

The transcription factor Lc-Maf, which is a splice variant of c-Maf, is expressed in cartilage undergoing endochondral ossification and participates in the regulation of type II collagen through a cartilage-specific Col2a1 enhancer element. Type XXVII and type XI collagens are also expressed in cartilage during endochondral ossification, and so enhancer/reporter assays were used to determine whether Lc-Maf could regulate cartilage-specific enhancers from the Col27a1 and Col11a2 genes. The Col27a1 enhancer was upregulated over 4-fold by Lc-Maf, while the Col11a2 enhancer was downregulated slightly. To confirm the results of these reporter assays, rat chondrosarcoma (RCS) cells were transiently transfected with anmore » Lc-Maf expression plasmid, and quantitative RT-PCR was performed to measure the expression of endogenous Col27a1 and Col11a2 genes. Endogenous Col27a1 was upregulated 6-fold by Lc-Maf overexpression, while endogenous Col11a2 was unchanged. Finally, in situ hybridization and immunohistochemistry were performed in the radius and ulna of embryonic day 17 mouse forelimbs undergoing endochondral ossification. Results demonstrated that Lc-Maf and Col27a1 mRNAs are coexpressed in proliferating and prehypertrophic regions, as would be predicted if Lc-Maf regulates Col27a1 expression. Type XXVII collagen protein was also most abundant in prehypertrophic and proliferating chondrocytes. Others have shown that mice that are null for Lc-Maf and c-Maf have expanded hypertrophic regions with reduced ossification and delayed vascularization. Separate studies have indicated that Col27a1 may serve as a scaffold for ossification and vascularization. The work presented here suggests that Lc-Maf may affect the process of endochondral ossification by participating in the regulation of Col27a1 expression.« less

Isolation and Functional Characterization of a Floral Repressor, BcMAF1, From Pak-choi (Brassica rapa ssp. Chinensis).

PubMed

Huang, Feiyi; Liu, Tongkun; Hou, Xilin

2018-01-01

MADS-box genes form a large gene family in plants and are involved in multiple biological processes, such as flowering. However, the regulation mechanism of MADS-box genes in flowering remains unresolved, especially under short-term cold conditions. In the present study, we isolated BcMAF1 , a Pak-choi ( Brassica rapa ssp. Chinensis ) MADS AFFECTING FLOWERING ( MAF ), as a floral repressor and functionally characterized BcMAF1 in Arabidopsis and Pak-choi. Subcellular localization and sequence analysis indicated that BcMAF1 was a nuclear protein and contained a conserved MADS-box domain. Expression analysis revealed that BcMAF1 had higher expression levels in leaves, stems, and petals, and could be induced by short-term cold conditions in Pak-choi. Overexpressing BcMAF1 in Arabidopsis showed that BcMAF1 had a negative function in regulating flowering, which was further confirmed by silencing endogenous BcMAF1 in Pak-choi. In addition, qPCR results showed that AtAP3 expression was reduced and AtMAF2 expression was induced in BcMAF1 -overexpressing Arabidopsis . Meanwhile, BcAP3 transcript was up-regulated and BcMAF2 transcript was down-regulated in BcMAF1 -silencing Pak-choi. Yeast one-hybrid and dual luciferase transient assays showed that BcMAF1 could bind to the promoters of BcAP3 and BcMAF2 . These results indicated that BcAP3 and BcMAF2 might be the targets of BcMAF1. Taken together, our results suggested that BcMAF1 could negatively regulate flowering by directly activating BcMAF2 and repressing BcAP3 .

The large Maf factor Traffic Jam controls gonad morphogenesis in Drosophila.

PubMed

Li, Michelle A; Alls, Jeffrey D; Avancini, Rita M; Koo, Karen; Godt, Dorothea

2003-11-01

Interactions between somatic and germline cells are critical for the normal development of egg and sperm. Here we show that the gene traffic jam (tj) produces a soma-specific factor that controls gonad morphogenesis and is required for female and male fertility. tj encodes the only large Maf factor in Drosophila melanogaster, an orthologue of the atypical basic Leu zipper transcription factors c-Maf and MafB/Kreisler in vertebrates. Expression of tj occurs in somatic gonadal cells that are in direct contact with germline cells throughout development. In tj mutant gonads, somatic cells fail to inter-mingle and properly envelop germline cells, causing an early block in germ cell differentiation. In addition, tj mutant somatic cells show an increase in the level of expression for several adhesion molecules. We propose that tj is a critical modulator of the adhesive properties of somatic cells, facilitating germline-soma interactions that are essential for germ cell differentiation.

Deregulated Methionine Adenosyltransferase α1, c-Myc and Maf Proteins Interplay Promotes Cholangiocarcinoma Growth in Mice and Humans

PubMed Central

Yang, Heping; Liu, Ting; Wang, Jiaohong; Li, Tony W.H.; Fan, Wei; Peng, Hui; Krishnan, Anuradha; Gores, Gregory J.; Mato, Jose M.; Lu, Shelly C.

2016-01-01

We reported c-Myc induction drives cholestatic liver injury and cholangiocarcinoma (CCA) in mice. We also showed induction of Maf proteins (MafG and c-Maf) contributed to cholestatic liver injury, whereas S-adenosylmethionine (SAMe) administration was protective. Here we determined whether there is interplay between c-Myc, Maf proteins and methionine adenosyltransferase α1 (MATα1), which is responsible for SAMe biosynthesis in liver. We used bile duct ligation (BDL) and lithocholic acid (LCA) treatment in mice as chronic cholestasis models, a murine CCA model, human CCA cell lines KMCH and Huh-28, human liver cancer HepG2, and human CCA specimens to study gene and protein expression, protein-protein interactions, molecular mechanisms and functional outcomes. We found c-Myc, MATα1 (encoded by MAT1A), MafG and c-Maf interact with each other directly. MAT1A expression fell in hepatocytes and bile duct epithelial cells during chronic cholestasis and in murine and human CCA. The opposite occurred with c-Myc, MafG and c-Maf expression. MATα1 interacts mainly with Mnt in normal liver but this switches to c-Maf, MafG and c-Myc in cholestatic livers and CCA. Promoter regions of these genes have E-boxes that are bound by MATα1 and Mnt in normal liver and benign bile duct epithelial cells that switched to c-Myc, c-Maf and MafG in cholestasis and CCA cells. E-box positively regulates c-Myc, MafG and c-Maf, but it negatively regulates MAT1A. MATα1 represses whereas c-Myc, MafG and c-Maf enhance E-box-driven promoter activity. Knocking down MAT1A or overexpressing MafG or c-Maf enhanced CCA growth and invasion in vivo. Conclusion We have uncovered a novel interplay between MATα1, c-Myc and Maf proteins and their deregulation during chronic cholestasis may facilitate CCA oncogenesis. PMID:26969892

Black Tea High-Molecular-Weight Polyphenol-Rich Fraction Promotes Hypertrophy during Functional Overload in Mice.

PubMed

Aoki, Yuki; Ozawa, Tetsuo; Takemasa, Tohru; Numata, Osamu

2017-03-29

Mitochondria activation factor (MAF) is a high-molecular-weight polyphenol extracted from black tea that stimulates training-induced 5' adenosine monophosphate-activated protein kinase (AMPK) activation and improves endurance capacity. Originally, MAF was purified from black tea using butanol and acetone, making it unsuitable for food preparation. Hence, we extracted a MAF-rich sample "E80" from black tea, using ethanol and water only. Here, we examined the effects of E80 on resistance training. Eight-week old C57BL/6 mice were fed with a normal diet or a diet containing 0.5% E80 for 4, 7 and 14 days under conditions of functional overload. It was found that E80 administration promoted overload-induced hypertrophy and induced phosphorylation of the Akt/mammalian target of rapamycin (mTOR) pathway proteins, such as Akt, P70 ribosomal protein S6 kinase (p70S6K), and S6 in the plantaris muscle. Therefore, functional overload and E80 administration accelerated mTOR signaling and increased protein synthesis in the muscle, thereby inducing hypertrophy.

A common variant of MAF/c-MAF, transcriptional factor gene in the kidney, is associated with gout susceptibility.

PubMed

Higashino, Toshihide; Matsuo, Hirotaka; Okada, Yukinori; Nakashima, Hiroshi; Shimizu, Seiko; Sakiyama, Masayuki; Tadokoro, Shin; Nakayama, Akiyoshi; Kawaguchi, Makoto; Komatsu, Mako; Hishida, Asahi; Nakatochi, Masahiro; Ooyama, Hiroshi; Imaki, Junko; Shinomiya, Nariyoshi

2018-01-01

Gout is a multifactorial disease characterized by acute inflammatory arthritis, and it is caused as a consequence of hyperuricemia. A recent meta-analysis of genome-wide association studies has newly identified the relationship between serum uric acid (SUA) levels and rs889472, a single nucleotide polymorphism of musculoaponeurotic fibrosarcoma oncogene (MAF/c-MAF). However, it remained unclear whether rs889472 is associated with gout susceptibility. In the present study, we investigate the association between c-MAF rs889472 and gout in Japanese male population. We genotyped 625 male patients who were clinically diagnosed as gout and 1221 male control subjects without hyperuricemia or a history of gout by TaqMan method. As a result, the major allele (C), which reportedly increases SUA levels, had a higher frequency in the gout cases (58.8%) than in the controls (55.0%). A logistic regression analysis showed a significant association between rs889472 and gout (p = 0.029, odds ratio = 1.17; 95% confidence interval 1.02-1.34). C-MAF is reported as a pivotal transcriptional factor in the development and differentiation of renal proximal tubular cells. Because urate is mainly regulated in renal proximal tubular cells, c-MAF may have an important role in urate regulation in the kidney and influence not only SUA but also gout susceptibility. Our finding shows that rs889472 of c-MAF is associated with gout susceptibility.

Mutation update of transcription factor genes FOXE3, HSF4, MAF, and PITX3 causing cataracts and other developmental ocular defects.

PubMed

Anand, Deepti; Agrawal, Smriti A; Slavotinek, Anne; Lachke, Salil A

2018-04-01

Mutations in the transcription factor genes FOXE3, HSF4, MAF, and PITX3 cause congenital lens defects including cataracts that may be accompanied by defects in other components of the eye or in nonocular tissues. We comprehensively describe here all the variants in FOXE3, HSF4, MAF, and PITX3 genes linked to human developmental defects. A total of 52 variants for FOXE3, 18 variants for HSF4, 20 variants for MAF, and 19 variants for PITX3 identified so far in isolated cases or within families are documented. This effort reveals FOXE3, HSF4, MAF, and PITX3 to have 33, 16, 18, and 7 unique causal mutations, respectively. Loss-of-function mutant animals for these genes have served to model the pathobiology of the associated human defects, and we discuss the currently known molecular function of these genes, particularly with emphasis on their role in ocular development. Finally, we make the detailed FOXE3, HSF4, MAF, and PITX3 variant information available in the Leiden Online Variation Database (LOVD) platform at https://www.LOVD.nl/FOXE3, https://www.LOVD.nl/HSF4, https://www.LOVD.nl/MAF, and https://www.LOVD.nl/PITX3. Thus, this article informs on key variants in transcription factor genes linked to cataract, aphakia, corneal opacity, glaucoma, microcornea, microphthalmia, anterior segment mesenchymal dysgenesis, and Ayme-Gripp syndrome, and facilitates their access through Web-based databases. © 2018 Wiley Periodicals, Inc.

The effects of different irrigation protocols on removing calcium hydroxide from the root canals.

PubMed

Üstün, Y; Aslan, T; Sagsen, B; Dincer, A N

2016-01-01

The aim of this study was to evaluate the efficiencies of different irrigation protocols and solutions in the removal of calcium hydroxide (Ca[OH]2). Sixty-eight maxillary incisors were used. Root canals were prepared and filled with Ca(OH)2. Two control (n = 4) and six experimental groups (n = 10) were adjusted: Group 1:1% peracetic acid (PAA) + master apical file (MAF); Group 2: 17% ethylenediaminetetraacetic acid (EDTA) + MAF; Group 3: 9% 1-hydroxyethylidene-1,1-bisphosphonate (HEBP) + MAF; Group 4: 1% PAA + ultrasonic activation (UA); Group 5: 17% EDTA + UA; Group 6: 9% HEBP + UA. The cleanliness of root canal thirds were evaluated with scanning electron microscopy. Statistical analysis were performed (α = 0.05). At coronal thirds; PAA + UA was superior to EDTA + MAF, HEBP + MAF; and PAA + MAF was superior to EDTA + MAF, HEBP + MAF (P < 0.05). At middle thirds; PAA + MAF and PAA + UA were superior to EDTA + MAF and EDTA + UA; and, PAA + UA was superior to HEBP + MAF (P < 0.05). There were no significant differences among the rest of the experimental groups (P > 0.05). Complete removal of Ca(OH)2could not be achieved by none of the irrigants at all root thirds.

Aldosterone induces clonal β-cell failure through glucocorticoid receptor

PubMed Central

Chen, Fang; Liu, Jia; Wang, Yanyang; Wu, Tijun; Shan, Wei; Zhu, Yunxia; Han, Xiao

2015-01-01

Aldosterone excess causes insulin resistance in peripheral tissues and directly impairs the function of clonal β-cell. The aim of this study was to investigate the molecular mechanisms involved in the aldosterone-induced impairment of clonal β-cells. As expected, aldosterone induced apoptosis and β-cell dysfunction, including impairment of insulin synthesis and secretion, which were reversed by Glucocorticoid receptor (GR) antagonists or GR-specific siRNA. However, mineralocorticoid receptor (MR) antagonists or MR-specific siRNA had no effect on impairment of clonal β-cells induced by aldosterone. Besides, aldosterone significantly decreased expression and activity of MafA, while activated JNK and p38 MAPK in a GR-dependent manner. In addition, JNK inhibitors (SP600125) and/or p38 inhibitors (SB203580) could abolish the effect of aldosterone on MafA expression and activity. Importantly, overexpression of JNK1 or p38 reversed the protective effect of a GR antagonist on the decrease of MafA expression and activity. Furthermore, aldosterone inhibits MafA expression at the transcriptional and post-transcriptional level through activation of JNK and p38, respectively. Consequently, overexpression of MafA increased synthesis and secretion of insulin, and decreased apoptosis in clonal β-cells exposed to aldosterone. These findings identified aldosterone as an inducer of clonal β-cell failure that operates through the GR-MAPK-MafA signaling pathway. PMID:26287126

Effect of paricalcitol and GcMAF on angiogenesis and human peripheral blood mononuclear cell proliferation and signaling.

PubMed

Pacini, Stefania; Morucci, Gabriele; Punzi, Tiziana; Gulisano, Massimo; Ruggiero, Marco; Amato, Marcello; Aterini, Stefano

2012-01-01

In addition to its role in calcium homeostasis and bone mineralization, vitamin D is involved in immune defence, cardiovascular function, inflammation and angiogenesis, and these pleiotropic effects are of interested in the treatment of chronic kidney disease. Here we investigated the effects of paricalcitol, a nonhypercalcemic vitamin D analogue, on human peripheral blood mononuclear cell proliferation and signaling, and on angiogenesis. These effects were compared with those of a known inhibitor of angiogenesis pertaining to the vitamin D axis, the vitamin D-binding protein-derived Gc-macrophage activating factor (GcMAF). Since the effects of vitamin D receptor agonists are associated with polymorphisms of the gene coding for the receptor, we measured the effects of both compounds on mononuclear cells harvested from subjects harboring different BsmI polymorphisms. Paricalcitol inhibited mononuclear cell viability with the bb genotype showing the highest effect. GcMAF, on the contrary, stimulated cell proliferation, with the bb genotype showing the highest stimulatory effect. Both compounds stimulated 3'-5'-cyclic adenosine monophosphate formation in mononuclear cells with the highest effect on the bb genotype. Paricalcitol and GcMAF inhibited the angiogenesis induced by proinflammatory prostaglandin E1. Polymorphisms of the vitamin D receptor gene, known to be associated with the highest responses to vitamin D receptor agonists, are also associated with the highest responses to GcMAF. These results highlight the role of the vitamin D axis in chronic kidney disease, an axis which includes vitamin D, its receptor and vitamin D-binding protein-derived GcMAF.

A designed glycoprotein analogue of Gc-MAF exhibits native-like phagocytic activity.

PubMed

Bogani, Federica; McConnell, Elizabeth; Joshi, Lokesh; Chang, Yung; Ghirlanda, Giovanna

2006-06-07

Rational protein design has been successfully used to create mimics of natural proteins that retain native activity. In the present work, de novo protein engineering is explored to develop a mini-protein analogue of Gc-MAF, a glycoprotein involved in the immune system activation that has shown anticancer activity in mice. Gc-MAF is derived in vivo from vitamin D binding protein (VDBP) via enzymatic processing of its glycosaccharide to leave a single GalNAc residue located on an exposed loop. We used molecular modeling tools in conjunction with structural analysis to splice the glycosylated loop onto a stable three-helix bundle (alpha3W, PDB entry 1LQ7). The resulting 69-residue model peptide, MM1, has been successfully synthesized by solid-phase synthesis both in the aglycosylated and the glycosylated (GalNAc-MM1) form. Circular dichroism spectroscopy confirmed the expected alpha-helical secondary structure. The thermodynamic stability as evaluated from chemical and thermal denaturation is comparable with that of the scaffold protein, alpha3W, indicating that the insertion of the exogenous loop of Gc-MAF did not significantly perturb the overall structure. GalNAc-MM1 retains the macrophage stimulation activity of natural Gc-MAF; in vitro tests show an identical enhancement of Fc-receptor-mediated phagocytosis in primary macrophages. GalNAc-MM1 provides a framework for the development of mutants with increased activity that could be used in place of Gc-MAF as an immunomodulatory agent in therapy.

Degalactosylated/Desialylated Bovine Colostrum Induces Macrophage Phagocytic Activity Independently of Inflammatory Cytokine Production.

PubMed

Uto, Yoshihiro; Kawai, Tomohito; Sasaki, Toshihide; Hamada, Ken; Yamada, Hisatsugu; Kuchiike, Daisuke; Kubo, Kentaro; Inui, Toshio; Mette, Martin; Tokunaga, Ken; Hayakawa, Akio; Go, Akiteru; Oosaki, Tomohiro

2015-08-01

Colostrum contains antibodies, such as immunoglobulin G (IgG), immunoglobulin A (IgA) and immunoglobulin M (IgM), and, therefore, has potent immunomodulating activity. In particular, IgA has an O-linked sugar chain similar to that in the group-specific component (Gc) protein, a precursor of the Gc protein-derived macrophage-activating factor (GcMAF). In the present study, we investigated the macrophage-activating effects of degalactosylated/desialylated bovine colostrum. We detected the positive band in degalactosylated/ desialylated bovine colostrum by western blotting using Helix pomatia agglutinin lectin. We also found that degalactosylated/ desialylated bovine colostrum could significantly enhance the phagocytic activity of mouse peritoneal macrophages in vitro and of intestinal macrophages in vivo. Besides, degalactosylated/desialylated bovine colostrum did not mediate the production of inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). Similar to the use of GcMAF, degalactosylated/desialylated bovine colostrum can be used as a potential macrophage activator for various immunotherapies. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

A New Family of Secreted Toxins in Pathogenic Neisseria Species

PubMed Central

Jamet, Anne; Jousset, Agnès B.; Euphrasie, Daniel; Mukorako, Paulette; Boucharlat, Alix; Ducousso, Alexia; Charbit, Alain; Nassif, Xavier

2015-01-01

The genus Neisseria includes both commensal and pathogenic species which are genetically closely related. However, only meningococcus and gonococcus are important human pathogens. Very few toxins are known to be secreted by pathogenic Neisseria species. Recently, toxins secreted via type V secretion system and belonging to the widespread family of contact-dependent inhibition (CDI) toxins have been described in numerous species including meningococcus. In this study, we analyzed loci containing the maf genes in N. meningitidis and N. gonorrhoeae and proposed a novel uniform nomenclature for maf genomic islands (MGIs). We demonstrated that mafB genes encode secreted polymorphic toxins and that genes immediately downstream of mafB encode a specific immunity protein (MafI). We focused on a MafB toxin found in meningococcal strain NEM8013 and characterized its EndoU ribonuclease activity. maf genes represent 2% of the genome of pathogenic Neisseria, and are virtually absent from non-pathogenic species, thus arguing for an important biological role. Indeed, we showed that overexpression of one of the four MafB toxins of strain NEM8013 provides an advantage in competition assays, suggesting a role of maf loci in niche adaptation. PMID:25569427

A combined approach based on MAF analysis and AHP method to fault detection mapping: A case study from a gas field, southwest of Iran

NASA Astrophysics Data System (ADS)

Shakiba, Sima; Asghari, Omid; Khah, Nasser Keshavarz Faraj

2018-01-01

A combined geostatitical methodology based on Min/Max Auto-correlation Factor (MAF) analysis and Analytical Hierarchy Process (AHP) is presented to generate a suitable Fault Detection Map (FDM) through seismic attributes. Five seismic attributes derived from a 2D time slice obtained from data related to a gas field located in southwest of Iran are used including instantaneous amplitude, similarity, energy, frequency, and Fault Enhancement Filter (FEF). The MAF analysis is implemented to reduce dimension of input variables, and then AHP method is applied on three obtained de-correlated MAF factors as evidential layer. Three Decision Makers (DMs) are used to construct PCMs for determining weights of selected evidential layer. Finally, weights obtained by AHP were multiplied in normalized valued of each alternative (MAF layers) and the concluded weighted layers were integrated in order to prepare final FDM. Results proved that applying algorithm proposed in this study generate a map more acceptable than the each individual attribute and sharpen the non-surface discontinuities as well as enhancing continuity of detected faults.

Protection and governance of MPEG-21 music player MAF contents using MPEG-21 IPMP tools

NASA Astrophysics Data System (ADS)

Hendry; Kim, Munchurl

2006-02-01

MPEG (Moving Picture Experts Groups) is currently standardizing Multimedia Application Format (MAF) which targets to provide simple but practical multimedia applications to the industry. One of the interesting and on-going working items of MAF activity is the so-called Music Player MAF which combines MPEG-1/2 layer III (MP3), JPEG image, and metadata into a standard format. In this paper, we propose a protection and governance mechanism to the Music Player MAF by incorporating other MPEG technology, MPEG-21 IPMP (Intellectual Property Management and Protection). We show, in this paper, use-case of the distribution and consumption of this Music Player contents, requirements, and how this protection and governance can be implemented in conjunction with the current Music Player MAF architecture and file system. With the use of MPEG-21 IPMP, the protection and governance to the content of Music Player MAF fulfils flexibility, extensibility, and granular in protection requirements.

MafA is required for postnatal proliferation of pancreatic β-cells.

PubMed

Eto, Koki; Nishimura, Wataru; Oishi, Hisashi; Udagawa, Haruhide; Kawaguchi, Miho; Hiramoto, Masaki; Fujiwara, Toshiyoshi; Takahashi, Satoru; Yasuda, Kazuki

2014-01-01

The postnatal proliferation and maturation of insulin-secreting pancreatic β-cells are critical for glucose metabolism and disease development in adults. Elucidation of the molecular mechanisms underlying these events will be beneficial to direct the differentiation of stem cells into functional β-cells. Maturation of β-cells is accompanied by increased expression of MafA, an insulin gene transcription factor. Transcriptome analysis of MafA knockout islets revealed MafA is required for the expression of several molecules critical for β-cell function, including Glut2, ZnT8, Granuphilin, Vdr, Pcsk1 and Urocortin 3, as well as Prolactin receptor (Prlr) and its downstream target Cyclin D2 (Ccnd2). Inhibition of MafA expression in mouse islets or β-cell lines resulted in reduced expression of Prlr and Ccnd2, and MafA transactivated the Prlr promoter. Stimulation of β-cells by prolactin resulted in the phosphorylation and translocation of Stat5B and an increased nuclear pool of Ccnd2 via Prlr and Jak2. Consistent with these results, the loss of MafA resulted in impaired proliferation of β-cells at 4 weeks of age. These results suggest that MafA regulates the postnatal proliferation of β-cells via prolactin signaling.

Purified umbilical cord derived mesenchymal stem cell treatment in a case of systemic lupus erythematosus.

PubMed

Phillips, Christopher D; Wongsaisri, Pornpatcharin; Htut, Thein; Grossman, Terry

2017-12-01

Systemic lupus erythematosus (SLE) is a multiple organ system autoimmune disorder for which there is no known cure. We report a case of a young adult lady with SLE and Sjogren's with diagnostic and clinical resolution following purified umbilical cord derived mesenchymal stem cell (MSC) and globulin component protein macrophage activating factor (GcMAF) therapy in a combined multidisciplinary integrative medicine protocol. Our patient had complete reversal of all clinical and laboratory markers. We recommend a prospective randomized double blind study to assess the sustained efficacy of MSC and GcMAF in the treatment of autoimmune connective tissue diseases such as systemic lupus erythematosus.

Glycosylation status of vitamin D binding protein in cancer patients

PubMed Central

Rehder, Douglas S; Nelson, Randall W; Borges, Chad R

2009-01-01

On the basis of the results of activity studies, previous reports have suggested that vitamin D binding protein (DBP) is significantly or even completely deglycosylated in cancer patients, eliminating the molecular precursor of the immunologically important Gc macrophage activating factor (GcMAF), a glycosidase-derived product of DBP. The purpose of this investigation was to directly determine the relative degree of O-linked trisaccharide glycosylation of serum-derived DBP in human breast, colorectal, pancreatic, and prostate cancer patients. Results obtained by electrospray ionization-based mass spectrometric immunoassay showed that there was no significant depletion of DBP trisaccharide glycosylation in the 56 cancer patients examined relative to healthy controls. These results suggest that alternative hypotheses regarding the molecular and/or structural origins of GcMAF must be considered to explain the relative inability of cancer patient serum to activate macrophages. PMID:19642159

Glycosylation status of vitamin D binding protein in cancer patients.

PubMed

Rehder, Douglas S; Nelson, Randall W; Borges, Chad R

2009-10-01

On the basis of the results of activity studies, previous reports have suggested that vitamin D binding protein (DBP) is significantly or even completely deglycosylated in cancer patients, eliminating the molecular precursor of the immunologically important Gc macrophage activating factor (GcMAF), a glycosidase-derived product of DBP. The purpose of this investigation was to directly determine the relative degree of O-linked trisaccharide glycosylation of serum-derived DBP in human breast, colorectal, pancreatic, and prostate cancer patients. Results obtained by electrospray ionization-based mass spectrometric immunoassay showed that there was no significant depletion of DBP trisaccharide glycosylation in the 56 cancer patients examined relative to healthy controls. These results suggest that alternative hypotheses regarding the molecular and/or structural origins of GcMAF must be considered to explain the relative inability of cancer patient serum to activate macrophages.

RNA Polymerase III Output Is Functionally Linked to tRNA Dimethyl-G26 Modification

PubMed Central

Arimbasseri, Aneeshkumar G.; Blewett, Nathan H.; Iben, James R.; Lamichhane, Tek N.; Cherkasova, Vera; Hafner, Markus; Maraia, Richard J.

2015-01-01

Control of the differential abundance or activity of tRNAs can be important determinants of gene regulation. RNA polymerase (RNAP) III synthesizes all tRNAs in eukaryotes and it derepression is associated with cancer. Maf1 is a conserved general repressor of RNAP III under the control of the target of rapamycin (TOR) that acts to integrate transcriptional output and protein synthetic demand toward metabolic economy. Studies in budding yeast have indicated that the global tRNA gene activation that occurs with derepression of RNAP III via maf1-deletion is accompanied by a paradoxical loss of tRNA-mediated nonsense suppressor activity, manifested as an antisuppression phenotype, by an unknown mechanism. We show that maf1-antisuppression also occurs in the fission yeast S. pombe amidst general activation of RNAP III. We used tRNA-HydroSeq to document that little changes occurred in the relative levels of different tRNAs in maf1Δ cells. By contrast, the efficiency of N2,N2-dimethyl G26 (m2 2G26) modification on certain tRNAs was decreased in response to maf1-deletion and associated with antisuppression, and was validated by other methods. Over-expression of Trm1, which produces m2 2G26, reversed maf1-antisuppression. A model that emerges is that competition by increased tRNA levels in maf1Δ cells leads to m2 2G26 hypomodification due to limiting Trm1, reducing the activity of suppressor-tRNASerUCA and accounting for antisuppression. Consistent with this, we show that RNAP III mutations associated with hypomyelinating leukodystrophy decrease tRNA transcription, increase m2 2G26 efficiency and reverse antisuppression. Extending this more broadly, we show that a decrease in tRNA synthesis by treatment with rapamycin leads to increased m2 2G26 modification and that this response is conserved among highly divergent yeasts and human cells. PMID:26720005

c-Maf is required for the development of dorsal horn laminae III/IV neurons and mechanoreceptive DRG axon projections.

PubMed

Hu, Jia; Huang, Tianwen; Li, Tingting; Guo, Zhen; Cheng, Leping

2012-04-18

Establishment of proper connectivity between peripheral sensory neurons and their central targets is required for an animal to sense and respond to various external stimuli. Dorsal root ganglion (DRG) neurons convey sensory signals of different modalities via their axon projections to distinct laminae in the dorsal horn of the spinal cord. In this study, we found that c-Maf was expressed predominantly in the interneurons of laminae III/IV, which primarily receive inputs from mechanoreceptive DRG neurons. In the DRG, c-Maf⁺ neurons also coexpressed neurofilament-200, a marker for the medium- and large-diameter myelinated afferents that transmit non-noxious information. Furthermore, mouse embryos deficient in c-Maf displayed abnormal development of dorsal horn laminae III/IV neurons, as revealed by the marked reduction in the expression of several marker genes for these neurons, including those for transcription factors MafA and Rora, GABA(A) receptor subunit α5, and neuropeptide cholecystokinin. In addition, among the four major subpopulations of DRG neurons marked by expression of TrkA, TrkB, TrkC, and MafA/GFRα2/Ret, c-Maf was required selectively for the proper differentiation of MafA⁺/Ret⁺/GFRα2⁺ low-threshold mechanoreceptors (LTMs). Last, we found that the central and peripheral projections of mechanoreceptive DRG neurons were compromised in c-Maf deletion mice. Together, our results indicate that c-Maf is required for the proper development of MafA⁺/Ret⁺/GFRα2⁺ LTMs in the DRG, their afferent projections in the dorsal horn and Pacinian corpuscles, as well as neurons in laminae III/IV of the spinal cord.

Clinical experience of integrative cancer immunotherapy with GcMAF.

PubMed

Inui, Toshio; Kuchiike, Daisuke; Kubo, Kentaro; Mette, Martin; Uto, Yoshihiro; Hori, Hitoshi; Sakamoto, Norihiro

2013-07-01

Immunotherapy has become an attractive new strategy in the treatment of cancer. The laboratory and clinical study of cancer immunotherapy is rapidly advancing. However, in the clinical setting, the results of cancer immunotherapy are mixed. We therefore contend that cancer immunotherapy should be customized to each patient individually based on their immune status and propose an integrative immunotherapy approach with second-generation group-specific component macrophage activating factor (GcMAF)-containing human serum. The standard protocol of our integrative cancer immunotherapy is as follows: i) 0.5 ml GcMAF-containing human serum is administered intramuscularly or subcutaneously once or twice per week for the duration of cancer therapy until all cancer cells are eradicated; ii) hyper T/natural killer (NK) cell therapy is given once per week for six weeks; iii) high-dose vitamin C is administered intravenously twice per week; iv) alpha lipoic acid (600 mg) is administered orally daily; v) vitamin D3 (5,000-10,000 IU) is administered orally daily. By March 2013, Saisei Mirai have treated over 345 patients with GcMAF. Among them we here present the cases of three patients for whom our integrative immunotherapy was remarkably effective. The results of our integrative immunotherapy seem hopeful. We also plan to conduct a comparative clinical study.>

Methylammonium formate as a mobile phase modifier for reversed-phase liquid chromatography

PubMed Central

Grossman, Shau; Danielson, Neil D.

2009-01-01

Although alkylammonium ionic liquids such as ethylammonium nitrate and ethylammonium formate have been used as mobile phase “solvents” for liquid chromatography (LC), we have shown that methylammonium formate (MAF), in part because of its lower viscosity, can be an effective replacement for methanol (MeOH) in reversed-phase LC. Plots of log retention factor versus the fraction of MeOH and MAF in the mobile phase indicate quite comparable solvent strength slope values of 2.50 and 2.05, respectively. Using a polar endcapped C18 column, furazolidone and nitrofurantoin using 20% MAF-80% water could be separated in 22 min but no baseline separation was possible using MeOH as the modifier, even down to 10%. Suppression of silanol peak broadening effects by MAF is important permitting a baseline separation of pyridoxine, thiamine, and nicotinamide using 5% MAF-95% water at 0.7 mL/min. Using 5% MeOH-95% water, severe peak broadening for thiamine is evident. The compatibility of MAF as a mobile phase modifer for LC with mass spectrometry detection of water soluble vitamins is also shown. PMID:18849044

Facilitated recycling protects human RNA polymerase III from repression by Maf1 in vitro.

PubMed

Cabart, Pavel; Lee, JaeHoon; Willis, Ian M

2008-12-26

Yeast cells synthesize approximately 3-6 million molecules of tRNA every cell cycle at a rate of approximately 2-4 transcripts/gene/s. This high rate of transcription is achieved through many rounds of reinitiation by RNA polymerase (pol) III on stable DNA-bound complexes of the initiation factor TFIIIB. Studies in yeast have shown that the rate of reinitiation is increased by facilitated recycling, a process that involves the repeated reloading of the polymerase on the same transcription unit. However, when nutrients become limiting or stress conditions are encountered, RNA pol III transcription is rapidly repressed through the action of the conserved Maf1 protein. Here we examine the relationship between Maf1-mediated repression and facilitated recycling in a human RNA pol III in vitro system. Using an immobilized template transcription assay, we demonstrate that facilitated recycling is conserved from yeast to humans. We assessed the ability of recombinant human Maf1 to inhibit different steps in transcription before and after preinitiation complex assembly. We show that recombinant Maf1 can inhibit the recruitment of TFIIIB and RNA pol III to immobilized templates. However, RNA pol III bound to preinitiation complexes or in elongation complexes is protected from repression by Maf1 and can undergo several rounds of initiation. This indicates that recombinant Maf1 is unable to inhibit facilitated recycling. The data suggest that additional biochemical steps may be necessary for rapid Maf1-dependent repression of RNA pol III transcription.

The anabolic effects of vitamin D-binding protein-macrophage activating factor (DBP-MAF) and a novel small peptide on bone.

PubMed

Schneider, Gary B; Grecco, Kristina J; Safadi, Fayez F; Popoff, Steven N

2003-01-01

Vitamin D-binding protein-macrophage activating factor (DBP-MAF) has previously been shown to stimulate bone resorption and correct the skeletal defects associated with osteopetrosis in two nonallelic mutations in rats. This same protein and a small fragment of the protein have now been shown to demonstrate an anabolic effect on the skeleton of both newborn and young adult, intact rats. The novel peptide fragment was synthetically produced based on the human amino acid sequence at the site of glycosylation in the third domain of the native protein (DBP). The peptide tested is 14 amino acids in length and demonstrates no homologies other than to that region of DBP. Newborn rats were injected i.p. with saline, peptide (0.4 ng/g body wt.) or DBP-MAF (2 ng/g body wt.) every other day from birth to 14 days of age. On day 16 the rats were euthanized and the long bones collected for bone densitometry by pQCT. After 2 weeks of treatment with either the whole protein (DBP-MAF) or the small peptide, bone density was significantly increased in the treated animals compared to the saline controls. Young adult female rats (180 grams) were given s.c. injections of saline or peptide (0.4 ng/g body wt. or 5 ng/g body wt.) every other day for 2 weeks; 2 days after the final injections, the rats were euthanized and the femurs and tibias collected for bone densitometry. Both doses of the peptide resulted in significant increases in bone density as determined by pQCT. Young adult rats were injected locally with a single dose of the peptide (1 microg) or saline into the marrow cavity of the distal femur. One week after the single injection, the bones were collected for radiographic and histological evaluation. The saline controls showed no evidence of new bone formation, whereas the peptide-treated animals demonstrated osteoinduction in the marrow cavity and osteogenesis of surrounding cortical and metaphyseal bone. These data suggest that DBP-MAF and the synthetic peptide represent therapeutic opportunities for the treatment of a number of bone diseases and skeletal disorders. Systemic administration could be used to treat osteoporosis and a number of other osteopenias, and local administration could be effective in fractures, bony defect repairs, spinal surgery, and joint replacement.

Psychometric evaluation of the Arabic version of the multidimensional assessment of fatigue scale (MAF) for use in patients with ankylosing spondylitis.

PubMed

Bahouq, Hanane; Rostom, Samira; Bahiri, Rachid; Hakkou, Jinane; Aissaoui, Nawal; Hajjaj-Hassouni, Najia

2012-12-01

Fatigue is a frequent symptom during ankylosing spondylitis (AS) often under estimated which needs to be measured properly with respect to its intensity by appropriate measures, such as the multidimensional assessment of fatigue (MAF). The aims of this study were to translate into the classic Arabic version of the MAF questionnaire and to validate its use for assessing fatigue in Moroccan patients with AS. The MAF contains 16 items with a global fatigue index (IGF). The MAF was translated and back-translated to arabic, pretested and reviewed by a committee following the Guillemin criteria (J Clin Epidemiol 46:1417-1432, 1993). It was then validate on 110 Moroccan patients with AS. Reliability for the 3-day test-retest was assessed using internal consistency by Cronbach's alpha coefficient and the intra-class correlation coefficient (ICC). External construct validity was assessed by correlation with pain, activity of disease and other keys variable. The reproducibility of the 15 items was satisfactory with a kappa statistics of agreement superior to 0.6. The ICC for IGF score reproducibility was good and reached 0.98 (IC 95%, 0.96-0.99). The internal consistency was at 0.991 with Cronbach's alpha coefficient. The construct validity showed a positive correlation between MAF and the axial (r = 0.34) and peripheral (r = 0.32) visual analogical scale, the Bath ankylosing spondylitis disease activity index (BASDAI) (r = 0.77), the first item of BASDAI (r = 0.85), the functional disability by the Bath ankylosing spondylitis functional index (r = 0.64), the erythrocyte sedimentation rate (r = 0.43) and the C reactive protein (r = 0.30) (for all P < 0.001). There was no statistical correlation between MAF and the other variables. The Arabic version of the MAF has good comprehensibility, internal consistency, reliability and validity for the evaluation of Arabic speaking patients with AS.

Identification and Characterization of FGF2-Dependent mRNA: microRNA Networks During Lens Fiber Cell Differentiation

PubMed Central

Wolf, Louise; Gao, Chun S.; Gueta, Karen; Xie, Qing; Chevallier, Tiphaine; Podduturi, Nikhil R.; Sun, Jian; Conte, Ivan; Zelenka, Peggy S.; Ashery-Padan, Ruth; Zavadil, Jiri; Cvekl, Ales

2013-01-01

MicroRNAs (miRNAs) and fibroblast growth factor (FGF) signaling regulate a wide range of cellular functions, including cell specification, proliferation, migration, differentiation, and survival. In lens, both these systems control lens fiber cell differentiation; however, a possible link between these processes remains to be examined. Herein, the functional requirement for miRNAs in differentiating lens fiber cells was demonstrated via conditional inactivation of Dicer1 in mouse (Mus musculus) lens. To dissect the miRNA-dependent pathways during lens differentiation, we used a rat (Rattus norvegicus) lens epithelial explant system, induced by FGF2 to differentiate, followed by mRNA and miRNA expression profiling. Transcriptome and miRNome analysis identified extensive FGF2-regulated cellular responses that were both independent and dependent on miRNAs. We identified 131 FGF2-regulated miRNAs. Seventy-six of these miRNAs had at least two in silico predicted and inversely regulated target mRNAs. Genes modulated by the greatest number of FGF-regulated miRNAs include DNA-binding transcription factors Nfib, Nfat5/OREBP, c-Maf, Ets1, and N-Myc. Activated FGF signaling influenced bone morphogenetic factor/transforming growth factor-β, Notch, and Wnt signaling cascades implicated earlier in lens differentiation. Specific miRNA:mRNA interaction networks were predicted for c-Maf, N-Myc, and Nfib (DNA-binding transcription factors); Cnot6, Cpsf6, Dicer1, and Tnrc6b (RNA to miRNA processing); and Ash1l, Med1/PBP, and Kdm5b/Jarid1b/Plu1 (chromatin remodeling). Three miRNAs, including miR-143, miR-155, and miR-301a, down-regulated expression of c-Maf in the 3′-UTR luciferase reporter assays. These present studies demonstrate for the first time global impact of activated FGF signaling in lens cell culture system and predicted novel gene regulatory networks connected by multiple miRNAs that regulate lens differentiation. PMID:24142921

MafB deficiency causes defective respiratory rhythmogenesis and fatal central apnea at birth.

PubMed

Blanchi, Bruno; Kelly, Louise M; Viemari, Jean-Charles; Lafon, Isabelle; Burnet, Henri; Bévengut, Michelle; Tillmanns, Silke; Daniel, Laurent; Graf, Thomas; Hilaire, Gerard; Sieweke, Michael H

2003-10-01

The genetic basis for the development of brainstem neurons that generate respiratory rhythm is unknown. Here we show that mice deficient for the transcription factor MafB die from central apnea at birth and are defective for respiratory rhythmogenesis in vitro. MafB is expressed in a subpopulation of neurons in the preBötzinger complex (preBötC), a putative principal site of rhythmogenesis. Brainstems from Mafb(-/-) mice are insensitive to preBötC electrolytic lesion or stimulation and modulation of rhythmogenesis by hypoxia or peptidergic input. Furthermore, in Mafb(-/-) mice the preBötC, but not major neuromodulatory groups, presents severe anatomical defects with loss of cellularity. Our results show an essential role of MafB in central respiratory control, possibly involving the specification of rhythmogenic preBötC neurons.

The Evolution of Host Mitochondrial Association and its Impact on Toxoplasma gondii Infection

NASA Astrophysics Data System (ADS)

English, Elizabeth D.

The association of intracellular pathogens with host mitochondria has been observed across taxa, from bacterial pathogens, such as Legionella pneumophila and Chlamydia trachomati, to the eukaryotic pathogen Toxoplasma gondii. However the functional impact of host mitochondrial association (HMA) remains difficult to assess in most of these species because in many cases the genes responsible for this phenomenon have not yet been identified. The recent discovery of the T. gondii gene responsible for HMA, Mitochondrial Association Factor 1 ( MAF1) has provided us with the tools to begin to understand the evolution and impact of HMA. Here we use multispecies sequence analysis to determine that the MAF1 locus is tandemly duplicated and diversified in both T. gondii and its nearest extant relative Hammondia hammondi, but not another close relative Neospora caninum. Using cross-species complementation we find that T. gondii and H. hammondi harbor copies of MAF1 able to mediate HMA, while N. caninum does not. We have begun mutational analysis using naturally occurring HMA+ and HMA- paralogs of MAF1 in order to determine the portions of MAF1 protein necessary for HMA. Additionally, we have identified the first in vivo phenotypes associated with HMA using multiple mouse models, for both acute and chronic infection. Taken together these data indicate that HMA likely evolved via neofunctionalization of a duplicated ancestral MAF1 gene, and that the neofunctionalized, HMA competent copy of MAF1 provides a selective advantage.

Examining brain structures associated with the motive to achieve success and the motive to avoid failure: A voxel-based morphometry study.

PubMed

Ming, Dan; Chen, Qunlin; Yang, Wenjing; Chen, Rui; Wei, Dongtao; Li, Wenfu; Qiu, Jiang; Xu, Zhan; Zhang, Qinglin

2016-01-01

The motive to achieve success (MAS) and motive to avoid failure (MAF) are two different but classical kinds of achievement motivation. Though many functional magnetic resonance imaging studies have explored functional activation in motivation-related conditions, research has been silent as to the brain structures associated with individual differences in achievement motivation, especially with respect to MAS and MAF. In this study, the voxel-based morphometry method was used to uncover focal differences in brain structures related to MAS and MAF measured by the Mehrabian Achieving Tendency Scale in 353 healthy young Chinese adults. The results showed that the brain structures associated with individual differences in MAS and MAF were distinct. MAS was negatively correlated with regional gray matter volume (rGMV) in the medial prefrontal cortex (mPFC)/orbitofrontal cortex while MAF was negatively correlated with rGMV in the mPFC/subgenual cingulate gyrus. After controlling for mutual influences of MAS and MAF scores, MAS scores were found to be related to rGMV in the mPFC/orbitofrontal cortex and another cluster containing the parahippocampal gyrus and precuneus. These results may predict that compared with MAF, the generation process of MAS may be more complex and rational, thus in the real world, perhaps MAS is more beneficial to personal growth and guaranteeing the quality of task performance.

We Can Still Be Friends: IFN-γ Breaks Up Macrophage Enhancers.

PubMed

Novakovic, Boris; Wang, Cheng; Logie, Colin

2017-08-15

Interferon (IFN)-γ can prime macrophages for inflammatory responses by several mechanisms, including enhancer establishment and gene activation. In this issue of Immunity, Kang et al. (2017) provide insight into the mechanisms of IFN-γ-mediated gene repression as they show that IFN-γ promotes the disassembly of select active enhancers by interfering with enhancer-binding transcription factor MAF. Copyright © 2017 Elsevier Inc. All rights reserved.

Sequential and combinatorial roles of maf family genes define proper lens development.

PubMed

Reza, Hasan Mahmud; Urano, Atsuyo; Shimada, Naoko; Yasuda, Kunio

2007-01-16

Maf proteins have been shown to play pivotal roles in lens development in vertebrates. The developing chick lens expresses at least three large Maf proteins. However, the transcriptional relationship among the three large maf genes and their various roles in transactivating the downstream genes largely remain to be elucidated. Chick embryos were electroporated with wild-type L-maf, c-maf, and mafB by in ovo electroporation, and their effects on gene expression were determined by in situ hybridization using specific probes or by immunostaining. Endogenous gene expression was determined using nonelectroporated samples. A regulation mechanism exists among the members of maf family gene. An early-expressed member of this gene family typically stimulates the expression of later-expressed members. We also examined the regulation of various lens-expressing genes with a focus on the interaction between different Maf proteins. We found that the transcriptional ability of Maf proteins varies, even when the target is the same, in parallel with their discrete functions. L-Maf and c-Maf have no effect on E-cadherin expression, whereas MafB enhances its expression and thereby impedes lens vesicle formation. This study also revealed that Maf proteins can regulate the expression of gap junction genes, connexins, and their interacting partner, major intrinsic protein (MIP), during lens development. Misexpression of L-Maf and c-Maf induces ectopic expression of Cx43 and MIP; in contrast, MafB appears to have no effect on Cx43, but induces MIP significantly as evidenced from our gain-of-function experiments. Our results indicate that large Maf function is indispensable for chick lens initiation and development. In addition, L-Maf positively regulates most of the essential genes in this program and directs a series of molecular events leading to proper formation of the lens.

Power considerations for λ inflation factor in meta-analyses of genome-wide association studies.

PubMed

Georgiopoulos, Georgios; Evangelou, Evangelos

2016-05-19

The genomic control (GC) approach is extensively used to effectively control false positive signals due to population stratification in genome-wide association studies (GWAS). However, GC affects the statistical power of GWAS. The loss of power depends on the magnitude of the inflation factor (λ) that is used for GC. We simulated meta-analyses of different GWAS. Minor allele frequency (MAF) ranged from 0·001 to 0·5 and λ was sampled from two scenarios: (i) random scenario (empirically-derived distribution of real λ values) and (ii) selected scenario from simulation parameter modification. Adjustment for λ was considered under single correction (within study corrected standard errors) and double correction (additional λ corrected summary estimate). MAF was a pivotal determinant of observed power. In random λ scenario, double correction induced a symmetric power reduction in comparison to single correction. For MAF 1·2 and MAF >5%. Our results provide a quick but detailed index for power considerations of future meta-analyses of GWAS that enables a more flexible design from early steps based on the number of studies accumulated in different groups and the λ values observed in the single studies.

Maf promotes osteoblast differentiation in mice by mediating the age-related switch in mesenchymal cell differentiation

PubMed Central

Nishikawa, Keizo; Nakashima, Tomoki; Takeda, Shu; Isogai, Masashi; Hamada, Michito; Kimura, Ayako; Kodama, Tatsuhiko; Yamaguchi, Akira; Owen, Michael J.; Takahashi, Satoru; Takayanagi, Hiroshi

2010-01-01

Aging leads to the disruption of the homeostatic balance of multiple biological systems. In bone marrow multipotent mesenchymal cells undergo differentiation into various anchorage-dependent cell types, including osteoblasts and adipocytes. With age as well as with treatment of antidiabetic drugs such as thiazolidinediones, mesenchymal cells favor differentiation into adipocytes, resulting in an increased number of adipocytes and a decreased number of osteoblasts, causing osteoporosis. The mechanism behind this differentiation switch is unknown. Here we show an age-related decrease in the expression of Maf in mouse mesenchymal cells, which regulated mesenchymal cell bifurcation into osteoblasts and adipocytes by cooperating with the osteogenic transcription factor Runx2 and inhibiting the expression of the adipogenic transcription factor Pparg. The crucial role of Maf in both osteogenesis and adipogenesis was underscored by in vivo observations of delayed bone formation in perinatal Maf–/– mice and an accelerated formation of fatty marrow associated with bone loss in aged Maf+/– mice. This study identifies a transcriptional mechanism for an age-related switch in cell fate determination and may provide a molecular basis for novel therapeutic strategies against age-related bone diseases. PMID:20877012

Antibiotic eluting clay mineral (Laponite®) for wound healing application: an in vitro study.

PubMed

Ghadiri, M; Chrzanowski, W; Rohanizadeh, R

2014-11-01

Different materials in form of sponge, hydrogel and film have been developed and formulated for treating and dressing burn wounds. In this study, the potential of Laponite, a gel forming clay, in combination with an antimicrobial agent (mafenide), as a wound dressing material was tested in vitro. Laponite/mafenide (Lap/Maf) hydrogel was formulated in three different ratios of Lap/Maf 1:1, 1:2, 1:3. Laponite/mafenide/alginate (Lap/Maf/Alg) film was also formulated by combining Lap/Maf gel (1:1) with alginate. Intercalation rate of mafenide into the layers of Laponite nanoparticles and physico-chemical properties, including wound dressing characteristics of materials were studied using various analytical methods. Furthermore, the degradation of materials and the release profile of mafenide were investigated in simulated wound exudates fluid and antibacterial effectiveness of the eluted mafenide was tested on a range of bacterial species. The cytotoxicity of materials was also evaluated in skin fibroblast culture. The results showed that mafenide molecules were intercalated between the nano-sized layers of Laponite. The eluted mafenide showed active antibacterial effects against all three tested bacteria. All intercalated mafenide released from Lap/Maf 1:1 and 1:2 gel formulations and nearly 80% release from 1:3 formulation during test period. No significant difference was observed in release profile of mafenide between Lap/Maf/Alg film and Lap/Maf formulations. Wound dressing tests on Lap/Maf/Alg film showed it is a breathable dressing and has capacity to absorb wound exudates. The study showed that prepared Lap/Maf composite has the potential to be used as an antibiotic eluting gel or film for wound healing application. Additionally, Laponite has shown benefits in wound healing processes by releasing Mg(2+) ions and thereby reducing the cytotoxic effect of mafenide on fibroblast cells.

Host Mitochondrial Association Evolved in the Human Parasite Toxoplasma gondii via Neofunctionalization of a Gene Duplicate

PubMed Central

Adomako-Ankomah, Yaw; English, Elizabeth D.; Danielson, Jeffrey J.; Pernas, Lena F.; Parker, Michelle L.; Boulanger, Martin J.; Dubey, Jitender P.; Boyle, Jon P.

2016-01-01

In Toxoplasma gondii, an intracellular parasite of humans and other animals, host mitochondrial association (HMA) is driven by a gene family that encodes multiple mitochondrial association factor 1 (MAF1) proteins. However, the importance of MAF1 gene duplication in the evolution of HMA is not understood, nor is the impact of HMA on parasite biology. Here we used within- and between-species comparative analysis to determine that the MAF1 locus is duplicated in T. gondii and its nearest extant relative Hammondia hammondi, but not another close relative, Neospora caninum. Using cross-species complementation, we determined that the MAF1 locus harbors multiple distinct paralogs that differ in their ability to mediate HMA, and that only T. gondii and H. hammondi harbor HMA+ paralogs. Additionally, we found that exogenous expression of an HMA+ paralog in T. gondii strains that do not normally exhibit HMA provides a competitive advantage over their wild-type counterparts during a mouse infection. These data indicate that HMA likely evolved by neofunctionalization of a duplicate MAF1 copy in the common ancestor of T. gondii and H. hammondi, and that the neofunctionalized gene duplicate is selectively advantageous. PMID:26920761

A possible new role for vitamin D-binding protein in osteoclast control: inhibition of extracellular Ca2+ sensing at low physiological concentrations.

PubMed

Adebanjo, O A; Moonga, B S; Haddad, J G; Huang, C L; Zaidi, M

1998-08-28

Upon removal of its sialic acid or galactose residue, vitamin D-binding protein (DBP) becomes a potent macrophage-activating factor, DBP-MAF. Here we document a new function of DBP-MAF and its parent molecule, DBP, in osteoclast control. We show that all DBPs potently inhibit extracellular Ca2+ (cation) sensing at low nanomolar concentrations with the following rank order of potency: native DBP = sialidase-treated DBP > beta-galactosidase-treated DBP. This attenuation remains unaffected despite co-incubation either with the native DBP ligand, 1,25-dihydroxyvitamin D3, or with an asialoglycoprotein receptor modulator, asialoorosomucoid. Taken together, the results suggest that circulating DBP may play a role in the systemic control of osteoclastic bone resorption, a hitherto unrecognized action of the protein.

mTORC1 Directly Phosphorylates and Regulates Human MAF1▿

PubMed Central

Michels, Annemieke A.; Robitaille, Aaron M.; Buczynski-Ruchonnet, Diane; Hodroj, Wassim; Reina, Jaime H.; Hall, Michael N.; Hernandez, Nouria

2010-01-01

mTORC1 is a central regulator of growth in response to nutrient availability, but few direct targets have been identified. RNA polymerase (pol) III produces a number of essential RNA molecules involved in protein synthesis, RNA maturation, and other processes. Its activity is highly regulated, and deregulation can lead to cell transformation. The human phosphoprotein MAF1 becomes dephosphorylated and represses pol III transcription after various stresses, but neither the significance of the phosphorylations nor the kinase involved is known. We find that human MAF1 is absolutely required for pol III repression in response to serum starvation or TORC1 inhibition by rapamycin or Torin1. The protein is phosphorylated mainly on residues S60, S68, and S75, and this inhibits its pol III repression function. The responsible kinase is mTORC1, which phosphorylates MAF1 directly. Our results describe molecular mechanisms by which mTORC1 controls human MAF1, a key repressor of RNA polymerase III transcription, and add a new branch to the signal transduction cascade immediately downstream of TORC1. PMID:20516213

mTORC1 directly phosphorylates and regulates human MAF1.

PubMed

Michels, Annemieke A; Robitaille, Aaron M; Buczynski-Ruchonnet, Diane; Hodroj, Wassim; Reina, Jaime H; Hall, Michael N; Hernandez, Nouria

2010-08-01

mTORC1 is a central regulator of growth in response to nutrient availability, but few direct targets have been identified. RNA polymerase (pol) III produces a number of essential RNA molecules involved in protein synthesis, RNA maturation, and other processes. Its activity is highly regulated, and deregulation can lead to cell transformation. The human phosphoprotein MAF1 becomes dephosphorylated and represses pol III transcription after various stresses, but neither the significance of the phosphorylations nor the kinase involved is known. We find that human MAF1 is absolutely required for pol III repression in response to serum starvation or TORC1 inhibition by rapamycin or Torin1. The protein is phosphorylated mainly on residues S60, S68, and S75, and this inhibits its pol III repression function. The responsible kinase is mTORC1, which phosphorylates MAF1 directly. Our results describe molecular mechanisms by which mTORC1 controls human MAF1, a key repressor of RNA polymerase III transcription, and add a new branch to the signal transduction cascade immediately downstream of TORC1.

Genetic association with low concentrations of high density lipoprotein-cholesterol in a pediatric population of the Middle East and North Africa: the CASPIAN-III study.

PubMed

Kelishadi, Roya; Haghjooy Javanmard, Shaghayegh; Tajadini, Mohammad Hasan; Mansourian, Marjan; Motlagh, Mohammad Esmaeil; Ardalan, Gelayol; Ban, Matthew

2014-11-01

Depressed high-density lipoprotein cholesterol (HDL-C) is prevalent the Middle East and North Africa. Some studies have documented associations between HDL-C and several single nucleotide polymorphisms (SNPs) in candidate gene polymorphisms. We investigated the associations between SNP genotypes and HDL-C levels in Iranian students, aged 10-18 years. Genotyping was performed in 750 randomly selected participants among those with low HDL-C levels (below 5th percentile), intermediate HDL-C levels (5-95th) and high HDL-C levels (above the 95th percentile). Minor allele frequencies (MAFs) of the SNPs of interest were compared between the three HDL-C groups. The vast majority of pairwise comparisons of MAFs between HDL-C groups were significant. Pairwise comparisons between low and high HDL-C groups showed significant between-group differences in MAFs for all SNPs, except for APOC3 rs5128. Pairwise comparisons between low and intermediate HDL-C groups showed significant between-group differences in MAFs for all SNPs, except for APOC3 rs5128 and APOA1 rs2893157. Pairwise comparisons between intermediate and high HDL-C groups showed significant between-group differences in MAFs for all SNPs, except for ABCA1 APOC3 rs5128 and APOA1 rs2893157. After adjustment for confounding factors, including age, sex, body mass index, low physical activity, consumption of saturated fats, and socioeconomic status, ABCA1 r1587K and CETP A373P significantly increased the risk of depressed HDL-C, and CETP Taq1 had a protective role. This study replicated several associations between HDL-C levels and candidate gene SNPs from genome-wide associations with HDL-C in Iranians from the pediatric age group. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Host Mitochondrial Association Evolved in the Human Parasite Toxoplasma gondii via Neofunctionalization of a Gene Duplicate.

PubMed

Adomako-Ankomah, Yaw; English, Elizabeth D; Danielson, Jeffrey J; Pernas, Lena F; Parker, Michelle L; Boulanger, Martin J; Dubey, Jitender P; Boyle, Jon P

2016-05-01

In Toxoplasma gondii, an intracellular parasite of humans and other animals, host mitochondrial association (HMA) is driven by a gene family that encodes multiple mitochondrial association factor 1 (MAF1) proteins. However, the importance of MAF1 gene duplication in the evolution of HMA is not understood, nor is the impact of HMA on parasite biology. Here we used within- and between-species comparative analysis to determine that the MAF1 locus is duplicated in T. gondii and its nearest extant relative Hammondia hammondi, but not another close relative, Neospora caninum Using cross-species complementation, we determined that the MAF1 locus harbors multiple distinct paralogs that differ in their ability to mediate HMA, and that only T. gondii and H. hammondi harbor HMA(+) paralogs. Additionally, we found that exogenous expression of an HMA(+) paralog in T. gondii strains that do not normally exhibit HMA provides a competitive advantage over their wild-type counterparts during a mouse infection. These data indicate that HMA likely evolved by neofunctionalization of a duplicate MAF1 copy in the common ancestor of T. gondii and H. hammondi, and that the neofunctionalized gene duplicate is selectively advantageous. Copyright © 2016 by the Genetics Society of America.

SU-E-I-53: Comparison of Kerma-Area-Product Between the Micro-Angiographic Fluoroscope (MAF) and a Flat Panel Detector (FPD) as Used in Neuro-Endovascular Procedures

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

Vijayan, S; Rana, V; Nagesh, S Setlur

Purpose: To determine the reduction of integral dose to the patient when using the micro-angiographic fluoroscope (MAF) compared to when using the standard flat-panel detector (FPD) for the techniques used during neurointerventional procedures. Methods: The MAF is a small field-of-view, high resolution x-ray detector which captures 1024 x 1024 pixels with an effective pixel size of 35μm and is capable of real-time imaging up to 30 frames per second. The MAF was used in neuro-interventions during those parts of the procedure when high resolution was needed and the FPD was used otherwise. The technique parameters were recorded when each detectormore » was used and the kerma-area-product (KAP) per image frame was determined. KAP values were calculated for seven neuro interventions using premeasured calibration files of output as a function of kVp and beam filtration and included the attenuation of the patient table for the frontal projections to be more representative of integral patient dose. The air kerma at the patient entrance was multiplied by the beam area at that point to obtain the KAP values. The ranges of KAP values per frame were determined for the range of technique parameters used during the clinical procedures. To appreciate the benefit of the higher MAF resolution in the region of interventional activity, DA technique parameters were generally used with the MAF. Results: The lowest and highest values of KAP per frame for the MAF in DA mode were 4 and 50 times lower, respectively, compared to those of the FPD in pulsed fluoroscopy mode. Conclusion: The MAF was used in those parts of the clinical procedures when high resolution and image quality was essential. The integral patient dose as represented by the KAP value was substantially lower when using the MAF than when using the FPD due to the much smaller volume of tissue irradiated. This research was supported in part by Toshiba Medical Systems Corporation and NIH Grant R01EB002873.« less

Myelo-erythroid commitment after burn injury is under β-adrenergic control via MafB regulation.

PubMed

Hasan, Shirin; Johnson, Nicholas B; Mosier, Michael J; Shankar, Ravi; Conrad, Peggie; Szilagyi, Andrea; Gamelli, Richard L; Muthumalaiappan, Kuzhali

2017-03-01

Severely injured burn patients receive multiple blood transfusions for anemia of critical illness despite the adverse consequences. One limiting factor to consider alternate treatment strategies is the lack of a reliable test platform to study molecular mechanisms of impaired erythropoiesis. This study illustrates how conditions resulting in a high catecholamine microenvironment such as burns can instigate myelo-erythroid reprioritization influenced by β-adrenergic stimulation leading to anemia. In a mouse model of scald burn injury, we observed, along with a threefold increase in bone marrow LSK cells (lin neg Sca1 + cKit + ), that the myeloid shift is accompanied with a significant reduction in megakaryocyte erythrocyte progenitors (MEPs). β-Blocker administration (propranolol) for 6 days after burn, not only reduced the number of LSKs and MafB + cells in multipotent progenitors, but also influenced myelo-erythroid bifurcation by increasing the MEPs and reducing the granulocyte monocyte progenitors in the bone marrow of burn mice. Furthermore, similar results were observed in burn patients' peripheral blood mononuclear cell-derived ex vivo culture system, demonstrating that commitment stage of erythropoiesis is impaired in burn patients and intervention with propranolol (nonselective β1,2-adrenergic blocker) increases MEPs. Also, MafB + cells that were significantly increased following standard burn care could be mitigated when propranolol was administered to burn patients, establishing the mechanistic regulation of erythroid commitment by myeloid regulatory transcription factor MafB. Overall, results demonstrate that β-adrenergic blockers following burn injury can redirect the hematopoietic commitment toward erythroid lineage by lowering MafB expression in multipotent progenitors and be of potential therapeutic value to increase erythropoietin responsiveness in burn patients. Copyright © 2017 the American Physiological Society.

Myelo-erythroid commitment after burn injury is under β-adrenergic control via MafB regulation

PubMed Central

Hasan, Shirin; Johnson, Nicholas B.; Mosier, Michael J.; Shankar, Ravi; Conrad, Peggie; Szilagyi, Andrea; Gamelli, Richard L.

2017-01-01

Severely injured burn patients receive multiple blood transfusions for anemia of critical illness despite the adverse consequences. One limiting factor to consider alternate treatment strategies is the lack of a reliable test platform to study molecular mechanisms of impaired erythropoiesis. This study illustrates how conditions resulting in a high catecholamine microenvironment such as burns can instigate myelo-erythroid reprioritization influenced by β-adrenergic stimulation leading to anemia. In a mouse model of scald burn injury, we observed, along with a threefold increase in bone marrow LSK cells (linneg Sca1+cKit+), that the myeloid shift is accompanied with a significant reduction in megakaryocyte erythrocyte progenitors (MEPs). β-Blocker administration (propranolol) for 6 days after burn, not only reduced the number of LSKs and MafB+ cells in multipotent progenitors, but also influenced myelo-erythroid bifurcation by increasing the MEPs and reducing the granulocyte monocyte progenitors in the bone marrow of burn mice. Furthermore, similar results were observed in burn patients’ peripheral blood mononuclear cell-derived ex vivo culture system, demonstrating that commitment stage of erythropoiesis is impaired in burn patients and intervention with propranolol (nonselective β1,2-adrenergic blocker) increases MEPs. Also, MafB+ cells that were significantly increased following standard burn care could be mitigated when propranolol was administered to burn patients, establishing the mechanistic regulation of erythroid commitment by myeloid regulatory transcription factor MafB. Overall, results demonstrate that β-adrenergic blockers following burn injury can redirect the hematopoietic commitment toward erythroid lineage by lowering MafB expression in multipotent progenitors and be of potential therapeutic value to increase erythropoietin responsiveness in burn patients. PMID:28031160

Crystal Structure and Regulation of the Citrus Pol III Repressor MAF1 by Auxin and Phosphorylation.

PubMed

Soprano, Adriana Santos; Giuseppe, Priscila Oliveira de; Shimo, Hugo Massayoshi; Lima, Tatiani Brenelli; Batista, Fernanda Aparecida Heleno; Righetto, Germanna Lima; Pereira, José Geraldo de Carvalho; Granato, Daniela Campos; Nascimento, Andrey Fabricio Ziem; Gozzo, Fabio Cesar; de Oliveira, Paulo Sérgio Lopes; Figueira, Ana Carolina Migliorini; Smetana, Juliana Helena Costa; Paes Leme, Adriana Franco; Murakami, Mario Tyago; Benedetti, Celso Eduardo

2017-09-05

MAF1 is the main RNA polymerase (Pol) III repressor that controls cell growth in eukaryotes. The Citrus ortholog, CsMAF1, was shown to restrict cell growth in citrus canker disease but its role in plant development and disease is still unclear. We solved the crystal structure of the globular core of CsMAF1, which reveals additional structural elements compared with the previously available structure of hMAF1, and explored the dynamics of its flexible regions not present in the structure. CsMAF1 accumulated in the nucleolus upon leaf excision, and this translocation was inhibited by auxin and by mutation of the PKA phosphorylation site, S45, to aspartate. Additionally, mTOR phosphorylated recombinant CsMAF1 and the mTOR inhibitor AZD8055 blocked canker formation in normal but not CsMAF1-silenced plants. These results indicate that the role of TOR on cell growth induced by Xanthomonas citri depends on CsMAF1 and that auxin controls CsMAF1 interaction with Pol III in citrus. Copyright © 2017 Elsevier Ltd. All rights reserved.

A remarkable adsorbent for removal of contaminants of emerging concern from water: Porous carbon derived from metal azolate framework-6.

PubMed

Bhadra, Biswa Nath; Jhung, Sung Hwa

2017-10-15

A series of metal-azolate frameworks or MAFs-MAF-4, -5, and -6-were synthesized and pyrolyzed to prepare porous carbons derived from MAFs (CDM-4, -5, -6, respectively). Not only the obtained carbons but also MAFs were characterized and applied for the adsorption of organic contaminants of emerging concern (CECs, including pharmaceuticals and personal care products) such as salicylic acid, clofibric acid, diclofenac sodium, bisphenol-A, and oxybenzone (OXB) from water. CDM-6 was found to be the most remarkable adsorbent among the tested ones (including activated carbon) for all the adsorbates. OXB was taken as a representative adsorbate for detailed adsorption studies as well as understanding the adsorption mechanism. H-bonding (H-acceptor: CDM; H-donor: CECs) was suggested as the principal mechanism for the adsorption of tested adsorbates. Finally, CDMs, especially CDM-6, were suggested as highly efficient and easily recyclable adsorbents for water purification. Copyright © 2017 Elsevier B.V. All rights reserved.

Activation of beta-major globin gene transcription is associated with recruitment of NF-E2 to the beta-globin LCR and gene promoter.

PubMed

Sawado, T; Igarashi, K; Groudine, M

2001-08-28

The mouse beta-globin gene locus control region (LCR), located upstream of the beta-globin gene cluster, is essential for the activated transcription of genes in the cluster. The LCR contains multiple binding sites for transactivators, including Maf-recognition elements (MAREs). However, little is known about the specific proteins that bind to these sites or the time at which they bind during erythroid differentiation. We have performed chromatin immunoprecipitation experiments to determine the recruitment of the erythroid-specific transactivator p45 NF-E2/MafK (p18 NF-E2) heterodimer and small Maf proteins to various regions in the globin gene locus before and after the induction of murine erythroleukemia (MEL) cell differentiation. We report that, before induction, the LCR is occupied by small Maf proteins, and, on erythroid maturation, the NF-E2 complex is recruited to the LCR and the active globin promoters, even though the promoters do not contain MAREs. This differentiation-coupled recruitment of NF-E2 complex correlates with a greater than 100-fold increase in beta-major globin transcription, but is not associated with a significant change in locus-wide histone H3 acetylation. These findings suggest that the beta-globin gene locus exists in a constitutively open chromatin conformation before terminal differentiation, and we speculate that recruitment of NF-E2 complex to the LCR and active promoters may be a rate-limiting step in the activation of beta-globin gene expression.

Glycan structure of Gc Protein-derived Macrophage Activating Factor as revealed by mass spectrometry.

PubMed

Borges, Chad R; Rehder, Douglas S

2016-09-15

Disagreement exists regarding the O-glycan structure attached to human vitamin D binding protein (DBP). Previously reported evidence indicated that the O-glycan of the Gc1S allele product is the linear core 1 NeuNAc-Gal-GalNAc-Thr trisaccharide. Here, glycan structural evidence is provided from glycan linkage analysis and over 30 serial glycosidase-digestion experiments which were followed by analysis of the intact protein by electrospray ionization mass spectrometry (ESI-MS). Results demonstrate that the O-glycan from the Gc1F protein is the same linear trisaccharide found on the Gc1S protein and that the hexose residue is galactose. In addition, the putative anti-cancer derivative of DBP known as Gc Protein-derived Macrophage Activating Factor (GcMAF, which is formed by the combined action of β-galactosidase and neuraminidase upon DBP) was analyzed intact by ESI-MS, revealing that the activating E. coli β-galactosidase cleaves nothing from the protein-leaving the glycan structure of active GcMAF as a Gal-GalNAc-Thr disaccharide, regardless of the order in which β-galactosidase and neuraminidase are applied. Moreover, glycosidase digestion results show that α-N-Acetylgalactosamindase (nagalase) lacks endoglycosidic function and only cleaves the DBP O-glycan once it has been trimmed down to a GalNAc-Thr monosaccharide-precluding the possibility of this enzyme removing the O-glycan trisaccharide from cancer-patient DBP in vivo. Copyright © 2016 Elsevier Inc. All rights reserved.

A programmable synthetic lineage-control network that differentiates human IPSCs into glucose-sensitive insulin-secreting beta-like cells

PubMed Central

Saxena, Pratik; Heng, Boon Chin; Bai, Peng; Folcher, Marc; Zulewski, Henryk; Fussenegger, Martin

2016-01-01

Synthetic biology has advanced the design of standardized transcription control devices that programme cellular behaviour. By coupling synthetic signalling cascade- and transcription factor-based gene switches with reverse and differential sensitivity to the licensed food additive vanillic acid, we designed a synthetic lineage-control network combining vanillic acid-triggered mutually exclusive expression switches for the transcription factors Ngn3 (neurogenin 3; OFF-ON-OFF) and Pdx1 (pancreatic and duodenal homeobox 1; ON-OFF-ON) with the concomitant induction of MafA (V-maf musculoaponeurotic fibrosarcoma oncogene homologue A; OFF-ON). This designer network consisting of different network topologies orchestrating the timely control of transgenic and genomic Ngn3, Pdx1 and MafA variants is able to programme human induced pluripotent stem cells (hIPSCs)-derived pancreatic progenitor cells into glucose-sensitive insulin-secreting beta-like cells, whose glucose-stimulated insulin-release dynamics are comparable to human pancreatic islets. Synthetic lineage-control networks may provide the missing link to genetically programme somatic cells into autologous cell phenotypes for regenerative medicine. PMID:27063289

β1-integrin controls cell fate specification in early lens development

PubMed Central

Pathania, Mallika; Wang, Yan; Simirskii, Vladimir N.; Duncan, Melinda K.

2016-01-01

Integrins are heterodimeric cell surface molecules that mediate cell-extracellular matrix (ECM) adhesion, ECM assembly, and regulation of both ECM and growth factor induced signaling. However, the developmental context of these diverse functions is not clear. Loss of β1-integrin from the lens vesicle (mouse E10.5) results in abnormal exit of anterior lens epithelial cells (LECs) from the cell cycle and their aberrant elongation toward the presumptive cornea by E12.5. These cells lose expression of LEC markers and initiate expression of the Maf (also known as c-Maf) and Prox1 transcription factors as well as other lens fiber cell markers, β1-integrin null LECs also upregulate the ERK, AKT and Smad1/5/8 phosphorylation indicative of BMP and FGF signaling. By E14.5, β1-integrin null lenses have undergone a complete conversion of all lens epithelial cells into fiber cells. These data suggest that shortly after lens vesicle closure, β1-integrin blocks inappropriate differentiation of the lens epithelium into fibers, potentially by inhibiting BMP and/or FGF receptor activation. Thus, β1-integrin has an important role in fine-tuning the response of the early lens to the gradient of growth factors that regulate lens fiber cell differentiation. PMID:27596755

Psychometric evaluation of the Multidimensional Assessment of Fatigue scale for use with pregnant and postpartum women.

PubMed

Fairbrother, Nichole; Hutton, Eileen K; Stoll, Kathrin; Hall, Wendy; Kluka, Sandy

2008-06-01

Although fatigue is a common experience for pregnant women and new mothers, few measures of fatigue have been validated for use with this population. To address this gap, the authors assessed psychometric properties of the Multidimensional Assessment of Fatigue (MAF) scale, which was used in 2 independent samples of pregnant women. Results indicated that the psychometric properties of the scale were very similar across samples and time points. The scale possesses a high level of internal consistency, has good convergent validity with measures of sleep quality and depression, and discriminates well from a measure of social support. Contrary to previous evaluations of the MAF, data strongly suggest that the scale represents a unidimensional construct best represented by a single factor. Results indicate that the MAF is a useful measure of fatigue among pregnant and postpartum women.

SU-E-CAMPUS-I-04: Automatic Skin-Dose Mapping for An Angiographic System with a Region-Of-Interest, High-Resolution Detector

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

Vijayan, S; Rana, V; Setlur Nagesh, S

2014-06-15

Purpose: Our real-time skin dose tracking system (DTS) has been upgraded to monitor dose for the micro-angiographic fluoroscope (MAF), a high-resolution, small field-of-view x-ray detector. Methods: The MAF has been mounted on a changer on a clinical C-Arm gantry so it can be used interchangeably with the standard flat-panel detector (FPD) during neuro-interventional procedures when high resolution is needed in a region-of-interest. To monitor patient skin dose when using the MAF, our DTS has been modified to automatically account for the change in scatter for the very small MAF FOV and to provide separated dose distributions for each detector. Themore » DTS is able to provide a color-coded mapping of the cumulative skin dose on a 3D graphic model of the patient. To determine the correct entrance skin exposure to be applied by the DTS, a correction factor was determined by measuring the exposure at the entrance surface of a skull phantom with an ionization chamber as a function of entrance beam size for various beam filters and kVps. Entrance exposure measurements included primary radiation, patient backscatter and table forward scatter. To allow separation of the dose from each detector, a parameter log is kept that allows a replay of the procedure exposure events and recalculation of the dose components.The graphic display can then be constructed showing the dose distribution from the MAF and FPD separately or together. Results: The DTS is able to provide separate displays of dose for the MAF and FPD with field-size specific scatter corrections. These measured corrections change from about 49% down to 10% when changing from the FPD to the MAF. Conclusion: The upgraded DTS allows identification of the patient skin dose delivered when using each detector in order to achieve improved dose management as well as to facilitate peak skin-dose reduction through dose spreading. Research supported in part by Toshiba Medical Systems Corporation and NIH Grants R43FD0158401, R44FD0158402 and R01EB002873.« less

A validity and reliability study of the Turkish Multidimensional Assessment of Fatigue (MAF) scale in chronic musculoskeletal physical therapy patients.

PubMed

Yildirim, Yücel; Ergin, Gülbin

2013-01-01

Fatigue is primarily a subjective experience and self-report is the most common approach used to measure fatigue. Numerous self-report instruments have been developed to measure fatigue. Unfortunately, each of these measures was tailored for the situation in which fatigue was studied. Therefore, the aim of this study was to determine the reliability and validity of the Turkish language version of the Multidimensional Assessment of Fatigue Scale (MAF-T) in chronic musculoskeletal physical therapy patients. The MAF-T was supplied by the MAPI Research Institute, and 69 chronic musculoskeletal physical therapy patients were evaluated. To validate MAF-T, all participants completed the MAF-T and Short Form-36 (SF-36). The MAF was administered again one week later to assess test-retest reliability. Using Cronbach α, the internal consistency reliability of the MAF-T was 0.90, the Intraclass Correlation Coefficient (ICC) reliability was 0.96. Item-discriminant validity was calculated between r=0.14 and r=0.82. The correlations between the total scores of the MAF-T scale and the subscale scores of SF-36 were negative and significant (p< 0.01). The MAF-T is a valid and reliable scale for assessing fatigue in chronic musculoskeletal physical therapy patients.

Prostaglandin E2 inhibits Tr1 cell differentiation through suppression of c-Maf

PubMed Central

Hooper, Kirsten Mary; Kong, Weimin

2017-01-01

Prostaglandin E2 (PGE2), a major lipid mediator abundant at inflammatory sites, acts as a proinflammatory agent in models of inflammatory/autoimmune diseases by promoting CD4 Th1/Th17 differentiation. Regulatory T cells, including the IL-10 producing Tr1 cells counterbalance the proinflammatory activity of effector Th1/Th17 cells. Tr1 cell differentiation and function are induced by IL-27, and depend primarily on sustained expression of c-Maf in addition to AhR and Blimp-1. In agreement with the in vivo proinflammatory role of PGE2, here we report for the first time that PGE2 inhibits IL-27-induced differentiation and IL-10 production of murine CD4+CD49b+LAG-3+Foxp3- Tr1 cells. The inhibitory effect of PGE2 was mediated through EP4 receptors and induction of cAMP, leading to a significant reduction in c-Maf expression. Although PGE2 reduced IL-21 production in differentiating Tr1 cells, its inhibitory effect on Tr1 differentiation and c-Maf expression also occurred independent of IL-21 signaling. PGE2 did not affect STAT1/3 activation, AhR expression and only marginally reduced Egr-2/Blimp-1 expression. The effect of PGE2 on CD4+CD49b+LAG-3+ Tr1 differentiation was not associated with either induction of Foxp3 or IL-17 production, suggesting a lack of transdifferentiation into Foxp3+ Treg or effector Th17 cells. We recently reported that PGE2 inhibits the expression and production of IL-27 from activated conventional dendritic cells (cDC) in vivo and in vitro. The present study indicates that PGE2 also reduces murine Tr1 differentiation and function directly by acting on IL-27-differentiating Tr1 cells. Together, the ability of PGE2 to inhibit IL-27 production by cDC, and the direct inhibitory effect on Tr1 differentiation mediated through reduction in c-Maf expression, represent a new mechanistic perspective for the proinflammatory activity of PGE2. PMID:28604806

Establishment and characterization of a fin cell line from blunt snout bream, Megalobrama amblycephala.

PubMed

Zhu, Dong-Mei; Yang, Kun; Wang, Wei-Min; Song, Wen

2013-12-01

This study established and characterized a new cell line (MAF) from the fin of blunt snout bream (Megalobrama amblycephala), a freshwater fish cultivated in China. MAF cells proliferated well in medium 199 supplemented with 10 % fetal bovine serum at 28 °C and have been subcultured more than 95 times in almost a year. MAF cells were revived at 90-95 % viability after 3-6 months of storage in liquid nitrogen. Karyotyping indicated that the modal chromosome number of MAF cells was 48. The MAF cell line consisted predominantly of fibroblastic and epithelial-like cells from M. amblycephala, which was confirmed by immunofluorescence and mitochondrial 12s rRNA sequencing. Viral susceptibility tests showed that MAF cells were susceptible to infection by snakehead rhabdovirus, spring viremia carp virus, and channel catfish virus, which was demonstrated by the presence of cytopathic effect, high viral titers, and PCR products. Bacterial cytotoxicity studies showed that extracellular products from Aeromonas hydrophila were toxic to MAF cells. Cu²⁺ was also cytotoxic to MAF cells, and the 24-h IC₅₀ value was 144.48 μmol/l. When MAF cells were transfected with pEGFP-N1 plasmid, bright fluorescent signals were observed, and the transfection efficiency reached up to 5 %. These results suggest that the MAF cell line may provide a valuable tool for studying virus pathogenesis, as well as cytotoxicity testing and genetic manipulation studies.

Functional Investigations of HNF1A Identify Rare Variants as Risk Factors for Type 2 Diabetes in the General Population

PubMed Central

Najmi, Laeya Abdoli; Aukrust, Ingvild; Flannick, Jason; Molnes, Janne; Burtt, Noel; Molven, Anders; Groop, Leif; Altshuler, David; Johansson, Stefan; Njølstad, Pål Rasmus

2017-01-01

Variants in HNF1A encoding hepatocyte nuclear factor 1α (HNF-1A) are associated with maturity-onset diabetes of the young form 3 (MODY 3) and type 2 diabetes. We investigated whether functional classification of HNF1A rare coding variants can inform models of diabetes risk prediction in the general population by analyzing the effect of 27 HNF1A variants identified in well-phenotyped populations (n = 4,115). Bioinformatics tools classified 11 variants as likely pathogenic and showed no association with diabetes risk (combined minor allele frequency [MAF] 0.22%; odds ratio [OR] 2.02; 95% CI 0.73–5.60; P = 0.18). However, a different set of 11 variants that reduced HNF-1A transcriptional activity to <60% of normal (wild-type) activity was strongly associated with diabetes in the general population (combined MAF 0.22%; OR 5.04; 95% CI 1.99–12.80; P = 0.0007). Our functional investigations indicate that 0.44% of the population carry HNF1A variants that result in a substantially increased risk for developing diabetes. These results suggest that functional characterization of variants within MODY genes may overcome the limitations of bioinformatics tools for the purposes of presymptomatic diabetes risk prediction in the general population. PMID:27899486

Potential PM2.5 impacts of festival-related burning and other inputs on air quality in an urban area of southern Taiwan.

PubMed

Tsai, Ying I; Sopajaree, Khajornsak; Kuo, Su-Ching; Yu, Sung-Po

2015-09-15

The Mid-Autumn Festival (MAF), or Moon Festival, is a harvest festival in Taiwan, celebrated by families across the island with evening barbecues outside. This study investigated the potential impact of these activities on the air quality in Tainan, a city in southern Taiwan. Fine particulate matter (PM2.5) was examined in the period leading up to the MAF (pre-MAF), during the Festival (MAF), after the Festival (post-MAF), and in the period after this (a period of moderate air quality: MAQ). Gaseous pollutants in PM2.5 were, from highest to lowest mean concentration, NH3, SO2, HCl, HNO3, HNO2, and oxalic acid, while inorganic salts were mainly in the form of the photochemical products SO4(2-), NH4(+), and NO3(-). These inorganic salts accounted for 37.6%-44.5% of the PM2.5 mass concentration, while a further 26.3%-42.8% of the PM2.5 mass was total carbon (TC). TC was mostly composed of organic carbon (OC) produced by photochemical reactions. Of this, 9.8%-14.9% was carboxylates, of which oxalate was the most abundant compound, accounting for 22.8%-31.9% of carboxylates. The presence of phthalates in the PM2.5 indicated emissions from the plastics industry. Although a noticeable amount of aerosol was produced by festival activities and burning of softwood and hardwood, onshore air currents during the festival prevented potential high aerosol loading. During the moderate air quality period following post-MAF, the concentration of total carbohydrates was 1.44-2.64 times the amount during the festival. Levoglucosan and myo-inositol accounted for 81.7%-89.6% of the total carbohydrate concentration. The average Levo/Manno ratio was 18.64 ± 5.24. The concentration of levoglucosan was closely related to that of PO4(3-), erythritol, and galactose. Backward trajectories indicated that biomass burning in China affected the air quality of Tainan City. Copyright © 2015 Elsevier B.V. All rights reserved.

c-MAF-dependent regulatory T cells mediate immunological tolerance to a gut pathobiont.

PubMed

Xu, Mo; Pokrovskii, Maria; Ding, Yi; Yi, Ren; Au, Christy; Harrison, Oliver J; Galan, Carolina; Belkaid, Yasmine; Bonneau, Richard; Littman, Dan R

2018-02-15

Both microbial and host genetic factors contribute to the pathogenesis of autoimmune diseases. There is accumulating evidence that microbial species that potentiate chronic inflammation, as in inflammatory bowel disease, often also colonize healthy individuals. These microorganisms, including the Helicobacter species, can induce pathogenic T cells and are collectively referred to as pathobionts. However, how such T cells are constrained in healthy individuals is not yet understood. Here we report that host tolerance to a potentially pathogenic bacterium, Helicobacter hepaticus, is mediated by the induction of RORγt + FOXP3 + regulatory T (iT reg ) cells that selectively restrain pro-inflammatory T helper 17 (T H 17) cells and whose function is dependent on the transcription factor c-MAF. Whereas colonization of wild-type mice by H. hepaticus promoted differentiation of RORγt-expressing microorganism-specific iT reg cells in the large intestine, in disease-susceptible IL-10-deficient mice, there was instead expansion of colitogenic T H 17 cells. Inactivation of c-MAF in the T reg cell compartment impaired differentiation and function, including IL-10 production, of bacteria-specific iT reg cells, and resulted in the accumulation of H. hepaticus-specific inflammatory T H 17 cells and spontaneous colitis. By contrast, RORγt inactivation in T reg cells had only a minor effect on the bacteria-specific T reg and T H 17 cell balance, and did not result in inflammation. Our results suggest that pathobiont-dependent inflammatory bowel disease is driven by microbiota-reactive T cells that have escaped this c-MAF-dependent mechanism of iT reg -T H 17 homeostasis.

Insulin Transactivator MafA Regulates Intrathymic Expression of Insulin and Affects Susceptibility to Type 1 Diabetes

PubMed Central

Noso, Shinsuke; Kataoka, Kohsuke; Kawabata, Yumiko; Babaya, Naru; Hiromine, Yoshihisa; Yamaji, Kaori; Fujisawa, Tomomi; Aramata, Shinsaku; Kudo, Takashi; Takahashi, Satoru; Ikegami, Hiroshi

2010-01-01

OBJECTIVE Tissue-specific self-antigens are ectopically expressed within the thymus and play an important role in the induction of central tolerance. Insulin is expressed in both pancreatic islets and the thymus and is considered to be the primary antigen for type 1 diabetes. Here, we report the role of the insulin transactivator MafA in the expression of insulin in the thymus and susceptibility to type 1 diabetes. RESEARCH DESIGN AND METHODS The expression profiles of transcriptional factors (Pdx1, NeuroD, Mafa, and Aire) in pancreatic islets and the thymus were examined in nonobese diabetic (NOD) and control mice. Thymic Ins2 expression and serum autoantibodies were examined in Mafa knockout mice. Luciferase reporter assay was performed for newly identified polymorphisms of mouse Mafa and human MAFA. A case-control study was applied for human MAFA polymorphisms. RESULTS Mafa, Ins2, and Aire expression was detected in the thymus. Mafa expression was lower in NOD thymus than in the control and was correlated with Ins2 expression. Targeted disruption of MafA reduced thymic Ins2 expression and induced autoantibodies against pancreatic islets. Functional polymorphisms of MafA were newly identified in NOD mice and humans, and polymorphisms of human MAFA were associated with susceptibility to type 1 diabetes but not to autoimmune thyroid disease. CONCLUSIONS These data indicate that functional polymorphisms of MafA are associated with reduced expression of insulin in the thymus and susceptibility to type 1 diabetes in the NOD mouse as well as human type 1 diabetes. PMID:20682694

Label-free structural characterization of mitomycin C-modulated wound healing after photorefractive keratectomy by the use of multiphoton microscopy

NASA Astrophysics Data System (ADS)

Lo, Wen; Wang, Tsung-Jen; Chen, Wei-Liang; Hsueh, Chiu-Mei; Chen, Shean-Jen; Chen, Yang-Fang; Chou, Hsiu-Chu; Lin, Pi-Jung; Hu, Fung-Rong; Dong, Chen-Yuan

2010-05-01

We applied multiphoton autofluorescence (MAF) and second-harmonic generation (SHG) microscopy to monitor corneal wound healing after photorefractive keratectomy (PRK). Our results show that keratocyte activation can be observed by an increase in its MAF, while SHG imaging of corneal stroma can show the depletion of Bowman's layer after PRK and the reticular collagen deposition in the wound healing stage. Furthermore, quantification of the keratocyte activation and collagen deposition in conjunction with immunohistochemistry and histological images demonstrate the effectiveness of mitomycin C (MMC) in suppressing myofibroblast proliferation and collagen regeneration in the post-PRK wound healing process.

Impact of QTL minor allele frequency on genomic evaluation using real genotype data and simulated phenotypes in Japanese Black cattle.

PubMed

Uemoto, Yoshinobu; Sasaki, Shinji; Kojima, Takatoshi; Sugimoto, Yoshikazu; Watanabe, Toshio

2015-11-19

Genetic variance that is not captured by single nucleotide polymorphisms (SNPs) is due to imperfect linkage disequilibrium (LD) between SNPs and quantitative trait loci (QTLs), and the extent of LD between SNPs and QTLs depends on different minor allele frequencies (MAF) between them. To evaluate the impact of MAF of QTLs on genomic evaluation, we performed a simulation study using real cattle genotype data. In total, 1368 Japanese Black cattle and 592,034 SNPs (Illumina BovineHD BeadChip) were used. We simulated phenotypes using real genotypes under different scenarios, varying the MAF categories, QTL heritability, number of QTLs, and distribution of QTL effect. After generating true breeding values and phenotypes, QTL heritability was estimated and the prediction accuracy of genomic estimated breeding value (GEBV) was assessed under different SNP densities, prediction models, and population size by a reference-test validation design. The extent of LD between SNPs and QTLs in this population was higher in the QTLs with high MAF than in those with low MAF. The effect of MAF of QTLs depended on the genetic architecture, evaluation strategy, and population size in genomic evaluation. In genetic architecture, genomic evaluation was affected by the MAF of QTLs combined with the QTL heritability and the distribution of QTL effect. The number of QTL was not affected on genomic evaluation if the number of QTL was more than 50. In the evaluation strategy, we showed that different SNP densities and prediction models affect the heritability estimation and genomic prediction and that this depends on the MAF of QTLs. In addition, accurate QTL heritability and GEBV were obtained using denser SNP information and the prediction model accounted for the SNPs with low and high MAFs. In population size, a large sample size is needed to increase the accuracy of GEBV. The MAF of QTL had an impact on heritability estimation and prediction accuracy. Most genetic variance can be captured using denser SNPs and the prediction model accounted for MAF, but a large sample size is needed to increase the accuracy of GEBV under all QTL MAF categories.

Evaluation and Comparison of High-Resolution (HR) and High-Light (HL) Phosphors in the Micro-Angiographic Fluoroscope (MAF) using Generalized Linear Systems Analyses (GMTF, GDQE) that include the Effect of Scatter, Magnification and Detector Characteristics.

PubMed

Gupta, Sandesh K; Jain, Amit; Bednarek, Daniel R; Rudin, Stephen

2011-01-01

In this study, we evaluated the imaging characteristics of the high-resolution, high-sensitivity micro-angiographic fluoroscope (MAF) with 35-micron pixel-pitch when used with different commercially-available 300 micron thick phosphors: the high resolution (HR) and high light (HL) from Hamamatsu. The purpose of this evaluation was to see if the HL phosphor with its higher screen efficiency could be replaced with the HR phosphor to achieve improved resolution without an increase in noise resulting from the HR's decreased light-photon yield. We designated the detectors MAF-HR and MAF-HL and compared them with a standard flat panel detector (FPD) (194 micron pixel pitch and 600 micron thick CsI(Tl)). For this comparison, we used the generalized linear-system metrics of GMTF, GNNPS and GDQE which are more realistic measures of total system performance since they include the effect of scattered radiation, focal spot distribution, and geometric un-sharpness. Magnifications (1.05-1.15) and scatter fractions (0.28 and 0.33) characteristic of a standard head phantom were used. The MAF-HR performed significantly better than the MAF-HL at high spatial frequencies. The ratio of GMTF and GDQE of the MAF-HR compared to the MAF-HL at 3(6) cycles/mm was 1.45(2.42) and 1.23(2.89), respectively. Despite significant degradation by inclusion of scatter and object magnification, both MAF-HR and MAF-HL provide superior performance over the FPD at higher spatial frequencies with similar performance up to the FPD's Nyquist frequency of 2.5 cycles/mm. Both substantially higher resolution and improved GDQE can be achieved with the MAF using the HR phosphor instead of the HL phosphor.

Theoretical performance analysis for CMOS based high resolution detectors.

PubMed

Jain, Amit; Bednarek, Daniel R; Rudin, Stephen

2013-03-06

High resolution imaging capabilities are essential for accurately guiding successful endovascular interventional procedures. Present x-ray imaging detectors are not always adequate due to their inherent limitations. The newly-developed high-resolution micro-angiographic fluoroscope (MAF-CCD) detector has demonstrated excellent clinical image quality; however, further improvement in performance and physical design may be possible using CMOS sensors. We have thus calculated the theoretical performance of two proposed CMOS detectors which may be used as a successor to the MAF. The proposed detectors have a 300 μm thick HL-type CsI phosphor, a 50 μm-pixel CMOS sensor with and without a variable gain light image intensifier (LII), and are designated MAF-CMOS-LII and MAF-CMOS, respectively. For the performance evaluation, linear cascade modeling was used. The detector imaging chains were divided into individual stages characterized by one of the basic processes (quantum gain, binomial selection, stochastic and deterministic blurring, additive noise). Ranges of readout noise and exposure were used to calculate the detectors' MTF and DQE. The MAF-CMOS showed slightly better MTF than the MAF-CMOS-LII, but the MAF-CMOS-LII showed far better DQE, especially for lower exposures. The proposed detectors can have improved MTF and DQE compared with the present high resolution MAF detector. The performance of the MAF-CMOS is excellent for the angiography exposure range; however it is limited at fluoroscopic levels due to additive instrumentation noise. The MAF-CMOS-LII, having the advantage of the variable LII gain, can overcome the noise limitation and hence may perform exceptionally for the full range of required exposures; however, it is more complex and hence more expensive.

Macular auto-fluorescence is a follow-up parameter for cystoids macular edema.

PubMed

Zhang, XinYuan; Gong, XiaoHong; Wang, YanHong; Wang, NingLi

2015-08-01

This study aimed to evaluate if macular autofluorescence (MAF) is a valuable, non-invasive follow-up parameter for cystoid macular edema. A total of 71 eyes (71 cases) with cystoid macular edema (CME) were included in the study. Macular pigment (MP) was evaluated using HRA2 (infrared) IF and FA models. The density of MP was graded into three categories: without, partial, and normal amount of MP. A comparison was made between the baseline (before the first administration) level and at the fourth month, following three consecutive intravitreal lucentis injections every month. The morphology and distribution of MAF, and the density and distribution of MP were regarded as the main outcome measures. At the baseline visit, all eyes with CME had petaloid/irregular-shaped MAF in the macular area (100%). No MAF was detected in the control eyes (0). There was significant difference in MAF between the CME and normal groups (P=0.000). At the fourth monthly visit, normal levels of MP density without MAF was detected in 68 eyes (95.8%) with the best corrected spectacular visual acuity increasing to at least 1 line accordingly. We conclude that macular MAF can be used as a follow-up parameter for patients with CME. MP and MAF can indirectly reflect the fovea cone function.

Loss of the RNA polymerase III repressor MAF1 confers obesity resistance

PubMed Central

Bonhoure, Nicolas; Byrnes, Ashlee; Moir, Robyn D.; Hodroj, Wassim; Preitner, Frédéric; Praz, Viviane; Marcelin, Genevieve; Chua, Streamson C.; Martinez-Lopez, Nuria; Singh, Rajat; Moullan, Norman; Auwerx, Johan; Willemin, Gilles; Shah, Hardik; Hartil, Kirsten; Vaitheesvaran, Bhavapriya; Kurland, Irwin

2015-01-01

MAF1 is a global repressor of RNA polymerase III transcription that regulates the expression of highly abundant noncoding RNAs in response to nutrient availability and cellular stress. Thus, MAF1 function is thought to be important for metabolic economy. Here we show that a whole-body knockout of Maf1 in mice confers resistance to diet-induced obesity and nonalcoholic fatty liver disease by reducing food intake and increasing metabolic inefficiency. Energy expenditure in Maf1−/− mice is increased by several mechanisms. Precursor tRNA synthesis was increased in multiple tissues without significant effects on mature tRNA levels, implying increased turnover in a futile tRNA cycle. Elevated futile cycling of hepatic lipids was also observed. Metabolite profiling of the liver and skeletal muscle revealed elevated levels of many amino acids and spermidine, which links the induction of autophagy in Maf1−/− mice with their extended life span. The increase in spermidine was accompanied by reduced levels of nicotinamide N-methyltransferase, which promotes polyamine synthesis, enables nicotinamide salvage to regenerate NAD+, and is associated with obesity resistance. Consistent with this, NAD+ levels were increased in muscle. The importance of MAF1 for metabolic economy reveals the potential for MAF1 modulators to protect against obesity and its harmful consequences. PMID:25934505

Design, construction, and evaluation of new high resolution medical imaging detector/systems

NASA Astrophysics Data System (ADS)

Jain, Amit

Increasing need of minimally invasive endovascular image guided interventional procedures (EIGI) for accurate and successful treatment of vascular disease has set a quest for better image quality. Current state of the art detectors are not up to the mark for these complex procedures due to their inherent limitations. Our group has been actively working on the design and construction of a high resolution, region of interest CCD-based X-ray imager for some time. As a part of that endeavor, a Micro-angiographic fluoroscope (MAF) was developed to serve as a high resolution, ROI X-ray imaging detector in conjunction with large lower resolution full field of view (FOV) state-of-the-art x-ray detectors. The newly developed MAF is an indirect x-ray imaging detector capable of providing real-time images with high resolution, high sensitivity, no lag and low instrumentation noise. It consists of a CCD camera coupled to a light image intensifier (LII) through a fiber optic taper. The CsI(Tl) phosphor serving as the front end is coupled to the LII. For this work, the MAF was designed and constructed. The linear system cascade theory was used to evaluate the performance theoretically. Linear system metrics such as MTF and DQE were used to gauge the detector performance experimentally. The capabilities of the MAF as a complete system were tested using generalized linear system metrics. With generalized linear system metrics the effects of finite size focal spot, geometric magnification and the presence of scatter are included in the analysis and study. To minimize the effect of scatter, an anti-scatter grid specially designed for the MAF was also studied. The MAF was compared with the flat panel detector using signal-to-noise ratio and the two dimensional linear system metrics. The signal-to-noise comparison was carried out to point out the effect of pixel size and Point Spread Function of the detector. The two dimensional linear system metrics were used to investigate the comparative performance of both the detectors in similar simulated clinical neuro-vascular conditions. The last part of this work presents a unique quality of the MAF: operation in single photon mode. The successful operation of the MAF was demonstrated with considerable improvement in spatial and contrast resolution over conventional energy integrating mode. The work presented shows the evolution of a high resolution, high sensitivity, and region of interest x-ray imaging detector as an attractive and capable x-ray imager for the betterment of complex EIGI procedures. The capability of single photon counting mode imaging provides the potential for additional uses of the MAF including the possibility of use in dual modality imaging with radionuclide sources as well as x-rays.

Maf1 Protein, Repressor of RNA Polymerase III, Indirectly Affects tRNA Processing*

PubMed Central

Karkusiewicz, Iwona; Turowski, Tomasz W.; Graczyk, Damian; Towpik, Joanna; Dhungel, Nripesh; Hopper, Anita K.; Boguta, Magdalena

2011-01-01

Maf1 is negative regulator of RNA polymerase III in yeast. We observed high levels of both primary transcript and end-matured, intron-containing pre-tRNAs in the maf1Δ strain. This pre-tRNA accumulation could be overcome by transcription inhibition, arguing against a direct role of Maf1 in tRNA maturation and suggesting saturation of processing machinery by the increased amounts of primary transcripts. Saturation of the tRNA exportin, Los1, is one reason why end-matured intron-containing pre-tRNAs accumulate in maf1Δ cells. However, it is likely possible that other components of the processing pathway are also limiting when tRNA transcription is increased. According to our model, Maf1-mediated transcription control and nuclear export by Los1 are two major stages of tRNA biosynthesis that are regulated by environmental conditions in a coordinated manner. PMID:21940626

Maf1 protein, repressor of RNA polymerase III, indirectly affects tRNA processing.

PubMed

Karkusiewicz, Iwona; Turowski, Tomasz W; Graczyk, Damian; Towpik, Joanna; Dhungel, Nripesh; Hopper, Anita K; Boguta, Magdalena

2011-11-11

Maf1 is negative regulator of RNA polymerase III in yeast. We observed high levels of both primary transcript and end-matured, intron-containing pre-tRNAs in the maf1Δ strain. This pre-tRNA accumulation could be overcome by transcription inhibition, arguing against a direct role of Maf1 in tRNA maturation and suggesting saturation of processing machinery by the increased amounts of primary transcripts. Saturation of the tRNA exportin, Los1, is one reason why end-matured intron-containing pre-tRNAs accumulate in maf1Δ cells. However, it is likely possible that other components of the processing pathway are also limiting when tRNA transcription is increased. According to our model, Maf1-mediated transcription control and nuclear export by Los1 are two major stages of tRNA biosynthesis that are regulated by environmental conditions in a coordinated manner.

Novel Genetic Loci Associated with Retinal Microvascular Diameter

PubMed Central

Jensen, Richard A.; Sim, Xueling; Smith, Albert Vernon; Li, Xiaohui; Jakobsdóttir, Jóhanna; Cheng, Ching-Yu; Brody, Jennifer A.; Cotch, Mary Frances; Mcknight, Barbara; Klein, Ronald; Wang, Jie Jin; Kifley, Annette; Harris, Tamara B.; Launer, Lenore J.; Taylor, Kent D.; Klein, Barbara E.K.; Raffel, Leslie J.; Li, Xiang; Ikram, M. Arfan; Klaver, Caroline C.; van der Lee, Sven J.; Mutlu, Unal; Hofman, Albert; Uitterlinden, Andre G.; Liu, Chunyu; Kraja, Aldi T.; Mitchell, Paul; Gudnason, Vilmundur; Rotter, Jerome I.; Boerwinkle, Eric; van Duijn, Cornelia M.; Psaty, Bruce M.; Wong, Tien Y.

2015-01-01

Background There is increasing evidence that retinal microvascular diameters are associated with cardio- and cerebrovascular conditions. The shared genetic effects of these associations are currently unknown. The aim of this study was to increase our understanding of the genetic factors that mediate retinal vessel size. Methods and Results This study extends previous genome-wide association study results using 24,000+ multi-ethnic participants from 7 discovery and 5,000+ subjects of European ancestry from 2 replication cohorts. Using the Illumina HumanExome BeadChip, we investigate the association of single nucleotide polymorphisms (SNPs) and variants collectively across genes with summary measures of retinal vessel diameters, referred to as the central retinal venule equivalent (CRVE) and the central retinal arteriole equivalent (CRAE). We report 4 new loci associated with CRVE, one of which is also associated with CRAE. The 4 SNPs are rs7926971 in TEAD1 (p=3.1×10−11, minor allele frequency (MAF)=0.43), rs201259422 in TSPAN10 (p=4.4×10−9, MAF=0.27), rs5442 in GNB3 (p=7.0×10−10, MAF=0.05) and rs1800407 in OCA2 (p=3.4×10−8, MAF=0.05). The latter SNP, rs1800407, was also associated with CRAE (p=6.5×10−12). Results from the gene-based burden tests were null. In phenotype look-ups, SNP rs201255422 was associated with both systolic (p=0.001) and diastolic blood pressure (p=8.3×10−04). Conclusions Our study expands the understanding of genetic factors influencing the size of the retinal microvasculature. These findings may also provide insight into the relationship between retinal and systemic microvascular disease. PMID:26567291

Loss of the RNA polymerase III repressor MAF1 confers obesity resistance.

PubMed

Bonhoure, Nicolas; Byrnes, Ashlee; Moir, Robyn D; Hodroj, Wassim; Preitner, Frédéric; Praz, Viviane; Marcelin, Genevieve; Chua, Streamson C; Martinez-Lopez, Nuria; Singh, Rajat; Moullan, Norman; Auwerx, Johan; Willemin, Gilles; Shah, Hardik; Hartil, Kirsten; Vaitheesvaran, Bhavapriya; Kurland, Irwin; Hernandez, Nouria; Willis, Ian M

2015-05-01

MAF1 is a global repressor of RNA polymerase III transcription that regulates the expression of highly abundant noncoding RNAs in response to nutrient availability and cellular stress. Thus, MAF1 function is thought to be important for metabolic economy. Here we show that a whole-body knockout of Maf1 in mice confers resistance to diet-induced obesity and nonalcoholic fatty liver disease by reducing food intake and increasing metabolic inefficiency. Energy expenditure in Maf1(-/-) mice is increased by several mechanisms. Precursor tRNA synthesis was increased in multiple tissues without significant effects on mature tRNA levels, implying increased turnover in a futile tRNA cycle. Elevated futile cycling of hepatic lipids was also observed. Metabolite profiling of the liver and skeletal muscle revealed elevated levels of many amino acids and spermidine, which links the induction of autophagy in Maf1(-/-) mice with their extended life span. The increase in spermidine was accompanied by reduced levels of nicotinamide N-methyltransferase, which promotes polyamine synthesis, enables nicotinamide salvage to regenerate NAD(+), and is associated with obesity resistance. Consistent with this, NAD(+) levels were increased in muscle. The importance of MAF1 for metabolic economy reveals the potential for MAF1 modulators to protect against obesity and its harmful consequences. © 2015 Bonhoure et al.; Published by Cold Spring Harbor Laboratory Press.

Ebselen treatment prevents islet apoptosis, maintains intranuclear Pdx-1 and MafA levels, and preserves β-cell mass and function in ZDF rats.

PubMed

Mahadevan, Jana; Parazzoli, Susan; Oseid, Elizabeth; Hertzel, Ann V; Bernlohr, David A; Vallerie, Sara N; Liu, Chang-qin; Lopez, Melissa; Harmon, Jamie S; Robertson, R Paul

2013-10-01

We reported earlier that β-cell-specific overexpression of glutathione peroxidase (GPx)-1 significantly ameliorated hyperglycemia in diabetic db/db mice and prevented glucotoxicity-induced deterioration of β-cell mass and function. We have now ascertained whether early treatment of Zucker diabetic fatty (ZDF) rats with ebselen, an oral GPx mimetic, will prevent β-cell deterioration. No other antihyperglycemic treatment was given. Ebselen ameliorated fasting hyperglycemia, sustained nonfasting insulin levels, lowered nonfasting glucose levels, and lowered HbA1c levels with no effects on body weight. Ebselen doubled β-cell mass, prevented apoptosis, prevented expression of oxidative stress markers, and enhanced intranuclear localization of pancreatic and duodenal homeobox (Pdx)-1 and v-maf musculoaponeurotic fibrosarcoma oncogene family, protein A (MafA), two critical insulin transcription factors. Minimal β-cell replication was observed in both groups. These findings indicate that prevention of oxidative stress is the mechanism whereby ebselen prevents apoptosis and preserves intranuclear Pdx-1 and MafA, which, in turn, is a likely explanation for the beneficial effects of ebselen on β-cell mass and function. Since ebselen is an oral antioxidant currently used in clinical trials, it is a novel therapeutic candidate to ameliorate fasting hyperglycemia and further deterioration of β-cell mass and function in humans undergoing the onset of type 2 diabetes.

Arabidopsis WPP-Domain Proteins Are Developmentally Associated with the Nuclear Envelope and Promote Cell DivisionW⃞

PubMed Central

Patel, Shalaka; Rose, Annkatrin; Meulia, Tea; Dixit, Ram; Cyr, Richard J.; Meier, Iris

2004-01-01

The nuclear envelope (NE) acts as a selective barrier to macromolecule trafficking between the nucleus and the cytoplasm and undergoes a complex reorganization during mitosis. Different eukaryotic kingdoms show specializations in NE function and composition. In contrast with vertebrates, the protein composition of the NE and the function of NE proteins are barely understood in plants. MFP1 attachment factor 1 (MAF1) is a plant-specific NE-associated protein first identified in tomato (Lycopersicon esculentum). Here, we demonstrate that two Arabidopsis thaliana MAF1 homologs, WPP1 and WPP2, are associated with the NE specifically in undifferentiated cells of the root tip. Reentry into cell cycle after callus induction from differentiated root segments reprograms their NE association. Based on green fluorescent protein fusions and immunogold labeling data, the proteins are associated with the outer NE and the nuclear pores in interphase cells and with the immature cell plate during cytokinesis. RNA interference–based suppression of the Arabidopsis WPP family causes shorter primary roots, a reduced number of lateral roots, and reduced mitotic activity of the root meristem. Together, these data demonstrate the existence of regulated NE targeting in plants and identify a class of plant-specific NE proteins involved in mitotic activity. PMID:15548735

The Morelia-Acambay Fault System

NASA Astrophysics Data System (ADS)

Velázquez Bucio, M.; Soria-Caballero, D.; Garduño-Monroy, V.; Mennella, L.

2013-05-01

The Trans-Mexican Volcanic Belt (TMVB) is one of the most actives and representative zones of Mexico geologically speaking. Research carried out in this area gives stratigraphic, seismologic and historical evidence of its recent activity during the quaternary (Martinez and Nieto, 1990). Specifically the Morelia-Acambay faults system (MAFS) consist in a series of normal faults of dominant direction E - W, ENE - WSW y NE - SW which is cut in center west of the Trans-Mexican Volcanic Belt. This fault system appeared during the early Miocene although the north-south oriented structures are older and have been related to the activity of the tectonism inherited from the "Basin and Range" system, but that were reactivated by the east- west faults. It is believed that the activity of these faults has contributed to the creation and evolution of the longed lacustrine depressions such as: Chapala, Zacapu, Cuitzeo, Maravatio y Acambay also the location of monogenetic volcanoes that conformed the Michoacan-Guanajuato volcanic field (MGVF) and tend to align in the direction of the SFMA dominant effort. In a historical time different segments of the MAFS have been the epicenter of earthquakes from moderated to strong magnitude like the events of 1858 in Patzcuaro, Acambay in 1912, 1979 in Maravatio and 2007 in Morelia, among others. Several detailed analysis and semi-detailed analysis through a GIS platform based in the vectorial archives and thematic charts 1:50 000 scaled from the data base of the INEGI which has allowed to remark the influence of the MAFS segments about the morphology of the landscape and the identification of other structures related to the movement of the existent faults like fractures, alignments, collapses and others from the zone comprehended by the northwest of Morelia in Michoacán to the East of Acambay, Estado de México. Such analysis suggests that the fault segments possess a normal displacement plus a left component. In addition it can be associated to an alignment or different structures oblique directed to the principal fault trace which sometimes shows inverted moves suggest that the MAFS is a system with ''en echelon'' geometry which respond to transtensive tectonic activity. Recent research based in cinematic indicators from some of the most important faults of the MAFS concludes with evidence of the existence of a transtensive deformation in the center section of the TMVB, which can be explained through the oblique convergence model of plates Northamerica, Rivera and Cocos added to the division of the subduction angle at the North of the Mesoamerican trench.

SU-E-I-26: Estimation of Micro-Angiographic Fluoroscope (MAF) Gain Settings for Digital Subtraction Angiography (DSA) Based on the Fluoroscopic Exposure.

PubMed

Ionita, C; Loughran, B; Nagesh, S Setlur; Jain, A; Bednarek, D; Rudin, S

2012-06-01

The MAF is a new high-resolution detector which is being clinically evaluated in neuro-vascular procedures. The detector contains a large-dynamic-range, high-sensitivity light image intensifier with variable gain. Since the MAF is a research prototype only partially integrated with the clinical system, x-ray technique parameters must be set manually. To improve workflow we developed an automatic method to estimate and set the proper LII voltage (MAF gain) for DSA acquisition based on the fluoroscopic parameters. The detector entrance exposure (XD) can be written as the x-ray tube output exposure (Xo) times an object attenuation factor and an inverse-square correction. If the object attenuation, scatter and distances are unchanged and the effect of x-ray kVp changes are neglected, then the DSA XD can be expressed as the ratio of Xo(DSA)/Xo(Fluoroscopy) multiplied with XD(fluoroscopy). We measured Xo for fluoroscopy and DSA for mAs and kVp ranges appropriate to neuro- vascular interventions and fit the data with a 2D function. To estimate the XD(Fluoroscopy) we derived a curve of XD versus LII-voltage for a mid- dynamic-range average pixel gray-level. Since the MAF system during clinical fluoroscopy automatically adjusts the LII voltage until the desired gray-level value is achieved, by reading that voltage we can estimate the XD(Fluoroscopy). Using the 2D-fit function, Xo(DSA) is automatically calculated for the kVp and mA values set and XD(DSA) can be estimated using the relation above. Using the inverse LII calibration curve, the proper LII-voltage can be determined for the desired average gray-level. The algorithm was implemented and evaluated in thirty-two in-vivo DSA runs on rabbits. The proper LII voltage was selected in all cases with no failures. Using the fluoroscopic LII gain setting to determine the appropriate DSA setting can greatly improve the workflow in clinical evaluations of the MAF. NIH Grants R01-EB008425, R01-EB002873 and an equipment grant from Toshiba Medical Systems Corp. © 2012 American Association of Physicists in Medicine.

A Systematic Review of Studies Using the Multidimensional Assessment of Fatigue Scale.

PubMed

Belza, Basia; Miyawaki, Christina E; Liu, Minhui; Aree-Ue, Suparb; Fessel, Melissa; Minott, Kenya R; Zhang, Xi

2018-04-01

To review how the Multidimensional Assessment of Fatigue (MAF) has been used and evaluate its psychometric properties. We conducted a database search using "multidimensional assessment of fatigue" or "MAF" as key terms from 1993 to 2015, and located 102 studies. Eighty-three were empirical studies and 19 were reviews/evaluations. Research was conducted in 17 countries; 32 diseases were represented. Nine language versions of the MAF were used. The mean of the Global Fatigue Index ranged from 10.9 to 49.4. The MAF was reported to be easy-to-use, had strong reliability and validity, and was used in populations who spoke languages other than English. The MAF is an acceptable assessment tool to measure fatigue and intervention effectiveness in various languages, diseases, and settings across the world.

Investigation of rare and low-frequency variants using high-throughput sequencing with pooled DNA samples

PubMed Central

Wang, Jingwen; Skoog, Tiina; Einarsdottir, Elisabet; Kaartokallio, Tea; Laivuori, Hannele; Grauers, Anna; Gerdhem, Paul; Hytönen, Marjo; Lohi, Hannes; Kere, Juha; Jiao, Hong

2016-01-01

High-throughput sequencing using pooled DNA samples can facilitate genome-wide studies on rare and low-frequency variants in a large population. Some major questions concerning the pooling sequencing strategy are whether rare and low-frequency variants can be detected reliably, and whether estimated minor allele frequencies (MAFs) can represent the actual values obtained from individually genotyped samples. In this study, we evaluated MAF estimates using three variant detection tools with two sets of pooled whole exome sequencing (WES) and one set of pooled whole genome sequencing (WGS) data. Both GATK and Freebayes displayed high sensitivity, specificity and accuracy when detecting rare or low-frequency variants. For the WGS study, 56% of the low-frequency variants in Illumina array have identical MAFs and 26% have one allele difference between sequencing and individual genotyping data. The MAF estimates from WGS correlated well (r = 0.94) with those from Illumina arrays. The MAFs from the pooled WES data also showed high concordance (r = 0.88) with those from the individual genotyping data. In conclusion, the MAFs estimated from pooled DNA sequencing data reflect the MAFs in individually genotyped samples well. The pooling strategy can thus be a rapid and cost-effective approach for the initial screening in large-scale association studies. PMID:27633116

Application of Vibration and Oil Analysis for Reliability Information on Helicopter Main Rotor Gearbox

NASA Astrophysics Data System (ADS)

Murrad, Muhamad; Leong, M. Salman

Based on the experiences of the Malaysian Armed Forces (MAF), failure of the main rotor gearbox (MRGB) was one of the major contributing factors to helicopter breakdowns. Even though vibration and oil analysis are the effective techniques for monitoring the health of helicopter components, these two techniques were rarely combined to form an effective assessment tool in MAF. Results of the oil analysis were often used only for oil changing schedule while assessments of MRGB condition were mainly based on overall vibration readings. A study group was formed and given a mandate to improve the maintenance strategy of S61-A4 helicopter fleet in the MAF. The improvement consisted of a structured approach to the reassessment/redefinition suitable maintenance actions that should be taken for the MRGB. Basic and enhanced tools for condition monitoring (CM) are investigated to address the predominant failures of the MRGB. Quantitative accelerated life testing (QALT) was considered in this work with an intent to obtain the required reliability information in a shorter time with tests under normal stress conditions. These tests when performed correctly can provide valuable information about MRGB performance under normal operating conditions which enable maintenance personnel to make decision more quickly, accurately and economically. The time-to-failure and probability of failure information of the MRGB were generated by applying QALT analysis principles. This study is anticipated to make a dramatic change in its approach to CM, bringing significant savings and various benefits to MAF.

Substituting freshwater: Can ocean desalination and water recycling capacities substitute for groundwater depletion in California?

PubMed

Badiuzzaman, Pierre; McLaughlin, Eoin; McCauley, Darren

2017-12-01

While the sustainability of resource depletion is a longstanding environmental concern, wider attention has recently been given to growing water scarcity and groundwater depletion. This study seeks to test the substitutability assumption embedded in weak sustainability indicators using a case study of Californian water supply. The volume of groundwater depletion is used as a proxy for unsustainable water consumption, and defined by synthesising existing research estimates into low, medium and high depletion baselines. These are compared against projected water supply increases from ocean desalination and water recycling by 2035, to determine whether new, drought-proof water sources can substitute for currently unsustainable groundwater consumption. Results show that the maximum projected supply of new water, 2.47 million acre-feet per year (MAF/yr), is sufficient to meet low depletion estimates of 2.02 MAF/yr, but fails to come near the high depletion estimate of 3.44 MAF/yr. This does not necessarily indicate physical limitations of substitutability, but more so socio-economic limitations influenced by high comparative costs. By including capacities in demand-substitutability via urban water conservation, maximum predicted capacities reach 5.57 MAF/yr, indicating wide room for substitution. Based on these results, investment in social and institutional capital is an important factor to enhance demand-side substitutability of water and other natural resources, which has been somewhat neglected by the literature on the substitutability of natural resources. Copyright © 2017 Elsevier Ltd. All rights reserved.

The LSST metrics analysis framework (MAF)

NASA Astrophysics Data System (ADS)

Jones, R. L.; Yoachim, Peter; Chandrasekharan, Srinivasan; Connolly, Andrew J.; Cook, Kem H.; Ivezic, Željko; Krughoff, K. S.; Petry, Catherine; Ridgway, Stephen T.

2014-07-01

We describe the Metrics Analysis Framework (MAF), an open-source python framework developed to provide a user-friendly, customizable, easily-extensible set of tools for analyzing data sets. MAF is part of the Large Synoptic Survey Telescope (LSST) Simulations effort. Its initial goal is to provide a tool to evaluate LSST Operations Simulation (OpSim) simulated surveys to help understand the effects of telescope scheduling on survey performance, however MAF can be applied to a much wider range of datasets. The building blocks of the framework are Metrics (algorithms to analyze a given quantity of data), Slicers (subdividing the overall data set into smaller data slices as relevant for each Metric), and Database classes (to access the dataset and read data into memory). We describe how these building blocks work together, and provide an example of using MAF to evaluate different dithering strategies. We also outline how users can write their own custom Metrics and use these within the framework.

Validity and reliability of the multidimensional assessment of fatigue scale in Iranian patients with relapsing-remitting subtype of multiple sclerosis.

PubMed

Behrangrad, Shabnam; Kordi Yoosefinejad, Amin

2018-03-01

The purpose of this study is to investigate the validity and reliability of the Persian version of the Multidimensional Assessment of Fatigue Scale (MAFS) in an Iranian population with multiple sclerosis. A self-reported survey on fatigue including the MAFS, Fatigue Impact Scale and demographic measures was completed by 130 patients with multiple sclerosis and 60 healthy persons sampled with a convenience method. Test-retest reliability and validity were evaluated 3 days apart. Construct validity of the MAFS was assessed with the Fatigue Impact Scale. The MAFS had high internal consistency (Cronbach's alpha >0.9) and 3-d test-retest reliability (intraclass correlation coefficient = 0.99). Correlation between the Fatigue Impact Scale and MAFS was high (r = 0.99). Correlation between MAFS scores and the Expanded Disability Status Scale was also strong (r = 0.85). Questionnaire items showed acceptable item-scale correlation (0.968-0.993). The Persian version of the MAFS appears to be a valid and reliable questionnaire. It is an appropriate short multidimensional instrument to assess fatigue in patients with multiple sclerosis in clinical practice and research. Implications for Rehabilitation The Persian version of Multidimensional Assessment of Fatigue is a valid and reliable instrument for the assessment and monitoring the fatigue in Persian-language patients with multiple sclerosis. It is very easy to administer and a time efficient scale in comparison to other instruments evaluating fatigue in patients with multiple sclerosis.

Mobile Health Technology for Atrial Fibrillation Management Integrating Decision Support, Education, and Patient Involvement: mAF App Trial.

PubMed

Guo, Yutao; Chen, Yundai; Lane, Deirdre A; Liu, Lihong; Wang, Yutang; Lip, Gregory Y H

2017-12-01

Mobile Health technology for the management of patients with atrial fibrillation is unknown. The simple mobile AF (mAF) App was designed to incorporate clinical decision-support tools (CHA 2 DS 2 -VASc [Congestive heart failure, Hypertension, Age ≥75 years, Diabetes Mellitus, Prior Stroke or TIA, Vascular disease, Age 65-74 years, Sex category], HAS-BLED [Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly, Drugs/alcohol concomitantly], SAMe-TT 2 R 2 [Sex, Age <60 years, Medical history, Treatment, Tobacco use, Race] scores), educational materials, and patient involvement strategies with self-care protocols and structured follow-up. Patients with atrial fibrillation were randomized into 2 groups (mAF App vs usual care) in a cluster randomized design pilot study. Patients' knowledge, quality of life, drug adherence, and anticoagulation satisfaction were evaluated at baseline, 1 month, and 3 months. Usability, feasibility, and acceptability of the mAF App were assessed at 1 month. A total of 113 patients were randomized to mAF App intervention (mean age, 67.4 years; 57.5% were male; mean follow-up, 69 days), and 96 patients were randomized to usual care (mean age, 70.9 years; 55.2% were male; mean follow-up, 95 days). More than 90% of patients reported that the mAF App was easy, user-friendly, helpful, and associated with significant improvements in knowledge compared with the usual care arm (P values for trend <.05). Drug adherence and anticoagulant satisfaction were significantly better with the mAF App versus usual care (all P < .05). Quality of life scores were significantly increased in the mAF App arm versus usual care, with anxiety and depression reduced (all P < .05). The pilot mAFA Trial is the first prospective randomized trial of Mobile Health technology in patients with atrial fibrillation, demonstrating that the mAF App, integrating clinical decision support, education, and patient-involvement strategies, significantly improved knowledge, drug adherence, quality of life, and anticoagulation satisfaction. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Generation of glucose-sensitive insulin-secreting beta-like cells from human embryonic stem cells by incorporating a synthetic lineage-control network.

PubMed

Saxena, Pratik; Bojar, Daniel; Zulewski, Henryk; Fussenegger, Martin

2017-10-10

We previously reported novel technology to differentiate induced pluripotent stem cells (IPSCs) into glucose-sensitive insulin-secreting beta-like cells by engineering a synthetic lineage-control network regulated by the licensed food additive vanillic acid. This genetic network was able to program intricate expression dynamics of the key transcription factors Ngn3 (neurogenin 3, OFF-ON-OFF), Pdx1 (pancreatic and duodenal homeobox 1, ON-OFF-ON) and MafA (V-maf musculoaponeurotic fibrosarcoma oncogene homologue A, OFF-ON) to guide the differentiation of IPSC-derived pancreatic progenitor cells to beta-like cells. In the present study, we show for the first time that this network can also program the expression dynamics of Ngn3, Pdx1 and MafA in human embryonic stem cell (hESC)-derived pancreatic progenitor cells and drive differentiation of these cells into glucose-sensitive insulin-secreting beta-like cells. Therefore, synthetic lineage-control networks appear to be a robust methodology for differentiating pluripotent stem cells into somatic cell types for basic research and regenerative medicine. Copyright © 2017 Elsevier B.V. All rights reserved.

Islet-specific monoamine oxidase A and B expression depends on MafA transcriptional activity and is compromised in type 2 diabetes.

PubMed

Ganic, Elvira; Johansson, Jenny K; Bennet, Hedvig; Fex, Malin; Artner, Isabella

2015-12-25

Lack or dysfunction of insulin producing β cells results in the development of type 1 and type 2 diabetes mellitus, respectively. Insulin secretion is controlled by metabolic stimuli (glucose, fatty acids), but also by monoamine neurotransmitters, like dopamine, serotonin, and norepinephrine. Intracellular monoamine levels are controlled by monoamine oxidases (Mao) A and B. Here we show that MaoA and MaoB are expressed in mouse islet β cells and that inhibition of Mao activity reduces insulin secretion in response to metabolic stimuli. Moreover, analysis of MaoA and MaoB protein expression in mouse and human type 2 diabetic islets shows a significant reduction of MaoB in type 2 diabetic β cells suggesting that loss of Mao contributes to β cell dysfunction. MaoB expression was also reduced in β cells of MafA-deficient mice, a mouse model for β cell dysfunction, and biochemical studies showed that MafA directly binds to and activates MaoA and MaoB transcriptional control sequences. Taken together, our results show that MaoA and MaoB expression in pancreatic islets is required for physiological insulin secretion and lost in type 2 diabetic mouse and human β cells. These findings demonstrate that regulation of monoamine levels by Mao activity in β cells is pivotal for physiological insulin secretion and that loss of MaoB expression may contribute to the β cell dysfunction in type 2 diabetes. Copyright © 2015 Elsevier Inc. All rights reserved.

Lost in Translation: Bioinformatic Analysis of Variations Affecting the Translation Initiation Codon in the Human Genome.

PubMed

Abad, Francisco; de la Morena-Barrio, María Eugenia; Fernández-Breis, Jesualdo Tomás; Corral, Javier

2018-06-01

Translation is a key biological process controlled in eukaryotes by the initiation AUG codon. Variations affecting this codon may have pathological consequences by disturbing the correct initiation of translation. Unfortunately, there is no systematic study describing these variations in the human genome. Moreover, we aimed to develop new tools for in silico prediction of the pathogenicity of gene variations affecting AUG codons, because to date, these gene defects have been wrongly classified as missense. Whole-exome analysis revealed the mean of 12 gene variations per person affecting initiation codons, mostly with high (> 0:01) minor allele frequency (MAF). Moreover, analysis of Ensembl data (December 2017) revealed 11,261 genetic variations affecting the initiation AUG codon of 7,205 genes. Most of these variations (99.5%) have low or unknown MAF, probably reflecting deleterious consequences. Only 62 variations had high MAF. Genetic variations with high MAF had closer alternative AUG downstream codons than did those with low MAF. Besides, the high-MAF group better maintained both the signal peptide and reading frame. These differentiating elements could help to determine the pathogenicity of this kind of variation. Data and scripts in Perl and R are freely available at https://github.com/fanavarro/hemodonacion. jfernand@um.es. Supplementary data are available at Bioinformatics online.

Developing and testing a global-scale regression model to quantify mean annual streamflow

NASA Astrophysics Data System (ADS)

Barbarossa, Valerio; Huijbregts, Mark A. J.; Hendriks, A. Jan; Beusen, Arthur H. W.; Clavreul, Julie; King, Henry; Schipper, Aafke M.

2017-01-01

Quantifying mean annual flow of rivers (MAF) at ungauged sites is essential for assessments of global water supply, ecosystem integrity and water footprints. MAF can be quantified with spatially explicit process-based models, which might be overly time-consuming and data-intensive for this purpose, or with empirical regression models that predict MAF based on climate and catchment characteristics. Yet, regression models have mostly been developed at a regional scale and the extent to which they can be extrapolated to other regions is not known. In this study, we developed a global-scale regression model for MAF based on a dataset unprecedented in size, using observations of discharge and catchment characteristics from 1885 catchments worldwide, measuring between 2 and 106 km2. In addition, we compared the performance of the regression model with the predictive ability of the spatially explicit global hydrological model PCR-GLOBWB by comparing results from both models to independent measurements. We obtained a regression model explaining 89% of the variance in MAF based on catchment area and catchment averaged mean annual precipitation and air temperature, slope and elevation. The regression model performed better than PCR-GLOBWB for the prediction of MAF, as root-mean-square error (RMSE) values were lower (0.29-0.38 compared to 0.49-0.57) and the modified index of agreement (d) was higher (0.80-0.83 compared to 0.72-0.75). Our regression model can be applied globally to estimate MAF at any point of the river network, thus providing a feasible alternative to spatially explicit process-based global hydrological models.

Mammary cell-activating factor regulates the hormone-independent transcription of the early lactation protein (ELP) gene in a marsupial.

PubMed

Pharo, Elizabeth A; Renfree, Marilyn B; Cane, Kylie N

2016-11-15

The regulation of the tammar wallaby (Macropus eugenii) early lactation protein (ELP) gene is complex. ELP is responsive to the lactogenic hormones; insulin (I), hydrocortisone (HC) and prolactin (PRL) in mammary gland explants but could not be induced with lactogenic hormones in tammar primary mammary gland cells, nor in KIM-2 conditionally immortalised murine mammary epithelial cells. Similarly, ELP promoter constructs transiently-transfected into human embryonic kidney (HEK293T) cells constitutively expressing the prolactin receptor (PRLR) and Signal Transducer and Activator of Transcription (STAT)5A were unresponsive to prolactin, unlike the rat and mouse β-casein (CSN2) promoter constructs. Identification of the minimal promoter required for the hormone-independent transcription of tammar ELP in HEK293Ts and comparative analysis of the proximal promoters of marsupial ELP and the orthologous eutherian colostrum trypsin inhibitor (CTI) gene suggests that mammary cell-activating factor (MAF), an E26 transformation-specific (ETS) factor, may bind to an AGGAAG motif and activate tammar ELP. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

On the MAF solution of the uniformly lengthening pendulum via change of independent variable in the Bessel's equation

NASA Astrophysics Data System (ADS)

Deniz, Coşkun

Common recipe for the Lengthening Pendulum (LP) involves some change of variables to give a relationship with the Bessel's equation. In this work, semiclassical MAF (Modified Airy Function) solution of the LP is being obtained by first transforming the related Bessel's equation into the normal form via the suggested change of independent variable just as one of our recent work regarding the JWKB solution of the LP in (Deniz, 2017). MAF approximation of the first order Bessel Functions (ν = 1) of both type along with their zeros are being obtained analytically with a very good accuracy as a result of the appropriately chosen associated initial values and they are extended to the neighbouring orders (ν = 0 and 2) by the recursion relations. Although common numerical methods given in the literature require adiabatic LP systems where the lengthening rate is small, MAF solution presented here can safely be used for higher lengthening rates and a criterion for its validity is determined via the use of MAF applicability criterion given in the literature. As a result, the semiclassical MAF method which is normally used for the quantum mechanical and optical waveguide systems is applied to the classical LP system successfully just as our previous work regarding the JWKB solution of the LP. Interestingly, we have very accurate results in the entire domain except for x ≈ 0 .

Lens-Specific Gene Recruitment of ζ-Crystallin through Pax6, Nrl-Maf, and Brain Suppressor Sites

PubMed Central

Sharon-Friling, Ronit; Richardson, Jill; Sperbeck, Sally; Lee, Douglas; Rauchman, Michael; Maas, Richard; Swaroop, Anand; Wistow, Graeme

1998-01-01

ζ-Crystallin is a taxon-specific crystallin, an enzyme which has undergone direct gene recruitment as a structural component of the guinea pig lens through a Pax6-dependent mechanism. Tissue specificity arises through a combination of effects involving three sites in the lens promoter. The Pax6 site (ZPE) itself shows specificity for an isoform of Pax6 preferentially expressed in lens cells. High-level expression of the promoter requires a second site, identical to an αCE2 site or half Maf response element (MARE), adjacent to the Pax6 site. A promoter fragment containing Pax6 and MARE sites gives lens-preferred induction of a heterologous promoter. Complexes binding the MARE in lens nuclear extracts are antigenically related to Nrl, and cotransfection with Nrl elevates ζ-crystallin promoter activity in lens cells. A truncated ζ promoter containing Nrl-MARE and Pax6 sites has a high level of expression in lens cells in transgenic mice but is also active in the brain. Suppression of the promoter in the brain requires sequences between −498 and −385, and a site in this region forms specific complexes in brain extract. A three-level model for lens-specific Pax6-dependent expression and gene recruitment is suggested: (i) binding of a specific isoform of Pax6; (ii) augmentation of expression through binding of Nrl or a related factor; and (iii) suppression of promoter activity in the central nervous system by an upstream negative element in the brain but not in the lens. PMID:9528779

Genome-Wide Meta-Analysis of Sciatica in Finnish Population.

PubMed

Lemmelä, Susanna; Solovieva, Svetlana; Shiri, Rahman; Benner, Christian; Heliövaara, Markku; Kettunen, Johannes; Anttila, Verneri; Ripatti, Samuli; Perola, Markus; Seppälä, Ilkka; Juonala, Markus; Kähönen, Mika; Salomaa, Veikko; Viikari, Jorma; Raitakari, Olli T; Lehtimäki, Terho; Palotie, Aarno; Viikari-Juntura, Eira; Husgafvel-Pursiainen, Kirsti

2016-01-01

Sciatica or the sciatic syndrome is a common and often disabling low back disorder in the working-age population. It has a relatively high heritability but poorly understood molecular mechanisms. The Finnish population is a genetic isolate where small founder population and bottleneck events have led to enrichment of certain rare and low frequency variants. We performed here the first genome-wide association (GWAS) and meta-analysis of sciatica. The meta-analysis was conducted across two GWAS covering 291 Finnish sciatica cases and 3671 controls genotyped and imputed at 7.7 million autosomal variants. The most promising loci (p<1x10-6) were replicated in 776 Finnish sciatica patients and 18,489 controls. We identified five intragenic variants, with relatively low frequencies, at two novel loci associated with sciatica at genome-wide significance. These included chr9:14344410:I (rs71321981) at 9p22.3 (NFIB gene; p = 1.30x10-8, MAF = 0.08) and four variants at 15q21.2: rs145901849, rs80035109, rs190200374 and rs117458827 (MYO5A; p = 1.34x10-8, MAF = 0.06; p = 2.32x10-8, MAF = 0.07; p = 3.85x10-8, MAF = 0.06; p = 4.78x10-8, MAF = 0.07, respectively). The most significant association in the meta-analysis, a single base insertion rs71321981 within the regulatory region of the transcription factor NFIB, replicated in an independent Finnish population sample (p = 0.04). Despite identifying 15q21.2 as a promising locus, we were not able to replicate it. It was differentiated; the lead variants within 15q21.2 were more frequent in Finland (6-7%) than in other European populations (1-2%). Imputation accuracies of the three significantly associated variants (chr9:14344410:I, rs190200374, and rs80035109) were validated by genotyping. In summary, our results suggest a novel locus, 9p22.3 (NFIB), which may be involved in susceptibility to sciatica. In addition, another locus, 15q21.2, emerged as a promising one, but failed to replicate.

Genome-Wide Meta-Analysis of Sciatica in Finnish Population

PubMed Central

Lemmelä, Susanna; Solovieva, Svetlana; Shiri, Rahman; Benner, Christian; Heliövaara, Markku; Kettunen, Johannes; Anttila, Verneri; Ripatti, Samuli; Perola, Markus; Seppälä, Ilkka; Juonala, Markus; Kähönen, Mika; Salomaa, Veikko; Viikari, Jorma; Raitakari, Olli T.; Lehtimäki, Terho; Palotie, Aarno; Viikari-Juntura, Eira; Husgafvel-Pursiainen, Kirsti

2016-01-01

Sciatica or the sciatic syndrome is a common and often disabling low back disorder in the working-age population. It has a relatively high heritability but poorly understood molecular mechanisms. The Finnish population is a genetic isolate where small founder population and bottleneck events have led to enrichment of certain rare and low frequency variants. We performed here the first genome-wide association (GWAS) and meta-analysis of sciatica. The meta-analysis was conducted across two GWAS covering 291 Finnish sciatica cases and 3671 controls genotyped and imputed at 7.7 million autosomal variants. The most promising loci (p<1x10-6) were replicated in 776 Finnish sciatica patients and 18,489 controls. We identified five intragenic variants, with relatively low frequencies, at two novel loci associated with sciatica at genome-wide significance. These included chr9:14344410:I (rs71321981) at 9p22.3 (NFIB gene; p = 1.30x10-8, MAF = 0.08) and four variants at 15q21.2: rs145901849, rs80035109, rs190200374 and rs117458827 (MYO5A; p = 1.34x10-8, MAF = 0.06; p = 2.32x10-8, MAF = 0.07; p = 3.85x10-8, MAF = 0.06; p = 4.78x10-8, MAF = 0.07, respectively). The most significant association in the meta-analysis, a single base insertion rs71321981 within the regulatory region of the transcription factor NFIB, replicated in an independent Finnish population sample (p = 0.04). Despite identifying 15q21.2 as a promising locus, we were not able to replicate it. It was differentiated; the lead variants within 15q21.2 were more frequent in Finland (6–7%) than in other European populations (1–2%). Imputation accuracies of the three significantly associated variants (chr9:14344410:I, rs190200374, and rs80035109) were validated by genotyping. In summary, our results suggest a novel locus, 9p22.3 (NFIB), which may be involved in susceptibility to sciatica. In addition, another locus, 15q21.2, emerged as a promising one, but failed to replicate. PMID:27764105

Emergence of novel and dominant acquired EGFR solvent-front mutations at Gly796 (G796S/R) together with C797S/R and L792F/H mutations in one EGFR (L858R/T790M) NSCLC patient who progressed on osimertinib.

PubMed

Ou, Sai-Hong Ignatius; Cui, Jean; Schrock, Alexa B; Goldberg, Michael E; Zhu, Viola W; Albacker, Lee; Stephens, Philip J; Miller, Vincent A; Ali, Siraj M

2017-06-01

Acquired epidermal growth factor receptor (EGFR) resistance mutations to osimertinib are common, including the EGFR C797S that abolishes the covalent binding of osimertinib to EGFR. Here we report the emergence of novel EGFR solvent front mutations at Gly796 (G796S/R) in addition to a hinge pocket L792F/H mutations, and C797S/G all in cis with T790M in a single patient on progression on osimertinib as detected by plasma circulating tumor DNA (ctDNA) assay in the course of clinical care. A 69-year-old Caucasian female former light-smoker presented with stage IV EGFR L858R positive adenocarcinoma who developed EGFR T790M mutation after 8 month treatment of erlotinib. The patient was initiated on osimertinib with disease shrinkage after 2 months, but tumor regrowth was observed after 5 months of osimertinib treatment. Assay of plasma ctDNA at this time revealed these different secondary resistance mutations all in trans with each other including distinct mutations at the same codon producing different amino acid changes: G796S/R (mutant allele frequency [MAF]; 14.4%), C797S/G (MAF: 2.26%), L792F/H (MAF: 0.36%), and V802F (MAF: 0.40%), in addition to the pre-existing L858R (MAF:17.9%) and T790M (MAF:18.2%) but all in cis with T790M. The G796S/R mutations are homologous with known reported solvent front mutations in ALK G1202R, ROS1 G2032R, TrkA G595R and TrkC G623R, all of which are associated with acquired resistance to type I TKIs. In silico modeling revealed mutation at G796 interferes with osimertinib binding to the EGFR kinase domain at the phenyl aromatic ring position as this residue forms a narrow "hydrophobic sandwich" with L718, while L792F/H mutation interferes with osimertinib binding at the methoxyl group on the phenyl ring. Multiple resistance mutations at differing allele frequencies including novel EGFR solvent front mutations can emerge in a single patient with progression on osimertinib potentially due to tumor hetereogeneity and definitely present a significant therapeutic and drug development challenge. Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.

High Fractional Occupancy of a Tandem Maf Recognition Element and Its Role in Long-Range β-Globin Gene Regulation

PubMed Central

Stees, Jared R.; Hossain, Mir A.; Sunose, Tomoki; Kudo, Yasushi; Pardo, Carolina E.; Nabilsi, Nancy H.; Darst, Russell P.; Poudyal, Rosha; Igarashi, Kazuhiko; Kladde, Michael P.

2015-01-01

Enhancers and promoters assemble protein complexes that ultimately regulate the recruitment and activity of RNA polymerases. Previous work has shown that at least some enhancers form stable protein complexes, leading to the formation of enhanceosomes. We analyzed protein-DNA interactions in the murine β-globin gene locus using the methyltransferase accessibility protocol for individual templates (MAPit). The data show that a tandem Maf recognition element (MARE) in locus control region (LCR) hypersensitive site 2 (HS2) reveals a remarkably high degree of occupancy during differentiation of mouse erythroleukemia cells. Most of the other transcription factor binding sites in LCR HS2 or in the adult β-globin gene promoter regions exhibit low fractional occupancy, suggesting highly dynamic protein-DNA interactions. Targeting of an artificial zinc finger DNA-binding domain (ZF-DBD) to the HS2 tandem MARE caused a reduction in the association of MARE-binding proteins and transcription complexes at LCR HS2 and the adult βmajor-globin gene promoter but did not affect expression of the βminor-globin gene. The data demonstrate that a stable MARE-associated footprint in LCR HS2 is important for the recruitment of transcription complexes to the adult βmajor-globin gene promoter during erythroid cell differentiation. PMID:26503787

Nonlinear Filtering Effects of Reservoirs on Flood Frequency Curves at the Regional Scale: RESERVOIRS FILTER FLOOD FREQUENCY CURVES

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

Wang, Wei; Li, Hong-Yi; Leung, L. Ruby

Anthropogenic activities, e.g., reservoir operation, may alter the characteristics of Flood Frequency Curve (FFC) and challenge the basic assumption of stationarity used in flood frequency analysis. This paper presents a combined data-modeling analysis of the nonlinear filtering effects of reservoirs on the FFCs over the contiguous United States. A dimensionless Reservoir Impact Index (RII), defined as the total upstream reservoir storage capacity normalized by the annual streamflow volume, is used to quantify reservoir regulation effects. Analyses are performed for 388 river stations with an average record length of 50 years. The first two moments of the FFC, mean annual maximummore » flood (MAF) and coefficient of variations (CV), are calculated for the pre- and post-dam periods and compared to elucidate the reservoir regulation effects as a function of RII. It is found that MAF generally decreases with increasing RII but stabilizes when RII exceeds a threshold value, and CV increases with RII until a threshold value beyond which CV decreases with RII. The processes underlying the nonlinear threshold behavior of MAF and CV are investigated using three reservoir models with different levels of complexity. All models capture the non-linear relationships of MAF and CV with RII, suggesting that the basic flood control function of reservoirs is key to the non-linear relationships. The relative roles of reservoir storage capacity, operation objectives, available storage prior to a flood event, and reservoir inflow pattern are systematically investigated. Our findings may help improve flood-risk assessment and mitigation in regulated river systems at the regional scale.« less

Saturn Apollo Program

NASA Image and Video Library

1967-11-01

This image depicts a Boeing worker installing an F-1 engine on the Saturn V S-IC flight stage at the Michoud Assembly Facility (MAF). The Saturn IB and Saturn V first stages were manufactured at the MAF, located 24 kilometers (approximately 15 miles) east of downtown New Orleans, Louisiana. The prime contractors, Chrysler and Boeing, jointly occupied the MAF. The basic manufacturing building boasted 43 acres under one roof. By 1964, NASA added a separate engineering and office building, vertical assembly building, and test stage building.

Gestational Diabetes Mellitus From Inactivation of Prolactin Receptor and MafB in Islet β-Cells.

PubMed

Banerjee, Ronadip R; Cyphert, Holly A; Walker, Emily M; Chakravarthy, Harini; Peiris, Heshan; Gu, Xueying; Liu, Yinghua; Conrad, Elizabeth; Goodrich, Lisa; Stein, Roland W; Kim, Seung K

2016-08-01

β-Cell proliferation and expansion during pregnancy are crucial for maintaining euglycemia in response to increased metabolic demands placed on the mother. Prolactin and placental lactogen signal through the prolactin receptor (PRLR) and contribute to adaptive β-cell responses in pregnancy; however, the in vivo requirement for PRLR signaling specifically in maternal β-cell adaptations remains unknown. We generated a floxed allele of Prlr, allowing conditional loss of PRLR in β-cells. In this study, we show that loss of PRLR signaling in β-cells results in gestational diabetes mellitus (GDM), reduced β-cell proliferation, and failure to expand β-cell mass during pregnancy. Targeted PRLR loss in maternal β-cells in vivo impaired expression of the transcription factor Foxm1, both G1/S and G2/M cyclins, tryptophan hydroxylase 1 (Tph1), and islet serotonin production, for which synthesis requires Tph1. This conditional system also revealed that PRLR signaling is required for the transient gestational expression of the transcription factor MafB within a subset of β-cells during pregnancy. MafB deletion in maternal β-cells also produced GDM, with inadequate β-cell expansion accompanied by failure to induce PRLR-dependent target genes regulating β-cell proliferation. These results unveil molecular roles for PRLR signaling in orchestrating the physiologic expansion of maternal β-cells during pregnancy. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Accurate and predictive antibody repertoire profiling by molecular amplification fingerprinting.

PubMed

Khan, Tarik A; Friedensohn, Simon; Gorter de Vries, Arthur R; Straszewski, Jakub; Ruscheweyh, Hans-Joachim; Reddy, Sai T

2016-03-01

High-throughput antibody repertoire sequencing (Ig-seq) provides quantitative molecular information on humoral immunity. However, Ig-seq is compromised by biases and errors introduced during library preparation and sequencing. By using synthetic antibody spike-in genes, we determined that primer bias from multiplex polymerase chain reaction (PCR) library preparation resulted in antibody frequencies with only 42 to 62% accuracy. Additionally, Ig-seq errors resulted in antibody diversity measurements being overestimated by up to 5000-fold. To rectify this, we developed molecular amplification fingerprinting (MAF), which uses unique molecular identifier (UID) tagging before and during multiplex PCR amplification, which enabled tagging of transcripts while accounting for PCR efficiency. Combined with a bioinformatic pipeline, MAF bias correction led to measurements of antibody frequencies with up to 99% accuracy. We also used MAF to correct PCR and sequencing errors, resulting in enhanced accuracy of full-length antibody diversity measurements, achieving 98 to 100% error correction. Using murine MAF-corrected data, we established a quantitative metric of recent clonal expansion-the intraclonal diversity index-which measures the number of unique transcripts associated with an antibody clone. We used this intraclonal diversity index along with antibody frequencies and somatic hypermutation to build a logistic regression model for prediction of the immunological status of clones. The model was able to predict clonal status with high confidence but only when using MAF error and bias corrected Ig-seq data. Improved accuracy by MAF provides the potential to greatly advance Ig-seq and its utility in immunology and biotechnology.

Accurate and predictive antibody repertoire profiling by molecular amplification fingerprinting

PubMed Central

Khan, Tarik A.; Friedensohn, Simon; de Vries, Arthur R. Gorter; Straszewski, Jakub; Ruscheweyh, Hans-Joachim; Reddy, Sai T.

2016-01-01

High-throughput antibody repertoire sequencing (Ig-seq) provides quantitative molecular information on humoral immunity. However, Ig-seq is compromised by biases and errors introduced during library preparation and sequencing. By using synthetic antibody spike-in genes, we determined that primer bias from multiplex polymerase chain reaction (PCR) library preparation resulted in antibody frequencies with only 42 to 62% accuracy. Additionally, Ig-seq errors resulted in antibody diversity measurements being overestimated by up to 5000-fold. To rectify this, we developed molecular amplification fingerprinting (MAF), which uses unique molecular identifier (UID) tagging before and during multiplex PCR amplification, which enabled tagging of transcripts while accounting for PCR efficiency. Combined with a bioinformatic pipeline, MAF bias correction led to measurements of antibody frequencies with up to 99% accuracy. We also used MAF to correct PCR and sequencing errors, resulting in enhanced accuracy of full-length antibody diversity measurements, achieving 98 to 100% error correction. Using murine MAF-corrected data, we established a quantitative metric of recent clonal expansion—the intraclonal diversity index—which measures the number of unique transcripts associated with an antibody clone. We used this intraclonal diversity index along with antibody frequencies and somatic hypermutation to build a logistic regression model for prediction of the immunological status of clones. The model was able to predict clonal status with high confidence but only when using MAF error and bias corrected Ig-seq data. Improved accuracy by MAF provides the potential to greatly advance Ig-seq and its utility in immunology and biotechnology. PMID:26998518

Whole-genome sequence-based analysis of thyroid function.

PubMed

Taylor, Peter N; Porcu, Eleonora; Chew, Shelby; Campbell, Purdey J; Traglia, Michela; Brown, Suzanne J; Mullin, Benjamin H; Shihab, Hashem A; Min, Josine; Walter, Klaudia; Memari, Yasin; Huang, Jie; Barnes, Michael R; Beilby, John P; Charoen, Pimphen; Danecek, Petr; Dudbridge, Frank; Forgetta, Vincenzo; Greenwood, Celia; Grundberg, Elin; Johnson, Andrew D; Hui, Jennie; Lim, Ee M; McCarthy, Shane; Muddyman, Dawn; Panicker, Vijay; Perry, John R B; Bell, Jordana T; Yuan, Wei; Relton, Caroline; Gaunt, Tom; Schlessinger, David; Abecasis, Goncalo; Cucca, Francesco; Surdulescu, Gabriela L; Woltersdorf, Wolfram; Zeggini, Eleftheria; Zheng, Hou-Feng; Toniolo, Daniela; Dayan, Colin M; Naitza, Silvia; Walsh, John P; Spector, Tim; Davey Smith, George; Durbin, Richard; Richards, J Brent; Sanna, Serena; Soranzo, Nicole; Timpson, Nicholas J; Wilson, Scott G

2015-03-06

Normal thyroid function is essential for health, but its genetic architecture remains poorly understood. Here, for the heritable thyroid traits thyrotropin (TSH) and free thyroxine (FT4), we analyse whole-genome sequence data from the UK10K project (N=2,287). Using additional whole-genome sequence and deeply imputed data sets, we report meta-analysis results for common variants (MAF≥1%) associated with TSH and FT4 (N=16,335). For TSH, we identify a novel variant in SYN2 (MAF=23.5%, P=6.15 × 10(-9)) and a new independent variant in PDE8B (MAF=10.4%, P=5.94 × 10(-14)). For FT4, we report a low-frequency variant near B4GALT6/SLC25A52 (MAF=3.2%, P=1.27 × 10(-9)) tagging a rare TTR variant (MAF=0.4%, P=2.14 × 10(-11)). All common variants explain ≥20% of the variance in TSH and FT4. Analysis of rare variants (MAF<1%) using sequence kernel association testing reveals a novel association with FT4 in NRG1. Our results demonstrate that increased coverage in whole-genome sequence association studies identifies novel variants associated with thyroid function.

Identification-While-Scanning of a Multi-Aircraft Formation Based on Sparse Recovery for Narrowband Radar.

PubMed

Jiang, Yuan; Xu, Jia; Peng, Shi-Bao; Mao, Er-Ke; Long, Teng; Peng, Ying-Ning

2016-11-23

It is known that the identification performance of a multi-aircraft formation (MAF) of narrowband radar mainly depends on the time on target (TOT). To realize the identification task in one rotated scan with limited TOT, the paper proposes a novel identification-while-scanning (IWS) method based on sparse recovery to maintain high rotating speed and super-resolution for MAF identification, simultaneously. First, a multiple chirp signal model is established for MAF in a single scan, where different aircraft may have different Doppler centers and Doppler rates. Second, based on the sparsity of MAF in the Doppler parameter space, a novel hierarchical basis pursuit (HBP) method is proposed to obtain satisfactory sparse recovery performance as well as high computational efficiency. Furthermore, the parameter estimation performance of the proposed IWS identification method is analyzed with respect to recovery condition, signal-to-noise ratio and TOT. It is shown that an MAF can be effectively identified via HBP with a TOT of only about one hundred microseconds for IWS applications. Finally, some numerical experiment results are provided to demonstrate the effectiveness of the proposed method based on both simulated and real measured data.

An LPV Adaptive Observer for Updating a Map Applied to an MAF Sensor in a Diesel Engine.

PubMed

Liu, Zhiyuan; Wang, Changhui

2015-10-23

In this paper, a new method for mass air flow (MAF) sensor error compensation and an online updating error map (or lookup table) due to installation and aging in a diesel engine is developed. Since the MAF sensor error is dependent on the engine operating point, the error model is represented as a two-dimensional (2D) map with two inputs, fuel mass injection quantity and engine speed. Meanwhile, the 2D map representing the MAF sensor error is described as a piecewise bilinear interpolation model, which can be written as a dot product between the regression vector and parameter vector using a membership function. With the combination of the 2D map regression model and the diesel engine air path system, an LPV adaptive observer with low computational load is designed to estimate states and parameters jointly. The convergence of the proposed algorithm is proven under the conditions of persistent excitation and given inequalities. The observer is validated against the simulation data from engine software enDYNA provided by Tesis. The results demonstrate that the operating point-dependent error of the MAF sensor can be approximated acceptably by the 2D map from the proposed method.

Modified artificial fish school algorithm for free space optical communication with sensor-less adaptive optics system

NASA Astrophysics Data System (ADS)

Cao, Jingtai; Zhao, Xiaohui; Li, Zhaokun; Liu, Wei; Gu, Haijun

2017-11-01

The performance of free space optical (FSO) communication system is limited by atmospheric turbulent extremely. Adaptive optics (AO) is the significant method to overcome the atmosphere disturbance. Especially, for the strong scintillation effect, the sensor-less AO system plays a major role for compensation. In this paper, a modified artificial fish school (MAFS) algorithm is proposed to compensate the aberrations in the sensor-less AO system. Both the static and dynamic aberrations compensations are analyzed and the performance of FSO communication before and after aberrations compensations is compared. In addition, MAFS algorithm is compared with artificial fish school (AFS) algorithm, stochastic parallel gradient descent (SPGD) algorithm and simulated annealing (SA) algorithm. It is shown that the MAFS algorithm has a higher convergence speed than SPGD algorithm and SA algorithm, and reaches the better convergence value than AFS algorithm, SPGD algorithm and SA algorithm. The sensor-less AO system with MAFS algorithm effectively increases the coupling efficiency at the receiving terminal with fewer numbers of iterations. In conclusion, the MAFS algorithm has great significance for sensor-less AO system to compensate atmospheric turbulence in FSO communication system.

The spectrum of metanephric adenofibroma and related lesions: clinicopathologic study of 25 cases from the National Wilms Tumor Study Group Pathology Center.

PubMed

Arroyo, M R; Green, D M; Perlman, E J; Beckwith, J B; Argani, P

2001-04-01

The authors report nine new metanephric adenofibroma (MAFs; previously termed nephrogenic adenofibroma) and 16 related tumors from the files of the National Wilms Tumor Study Group Pathology Center (NWTSGPC). All tumors contained a variable amount of a bland spindle cell stroma, which is essentially identical to the recently described metanephric stromal tumor (MST). Features that distinguish this stroma from congenital mesoblastic nephroma (CMN) include intratumoral angiodysplasia, concentric cuffing of entrapped tubules ("onion skinning"), and heterologous differentiation. The epithelial components of these lesions spanned a wide range of appearances. All tumors contained at least focally an inactive embryonal epithelium identical morphologically to metanephric adenoma (MA), and hence each case could be classified as containing MAF. The epithelium of nine tumors had this appearance throughout, and hence these were considered usual MAFs. The epithelium of four tumors demonstrated increased mitotic activity but was otherwise similar to MA. The epithelial component of seven tumors spanned a morphologic spectrum from inactive MA to malignant epithelial predominant Wilms tumor (WT), with gradual transitions noted in several cases. Five other tumors contained a carcinomatous component distinct from these lesions but identical morphologically to papillary renal cell carcinoma (PRCC). In one of these cases, this component had metastasized to the regional lymph nodes at the time of diagnosis. No tumor recurred during follow-up, although almost all patients received adjuvant therapy for WT regardless of their tumor's histology and NWTSGPC diagnosis. In conclusion, MAF is a biphasic tumor that spans the morphologic spectrum between benign pure stromal (MST) and pure epithelial (MA) lesions, and can merge with the morphology of WT, supporting the concept that these are all related lesions. A relationship to PRCC is also evident.

RFI to CMS: An Approach to Regulatory Acceptance of Site Remediation Technologies

NASA Technical Reports Server (NTRS)

Rowland, Martin A.

2001-01-01

Lockheed Martin made a smooth transition from RCRA Facility Investigation (RFI) at the National Aeronautics and Space Administrations'(NASA) Michoud Assembly Facility (MA-F) to its Corrective Measures Study (CMS) phase within the RCRA Corrective Action Process. We located trichloroethylene (TCE) contamination that resulted from the manufacture of the Apollo Program Saturn V rocket and the Space Shuttle External Tank, began the cleanup, and identified appropriate technologies for final remedies. This was accomplished by establishing a close working relationship with the state environmental regulatory agency through each step of the process, and resulted in receiving approvals for each of those steps. The agency has designated Lockheed Martin's management of the TCE-contamination at the MAF site as a model for other manufacturing sites in a similar situation. In February 1984, the Louisiana Department of Environmental Quality (LDEQ) issued a compliance order to begin the clean up of groundwater contaminated with TCE. In April 1984 Lockheed Martin began operating a groundwater recovery well to capture the TCE plume. The well not only removes contaminants, but also sustains an inward groundwater hydraulic gradient so that the potential offsite migration of the TCE plume is greatly diminished. This effort was successful, and for the agency to give orders and for a regulated industry to follow them is standard procedure, but this is a passive approach to solving environmental problems. The goal of the company thereafter was to take a leadership, proactive role and guide the MAF contamination clean up to its best conclusion at minimum time and lowest cost to NASA. To accomplish this goal, we have established a positive working relationship with LDEQ, involving them interactively in the implementation of advanced remedial activities at MAF as outlined in the following paragraphs.

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease.

PubMed

Sims, Rebecca; van der Lee, Sven J; Naj, Adam C; Bellenguez, Céline; Badarinarayan, Nandini; Jakobsdottir, Johanna; Kunkle, Brian W; Boland, Anne; Raybould, Rachel; Bis, Joshua C; Martin, Eden R; Grenier-Boley, Benjamin; Heilmann-Heimbach, Stefanie; Chouraki, Vincent; Kuzma, Amanda B; Sleegers, Kristel; Vronskaya, Maria; Ruiz, Agustin; Graham, Robert R; Olaso, Robert; Hoffmann, Per; Grove, Megan L; Vardarajan, Badri N; Hiltunen, Mikko; Nöthen, Markus M; White, Charles C; Hamilton-Nelson, Kara L; Epelbaum, Jacques; Maier, Wolfgang; Choi, Seung-Hoan; Beecham, Gary W; Dulary, Cécile; Herms, Stefan; Smith, Albert V; Funk, Cory C; Derbois, Céline; Forstner, Andreas J; Ahmad, Shahzad; Li, Hongdong; Bacq, Delphine; Harold, Denise; Satizabal, Claudia L; Valladares, Otto; Squassina, Alessio; Thomas, Rhodri; Brody, Jennifer A; Qu, Liming; Sánchez-Juan, Pascual; Morgan, Taniesha; Wolters, Frank J; Zhao, Yi; Garcia, Florentino Sanchez; Denning, Nicola; Fornage, Myriam; Malamon, John; Naranjo, Maria Candida Deniz; Majounie, Elisa; Mosley, Thomas H; Dombroski, Beth; Wallon, David; Lupton, Michelle K; Dupuis, Josée; Whitehead, Patrice; Fratiglioni, Laura; Medway, Christopher; Jian, Xueqiu; Mukherjee, Shubhabrata; Keller, Lina; Brown, Kristelle; Lin, Honghuang; Cantwell, Laura B; Panza, Francesco; McGuinness, Bernadette; Moreno-Grau, Sonia; Burgess, Jeremy D; Solfrizzi, Vincenzo; Proitsi, Petra; Adams, Hieab H; Allen, Mariet; Seripa, Davide; Pastor, Pau; Cupples, L Adrienne; Price, Nathan D; Hannequin, Didier; Frank-García, Ana; Levy, Daniel; Chakrabarty, Paramita; Caffarra, Paolo; Giegling, Ina; Beiser, Alexa S; Giedraitis, Vilmantas; Hampel, Harald; Garcia, Melissa E; Wang, Xue; Lannfelt, Lars; Mecocci, Patrizia; Eiriksdottir, Gudny; Crane, Paul K; Pasquier, Florence; Boccardi, Virginia; Henández, Isabel; Barber, Robert C; Scherer, Martin; Tarraga, Lluis; Adams, Perrie M; Leber, Markus; Chen, Yuning; Albert, Marilyn S; Riedel-Heller, Steffi; Emilsson, Valur; Beekly, Duane; Braae, Anne; Schmidt, Reinhold; Blacker, Deborah; Masullo, Carlo; Schmidt, Helena; Doody, Rachelle S; Spalletta, Gianfranco; Longstreth, W T; Fairchild, Thomas J; Bossù, Paola; Lopez, Oscar L; Frosch, Matthew P; Sacchinelli, Eleonora; Ghetti, Bernardino; Yang, Qiong; Huebinger, Ryan M; Jessen, Frank; Li, Shuo; Kamboh, M Ilyas; Morris, John; Sotolongo-Grau, Oscar; Katz, Mindy J; Corcoran, Chris; Dunstan, Melanie; Braddel, Amy; Thomas, Charlene; Meggy, Alun; Marshall, Rachel; Gerrish, Amy; Chapman, Jade; Aguilar, Miquel; Taylor, Sarah; Hill, Matt; Fairén, Mònica Díez; Hodges, Angela; Vellas, Bruno; Soininen, Hilkka; Kloszewska, Iwona; Daniilidou, Makrina; Uphill, James; Patel, Yogen; Hughes, Joseph T; Lord, Jenny; Turton, James; Hartmann, Annette M; Cecchetti, Roberta; Fenoglio, Chiara; Serpente, Maria; Arcaro, Marina; Caltagirone, Carlo; Orfei, Maria Donata; Ciaramella, Antonio; Pichler, Sabrina; Mayhaus, Manuel; Gu, Wei; Lleó, Alberto; Fortea, Juan; Blesa, Rafael; Barber, Imelda S; Brookes, Keeley; Cupidi, Chiara; Maletta, Raffaele Giovanni; Carrell, David; Sorbi, Sandro; Moebus, Susanne; Urbano, Maria; Pilotto, Alberto; Kornhuber, Johannes; Bosco, Paolo; Todd, Stephen; Craig, David; Johnston, Janet; Gill, Michael; Lawlor, Brian; Lynch, Aoibhinn; Fox, Nick C; Hardy, John; Albin, Roger L; Apostolova, Liana G; Arnold, Steven E; Asthana, Sanjay; Atwood, Craig S; Baldwin, Clinton T; Barnes, Lisa L; Barral, Sandra; Beach, Thomas G; Becker, James T; Bigio, Eileen H; Bird, Thomas D; Boeve, Bradley F; Bowen, James D; Boxer, Adam; Burke, James R; Burns, Jeffrey M; Buxbaum, Joseph D; Cairns, Nigel J; Cao, Chuanhai; Carlson, Chris S; Carlsson, Cynthia M; Carney, Regina M; Carrasquillo, Minerva M; Carroll, Steven L; Diaz, Carolina Ceballos; Chui, Helena C; Clark, David G; Cribbs, David H; Crocco, Elizabeth A; DeCarli, Charles; Dick, Malcolm; Duara, Ranjan; Evans, Denis A; Faber, Kelley M; Fallon, Kenneth B; Fardo, David W; Farlow, Martin R; Ferris, Steven; Foroud, Tatiana M; Galasko, Douglas R; Gearing, Marla; Geschwind, Daniel H; Gilbert, John R; Graff-Radford, Neill R; Green, Robert C; Growdon, John H; Hamilton, Ronald L; Harrell, Lindy E; Honig, Lawrence S; Huentelman, Matthew J; Hulette, Christine M; Hyman, Bradley T; Jarvik, Gail P; Abner, Erin; Jin, Lee-Way; Jun, Gyungah; Karydas, Anna; Kaye, Jeffrey A; Kim, Ronald; Kowall, Neil W; Kramer, Joel H; LaFerla, Frank M; Lah, James J; Leverenz, James B; Levey, Allan I; Li, Ge; Lieberman, Andrew P; Lunetta, Kathryn L; Lyketsos, Constantine G; Marson, Daniel C; Martiniuk, Frank; Mash, Deborah C; Masliah, Eliezer; McCormick, Wayne C; McCurry, Susan M; McDavid, Andrew N; McKee, Ann C; Mesulam, Marsel; Miller, Bruce L; Miller, Carol A; Miller, Joshua W; Morris, John C; Murrell, Jill R; Myers, Amanda J; O'Bryant, Sid; Olichney, John M; Pankratz, Vernon S; Parisi, Joseph E; Paulson, Henry L; Perry, William; Peskind, Elaine; Pierce, Aimee; Poon, Wayne W; Potter, Huntington; Quinn, Joseph F; Raj, Ashok; Raskind, Murray; Reisberg, Barry; Reitz, Christiane; Ringman, John M; Roberson, Erik D; Rogaeva, Ekaterina; Rosen, Howard J; Rosenberg, Roger N; Sager, Mark A; Saykin, Andrew J; Schneider, Julie A; Schneider, Lon S; Seeley, William W; Smith, Amanda G; Sonnen, Joshua A; Spina, Salvatore; Stern, Robert A; Swerdlow, Russell H; Tanzi, Rudolph E; Thornton-Wells, Tricia A; Trojanowski, John Q; Troncoso, Juan C; Van Deerlin, Vivianna M; Van Eldik, Linda J; Vinters, Harry V; Vonsattel, Jean Paul; Weintraub, Sandra; Welsh-Bohmer, Kathleen A; Wilhelmsen, Kirk C; Williamson, Jennifer; Wingo, Thomas S; Woltjer, Randall L; Wright, Clinton B; Yu, Chang-En; Yu, Lei; Garzia, Fabienne; Golamaully, Feroze; Septier, Gislain; Engelborghs, Sebastien; Vandenberghe, Rik; De Deyn, Peter P; Fernadez, Carmen Muñoz; Benito, Yoland Aladro; Thonberg, Hakan; Forsell, Charlotte; Lilius, Lena; Kinhult-Stählbom, Anne; Kilander, Lena; Brundin, RoseMarie; Concari, Letizia; Helisalmi, Seppo; Koivisto, Anne Maria; Haapasalo, Annakaisa; Dermecourt, Vincent; Fievet, Nathalie; Hanon, Olivier; Dufouil, Carole; Brice, Alexis; Ritchie, Karen; Dubois, Bruno; Himali, Jayanadra J; Keene, C Dirk; Tschanz, JoAnn; Fitzpatrick, Annette L; Kukull, Walter A; Norton, Maria; Aspelund, Thor; Larson, Eric B; Munger, Ron; Rotter, Jerome I; Lipton, Richard B; Bullido, María J; Hofman, Albert; Montine, Thomas J; Coto, Eliecer; Boerwinkle, Eric; Petersen, Ronald C; Alvarez, Victoria; Rivadeneira, Fernando; Reiman, Eric M; Gallo, Maura; O'Donnell, Christopher J; Reisch, Joan S; Bruni, Amalia Cecilia; Royall, Donald R; Dichgans, Martin; Sano, Mary; Galimberti, Daniela; St George-Hyslop, Peter; Scarpini, Elio; Tsuang, Debby W; Mancuso, Michelangelo; Bonuccelli, Ubaldo; Winslow, Ashley R; Daniele, Antonio; Wu, Chuang-Kuo; Peters, Oliver; Nacmias, Benedetta; Riemenschneider, Matthias; Heun, Reinhard; Brayne, Carol; Rubinsztein, David C; Bras, Jose; Guerreiro, Rita; Al-Chalabi, Ammar; Shaw, Christopher E; Collinge, John; Mann, David; Tsolaki, Magda; Clarimón, Jordi; Sussams, Rebecca; Lovestone, Simon; O'Donovan, Michael C; Owen, Michael J; Behrens, Timothy W; Mead, Simon; Goate, Alison M; Uitterlinden, Andre G; Holmes, Clive; Cruchaga, Carlos; Ingelsson, Martin; Bennett, David A; Powell, John; Golde, Todd E; Graff, Caroline; De Jager, Philip L; Morgan, Kevin; Ertekin-Taner, Nilufer; Combarros, Onofre; Psaty, Bruce M; Passmore, Peter; Younkin, Steven G; Berr, Claudine; Gudnason, Vilmundur; Rujescu, Dan; Dickson, Dennis W; Dartigues, Jean-François; DeStefano, Anita L; Ortega-Cubero, Sara; Hakonarson, Hakon; Campion, Dominique; Boada, Merce; Kauwe, John Keoni; Farrer, Lindsay A; Van Broeckhoven, Christine; Ikram, M Arfan; Jones, Lesley; Haines, Jonathan L; Tzourio, Christophe; Launer, Lenore J; Escott-Price, Valentina; Mayeux, Richard; Deleuze, Jean-François; Amin, Najaf; Holmans, Peter A; Pericak-Vance, Margaret A; Amouyel, Philippe; van Duijn, Cornelia M; Ramirez, Alfredo; Wang, Li-San; Lambert, Jean-Charles; Seshadri, Sudha; Williams, Julie; Schellenberg, Gerard D

2017-09-01

We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10 -4 ) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10 -8 ) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10 -10 , odds ratio (OR) = 0.68, minor allele frequency (MAF) cases = 0.0059, MAF controls = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10 -10 , OR = 1.43, MAF cases = 0.011, MAF controls = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10 -14 , OR = 1.67, MAF cases = 0.0143, MAF controls = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

Host mitochondrial association evolved in the human parasite Toxoplasma gondii via neofunctionalization of a gene duplicate

USDA-ARS?s Scientific Manuscript database

In Toxoplasma gondii, an intracellular parasite of humans and other warm-blooded animals, the ability to associate with host mitochondria (HMA) is driven by a locally expanded gene family that encodes multiple mitochondrial association factor 1 (MAF1) proteins. The importance of copy number in the e...

Allele frequencies of variants in ultra conserved elements identify selective pressure on transcription factor binding.

PubMed

Silla, Toomas; Kepp, Katrin; Tai, E Shyong; Goh, Liang; Davila, Sonia; Catela Ivkovic, Tina; Calin, George A; Voorhoeve, P Mathijs

2014-01-01

Ultra-conserved genes or elements (UCGs/UCEs) in the human genome are extreme examples of conservation. We characterized natural variations in 2884 UCEs and UCGs in two distinct populations; Singaporean Chinese (n = 280) and Italian (n = 501) by using a pooled sample, targeted capture, sequencing approach. We identify, with high confidence, in these regions the abundance of rare SNVs (MAF<0.5%) of which 75% is not present in dbSNP137. UCEs association studies for complex human traits can use this information to model expected background variation and thus necessary power for association studies. By combining our data with 1000 Genome Project data, we show in three independent datasets that prevalent UCE variants (MAF>5%) are more often found in relatively less-conserved nucleotides within UCEs, compared to rare variants. Moreover, prevalent variants are less likely to overlap transcription factor binding site. Using SNPfold we found no significant influence of RNA secondary structure on UCE conservation. All together, these results suggest UCEs are not under selective pressure as a stretch of DNA but are under differential evolutionary pressure on the single nucleotide level.

Characterization of corneal damage from Pseudomonas aeruginosa infection by the use of multiphoton microscopy

NASA Astrophysics Data System (ADS)

Chang, Yu-Lin; Chen, Wei-Liang; Lo, Wen; Chen, Shean-Jen; Tan, Hsin-Yuan; Dong, Chen-Yuan

2010-11-01

Using multiphoton autofluorescence (MAF) and second harmonic generation (SHG) microscopy, we investigate the morphology and the structure of the corneal epithelium and stroma collagen of bovine cornea following injection of Pseudomonas aeruginosa. We found that corneal epithelial cells are damaged and stromal collagen becoming increasingly autofluorescent with time. We also characterized infected cornea cultured for 0, 6, 12, and 24 h by quantitative ratiometric MAF to SHG index (MAFSI) analysis. MAFSI results show that the destruction of the stromal collagen corresponds to a decrease in SHG intensity and increase of MAF signal with time.

An LPV Adaptive Observer for Updating a Map Applied to an MAF Sensor in a Diesel Engine

PubMed Central

Liu, Zhiyuan; Wang, Changhui

2015-01-01

In this paper, a new method for mass air flow (MAF) sensor error compensation and an online updating error map (or lookup table) due to installation and aging in a diesel engine is developed. Since the MAF sensor error is dependent on the engine operating point, the error model is represented as a two-dimensional (2D) map with two inputs, fuel mass injection quantity and engine speed. Meanwhile, the 2D map representing the MAF sensor error is described as a piecewise bilinear interpolation model, which can be written as a dot product between the regression vector and parameter vector using a membership function. With the combination of the 2D map regression model and the diesel engine air path system, an LPV adaptive observer with low computational load is designed to estimate states and parameters jointly. The convergence of the proposed algorithm is proven under the conditions of persistent excitation and given inequalities. The observer is validated against the simulation data from engine software enDYNA provided by Tesis. The results demonstrate that the operating point-dependent error of the MAF sensor can be approximated acceptably by the 2D map from the proposed method. PMID:26512675

Evaluation of regulatory genetic variants in POU5F1 and risk of congenital heart disease in Han Chinese

NASA Astrophysics Data System (ADS)

Lin, Yuan; Ding, Chenyue; Zhang, Kai; Ni, Bixian; da, Min; Hu, Liang; Hu, Yuanli; Xu, Jing; Wang, Xiaowei; Chen, Yijiang; Mo, Xuming; Cui, Yugui; Shen, Hongbing; Sha, Jiahao; Liu, Jiayin; Hu, Zhibin

2015-10-01

OCT4 is a transcription factor of the POU family, which plays a key role in embryonic development and stem cell pluripotency. Previous studies have shown that Oct4 is required for cardiomyocyte differentiation in mice and its depletion could result in cardiac morphogenesis in embryo. However, whether the genetic variations in OCT4 coding gene, POU5F1, confer the predisposition to congenital heart disease (CHD) is unclear. This study sought to investigate the associations between low-frequency (defined here as having minor allele frequency (MAF) between 0.1%-5%) and rare (MAF below 0.1%) variants with potential function in POU5F1 and risk of CHD. We conducted association analysis in a two-stage case-control study with a total of 2,720 CHD cases and 3,331 controls in Chinese. The low-frequency variant rs3130933 was observed to be associated with a significantly increased risk of CHD [additive model: adjusted odds ratio (OR) = 2.15, adjusted P = 3.37 × 10-6]. Furthermore, luciferase activity assay showed that the variant A allele led to significantly lower expression levels as compared to the G allele. These findings indicate for the first time that low-frequency functional variant in POU5F1 may contribute to the risk of congenital heart malformations.

Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes.

PubMed

Albrechtsen, A; Grarup, N; Li, Y; Sparsø, T; Tian, G; Cao, H; Jiang, T; Kim, S Y; Korneliussen, T; Li, Q; Nie, C; Wu, R; Skotte, L; Morris, A P; Ladenvall, C; Cauchi, S; Stančáková, A; Andersen, G; Astrup, A; Banasik, K; Bennett, A J; Bolund, L; Charpentier, G; Chen, Y; Dekker, J M; Doney, A S F; Dorkhan, M; Forsen, T; Frayling, T M; Groves, C J; Gui, Y; Hallmans, G; Hattersley, A T; He, K; Hitman, G A; Holmkvist, J; Huang, S; Jiang, H; Jin, X; Justesen, J M; Kristiansen, K; Kuusisto, J; Lajer, M; Lantieri, O; Li, W; Liang, H; Liao, Q; Liu, X; Ma, T; Ma, X; Manijak, M P; Marre, M; Mokrosiński, J; Morris, A D; Mu, B; Nielsen, A A; Nijpels, G; Nilsson, P; Palmer, C N A; Rayner, N W; Renström, F; Ribel-Madsen, R; Robertson, N; Rolandsson, O; Rossing, P; Schwartz, T W; Slagboom, P E; Sterner, M; Tang, M; Tarnow, L; Tuomi, T; van't Riet, E; van Leeuwen, N; Varga, T V; Vestmar, M A; Walker, M; Wang, B; Wang, Y; Wu, H; Xi, F; Yengo, L; Yu, C; Zhang, X; Zhang, J; Zhang, Q; Zhang, W; Zheng, H; Zhou, Y; Altshuler, D; 't Hart, L M; Franks, P W; Balkau, B; Froguel, P; McCarthy, M I; Laakso, M; Groop, L; Christensen, C; Brandslund, I; Lauritzen, T; Witte, D R; Linneberg, A; Jørgensen, T; Hansen, T; Wang, J; Nielsen, R; Pedersen, O

2013-02-01

Human complex metabolic traits are in part regulated by genetic determinants. Here we applied exome sequencing to identify novel associations of coding polymorphisms at minor allele frequencies (MAFs) >1% with common metabolic phenotypes. The study comprised three stages. We performed medium-depth (8×) whole exome sequencing in 1,000 cases with type 2 diabetes, BMI >27.5 kg/m(2) and hypertension and in 1,000 controls (stage 1). We selected 16,192 polymorphisms nominally associated (p < 0.05) with case-control status, from four selected annotation categories or from loci reported to associate with metabolic traits. These variants were genotyped in 15,989 Danes to search for association with 12 metabolic phenotypes (stage 2). In stage 3, polymorphisms showing potential associations were genotyped in a further 63,896 Europeans. Exome sequencing identified 70,182 polymorphisms with MAF >1%. In stage 2 we identified 51 potential associations with one or more of eight metabolic phenotypes covered by 45 unique polymorphisms. In meta-analyses of stage 2 and stage 3 results, we demonstrated robust associations for coding polymorphisms in CD300LG (fasting HDL-cholesterol: MAF 3.5%, p = 8.5 × 10(-14)), COBLL1 (type 2 diabetes: MAF 12.5%, OR 0.88, p = 1.2 × 10(-11)) and MACF1 (type 2 diabetes: MAF 23.4%, OR 1.10, p = 8.2 × 10(-10)). We applied exome sequencing as a basis for finding genetic determinants of metabolic traits and show the existence of low-frequency and common coding polymorphisms with impact on common metabolic traits. Based on our study, coding polymorphisms with MAF above 1% do not seem to have particularly high effect sizes on the measured metabolic traits.

Can We Use Regression Modeling to Quantify Mean Annual Streamflow at a Global-Scale?

NASA Astrophysics Data System (ADS)

Barbarossa, V.; Huijbregts, M. A. J.; Hendriks, J. A.; Beusen, A.; Clavreul, J.; King, H.; Schipper, A.

2016-12-01

Quantifying mean annual flow of rivers (MAF) at ungauged sites is essential for a number of applications, including assessments of global water supply, ecosystem integrity and water footprints. MAF can be quantified with spatially explicit process-based models, which might be overly time-consuming and data-intensive for this purpose, or with empirical regression models that predict MAF based on climate and catchment characteristics. Yet, regression models have mostly been developed at a regional scale and the extent to which they can be extrapolated to other regions is not known. In this study, we developed a global-scale regression model for MAF using observations of discharge and catchment characteristics from 1,885 catchments worldwide, ranging from 2 to 106 km2 in size. In addition, we compared the performance of the regression model with the predictive ability of the spatially explicit global hydrological model PCR-GLOBWB [van Beek et al., 2011] by comparing results from both models to independent measurements. We obtained a regression model explaining 89% of the variance in MAF based on catchment area, mean annual precipitation and air temperature, average slope and elevation. The regression model performed better than PCR-GLOBWB for the prediction of MAF, as root-mean-square error values were lower (0.29 - 0.38 compared to 0.49 - 0.57) and the modified index of agreement was higher (0.80 - 0.83 compared to 0.72 - 0.75). Our regression model can be applied globally at any point of the river network, provided that the input parameters are within the range of values employed in the calibration of the model. The performance is reduced for water scarce regions and further research should focus on improving such an aspect for regression-based global hydrological models.

CYP2D6 gene variants: association with breast cancer specific survival in a cohort of breast cancer patients from the United Kingdom treated with adjuvant tamoxifen

PubMed Central

2010-01-01

Introduction Tamoxifen is one of the most effective adjuvant breast cancer therapies available. Its metabolism involves the phase I enzyme, cytochrome P4502D6 (CYP2D6), encoded by the highly polymorphic CYP2D6 gene. CYP2D6 variants resulting in poor metabolism of tamoxifen are hypothesised to reduce its efficacy. An FDA-approved pre-treatment CYP2D6 gene testing assay is available. However, evidence from published studies evaluating CYP2D6 variants as predictive factors of tamoxifen efficacy and clinical outcome are conflicting, querying the clinical utility of CYP2D6 testing. We investigated the association of CYP2D6 variants with breast cancer specific survival (BCSS) in breast cancer patients receiving tamoxifen. Methods This was a population based case-cohort study. We genotyped known functional variants (n = 7; minor allele frequency (MAF) > 0.01) and single nucleotide polymorphisms (SNPs) (n = 5; MAF > 0.05) tagging all known common variants (tagSNPs), in CYP2D6 in 6640 DNA samples from patients with invasive breast cancer from SEARCH (Studies of Epidemiology and Risk factors in Cancer Heredity); 3155 cases had received tamoxifen therapy. There were 312 deaths from breast cancer, in the tamoxifen treated patients, with over 18000 years of cumulative follow-up. The association between genotype and BCSS was evaluated using Cox proportional hazards regression analysis. Results In tamoxifen treated patients, there was weak evidence that the poor-metaboliser variant, CYP2D6*6 (MAF = 0.01), was associated with decreased BCSS (P = 0.02; HR = 1.95; 95% CI = 1.12-3.40). No other variants, including CYP2D6*4 (MAF = 0.20), previously reported to be associated with poorer clinical outcomes, were associated with differences in BCSS, in either the tamoxifen or non-tamoxifen groups. Conclusions CYP2D6*6 may affect BCSS in tamoxifen-treated patients. However, the absence of an association with survival in more frequent variants, including CYP2D6*4, questions the validity of the reported association between CYP2D6 genotype and treatment response in breast cancer. Until larger, prospective studies confirming any associations are available, routine CYP2D6 genetic testing should not be used in the clinical setting. PMID:20731819

The effect of rare alleles on estimated genomic relationships from whole genome sequence data.

PubMed

Eynard, Sonia E; Windig, Jack J; Leroy, Grégoire; van Binsbergen, Rianne; Calus, Mario P L

2015-03-12

Relationships between individuals and inbreeding coefficients are commonly used for breeding decisions, but may be affected by the type of data used for their estimation. The proportion of variants with low Minor Allele Frequency (MAF) is larger in whole genome sequence (WGS) data compared to Single Nucleotide Polymorphism (SNP) chips. Therefore, WGS data provide true relationships between individuals and may influence breeding decisions and prioritisation for conservation of genetic diversity in livestock. This study identifies differences between relationships and inbreeding coefficients estimated using pedigree, SNP or WGS data for 118 Holstein bulls from the 1000 Bull genomes project. To determine the impact of rare alleles on the estimates we compared three scenarios of MAF restrictions: variants with a MAF higher than 5%, variants with a MAF higher than 1% and variants with a MAF between 1% and 5%. We observed significant differences between estimated relationships and, although less significantly, inbreeding coefficients from pedigree, SNP or WGS data, and between MAF restriction scenarios. Computed correlations between pedigree and genomic relationships, within groups with similar relationships, ranged from negative to moderate for both estimated relationships and inbreeding coefficients, but were high between estimates from SNP and WGS (0.49 to 0.99). Estimated relationships from genomic information exhibited higher variation than from pedigree. Inbreeding coefficients analysis showed that more complete pedigree records lead to higher correlation between inbreeding coefficients from pedigree and genomic data. Finally, estimates and correlations between additive genetic (A) and genomic (G) relationship matrices were lower, and variances of the relationships were larger when accounting for allele frequencies than without accounting for allele frequencies. Using pedigree data or genomic information, and including or excluding variants with a MAF below 5% showed significant differences in relationship and inbreeding coefficient estimates. Estimated relationships and inbreeding coefficients are the basis for selection decisions. Therefore, it can be expected that using WGS instead of SNP can affect selection decision. Inclusion of rare variants will give access to the variation they carry, which is of interest for conservation of genetic diversity.

Solid Waste Management in Marine Amphibious Force (MAF) Operations: Analysis and Alternatives.

DTIC Science & Technology

1980-09-01

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Saturn Apollo Program

NASA Image and Video Library

1967-01-01

Workers at the Michoud Assembly Facility (MAF) near New Orleans, Louisiana, install the last engine on the S-IB stage. Developed by the Marshall Space Flight Center (MSFC) and built by the Chrysler Corporation at MAF, the S-IB stage utilized eight H-1 engines to produce a combined thrust of 1,600,000 pounds.

Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF

PubMed Central

Huffman, Jennifer E.; de Vries, Paul S.; Morrison, Alanna C.; Sabater-Lleal, Maria; Kacprowski, Tim; Auer, Paul L.; Brody, Jennifer A.; Chasman, Daniel I.; Chen, Ming-Huei; Guo, Xiuqing; Lin, Li-An; Marioni, Riccardo E.; Müller-Nurasyid, Martina; Yanek, Lisa R.; Pankratz, Nathan; Grove, Megan L.; de Maat, Moniek P. M.; Cushman, Mary; Wiggins, Kerri L.; Qi, Lihong; Sennblad, Bengt; Harris, Sarah E.; Polasek, Ozren; Riess, Helene; Rivadeneira, Fernando; Rose, Lynda M.; Goel, Anuj; Taylor, Kent D.; Teumer, Alexander; Uitterlinden, André G.; Vaidya, Dhananjay; Yao, Jie; Tang, Weihong; Levy, Daniel; Waldenberger, Melanie; Becker, Diane M.; Folsom, Aaron R.; Giulianini, Franco; Greinacher, Andreas; Hofman, Albert; Huang, Chiang-Ching; Kooperberg, Charles; Silveira, Angela; Starr, John M.; Strauch, Konstantin; Strawbridge, Rona J.; Wright, Alan F.; McKnight, Barbara; Franco, Oscar H.; Zakai, Neil; Mathias, Rasika A.; Psaty, Bruce M.; Ridker, Paul M.; Tofler, Geoffrey H.; Völker, Uwe; Watkins, Hugh; Fornage, Myriam; Hamsten, Anders; Deary, Ian J.; Boerwinkle, Eric; Koenig, Wolfgang; Rotter, Jerome I.; Hayward, Caroline; Dehghan, Abbas; Reiner, Alex P.; O’Donnell, Christopher J.

2015-01-01

Fibrinogen, coagulation factor VII (FVII), and factor VIII (FVIII) and its carrier von Willebrand factor (vWF) play key roles in hemostasis. Previously identified common variants explain only a small fraction of the trait heritabilities, and additional variations may be explained by associations with rarer variants with larger effects. The aim of this study was to identify low-frequency (minor allele frequency [MAF] ≥0.01 and <0.05) and rare (MAF <0.01) variants that influence plasma concentrations of these 4 hemostatic factors by meta-analyzing exome chip data from up to 76 000 participants of 4 ancestries. We identified 12 novel associations of low-frequency (n = 2) and rare (n = 10) variants across the fibrinogen, FVII, FVIII, and vWF traits that were independent of previously identified associations. Novel loci were found within previously reported genes and had effect sizes much larger than and independent of previously identified common variants. In addition, associations at KCNT1, HID1, and KATNB1 identified new candidate genes related to hemostasis for follow-up replication and functional genomic analysis. Newly identified low-frequency and rare-variant associations accounted for modest amounts of trait variance and therefore are unlikely to increase predicted trait heritability but provide new information for understanding individual variation in hemostasis pathways. PMID:26105150

Saturn Apollo Program

NASA Image and Video Library

1967-01-01

NASA used barges for transporting full-sized stages for the Saturn I, Saturn IB, and Saturn V vehicles between the Marshall Space Flight Center (MSFC), the manufacturing plant at the Michoud Assembly Facility (MAF), the Mississippi Test Facility for testing, and the Kennedy Space Center. The barges traveled from the MSFC dock to the MAF, a total of 1,086.7 miles up the Tennessee River and down the Mississippi River. The barges also transported the assembled stages of the Saturn vehicle from the MAF to the Kennedy Space Center, a total of 932.4 miles along the Gulf of Mexico and up along the Atlantic Ocean, for the final assembly and the launch. This photograph shows the barge Orion at the MSFC dock.

Regulation of the plasma cell transcription factor Blimp-1 gene by Bach2 and Bcl6.

PubMed

Ochiai, Kyoko; Muto, Akihiko; Tanaka, Hiromu; Takahashi, Shinichiro; Igarashi, Kazuhiko

2008-03-01

B lymphocyte-induced maturation protein 1 (Blimp-1) is a key regulator for plasma cell differentiation. Prior to the terminal differentiation into plasma cells, Blimp-1 expression is suppressed in B cells by transcription repressors BTB and CNC homology 2 (Bach2) and B cell lymphoma 6 (Bcl6). Bach2 binds to the Maf recognition element (MARE) of the promoter upstream region of the Blimp-1 gene (Prdm1) by forming a heterodimer with MafK. Bach2 and Bcl6 were found to interact with each other in B cells. While both Bach2 and Bcl6 possess the BTB domain which mediates protein-protein interactions, they interacted in a BTB-independent manner. Bcl6 is known to repress Prdm1 through a Bcl6 recognition element 1 in the intron 5, in which a putative, evolutionarily conserved MARE was identified. Both repressed the expression of a reporter gene containing the intron 5 region depending on the presence of the respective binding sites in 18-81 pre-B cells. Co-expression of Bach2 and Bcl6 resulted in further repression of the reporter plasmid. Chromatin immunoprecipitation assays showed MafK to bind to the intron MARE in various B cell lines, thus suggesting that it binds as a heterodimer with Bach2. Therefore, the interaction between Bach2 and Bcl6 might be crucial for the proper repression of Prdm1 in B cells.

The LSST Metrics Analysis Framework (MAF)

NASA Astrophysics Data System (ADS)

Jones, R. Lynne; Yoachim, Peter; Chandrasekharan, Srinivasan; Connolly, Andrew J.; Cook, Kem H.; Ivezic, Zeljko; Krughoff, K. Simon; Petry, Catherine E.; Ridgway, Stephen T.

2015-01-01

Studying potential observing strategies or cadences for the Large Synoptic Survey Telescope (LSST) is a complicated but important problem. To address this, LSST has created an Operations Simulator (OpSim) to create simulated surveys, including realistic weather and sky conditions. Analyzing the results of these simulated surveys for the wide variety of science cases to be considered for LSST is, however, difficult. We have created a Metric Analysis Framework (MAF), an open-source python framework, to be a user-friendly, customizable and easily extensible tool to help analyze the outputs of the OpSim.MAF reads the pointing history of the LSST generated by the OpSim, then enables the subdivision of these pointings based on position on the sky (RA/Dec, etc.) or the characteristics of the observations (e.g. airmass or sky brightness) and a calculation of how well these observations meet a specified science objective (or metric). An example simple metric could be the mean single visit limiting magnitude for each position in the sky; a more complex metric might be the expected astrometric precision. The output of these metrics can be generated for a full survey, for specified time intervals, or for regions of the sky, and can be easily visualized using a web interface.An important goal for MAF is to facilitate analysis of the OpSim outputs for a wide variety of science cases. A user can often write a new metric to evaluate OpSim for new science goals in less than a day once they are familiar with the framework. Some of these new metrics are illustrated in the accompanying poster, "Analyzing Simulated LSST Survey Performance With MAF".While MAF has been developed primarily for application to OpSim outputs, it can be applied to any dataset. The most obvious examples are examining pointing histories of other survey projects or telescopes, such as CFHT.

Optical clearing of the pancreas for visualization of mature β-cells and vessels in mice.

PubMed

Nishimura, Wataru; Sakaue-Sawano, Asako; Takahashi, Satoru; Miyawaki, Atsushi; Yasuda, Kazuki; Noda, Yasuko

2018-05-04

Glucose metabolism is regulated by insulin, which is produced from β-cells in the pancreas. Because insulin is secreted into vessels in response to blood glucose, vascular structures of the pancreas, especially the relationship between vessels and β-cells, are important for physiological and pathological glucose metabolism. Here, we developed a system to visualize vessels surrounding mature β-cells expressing transcription factor MafA in a three-dimensional manner. Optical clearing of the pancreas prevented light scattering of fluorescence driven by the bacterial artificial chromosome (BAC)-mafA promoter in β-cells. Reconstruction of confocal images demonstrated mature β-cells and the glomerular-like structures of β-cell vasculatures labeled with DyLight 488-conjugated lectin in normal mice as well as in low-dose streptozotocin-injected diabetes model mice with reduced β-cell mass. This technological innovation of organ imaging can be used to investigate morphological changes in vascular structures during transplantation, regeneration and diabetes development.

77 FR 66794 - Proposed Information Collection; Comment Request; Generic Clearance for Master Address File (MAF...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-11-07

... to measure the quality of the MAF. Test 22 is currently a one-time project scheduled for fiscal year... designed to be kept up-to-date, thereby eliminating the need to develop a completely new address list for future censuses and surveys. The Census Bureau plans to use the MTdb [[Page 66795

Saturn Apollo Program

NASA Image and Video Library

1967-01-01

Three S-IB stages near completion at the NASA's Michoud Assembly Facility (MAF) near New Orleans, Louisiana, in November 1967. Developed by the Marshall Space Flight Center and built by the Chrysler Corporation at MAF, the 90,000-pound booster utilized eight H-1 engines and each produced 200,000 pounds of thrust for the Saturn IB launch vehicle's first stage.

Saturn Apollo Program

NASA Image and Video Library

1968-01-01

The Saturn 1B S-IB (first) stage being prepared for shipment at Michoud Assembly Facility (MAF), near New Orleans, Louisiana. Developed by the Marshall Space Flight Center and built by the Chrysler Corporation at MAF, the S-IB stage utilized the eight H-1 engines and each produced 200,000 pounds of thrust, a combined thrust of 1,600,000 pounds.

Saturn Apollo Program

NASA Image and Video Library

1967-01-01

NASA used barges for transporting full-sized stages for the Saturn I, Saturn IB, and Saturn V vehicles between the Marshall Space Flight Center (MSFC), the manufacturing plant at the Michoud Assembly Facility (MAF), the Mississippi Test Facility for testing, and the Kennedy Space Center. The barges traveled from the MSFC dock to the MAF, a total of 1,086.7 miles up the Tennessee River and down the Mississippi River. The barges also transported the assembled stages of the Saturn vehicle from the MAF to the Kennedy Space Center, a total of 932.4 miles along the Gulf of Mexico and up along the Atlantic Ocean, for the final assembly and the launch. Pictured is the barge Palaemon carrying Saturn IV S-IB flight stage enroute to MSFC.

Alpinia officinarum Stimulates Osteoblast Mineralization and Inhibits Osteoclast Differentiation.

PubMed

Shim, Ki-Shuk; Lee, Chung-Jo; Yim, Nam-Hui; Gu, Min Jung; Ma, Jin Yeul

2016-01-01

Alpinia officinarum rhizome has been used as a traditional herbal remedy to treat inflammatory and internal diseases. Based on the previously observed inhibitory effect of A. officinarum rhizome in an arthritis model, we evaluated whether a water extract of A. officinarum rhizome (WEAO) would enhance in vitro osteoblast mineralization using calvarial osteoblast precursor cells or would inhibit in vitro osteoclast differentiation and bone resorption using bone marrow derived macrophages. In osteoblasts, WEAO enhanced the mRNA levels of transcription factor (runt-related transcription factor 2, smad1, smad5, and junB) and marker (bone morphogenetic protein-2, collagen type 1alpha1, and osteocalcin) genes related to osteoblast mineralization, consistent with increased alizarin red S staining intensity. WEAO markedly inhibited osteoclast differentiation by suppressing the receptor activator for nuclear factor-[Formula: see text]B ligand-induced downregulation of inhibitor of DNA binding 2 and V-maf musculoaponeurotic fibrosarcoma oncogene homolog B and the phosphorylation of c-Jun N-terminal kinase, p38, nuclear factor-[Formula: see text]B, c-Src, and Bruton's tyrosine kinase to induce nuclear factor of activated T cells cytoplasmic 1 expression. WEAO also suppressed the resorbing activity of mature osteoclasts by altering actin ring formation. Therefore, the results of this study demonstrate that WEAO stimulates osteoblast mineralization and inhibits osteoclast differentiation. Thus, WEAO may be a promising herbal candidate to treat or prevent pathological bone diseases by regulating the balance between osteoclast and osteoblast activity.

Transcript Profile of Flowering Regulatory Genes in VcFT-Overexpressing Blueberry Plants

PubMed Central

Walworth, Aaron E.; Chai, Benli; Song, Guo-qing

2016-01-01

In order to identify genetic components in flowering pathways of highbush blueberry (Vaccinium corymbosum L.), a transcriptome reference composed of 254,396 transcripts and 179,853 gene contigs was developed by assembly of 72.7 million reads using Trinity. Using this transcriptome reference and a query of flowering pathway genes of herbaceous plants, we identified potential flowering pathway genes/transcripts of blueberry. Transcriptome analysis of flowering pathway genes was then conducted on leaf tissue samples of transgenic blueberry cv. Aurora (‘VcFT-Aurora’), which overexpresses a blueberry FLOWERING LOCUS T-like gene (VcFT). Sixty-one blueberry transcripts of 40 genes showed high similarities to 33 known flowering-related genes of herbaceous plants, of which 17 down-regulated and 16 up-regulated genes were identified in ‘VcFT-Aurora’. All down-regulated genes encoded transcription factors/enzymes upstream in the signaling pathway containing VcFT. A blueberry CONSTANS-LIKE 5-like (VcCOL5) gene was down-regulated and associated with five other differentially expressed (DE) genes in the photoperiod-mediated flowering pathway. Three down-regulated genes, i.e., a MADS-AFFECTING FLOWERING 2-like gene (VcMAF2), a MADS-AFFECTING FLOWERING 5-like gene (VcMAF5), and a VERNALIZATION1-like gene (VcVRN1), may function as integrators in place of FLOWERING LOCUS C (FLC) in the vernalization pathway. Because no CONSTAN1-like or FLOWERING LOCUS C-like genes were found in blueberry, VcCOL5 and VcMAF2/VcMAF5 or VRN1 might be the major integrator(s) in the photoperiod- and vernalization-mediated flowering pathway, respectively. The major down-stream genes of VcFT, i.e., SUPPRESSOR of Overexpression of Constans 1-like (VcSOC1), LEAFY-like (VcLFY), APETALA1-like (VcAP1), CAULIFLOWER 1-like (VcCAL1), and FRUITFULL-like (VcFUL) genes were present and showed high similarity to their orthologues in herbaceous plants. Moreover, overexpression of VcFT promoted expression of all of these VcFT downstream genes. These results suggest that VcFT’s down-stream genes appear conserved in blueberry. PMID:27271296

Transcript Profile of Flowering Regulatory Genes in VcFT-Overexpressing Blueberry Plants.

PubMed

Walworth, Aaron E; Chai, Benli; Song, Guo-Qing

2016-01-01

In order to identify genetic components in flowering pathways of highbush blueberry (Vaccinium corymbosum L.), a transcriptome reference composed of 254,396 transcripts and 179,853 gene contigs was developed by assembly of 72.7 million reads using Trinity. Using this transcriptome reference and a query of flowering pathway genes of herbaceous plants, we identified potential flowering pathway genes/transcripts of blueberry. Transcriptome analysis of flowering pathway genes was then conducted on leaf tissue samples of transgenic blueberry cv. Aurora ('VcFT-Aurora'), which overexpresses a blueberry FLOWERING LOCUS T-like gene (VcFT). Sixty-one blueberry transcripts of 40 genes showed high similarities to 33 known flowering-related genes of herbaceous plants, of which 17 down-regulated and 16 up-regulated genes were identified in 'VcFT-Aurora'. All down-regulated genes encoded transcription factors/enzymes upstream in the signaling pathway containing VcFT. A blueberry CONSTANS-LIKE 5-like (VcCOL5) gene was down-regulated and associated with five other differentially expressed (DE) genes in the photoperiod-mediated flowering pathway. Three down-regulated genes, i.e., a MADS-AFFECTING FLOWERING 2-like gene (VcMAF2), a MADS-AFFECTING FLOWERING 5-like gene (VcMAF5), and a VERNALIZATION1-like gene (VcVRN1), may function as integrators in place of FLOWERING LOCUS C (FLC) in the vernalization pathway. Because no CONSTAN1-like or FLOWERING LOCUS C-like genes were found in blueberry, VcCOL5 and VcMAF2/VcMAF5 or VRN1 might be the major integrator(s) in the photoperiod- and vernalization-mediated flowering pathway, respectively. The major down-stream genes of VcFT, i.e., SUPPRESSOR of Overexpression of Constans 1-like (VcSOC1), LEAFY-like (VcLFY), APETALA1-like (VcAP1), CAULIFLOWER 1-like (VcCAL1), and FRUITFULL-like (VcFUL) genes were present and showed high similarity to their orthologues in herbaceous plants. Moreover, overexpression of VcFT promoted expression of all of these VcFT downstream genes. These results suggest that VcFT's down-stream genes appear conserved in blueberry.

Compensatory Response by Late Embryonic Tubular Epithelium to the Reduction in Pancreatic Progenitors

PubMed Central

Nishimura, Wataru; Kapoor, Archana; El Khattabi, Ilham; Jin, Wanzhu; Yasuda, Kazuki; Bonner-Weir, Susan; Sharma, Arun

2015-01-01

Early in pancreatic development, epithelial cells of pancreatic buds function as primary multipotent progenitor cells (1°MPC) that specify all three pancreatic cell lineages, i.e., endocrine, acinar and duct. Bipotent "Trunk" progenitors derived from 1°MPC are implicated in directly regulating the specification of endocrine progenitors. It is unclear if this specification process is initiated in the 1°MPC where some 1°MPC become competent for later specification of endocrine progenitors. Previously we reported that in Pdx1 tTA/+ ;tetO MafA (bigenic) mice inducing expression of transcription factor MafA in Pdx1-expressing (Pdx1+) cells throughout embryonic development inhibited the proliferation and differentiation of 1°MPC cells, resulting in reduced pancreatic mass and endocrine cells by embryonic day (E) 17.5. Induction of the transgene only until E12.5 in Pdx1+ 1°MPC was sufficient for this inhibition of endocrine cells and pancreatic mass at E17.5. However, by birth (P0), as we now report, such bigenic pups had significantly increased pancreatic and endocrine volumes with endocrine clusters containing all pancreatic endocrine cell types. The increase in endocrine cells resulted from a higher proliferation of tubular epithelial cells expressing the progenitor marker Glut2 in E17.5 bigenic embryos and increased number of Neurog3-expressing cells at E19.5. A BrdU-labeling study demonstrated that inhibiting proliferation of 1°MPC by forced MafA-expression did not lead to retention of those progenitors in E17.5 tubular epithelium. Our data suggest that the forced MafA expression in the 1°MPC inhibits their competency to specify endocrine progenitors only until E17.5, and after that compensatory proliferation of tubular epithelium gives rise to a distinct pool of endocrine progenitors. Thus, these bigenic mice provide a novel way to characterize the competency of 1°MPC for their ability to specify endocrine progenitors, a critical limitation in our understanding of endocrine differentiation. PMID:26540252

Nutrient/TOR-dependent regulation of RNA polymerase III controls tissue and organismal growth in Drosophila

PubMed Central

Marshall, Lynne; Rideout, Elizabeth J; Grewal, Savraj S

2012-01-01

The nutrient/target-of-rapamycin (TOR) pathway has emerged as a key regulator of tissue and organismal growth in metazoans. The signalling components of the nutrient/TOR pathway are well defined; however, the downstream effectors are less understood. Here, we show that the control of RNA polymerase (Pol) III-dependent transcription is an essential target of TOR in Drosophila. We find that TOR activity controls Pol III in growing larvae via inhibition of the repressor Maf1 and, in part, via the transcription factor Drosophila Myc (dMyc). Moreover, we show that loss of the Pol III factor, Brf, leads to reduced tissue and organismal growth and prevents TOR-induced cellular growth. TOR activity in the larval fat body, a tissue equivalent to vertebrate fat or liver, couples nutrition to insulin release from the brain. Accordingly, we find that fat-specific loss of Brf phenocopies nutrient limitation and TOR inhibition, leading to decreased systemic insulin signalling and reduced organismal growth. Thus, stimulation of Pol III is a key downstream effector of TOR in the control of cellular and systemic growth. PMID:22367393

Saturn Apollo Program

NASA Image and Video Library

1969-01-01

Workers at the Michoud Assembly Facility (MAF) near New Orleans, Louisiana, hoist the thrust structure assembly for the Saturn IB S-IB (first) stage. Developed by the Marshall Space Flight Center and built by the Chrysler Corporation at Michoud Assembly Facility (MAF), the S-IB utilized eight H-1 engines and each produced 200,000 pounds of thrust, a combined thrust of 1,600,000 pounds.

Mango seed uses: thermal behaviour of mango seed almond fat and its mixtures with cocoa butter.

PubMed

Solís-Fuentes, J A; Durán-de-Bazúa, M C

2004-03-01

This paper deals with the physicochemical characterization, including thermal behaviour, by differential scanning calorimetry of mango seed almond fat (MAF), alone and in mixtures with cocoa butter (CB). Results showed that mango almond seeds contain about 5.28-11.26% (dw) of fat. The refraction index is 1.466, the saponification index 189.0 and the iodine index 41.76. Fatty acids found in MAF are oleic, stearic, and palmitic acids (40.81%, 39.07% and 9.29% (w/w), respectively) as well as smaller amounts of linoleic, with arachidic, behenic, lignoceric, and linolenic acids, among others. Calorimetric analysis showed that MAF crystallizes between 14.6 and -24.27 degrees C with a DeltaHc of 56.06 J/g and melts between -17.1 and 53.8 degrees C, with fusion maxima at 18.54 degrees C and 40.0 degrees C for the alpha and beta polymorphic forms. Their fusion enthalpies are 70.12 and 115.7 J/g. The MAF solids content profile is very similar to that of CB, both in stabilized and non-stabilized samples. The mixing compatibility was analyzed using isosolids curves of mixtures of different compositions.

Detection of expressional changes induced by intrauterine growth restriction in the developing rat pancreas

PubMed Central

Zhang, Lin; Chen, Wei; Dai, Yuee

2016-01-01

Intrauterine growth retardation (IUGR) is a disorder that can result in permanent changes in the physiology and metabolism of the newborn, which increased the risk of disease in adulthood. Evidence supports IUGR as a risk factor for the development of diabetes mellitus, which could reflect changes in pancreas developmental pathways. We sought to characterize the IUGR-induced alterations of the complex pathways of pancreas development in a rat model of IUGR. We analyzed the pancreases of Sprague Dawley rats after inducing IUGR by feeding a maternal low calorie diet from gestational day 1 until term. IUGR altered the pancreatic structure, islet areas, and islet quantities and resulted in abnormal morphological changes during pancreatic development, as determined by HE staining and light microscopy. We identified multiple differentially expressed genes in the pancreas by RT-PCR. The genes of the insulin/FoxO1/Pdx1/MafA signaling pathway were first expressed at embryonic day 14 (E14). The expressions of insulin and MafA increased as the fetus grew while the expressions of FoxO1 and Pdx1 decreased. Compared with the control rats, the expressions of FoxO1, Pdx1, and MafA were lower in the IUGR rats, whereas insulin levels showed no change. Microarray profiling, in combination with quantitative real-time PCR, uncovered a subset of microRNAs that changed in their degree of expression throughout pancreatic development. In conclusion, our data support the hypothesis that IUGR influences the development of the rat pancreas. We also identified new pathways that appear to be programmed by IUGR. PMID:27190278

Exploratory Analysis of TP53 Mutations in Circulating Tumour DNA as Biomarkers of Treatment Response for Patients with Relapsed High-Grade Serous Ovarian Carcinoma: A Retrospective Study

PubMed Central

Piskorz, Anna M.; Biggs, Heather; Addley, Helen; Freeman, Sue; Moyle, Penelope; Sala, Evis; Sayal, Karen; Hosking, Karen; Gounaris, Ioannis; Earl, Helena M.; Rosenfeld, Nitzan; Brenton, James D.

2016-01-01

Background Circulating tumour DNA (ctDNA) carrying tumour-specific sequence alterations may provide a minimally invasive means to dynamically assess tumour burden and response to treatment in cancer patients. Somatic TP53 mutations are a defining feature of high-grade serous ovarian carcinoma (HGSOC). We tested whether these mutations could be used as personalised markers to monitor tumour burden and early changes as a predictor of response and time to progression (TTP). Methods and Findings We performed a retrospective analysis of serial plasma samples collected during routine clinical visits from 40 patients with HGSOC undergoing heterogeneous standard of care treatment. Patient-specific TP53 assays were developed for 31 unique mutations identified in formalin-fixed paraffin-embedded tumour DNA from these patients. These assays were used to quantify ctDNA in 318 plasma samples using microfluidic digital PCR. The TP53 mutant allele fraction (TP53MAF) was compared to serum CA-125, the current gold-standard response marker for HGSOC in blood, as well as to disease volume on computed tomography scans by volumetric analysis. Changes after one cycle of treatment were compared with TTP. The median TP53MAF prior to treatment in 51 relapsed treatment courses was 8% (interquartile range [IQR] 1.2%–22%) compared to 0.7% (IQR 0.3%–2.0%) for seven untreated newly diagnosed stage IIIC/IV patients. TP53MAF correlated with volumetric measurements (Pearson r = 0.59, p < 0.001), and this correlation improved when patients with ascites were excluded (r = 0.82). The ratio of TP53MAF to volume of disease was higher in relapsed patients (0.04% per cm3) than in untreated patients (0.0008% per cm3, p = 0.004). In nearly all relapsed patients with disease volume > 32 cm3, ctDNA was detected at ≥20 amplifiable copies per millilitre of plasma. In 49 treatment courses for relapsed disease, pre-treatment TP53MAF concentration, but not CA-125, was associated with TTP. Response to chemotherapy was seen earlier with ctDNA, with a median time to nadir of 37 d (IQR 28–54) compared with a median time to nadir of 84 d (IQR 42–116) for CA-125. In 32 relapsed treatment courses evaluable for response after one cycle of chemotherapy, a decrease in TP53MAF of >60% was an independent predictor of TTP in multivariable analysis (hazard ratio 0.22, 95% CI 0.07–0.67, p = 0.008). Conversely, a decrease in TP53MAF of ≤60% was associated with poor response and identified cases with TTP < 6 mo with 71% sensitivity (95% CI 42%–92%) and 88% specificity (95% CI 64%–99%). Specificity was improved when patients with recent drainage of ascites were excluded. Ascites drainage led to a reduction of TP53MAF concentration. The limitations of this study include retrospective design, small sample size, and heterogeneity of treatment within the cohort. Conclusions In this retrospective study, we demonstrated that ctDNA is correlated with volume of disease at the start of treatment in women with HGSOC and that a decrease of ≤60% in TP53MAF after one cycle of chemotherapy was associated with shorter TTP. These results provide evidence that ctDNA has the potential to be a highly specific early molecular response marker in HGSOC and warrants further investigation in larger cohorts receiving uniform treatment. PMID:27997533

Exploratory Analysis of TP53 Mutations in Circulating Tumour DNA as Biomarkers of Treatment Response for Patients with Relapsed High-Grade Serous Ovarian Carcinoma: A Retrospective Study.

PubMed

Parkinson, Christine A; Gale, Davina; Piskorz, Anna M; Biggs, Heather; Hodgkin, Charlotte; Addley, Helen; Freeman, Sue; Moyle, Penelope; Sala, Evis; Sayal, Karen; Hosking, Karen; Gounaris, Ioannis; Jimenez-Linan, Mercedes; Earl, Helena M; Qian, Wendi; Rosenfeld, Nitzan; Brenton, James D

2016-12-01

Circulating tumour DNA (ctDNA) carrying tumour-specific sequence alterations may provide a minimally invasive means to dynamically assess tumour burden and response to treatment in cancer patients. Somatic TP53 mutations are a defining feature of high-grade serous ovarian carcinoma (HGSOC). We tested whether these mutations could be used as personalised markers to monitor tumour burden and early changes as a predictor of response and time to progression (TTP). We performed a retrospective analysis of serial plasma samples collected during routine clinical visits from 40 patients with HGSOC undergoing heterogeneous standard of care treatment. Patient-specific TP53 assays were developed for 31 unique mutations identified in formalin-fixed paraffin-embedded tumour DNA from these patients. These assays were used to quantify ctDNA in 318 plasma samples using microfluidic digital PCR. The TP53 mutant allele fraction (TP53MAF) was compared to serum CA-125, the current gold-standard response marker for HGSOC in blood, as well as to disease volume on computed tomography scans by volumetric analysis. Changes after one cycle of treatment were compared with TTP. The median TP53MAF prior to treatment in 51 relapsed treatment courses was 8% (interquartile range [IQR] 1.2%-22%) compared to 0.7% (IQR 0.3%-2.0%) for seven untreated newly diagnosed stage IIIC/IV patients. TP53MAF correlated with volumetric measurements (Pearson r = 0.59, p < 0.001), and this correlation improved when patients with ascites were excluded (r = 0.82). The ratio of TP53MAF to volume of disease was higher in relapsed patients (0.04% per cm3) than in untreated patients (0.0008% per cm3, p = 0.004). In nearly all relapsed patients with disease volume > 32 cm3, ctDNA was detected at ≥20 amplifiable copies per millilitre of plasma. In 49 treatment courses for relapsed disease, pre-treatment TP53MAF concentration, but not CA-125, was associated with TTP. Response to chemotherapy was seen earlier with ctDNA, with a median time to nadir of 37 d (IQR 28-54) compared with a median time to nadir of 84 d (IQR 42-116) for CA-125. In 32 relapsed treatment courses evaluable for response after one cycle of chemotherapy, a decrease in TP53MAF of >60% was an independent predictor of TTP in multivariable analysis (hazard ratio 0.22, 95% CI 0.07-0.67, p = 0.008). Conversely, a decrease in TP53MAF of ≤60% was associated with poor response and identified cases with TTP < 6 mo with 71% sensitivity (95% CI 42%-92%) and 88% specificity (95% CI 64%-99%). Specificity was improved when patients with recent drainage of ascites were excluded. Ascites drainage led to a reduction of TP53MAF concentration. The limitations of this study include retrospective design, small sample size, and heterogeneity of treatment within the cohort. In this retrospective study, we demonstrated that ctDNA is correlated with volume of disease at the start of treatment in women with HGSOC and that a decrease of ≤60% in TP53MAF after one cycle of chemotherapy was associated with shorter TTP. These results provide evidence that ctDNA has the potential to be a highly specific early molecular response marker in HGSOC and warrants further investigation in larger cohorts receiving uniform treatment.

Comparison of Motive to Succeed, Motive to Avoid Failure, and Fear of Success Levels between Male and Female Intercollegiate Swimmers.

ERIC Educational Resources Information Center

Houseworth, Steven; Thirer, Joel

A study investigated sex based differences among intercollegiate athletes for the variables: motive to succeed (Ms), motive to avoid failure (Maf), and fear of success (FOS). Actual athletic competitions were used as target situations to elicit feelings of Ms, Maf, and FOS within each athlete. Mehrabian's scale of achieving tendencies, Martens'…

Appropriate therapy for type 2 diabetes mellitus in view of pancreatic β-cell glucose toxicity: "the earlier, the better".

PubMed

Kaneto, Hideaki; Matsuoka, Taka-Aki; Kimura, Tomohiko; Obata, Atsushi; Shimoda, Masashi; Kamei, Shinji; Mune, Tomoatsu; Kaku, Kohei

2016-03-01

Pancreatic β-cells secrete insulin when blood glucose levels become high; however, when β-cells are chronically exposed to hyperglycemia, β-cell function gradually deteriorates, which is known as β-cell glucose toxicity. In the diabetic state, nuclear expression of the pancreatic transcription factors pancreatic and duodenal homeobox 1 (PDX-1) and v-Maf musculoaponeurotic fibrosarcoma oncogene family, protein A (MafA) is decreased. In addition, incretin receptor expression in β-cells is decreased, which is likely involved in the impairment of incretin effects in diabetes. Clinically, it is important to select appropriate therapy for type 2 diabetes mellitus (T2DM) so that β-cell function can be preserved. In addition, when appropriate pharmacological interventions against β-cell glucose toxicity are started at the early stages of diabetes, β-cell function is substantially restored, which is not observed if treatment is started at advanced stages. These observations indicate that it is likely that downregulation of pancreatic transcription factors and/or incretin receptors is involved in β-cell dysfunction observed in T2DM and it is very important to start appropriate pharmacological intervention against β-cell glucose toxicity in the early stages of diabetes. © 2015 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.

MicroArray Facility: a laboratory information management system with extended support for Nylon based technologies.

PubMed

Honoré, Paul; Granjeaud, Samuel; Tagett, Rebecca; Deraco, Stéphane; Beaudoing, Emmanuel; Rougemont, Jacques; Debono, Stéphane; Hingamp, Pascal

2006-09-20

High throughput gene expression profiling (GEP) is becoming a routine technique in life science laboratories. With experimental designs that repeatedly span thousands of genes and hundreds of samples, relying on a dedicated database infrastructure is no longer an option.GEP technology is a fast moving target, with new approaches constantly broadening the field diversity. This technology heterogeneity, compounded by the informatics complexity of GEP databases, means that software developments have so far focused on mainstream techniques, leaving less typical yet established techniques such as Nylon microarrays at best partially supported. MAF (MicroArray Facility) is the laboratory database system we have developed for managing the design, production and hybridization of spotted microarrays. Although it can support the widely used glass microarrays and oligo-chips, MAF was designed with the specific idiosyncrasies of Nylon based microarrays in mind. Notably single channel radioactive probes, microarray stripping and reuse, vector control hybridizations and spike-in controls are all natively supported by the software suite. MicroArray Facility is MIAME supportive and dynamically provides feedback on missing annotations to help users estimate effective MIAME compliance. Genomic data such as clone identifiers and gene symbols are also directly annotated by MAF software using standard public resources. The MAGE-ML data format is implemented for full data export. Journalized database operations (audit tracking), data anonymization, material traceability and user/project level confidentiality policies are also managed by MAF. MicroArray Facility is a complete data management system for microarray producers and end-users. Particular care has been devoted to adequately model Nylon based microarrays. The MAF system, developed and implemented in both private and academic environments, has proved a robust solution for shared facilities and industry service providers alike.

MicroArray Facility: a laboratory information management system with extended support for Nylon based technologies

PubMed Central

Honoré, Paul; Granjeaud, Samuel; Tagett, Rebecca; Deraco, Stéphane; Beaudoing, Emmanuel; Rougemont, Jacques; Debono, Stéphane; Hingamp, Pascal

2006-01-01

Background High throughput gene expression profiling (GEP) is becoming a routine technique in life science laboratories. With experimental designs that repeatedly span thousands of genes and hundreds of samples, relying on a dedicated database infrastructure is no longer an option. GEP technology is a fast moving target, with new approaches constantly broadening the field diversity. This technology heterogeneity, compounded by the informatics complexity of GEP databases, means that software developments have so far focused on mainstream techniques, leaving less typical yet established techniques such as Nylon microarrays at best partially supported. Results MAF (MicroArray Facility) is the laboratory database system we have developed for managing the design, production and hybridization of spotted microarrays. Although it can support the widely used glass microarrays and oligo-chips, MAF was designed with the specific idiosyncrasies of Nylon based microarrays in mind. Notably single channel radioactive probes, microarray stripping and reuse, vector control hybridizations and spike-in controls are all natively supported by the software suite. MicroArray Facility is MIAME supportive and dynamically provides feedback on missing annotations to help users estimate effective MIAME compliance. Genomic data such as clone identifiers and gene symbols are also directly annotated by MAF software using standard public resources. The MAGE-ML data format is implemented for full data export. Journalized database operations (audit tracking), data anonymization, material traceability and user/project level confidentiality policies are also managed by MAF. Conclusion MicroArray Facility is a complete data management system for microarray producers and end-users. Particular care has been devoted to adequately model Nylon based microarrays. The MAF system, developed and implemented in both private and academic environments, has proved a robust solution for shared facilities and industry service providers alike. PMID:16987406

Variants in KCNJ11 and BAD do not predict response to ketogenic dietary therapies for epilepsy.

PubMed

Schoeler, Natasha E; Leu, Costin; White, Jon; Plagnol, Vincent; Ellard, Sian; Matarin, Mar; Yellen, Gary; Thiele, Elizabeth A; Mackay, Mark; McMahon, Jacinta M; Scheffer, Ingrid E; Sander, Josemir W; Cross, J Helen; Sisodiya, Sanjay M

2015-12-01

In the absence of specific metabolic disorders, predictors of response to ketogenic dietary therapies (KDT) are unknown. We aimed to determine whether variants in established candidate genes KCNJ11 and BAD influence response to KDT. We sequenced KCNJ11 and BAD in individuals without previously-known glucose transporter type 1 deficiency syndrome or other metabolic disorders, who received KDT for epilepsy. Hospital records were used to obtain demographic and clinical data. Two response phenotypes were used: ≥ 50% seizure reduction and seizure-freedom at 3-month follow-up. Case/control association tests were conducted with KCNJ11 and BAD variants with minor allele frequency (MAF)>0.01, using PLINK. Response to KDT in individuals with variants with MAF<0.01 was evaluated. 303 Individuals had KCNJ11 and 246 individuals had BAD sequencing data and diet response data. Six SNPs in KCNJ11 and two in BAD had MAF>0.01. Eight variants in KCNJ11 and seven in BAD (of which three were previously-unreported) had MAF<0.01. No significant results were obtained from association analyses, with either KDT response phenotype. P-values were similar when accounting for ethnicity using a stratified Cochran-Mantel-Haenszel test. There did not seem to be a consistent effect of rare variants on response to KDT, although the cohort size was too small to assess significance. Common variants in KCNJ11 and BAD do not predict response to KDT for epilepsy. We can exclude, with 80% power, association from variants with a MAF of >0.05 and effect size >3. A larger sample size is needed to detect associations from rare variants or those with smaller effect sizes. Copyright © 2015 Elsevier B.V. All rights reserved.

Traffic jam functions in a branched pathway from Notch activation to niche cell fate.

PubMed

Wingert, Lindsey; DiNardo, Stephen

2015-07-01

The niche directs key behaviors of its resident stem cells, and is thus crucial for tissue maintenance, repair and longevity. However, little is known about the genetic pathways that guide niche specification and development. The male germline stem cell niche in Drosophila houses two stem cell populations and is specified within the embryonic gonad, thus making it an excellent model for studying niche development. The hub cells that form the niche are specified early by Notch activation. Over the next few hours, these individual cells then cluster together and take up a defined position before expressing markers of hub cell differentiation. This timing suggests that there are other factors for niche development yet to be defined. Here, we have identified a role for the large Maf transcription factor Traffic jam (Tj) in hub cell specification downstream of Notch. Tj downregulation is the first detectable effect of Notch activation in hub cells. Furthermore, Tj depletion is sufficient to generate ectopic hub cells that can recruit stem cells. Surprisingly, ectopic niche cells in tj mutants remain dispersed in the absence of Notch activation. This led us to uncover a branched pathway downstream of Notch in which Bowl functions to direct hub cell assembly in parallel to Tj downregulation. © 2015. Published by The Company of Biologists Ltd.

Saturn Apollo Program

NASA Image and Video Library

1969-01-01

In one of the initial assembly steps for the Saturn IB launch vehicle's S-IB (first) stage, workers at the Michoud Assembly Facility (MAF) near New Orleans, Louisiana, position the thrust structure. Developed by the Marshall Space Flight Center and built by the Chrysler Corporation at Michoud Assembly Facility (MAF), the S-IB utilized eight H-1 engines and each produced 200,000 pounds of thrust, a combined thrust of 1,600,000 pounds.

Saturn Apollo Program

NASA Image and Video Library

1969-01-01

In one of the initial assembly steps for the Saturn IB launch vehicle's S-IB (first) stage, workers at the Michoud Assembly Facility (MAF) near New Orleans, Louisiana, complete the thrust structure. Developed by the Marshall Space Flight Center and built by the Chrysler Corporation at Michoud Assembly Facility (MAF), the S-IB utilized eight H-1 engines and each produced 200,000 pounds of thrust, a combined thrust of 1,600,000 pounds.

Saturn Apollo Program

NASA Image and Video Library

1969-01-01

In one of the initial assembly steps for the Saturn IB launch vehicle's S-IB (first) stage, workers at the Michoud Assembly Facility (MAF) near New Orleans, Louisiana, complete the lower shroud assembly. Developed by the Marshall Space Flight Center and built by the Chrysler Corporation at Michoud Assembly Facility (MAF), the S-IB utilized the eight H-1 engines and each produced 200,000 pounds of thrust, a combined thrust of 1,600,000 pounds.

A method to associate all possible combinations of genetic and environmental factors using GxE landscape plot.

PubMed

Nagaie, Satoshi; Ogishima, Soichi; Nakaya, Jun; Tanaka, Hiroshi

2015-01-01

Genome-wide association studies (GWAS) and linkage analysis has identified many single nucleotide polymorphisms (SNPs) related to disease. There are many unknown SNPs whose minor allele frequencies (MAFs) as low as 0.005 having intermediate effects with odds ratio between 1.5~3.0. Low frequency variants having intermediate effects on disease pathogenesis are believed to have complex interactions with environmental factors called gene-environment interactions (GxE). Hence, we describe a model using 3D Manhattan plot called GxE landscape plot to visualize the association of p-values for gene-environment interactions (GxE). We used the Gene-Environment iNteraction Simulator 2 (GENS2) program to simulate interactions between two genetic loci and one environmental factor in this exercise. The dataset used for training contains disease status, gender, 20 environmental exposures and 100 genotypes for 170 subjects, and p-values were calculated by Cochran-Mantel-Haenszel chi-squared test on known data. Subsequently, we created a 3D GxE landscape plot of negative logarithm of the association of p-values for all the possible combinations of genetic and environmental factors with their hierarchical clustering. Thus, the GxE landscape plot is a valuable model to predict association of p-values for GxE and similarity among genotypes and environments in the context of disease pathogenesis. GxE - Gene-environment interactions, GWAS - Genome-wide association study, MAFs - Minor allele frequencies, SNPs - Single nucleotide polymorphisms, EWAS - Environment-wide association study, FDR - False discovery rate, JPT+CHB - HapMap population of Japanese in Tokyo, Japan - Han Chinese in Beijing.

Reprogramming of Pancreatic Exocrine Cells AR42J Into Insulin-producing Cells Using mRNAs for Pdx1, Ngn3, and MafA Transcription Factors.

PubMed

Koblas, Tomas; Leontovyc, Ivan; Loukotova, Sarka; Kosinova, Lucie; Saudek, Frantisek

2016-05-17

Direct reprogramming of pancreatic nonendocrine cells into insulin-producing β-cells represents a promising approach for the treatment of insulin-dependent diabetes. However, its clinical application is limited by the potential for insertional mutagenesis associated with the viral vectors currently used for cell reprogramming. With the aim of developing a nonintegrative reprogramming strategy for derivation of insulin-producing cells, here, we evaluated a new approach utilizing synthetic messenger RNAs encoding reprogramming transcription factors. Administration of synthetic mRNAs encoding three key transcription regulators of β-cell differentiation-Pdx1, Neurogenin3, and MafA-efficiently reprogrammed the pancreatic exocrine cells into insulin-producing cells. In addition to the insulin genes expression, the synthetic mRNAs also induced the expressions of genes important for proper pancreatic β-cell function, including Sur1, Kir6.2, Pcsk1, and Pcsk2. Pretreating cells with the chromatin-modifying agent 5-Aza-2'-deoxycytidine further enhanced reprogramming efficiency, increasing the proportion of insulin-producing cells from 3.5 ± 0.9 to 14.3 ± 1.9% (n = 4). Moreover, 5-Aza-2'-deoxycytidine pretreatment enabled the reprogrammed cells to respond to glucose challenge with increased insulin secretion. In conclusion, our results support that the reprogramming of pancreatic exocrine cells into insulin-producing cells, induced by synthetic mRNAs encoding pancreatic transcription factors, represents a promising approach for cell-based diabetes therapy.

HES6 reverses nuclear reprogramming of insulin-producing cells following cell fusion

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

Ball, Andrew J.; Abrahamsson, Annelie E.; Tyrberg, Bjoern

2007-04-06

To examine the mechanism by which growth-stimulated pancreatic {beta}-cells dedifferentiate, somatic cell fusions were performed between MIN6, a highly differentiated mouse insulinoma, and {beta}lox5, a cell line derived from human {beta}-cells which progressively dedifferentiated in culture. MIN6/{beta}lox5 somatic cells hybrids underwent silencing of insulin expression and a marked decline in PDX1, NeuroD, and MafA, indicating that {beta}lox5 expresses a dominant transacting factor(s) that represses {beta}-cell differentiation. Expression of Hes1, which inhibits endocrine differentiation was higher in hybrid cells than in parental MIN6 cells. Hes6, a repressor of Hes1, was highly expressed in primary {beta}-cells as well as MIN6, but wasmore » repressed in hybrids. Hes6 overexpression using a retroviral vector led to a decrease in Hes1 levels, an increase in {beta}-cell transcription factors and partial restoration of insulin expression. We conclude that the balance of Notch activators and inhibitors may play an important role in maintaining the {beta}-cell differentiated state.« less

The Effect of Size and Taper of Apical Preparation in Reducing Intra-Canal Bacteria: A Quantitative SEM Study.

PubMed

Mohammadzadeh Akhlaghi, Nahid; Rahimifard, Nahid; Moshari, Amirabbas; Vatanpour, Mehdi; Darmiani, Soheila

2014-01-01

Bacteria and their byproducts are major etiologic factors in endodontic diseases. Prevention or reduction of root canal bacterial contamination is the main aim of endodontic treatment. The purpose of this in vitro study was to evaluate the effect of size and taper of master apical file (MAF) in reducing bacteria from the apical third of the curved canals using a quantitative scanning electron microscope (SEM) study. Eighty-nine human mandibular first molars with curved MB canals (20(º)-35(º)) were divided into one control group (n=5) (without rotary instrumentation) and 6 experimental groups (n=14). The canals were prepared using RaCe rotary files to the MAF sizes 25/0.04, 25/0.06, 30/0.04, 30/0.06, 35/0.04 and 35/0.06, in groups 1 to 6, respectively. All the experimental groups were finally rinsed with 2 mL of 17% EDTA followed by 3 mL of 5.25% NaOCl. The mesial roots were split longitudinally. Remaining bacteria in the apical third of MB canals were evaluated using SEM (2000×). Data analysis was performed using one way ANOVA with Tukey's post hoc test. The level of significance was set at 0.05. All the experimental groups showed significant bacterial reduction (P<0.001). Although the greater size and/or taper resulted in decrease in bacteria, differences between the groups were not significant. Based on this in vitro study the MAF #25/0.04 had no significant difference compared to other groups with greater apical size/taper; all groups could effectively reduce intra-canal bacteria.

Detection of expressional changes induced by intrauterine growth restriction in the developing rat pancreas.

PubMed

Zhang, Lin; Chen, Wei; Dai, Yuee; Zhu, Ziyang; Liu, Qianqi

2016-07-01

Intrauterine growth retardation (IUGR) is a disorder that can result in permanent changes in the physiology and metabolism of the newborn, which increased the risk of disease in adulthood. Evidence supports IUGR as a risk factor for the development of diabetes mellitus, which could reflect changes in pancreas developmental pathways. We sought to characterize the IUGR-induced alterations of the complex pathways of pancreas development in a rat model of IUGR. We analyzed the pancreases of Sprague Dawley rats after inducing IUGR by feeding a maternal low calorie diet from gestational day 1 until term. IUGR altered the pancreatic structure, islet areas, and islet quantities and resulted in abnormal morphological changes during pancreatic development, as determined by HE staining and light microscopy. We identified multiple differentially expressed genes in the pancreas by RT-PCR. The genes of the insulin/FoxO1/Pdx1/MafA signaling pathway were first expressed at embryonic day 14 (E14). The expressions of insulin and MafA increased as the fetus grew while the expressions of FoxO1 and Pdx1 decreased. Compared with the control rats, the expressions of FoxO1, Pdx1, and MafA were lower in the IUGR rats, whereas insulin levels showed no change. Microarray profiling, in combination with quantitative real-time PCR, uncovered a subset of microRNAs that changed in their degree of expression throughout pancreatic development. In conclusion, our data support the hypothesis that IUGR influences the development of the rat pancreas. We also identified new pathways that appear to be programmed by IUGR. © 2016 by the Society for Experimental Biology and Medicine.

Saturn Apollo Program

NASA Image and Video Library

1969-01-01

In the clustering procedure, an initial assembly step for the Saturn IB launch vehicle's S-IB (first) stage, workers at the Michoud Assembly Facility (MAF) near New Orleans, Louisiana, position the central liquid-oxygen tank. Developed by the Marshall Space Flight Center and built by the Chrysler Corporation at Michoud Assembly Facility (MAF), the S-IB utilized eight H-1 engines and each produced 200,000 pounds of thrust, a combined thrust of 1,600,000 pounds.

Improved imputation accuracy of rare and low-frequency variants using population-specific high-coverage WGS-based imputation reference panel.

PubMed

Mitt, Mario; Kals, Mart; Pärn, Kalle; Gabriel, Stacey B; Lander, Eric S; Palotie, Aarno; Ripatti, Samuli; Morris, Andrew P; Metspalu, Andres; Esko, Tõnu; Mägi, Reedik; Palta, Priit

2017-06-01

Genetic imputation is a cost-efficient way to improve the power and resolution of genome-wide association (GWA) studies. Current publicly accessible imputation reference panels accurately predict genotypes for common variants with minor allele frequency (MAF)≥5% and low-frequency variants (0.5≤MAF<5%) across diverse populations, but the imputation of rare variation (MAF<0.5%) is still rather limited. In the current study, we evaluate imputation accuracy achieved with reference panels from diverse populations with a population-specific high-coverage (30 ×) whole-genome sequencing (WGS) based reference panel, comprising of 2244 Estonian individuals (0.25% of adult Estonians). Although the Estonian-specific panel contains fewer haplotypes and variants, the imputation confidence and accuracy of imputed low-frequency and rare variants was significantly higher. The results indicate the utility of population-specific reference panels for human genetic studies.

Improved imputation accuracy of rare and low-frequency variants using population-specific high-coverage WGS-based imputation reference panel

PubMed Central

Mitt, Mario; Kals, Mart; Pärn, Kalle; Gabriel, Stacey B; Lander, Eric S; Palotie, Aarno; Ripatti, Samuli; Morris, Andrew P; Metspalu, Andres; Esko, Tõnu; Mägi, Reedik; Palta, Priit

2017-01-01

Genetic imputation is a cost-efficient way to improve the power and resolution of genome-wide association (GWA) studies. Current publicly accessible imputation reference panels accurately predict genotypes for common variants with minor allele frequency (MAF)≥5% and low-frequency variants (0.5≤MAF<5%) across diverse populations, but the imputation of rare variation (MAF<0.5%) is still rather limited. In the current study, we evaluate imputation accuracy achieved with reference panels from diverse populations with a population-specific high-coverage (30 ×) whole-genome sequencing (WGS) based reference panel, comprising of 2244 Estonian individuals (0.25% of adult Estonians). Although the Estonian-specific panel contains fewer haplotypes and variants, the imputation confidence and accuracy of imputed low-frequency and rare variants was significantly higher. The results indicate the utility of population-specific reference panels for human genetic studies. PMID:28401899

Measuring awareness of financial skills: reliability and validity of a new measure.

PubMed

Cramer, K; Tuokko, H A; Mateer, C A; Hultsch, D F

2004-03-01

This paper examines the psychometric properties of a three-part (participant, informant, and performance) Measure for assessing Awareness of Financial Skills (MAFS). The MAFS was administered to 10 seniors with dementia and 25 well-functioning seniors, and their informants. Measures of cognitive functioning, social desirability, neuroticism, and perceived control were administered to each participant to allow for an assessment of validity. Internal consistency estimates for the participant and informant questionnaires were found to be 0.92 and 0.97, respectively. Convergent validity analysis indicated that performance on this measure was related to level of cognitive functioning, with higher level of unawareness associated with decreased cognitive ability. Discriminant validity analysis showed that performance on this measure was not related to social desirability or neuroticism. This study provides evidence that the MAFS is a reliable and valid tool for assessing awareness of financial skills in older adults.

Multimodal, multiphoton microscopy and image correlation analysis for characterizing corneal thermal damage

NASA Astrophysics Data System (ADS)

Lo, Wen; Chang, Yu-Lin; Liu, Jia-Shiu; Hseuh, Chiu-Mei; Hovhannisyan, Vladimir; Chen, Shean-Jen; Tan, Hsin-Yuan; Dong, Chen-Yuan

2009-09-01

We used the combination of multiphoton autofluorescence (MAF), forward second-harmonic generation (FWSHG), and backward second-harmonic generation (BWSHG) imaging for the qualitative and quantitative characterization of thermal damage of ex vivo bovine cornea. We attempt to characterize the structural alterations by qualitative MAF, FWSHG, and BWSHG imaging in the temperature range of 37 to 90°C. In addition to measuring the absolute changes in the three types of signals at the stromal surface, we also performed image correlation analysis between FWSHG and BWSHG and demonstrate that with increasing thermal damage, image correlation between FWSHG and BWSHG significantly increases. Our results show that while MAF and BWSHG intensities may be used as preliminary indicators of the extent of corneal thermal damage, the most sensitive measures are provided by the decay in FWSHG intensity and the convergence of FWSHG and BWSHG images.

Specification and spatial arrangement of cells in the germline stem cell niche of the Drosophila ovary depend on the Maf transcription factor Traffic jam

PubMed Central

Panchal, Trupti; Chen, Xi; Poon, James; Kouptsova, Jane

2017-01-01

Germline stem cells in the Drosophila ovary are maintained by a somatic niche. The niche is structurally and functionally complex and contains four cell types, the escort, cap, and terminal filament cells and the newly identified transition cell. We find that the large Maf transcription factor Traffic jam (Tj) is essential for determining niche cell fates and architecture, enabling each niche in the ovary to support a normal complement of 2–3 germline stem cells. In particular, we focused on the question of how cap cells form. Cap cells express Tj and are considered the key component of a mature germline stem cell niche. We conclude that Tj controls the specification of cap cells, as the complete loss of Tj function caused the development of additional terminal filament cells at the expense of cap cells, and terminal filament cells developed cap cell characteristics when induced to express Tj. Further, we propose that Tj controls the morphogenetic behavior of cap cells as they adopted the shape and spatial organization of terminal filament cells but otherwise appeared to retain their fate when Tj expression was only partially reduced. Our data indicate that Tj contributes to the establishment of germline stem cells by promoting the cap cell fate, and controls the stem cell-carrying capacity of the niche by regulating niche architecture. Analysis of the interactions between Tj and the Notch (N) pathway indicates that Tj and N have distinct functions in the cap cell specification program. We propose that formation of cap cells depends on the combined activities of Tj and the N pathway, with Tj promoting the cap cell fate by blocking the terminal filament cell fate, and N supporting cap cells by preventing the escort cell fate and/or controlling the number of cap cell precursors. PMID:28542174

WE-G-204-05: Relative Object Detectability Evaluation of a New High Resolution A-Se Direct Detection System Compared to Indirect Micro-Angiographic Fluoroscopic (MAF) Detectors

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

Russ, M; Nagesh, S Setlur; Ionita, C

2015-06-15

Purpose: To evaluate the task specific imaging performance of a new 25µm pixel pitch, 1000µm thick amorphous selenium direct detection system with CMOS readout for typical angiographic exposure parameters using the relative object detectability (ROD) metric. Methods: The ROD metric uses a simulated object function weighted at each spatial frequency by the detectors’ detective quantum efficiency (DQE), which is an intrinsic performance metric. For this study, the simulated objects were aluminum spheres of varying diameter (0.05–0.6mm). The weighted object function is then integrated over the full range of detectable frequencies inherent to each detector, and a ratio is taken ofmore » the resulting value for two detectors. The DQE for the 25µm detector was obtained from a simulation of a proposed a-Se detector using an exposure of 200µR for a 50keV x-ray beam. This a-Se detector was compared to two microangiographic fluoroscope (MAF) detectors [the MAF-CCD with pixel size of 35µm and Nyquist frequency of 14.2 cycles/mm and the MAF-CMOS with pixel size of 75µm and Nyquist frequency of 6.6 cycles/mm] and a standard flat-panel detector (FPD with pixel size of 194µm and Nyquist frequency of 2.5cycles/mm). Results: ROD calculations indicated vastly superior performance by the a-Se detector in imaging small aluminum spheres. For the 50µm diameter sphere, the ROD values for the a-Se detector compared to the MAF-CCD, the MAF-CMOS, and the FPD were 7.3, 9.3 and 58, respectively. Detector performance in the low frequency regime was dictated by each detector’s DQE(0) value. Conclusion: The a-Se with CMOS readout is unique and appears to have distinctive advantages of incomparable high resolution, low noise, no readout lag, and expandable design. The a-Se direct detection system will be a powerful imaging tool in angiography, with potential break-through applications in diagnosis and treatment of neuro-vascular disease. Supported by NIH Grant: 2R01EB002873 and an equipment grant from Toshiba Medical Systems Corporation.« less

Saturn Apollo Program

NASA Image and Video Library

1965-01-01

In one of the initial assembly steps for the first stage (S-IB stage) of the Saturn IB launch vehicle, workers at the Michoud Assembly Facility (MAF) near New Orleans, Louisiana, position a "Spider Beam" to the central liquid-oxygen tank of the S-IB stage. Developed by the Marshall Space Flight Center (MSFC) and built by the Chrysler Corporation at MAF, the S-IB stage utilized eight H-1 engines to produce a combined thrust of 1,600,000 pounds.

One Size Doesn’t Fit All: Measuring Individual Privacy in Aggregate Genomic Data

PubMed Central

Simmons, Sean; Berger, Bonnie

2017-01-01

Even in the aggregate, genomic data can reveal sensitive information about individuals. We present a new model-based measure, PrivMAF, that provides provable privacy guarantees for aggregate data (namely minor allele frequencies) obtained from genomic studies. Unlike many previous measures that have been designed to measure the total privacy lost by all participants in a study, PrivMAF gives an individual privacy measure for each participant in the study, not just an average measure. These individual measures can then be combined to measure the worst case privacy loss in the study. Our measure also allows us to quantify the privacy gains achieved by perturbing the data, either by adding noise or binning. Our findings demonstrate that both perturbation approaches offer significant privacy gains. Moreover, we see that these privacy gains can be achieved while minimizing perturbation (and thus maximizing the utility) relative to stricter notions of privacy, such as differential privacy. We test PrivMAF using genotype data from the Wellcome Trust Case Control Consortium, providing a more nuanced understanding of the privacy risks involved in an actual genome-wide association studies. Interestingly, our analysis demonstrates that the privacy implications of releasing MAFs from a study can differ greatly from individual to individual. An implementation of our method is available at http://privmaf.csail.mit.edu. PMID:29202050

Efficient Iterative Methods Applied to the Solution of Transonic Flows

NASA Astrophysics Data System (ADS)

Wissink, Andrew M.; Lyrintzis, Anastasios S.; Chronopoulos, Anthony T.

1996-02-01

We investigate the use of an inexact Newton's method to solve the potential equations in the transonic regime. As a test case, we solve the two-dimensional steady transonic small disturbance equation. Approximate factorization/ADI techniques have traditionally been employed for implicit solutions of this nonlinear equation. Instead, we apply Newton's method using an exact analytical determination of the Jacobian with preconditioned conjugate gradient-like iterative solvers for solution of the linear systems in each Newton iteration. Two iterative solvers are tested; a block s-step version of the classical Orthomin(k) algorithm called orthogonal s-step Orthomin (OSOmin) and the well-known GMRES method. The preconditioner is a vectorizable and parallelizable version of incomplete LU (ILU) factorization. Efficiency of the Newton-Iterative method on vector and parallel computer architectures is the main issue addressed. In vectorized tests on a single processor of the Cray C-90, the performance of Newton-OSOmin is superior to Newton-GMRES and a more traditional monotone AF/ADI method (MAF) for a variety of transonic Mach numbers and mesh sizes. Newton-GMRES is superior to MAF for some cases. The parallel performance of the Newton method is also found to be very good on multiple processors of the Cray C-90 and on the massively parallel thinking machine CM-5, where very fast execution rates (up to 9 Gflops) are found for large problems.

MicroRNA Expression in Alpha and Beta Cells of Human Pancreatic Islets

PubMed Central

Vargas, Nancy; Rosero, Samuel; Piroso, Julieta; Ichii, Hirohito; Umland, Oliver; Zhijie, Jiang; Tsinoremas, Nicholas; Ricordi, Camillo; Inverardi, Luca; Domínguez-Bendala, Juan; Pastori, Ricardo L.

2013-01-01

microRNAs (miRNAs) play an important role in pancreatic development and adult β-cell physiology. Our hypothesis is based on the assumption that each islet cell type has a specific pattern of miRNA expression. We sought to determine the profile of miRNA expression in α-and β-cells, the main components of pancreatic islets, because this analysis may lead to a better understanding of islet gene regulatory pathways. Highly enriched (>98%) subsets of human α-and β-cells were obtained by flow cytometric sorting after intracellular staining with c-peptide and glucagon antibody. The method of sorting based on intracellular staining is possible because miRNAs are stable after fixation. MiRNA expression levels were determined by quantitative high throughput PCR-based miRNA array platform screening. Most of the miRNAs were preferentially expressed in β-cells. From the total of 667 miRNAs screened, the Significant Analysis of Microarray identified 141 miRNAs, of which only 7 were expressed more in α-cells (α-miRNAs) and 134 were expressed more in β-cells (β-miRNAs). Bioinformatic analysis identified potential targets of β-miRNAs analyzing the Beta Cell Gene Atlas, described in the T1Dbase, the web platform, supporting the type 1 diabetes (T1D) community. cMaf, a transcription factor regulating glucagon expression expressed selectively in α-cells (TFα) is targeted by β-miRNAs; miR-200c, miR-125b and miR-182. Min6 cells treated with inhibitors of these miRNAs show an increased expression of cMaf RNA. Conversely, over expression of miR-200c, miR-125b or miR-182 in the mouse alpha cell line αTC6 decreases the level of cMAF mRNA and protein. MiR-200c also inhibits the expression of Zfpm2, a TFα that inhibits the PI3K signaling pathway, at both RNA and protein levels. In conclusion, we identified miRNAs differentially expressed in pancreatic α- and β-cells and their potential transcription factor targets that could add new insights into different aspects of islet biology and pathophysiology. PMID:23383059

MicroRNA expression in alpha and beta cells of human pancreatic islets.

PubMed

Klein, Dagmar; Misawa, Ryosuke; Bravo-Egana, Valia; Vargas, Nancy; Rosero, Samuel; Piroso, Julieta; Ichii, Hirohito; Umland, Oliver; Zhijie, Jiang; Tsinoremas, Nicholas; Ricordi, Camillo; Inverardi, Luca; Domínguez-Bendala, Juan; Pastori, Ricardo L

2013-01-01

microRNAs (miRNAs) play an important role in pancreatic development and adult β-cell physiology. Our hypothesis is based on the assumption that each islet cell type has a specific pattern of miRNA expression. We sought to determine the profile of miRNA expression in α-and β-cells, the main components of pancreatic islets, because this analysis may lead to a better understanding of islet gene regulatory pathways. Highly enriched (>98%) subsets of human α-and β-cells were obtained by flow cytometric sorting after intracellular staining with c-peptide and glucagon antibody. The method of sorting based on intracellular staining is possible because miRNAs are stable after fixation. MiRNA expression levels were determined by quantitative high throughput PCR-based miRNA array platform screening. Most of the miRNAs were preferentially expressed in β-cells. From the total of 667 miRNAs screened, the Significant Analysis of Microarray identified 141 miRNAs, of which only 7 were expressed more in α-cells (α-miRNAs) and 134 were expressed more in β-cells (β-miRNAs). Bioinformatic analysis identified potential targets of β-miRNAs analyzing the Beta Cell Gene Atlas, described in the T1Dbase, the web platform, supporting the type 1 diabetes (T1D) community. cMaf, a transcription factor regulating glucagon expression expressed selectively in α-cells (TFα) is targeted by β-miRNAs; miR-200c, miR-125b and miR-182. Min6 cells treated with inhibitors of these miRNAs show an increased expression of cMaf RNA. Conversely, over expression of miR-200c, miR-125b or miR-182 in the mouse alpha cell line αTC6 decreases the level of cMAF mRNA and protein. MiR-200c also inhibits the expression of Zfpm2, a TFα that inhibits the PI3K signaling pathway, at both RNA and protein levels.In conclusion, we identified miRNAs differentially expressed in pancreatic α- and β-cells and their potential transcription factor targets that could add new insights into different aspects of islet biology and pathophysiology.

Sleep quality in fibromyalgia and rheumatoid arthritis: associations with pain, fatigue, depression, and disease activity.

PubMed

Ulus, Y; Akyol, Y; Tander, B; Durmus, D; Bilgici, A; Kuru, O

2011-01-01

The aim of this study was to compare the sleep quality in patients with rheumatoid arthritis (RA) and fibromyalgia syndrome (FMS); and to evaluate the relationship between sleep quality and pain, fatigue, depression, and disease activity in patients with RA and FMS. Forty RA, 40 FMS and 40 healthy controls were enrolled in the study. Disease activity and disease duration were reported in patients. Pain by visual analogue scale (VAS), fatigue by Multidimensional Assesment of Fatigue (MAF), depression by Beck Depression Index (BDI), and sleep quality by Pittsburgh Sleep Quality Index (PSQI) were gathered in all participants. All participants were aged between 20 and 65 years, with a mean age of 42.97±10.75 years. There was no significant difference with respect to demographic characteristics among the three study groups. Patients reported more depression than controls, but BDI scores were similar in FMS and RA patients. VAS pain scores and MAF scores were significantly different in the three groups (p<0.001). FMS and RA patients had poor sleep quality (p<0.001). FMS patients had daytime dysfunction due to sleep disorder and had worse habitual sleep efficiency than RA patients (p<0.05). In patients, positive correlations were found between PSQI and clinic assessment variables except disease duration. FMS and RA may have poor sleep quality when compared to subjects without rheumatologic disorders. The quality of sleep can be impaired by pain, fatigue, depression, and disease activity in such patients.

Gender Integration in the USAF Fighter Community: 25 Years of Progress and Persistent Challenges

DTIC Science & Technology

2017-04-25

experience. This work builds on the research of two AF Fellows who studied female aviators in the Mobility Air Force (MAF) in 2015 to address subtle...distilling the 25- year period under study . Prior to determining instructional fixes, great instructors listen to their students and other members...were a number of non-member Company Grade Officers (CGOs), to understand their experiences and thoughts on retention.18 As in the MAF studies , but to a

Saturn Apollo Program

NASA Image and Video Library

1969-01-01

In the "clustering" procedure, an initial assembly step for the first stage (S-IB stage) of the Saturn IB launch vehicle, workers at the Michoud Assembly Facility (MAF) near New Orleans, Louisiana, place the first of eight outboard fuel tanks (left) next to the central liquid-oxygen tank of S-IB stage. Developed by the Marshall Space Flight Center (MSFC) and built by the Chrysler Corporation at MAF, the S-IB stage utilized eight H-1 engines to produce a combined thrust of 1,600,000 pounds.

Saturn Apollo Program

NASA Image and Video Library

1969-01-01

In the clustering procedure, an initial assembly step for the Saturn IB launch vehicle's S-IB (first) stage, workers at the Michoud Assembly Facility (MAF) near New Orleans, Louisiana, place the first of eight outboard fuel tanks atop the central liquid-oxygen tank. Developed by the Marshall Space Flight Center and built by the Chrysler Corporation at Michoud Assembly Facility (MAF), the S-IB utilized eight H-1 engines and each produced 200,000 pounds of thrust, a combined thrust of 1,600,000 pounds.

Saturn Apollo Program

NASA Image and Video Library

1969-01-01

In the clustering procedure, an initial assembly step for the first stage (S-IB stage) of the Saturn IB launch vehicle, workers at the Michoud Assembly Facility (MAF) near New Orleans, Louisiana, place the first of eight outboard fuel tanks next to the central liquid-oxygen tank of the S-IB stage. Developed by the Marshall Space Flight Center (MSFC) and built by the Chrysler Corporation at MAF, the S-IB stage utilized eight H-1 engines to produce a combined thrust of 1,600,000 pounds.

Gene-environment interactions in cancer epidemiology: a National Cancer Institute Think Tank report.

PubMed

Hutter, Carolyn M; Mechanic, Leah E; Chatterjee, Nilanjan; Kraft, Peter; Gillanders, Elizabeth M

2013-11-01

Cancer risk is determined by a complex interplay of genetic and environmental factors. Genome-wide association studies (GWAS) have identified hundreds of common (minor allele frequency [MAF] > 0.05) and less common (0.01 < MAF < 0.05) genetic variants associated with cancer. The marginal effects of most of these variants have been small (odds ratios: 1.1-1.4). There remain unanswered questions on how best to incorporate the joint effects of genes and environment, including gene-environment (G × E) interactions, into epidemiologic studies of cancer. To help address these questions, and to better inform research priorities and allocation of resources, the National Cancer Institute sponsored a "Gene-Environment Think Tank" on January 10-11, 2012. The objective of the Think Tank was to facilitate discussions on (1) the state of the science, (2) the goals of G × E interaction studies in cancer epidemiology, and (3) opportunities for developing novel study designs and analysis tools. This report summarizes the Think Tank discussion, with a focus on contemporary approaches to the analysis of G × E interactions. Selecting the appropriate methods requires first identifying the relevant scientific question and rationale, with an important distinction made between analyses aiming to characterize the joint effects of putative or established genetic and environmental factors and analyses aiming to discover novel risk factors or novel interaction effects. Other discussion items include measurement error, statistical power, significance, and replication. Additional designs, exposure assessments, and analytical approaches need to be considered as we move from the current small number of success stories to a fuller understanding of the interplay of genetic and environmental factors. © 2013 WILEY PERIODICALS, INC.

Gene-Environment Interactions in Cancer Epidemiology: A National Cancer Institute Think Tank Report

PubMed Central

Hutter, Carolyn M.; Mechanic, Leah E.; Chatterjee, Nilanjan; Kraft, Peter; Gillander, Elizabeth M.

2014-01-01

Cancer risk is determined by a complex interplay of genetic and environmental factors. Genome-wide association studies (GWAS) have identified hundreds of common (minor allele frequency [MAF]>0.05) and less common (0.01

Cassava Brown Streak Virus (Potyviridae) Encodes a Putative Maf/HAM1 Pyrophosphatase Implicated in Reduction of Mutations and a P1 Proteinase That Suppresses RNA Silencing but Contains No HC-Pro ▿

PubMed Central

Mbanzibwa, Deusdedith R.; Tian, Yanping; Mukasa, Settumba B.; Valkonen, Jari P. T.

2009-01-01

The complete positive-sense single-stranded RNA genome of Cassava brown streak virus (CBSV; genus Ipomovirus; Potyviridae) was found to consist of 9,069 nucleotides and predicted to produce a polyprotein of 2,902 amino acids. It was lacking helper-component proteinase but contained a single P1 serine proteinase that strongly suppressed RNA silencing. Besides the exceptional structure of the 5′-proximal part of the genome, CBSV also contained a Maf/HAM1-like sequence (678 nucleotides, 226 amino acids) recombined between the replicase and coat protein domains in the 3′-proximal part of the genome, which is highly conserved in Potyviridae. HAM1 was flanked by consensus proteolytic cleavage sites for ipomovirus NIaPro cysteine proteinase. Homology of CBSV HAM1 with cellular Maf/HAM1 pyrophosphatases suggests that it may intercept noncanonical nucleoside triphosphates to reduce mutagenesis of viral RNA. PMID:19386713

Monitoring the process of pulmonary melanoma metastasis using large area and label-free nonlinear optical microscopy

NASA Astrophysics Data System (ADS)

Hua, Daozhu; Qi, Shuhong; Li, Hui; Zhang, Zhihong; Fu, Ling

2012-06-01

We performed large area nonlinear optical microscopy (NOM) for label-free monitoring of the process of pulmonary melanoma metastasis ex vivo with subcellular resolution in C57BL/6 mice. Multiphoton autofluorescence (MAF) and second harmonic generation (SHG) images of lung tissue are obtained in a volume of ~2.2 mm×2.2 mm×30 μm. Qualitative differences in morphologic features and quantitative measurement of pathological lung tissues at different time points are characterized. We find that combined with morphological features, the quantitative parameters, such as the intensity ratio of MAF and SHG between pathological tissue and normal tissue and the MAF to SHG index versus depth clearly shows the tissue physiological changes during the process of pulmonary melanoma metastasis. Our results demonstrate that large area NOM succeeds in monitoring the process of pulmonary melanoma metastasis, which can provide a powerful tool for the research in tumor pathophysiology and therapy evaluation.

Synthesis, spectroscopic, coordination and biological activities of some organometallic complexes derived from thio-Schiff base ligands

NASA Astrophysics Data System (ADS)

Abou-Hussein, Azza A.; Linert, Wolfgang

2014-01-01

Two series of mono- and binuclear complexes cyclic or acyclic thio-ferocine Schiff base ligands, derived from the condensation of 2-aminobenzenthiol (L) with monoacetyl ferrocene in the molar ratio 1:1 or in the molar ratio 1:2 for diacetyl ferocine have been prepared. The condensation reactions yield the corresponding Schiff Base ligands, HLa-Maf and H2Lb-Daf. The chelation of the ligands to metal ions occurs through the sulfur of the thiol group as well as the nitrogen atoms of the azomethine group of the ligands. HLa-Maf acts as monobasic bidentate or dibasic tetradentate, while H2Lb-Daf behaves as twice negatively cargend tetradentate ligand. The structures of these ligands were elucidated by elemental analysis, infrared, ultraviolet-visible spectra, as well as 1H NMR spectra. Reactions of the Schiff bases ligands with ruthenium(III), oxovanadium(IV) and dioxouranium(VI) afforded the corresponding transition metal complexes. The properties of the newly prepared complexes were analyse by elemental analyses, infrared, electronic spectra, 1H NMR as well as the magnetic susceptibility and conductivity measurement. The metal complexes exhibits different geometrical arrangements such as octahedral and square pyramidal coordination. Schiff base ligands and their metal complexes were tested against two pathogenic bacteria as Gram-positive and Gram-negative bacteria as well as one kind of fungi to study their biological activity. All the complexes exhibit antibacterial and antifungal activities against these organisms.

Efficient iterative methods applied to the solution of transonic flows

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

Wissink, A.M.; Lyrintzis, A.S.; Chronopoulos, A.T.

1996-02-01

We investigate the use of an inexact Newton`s method to solve the potential equations in the transonic regime. As a test case, we solve the two-dimensional steady transonic small disturbance equation. Approximate factorization/ADI techniques have traditionally been employed for implicit solutions of this nonlinear equation. Instead, we apply Newton`s method using an exact analytical determination of the Jacobian with preconditioned conjugate gradient-like iterative solvers for solution of the linear systems in each Newton iteration. Two iterative solvers are tested; a block s-step version of the classical Orthomin(k) algorithm called orthogonal s-step Orthomin (OSOmin) and the well-known GIVIRES method. The preconditionermore » is a vectorizable and parallelizable version of incomplete LU (ILU) factorization. Efficiency of the Newton-Iterative method on vector and parallel computer architectures is the main issue addressed. In vectorized tests on a single processor of the Cray C-90, the performance of Newton-OSOmin is superior to Newton-GMRES and a more traditional monotone AF/ADI method (MAF) for a variety of transonic Mach numbers and mesh sizes. Newton- GIVIRES is superior to MAF for some cases. The parallel performance of the Newton method is also found to be very good on multiple processors of the Cray C-90 and on the massively parallel thinking machine CM-5, where very fast execution rates (up to 9 Gflops) are found for large problems. 38 refs., 14 figs., 7 tabs.« less

Identification of seven novel loci associated with amino acid levels using single-variant and gene-based tests in 8545 Finnish men from the METSIM study.

PubMed

Teslovich, Tanya M; Kim, Daniel Seung; Yin, Xianyong; Stancáková, Alena; Jackson, Anne U; Wielscher, Matthias; Naj, Adam; Perry, John R B; Huyghe, Jeroen R; Stringham, Heather M; Davis, James P; Raulerson, Chelsea K; Welch, Ryan P; Fuchsberger, Christian; Locke, Adam E; Sim, Xueling; Chines, Peter S; Narisu, Narisu; Kangas, Antti J; Soininen, Pasi; Ala-Korpela, Mika; Gudnason, Vilmundur; Musani, Solomon K; Jarvelin, Marjo-Riitta; Schellenberg, Gerard D; Speliotes, Elizabeth K; Kuusisto, Johanna; Collins, Francis S; Boehnke, Michael; Laakso, Markku; Mohlke, Karen L

2018-05-01

Comprehensive metabolite profiling captures many highly heritable traits, including amino acid levels, which are potentially sensitive biomarkers for disease pathogenesis. To better understand the contribution of genetic variation to amino acid levels, we performed single variant and gene-based tests of association between nine serum amino acids (alanine, glutamine, glycine, histidine, isoleucine, leucine, phenylalanine, tyrosine, and valine) and 16.6 million genotyped and imputed variants in 8545 non-diabetic Finnish men from the METabolic Syndrome In Men (METSIM) study with replication in Northern Finland Birth Cohort (NFBC1966). We identified five novel loci associated with amino acid levels (P = < 5×10-8): LOC157273/PPP1R3B with glycine (rs9987289, P = 2.3×10-26); ZFHX3 (chr16:73326579, minor allele frequency (MAF) = 0.42%, P = 3.6×10-9), LIPC (rs10468017, P = 1.5×10-8), and WWOX (rs9937914, P = 3.8×10-8) with alanine; and TRIB1 with tyrosine (rs28601761, P = 8×10-9). Gene-based tests identified two novel genes harboring missense variants of MAF <1% that show aggregate association with amino acid levels: PYCR1 with glycine (Pgene = 1.5×10-6) and BCAT2 with valine (Pgene = 7.4×10-7); neither gene was implicated by single variant association tests. These findings are among the first applications of gene-based tests to identify new loci for amino acid levels. In addition to the seven novel gene associations, we identified five independent signals at established amino acid loci, including two rare variant signals at GLDC (rs138640017, MAF=0.95%, Pconditional = 5.8×10-40) with glycine levels and HAL (rs141635447, MAF = 0.46%, Pconditional = 9.4×10-11) with histidine levels. Examination of all single variant association results in our data revealed a strong inverse relationship between effect size and MAF (Ptrend<0.001). These novel signals provide further insight into the molecular mechanisms of amino acid metabolism and potentially, their perturbations in disease.

Estimated allele substitution effects underlying genomic evaluation models depend on the scaling of allele counts.

PubMed

Bouwman, Aniek C; Hayes, Ben J; Calus, Mario P L

2017-10-30

Genomic evaluation is used to predict direct genomic values (DGV) for selection candidates in breeding programs, but also to estimate allele substitution effects (ASE) of single nucleotide polymorphisms (SNPs). Scaling of allele counts influences the estimated ASE, because scaling of allele counts results in less shrinkage towards the mean for low minor allele frequency (MAF) variants. Scaling may become relevant for estimating ASE as more low MAF variants will be used in genomic evaluations. We show the impact of scaling on estimates of ASE using real data and a theoretical framework, and in terms of power, model fit and predictive performance. In a dairy cattle dataset with 630 K SNP genotypes, the correlation between DGV for stature from a random regression model using centered allele counts (RRc) and centered and scaled allele counts (RRcs) was 0.9988, whereas the overall correlation between ASE using RRc and RRcs was 0.27. The main difference in ASE between both methods was found for SNPs with a MAF lower than 0.01. Both the ratio (ASE from RRcs/ASE from RRc) and the regression coefficient (regression of ASE from RRcs on ASE from RRc) were much higher than 1 for low MAF SNPs. Derived equations showed that scenarios with a high heritability, a large number of individuals and a small number of variants have lower ratios between ASE from RRc and RRcs. We also investigated the optimal scaling parameter [from - 1 (RRcs) to 0 (RRc) in steps of 0.1] in the bovine stature dataset. We found that the log-likelihood was maximized with a scaling parameter of - 0.8, while the mean squared error of prediction was minimized with a scaling parameter of - 1, i.e., RRcs. Large differences in estimated ASE were observed for low MAF SNPs when allele counts were scaled or not scaled because there is less shrinkage towards the mean for scaled allele counts. We derived a theoretical framework that shows that the difference in ASE due to shrinkage is heavily influenced by the power of the data. Increasing the power results in smaller differences in ASE whether allele counts are scaled or not.

SU-D-204-05: Quantitative Comparison of a High Resolution Micro-Angiographic Fluoroscopic (MAF) Detector with a Standard Flat Panel Detector (FPD) Using the New Metric of Generalized Measured Relative Object Detectability (GM-ROD)

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

Russ, M; Ionita, C; Bednarek, D

Purpose: In endovascular image-guided neuro-interventions, visualization of fine detail is paramount. For example, the ability of the interventionist to visualize the stent struts depends heavily on the x-ray imaging detector performance. Methods: A study to examine the relative performance of the high resolution MAF-CMOS (pixel size 75µm, Nyquist frequency 6.6 cycles/mm) and a standard Flat Panel Detector (pixel size 194µm, Nyquist frequency 2.5 cycles/mm) detectors in imaging a neuro stent was done using the Generalized Measured Relative Object Detectability (GM-ROD) metric. Low quantum noise images of a deployed stent were obtained by averaging 95 frames obtained by both detectors withoutmore » changing other exposure or geometric parameters. The square of the Fourier transform of each image is taken and divided by the generalized normalized noise power spectrum to give an effective measured task-specific signal-to-noise ratio. This expression is then integrated from 0 to each of the detector’s Nyquist frequencies, and the GM-ROD value is determined by taking a ratio of the integrals for the MAF-CMOS to that of the FPD. The lower bound of integration can be varied to emphasize high frequencies in the detector comparisons. Results: The MAF-CMOS detector exhibits vastly superior performance over the FPD when integrating over all frequencies, yielding a GM-ROD value of 63.1. The lower bound of integration was stepped up in increments of 0.5 cycles/mm for higher frequency comparisons. As the lower bound increased, the GM-ROD value was augmented, reflecting the superior performance of the MAF-CMOS in the high frequency regime. Conclusion: GM-ROD is a versatile metric that can provide quantitative detector and task dependent comparisons that can be used as a basis for detector selection. Supported by NIH Grant: 2R01EB002873 and an equipment grant from Toshiba Medical Systems Corporation.« less

Interleukin 10 (IL10) proximal promoter polymorphisms beyond clinical response in classical Hodgkin lymphoma: Exploring the basis for the genetic control of the tumor microenvironment

PubMed Central

Minnicelli, Carolina; Segges, Priscilla; Stefanoff, Gustavo; Kristcevic, Flavia; Ezpeleta, Joaquin; Tapia, Elizabeth; Niedobitek, Gerald; Barros, Mário Henrique M.

2018-01-01

ABSTRACT Interleukin-10 (IL10) is an immune regulatory cytokine. Single nucleotide polymorphisms (SNPs) in IL10 promoter have been associated with prognosis in adult classical Hodgkin lymphoma (cHL). We analyzed IL10 SNPs −1082 and −592 in respect of therapy response, gene expression and tumor microenvironment (TME) composition in 98 pediatric patients with cHL. As confirmatory results, we found that −1082AA/AG; −592CC genotypes and ATA haplotype were associated with unfavourable prognosis: Progression-free survival (PFS) was shorter in −1082AA+AG (72.2%) than in GG patients (100%) (P = 0.024), and in −592AA (50%) and AC (74.2%) vs. CC patients (87.0%) (P = 0.009). In multivariate analysis, the −592CC genotype and the ATA haplotype retained prognostic impact (HR: 0.41, 95% CI 0.2–0.86; P = 0.018, and HR: 3.06 95% CI 1.03–9.12; P = 0.044, respectively). Our analysis further led to some new observations, namely: (1) Low IL10 mRNA expression was associated with −1082GG genotype (P = 0.014); (2) IL10 promoter polymorphisms influence TME composition;−1082GG/−592CC carriers showed low numbers of infiltrating cells expressing MAF transcription factor (20 vs. 78 and 49 vs. 108 cells/mm2, respectively; P< 0.05); while ATA haplotype (high expression) associated with high numbers of MAF+ cells (P = 0.005). Specifically, −1082GG patients exhibited low percentages of CD68+MAF+ (M2-like) intratumoral macrophages (15.04% vs. 47.26%, P = 0.017). Considering ours as an independent validation cohort, our results give support to the clinical importance of IL10 polymorphisms in the full spectrum of cHL, and advance the concept of genetic control of microenvironment composition as a basis for susceptibility and therapeutic response. PMID:29721365

Interleukin 10 (IL10) proximal promoter polymorphisms beyond clinical response in classical Hodgkin lymphoma: Exploring the basis for the genetic control of the tumor microenvironment.

PubMed

Vera-Lozada, Gabriela; Minnicelli, Carolina; Segges, Priscilla; Stefanoff, Gustavo; Kristcevic, Flavia; Ezpeleta, Joaquin; Tapia, Elizabeth; Niedobitek, Gerald; Barros, Mário Henrique M; Hassan, Rocio

2018-01-01

Interleukin-10 (IL10) is an immune regulatory cytokine. Single nucleotide polymorphisms (SNPs) in IL10 promoter have been associated with prognosis in adult classical Hodgkin lymphoma (cHL). We analyzed IL10 SNPs -1082 and -592 in respect of therapy response, gene expression and tumor microenvironment (TME) composition in 98 pediatric patients with cHL. As confirmatory results, we found that -1082AA/AG; -592CC genotypes and ATA haplotype were associated with unfavourable prognosis: Progression-free survival (PFS) was shorter in -1082AA+AG (72.2%) than in GG patients (100%) (P = 0.024), and in -592AA (50%) and AC (74.2%) vs. CC patients (87.0%) (P = 0.009). In multivariate analysis, the -592CC genotype and the ATA haplotype retained prognostic impact (HR: 0.41, 95% CI 0.2-0.86; P = 0.018, and HR: 3.06 95% CI 1.03-9.12; P = 0.044, respectively). Our analysis further led to some new observations, namely: (1) Low IL10 mRNA expression was associated with -1082GG genotype (P = 0.014); (2) IL10 promoter polymorphisms influence TME composition;-1082GG/-592CC carriers showed low numbers of infiltrating cells expressing MAF transcription factor (20 vs. 78 and 49 vs. 108 cells/mm 2 , respectively; P< 0.05); while ATA haplotype (high expression) associated with high numbers of MAF+ cells (P = 0.005). Specifically, -1082GG patients exhibited low percentages of CD68+MAF+ (M2-like) intratumoral macrophages (15.04% vs. 47.26%, P = 0.017). Considering ours as an independent validation cohort, our results give support to the clinical importance of IL10 polymorphisms in the full spectrum of cHL, and advance the concept of genetic control of microenvironment composition as a basis for susceptibility and therapeutic response.

Transmission of human mtDNA heteroplasmy in the Genome of the Netherlands families: support for a variable-size bottleneck

PubMed Central

Li, Mingkun; Rothwell, Rebecca; Vermaat, Martijn; Wachsmuth, Manja; Schröder, Roland; Laros, Jeroen F.J.; van Oven, Mannis; de Bakker, Paul I.W.; Bovenberg, Jasper A.; van Duijn, Cornelia M.; van Ommen, Gert-Jan B.; Slagboom, P. Eline; Swertz, Morris A.; Wijmenga, Cisca; Kayser, Manfred; Boomsma, Dorret I.; Zöllner, Sebastian; de Knijff, Peter; Stoneking, Mark

2016-01-01

Although previous studies have documented a bottleneck in the transmission of mtDNA genomes from mothers to offspring, several aspects remain unclear, including the size and nature of the bottleneck. Here, we analyze the dynamics of mtDNA heteroplasmy transmission in the Genomes of the Netherlands (GoNL) data, which consists of complete mtDNA genome sequences from 228 trios, eight dizygotic (DZ) twin quartets, and 10 monozygotic (MZ) twin quartets. Using a minor allele frequency (MAF) threshold of 2%, we identified 189 heteroplasmies in the trio mothers, of which 59% were transmitted to offspring, and 159 heteroplasmies in the trio offspring, of which 70% were inherited from the mothers. MZ twin pairs exhibited greater similarity in MAF at heteroplasmic sites than DZ twin pairs, suggesting that the heteroplasmy MAF in the oocyte is the major determinant of the heteroplasmy MAF in the offspring. We used a likelihood method to estimate the effective number of mtDNA genomes transmitted to offspring under different bottleneck models; a variable bottleneck size model provided the best fit to the data, with an estimated mean of nine individual mtDNA genomes transmitted. We also found evidence for negative selection during transmission against novel heteroplasmies (in which the minor allele has never been observed in polymorphism data). These novel heteroplasmies are enhanced for tRNA and rRNA genes, and mutations associated with mtDNA diseases frequently occur in these genes. Our results thus suggest that the female germ line is able to recognize and select against deleterious heteroplasmies. PMID:26916109

TIGER 2010 Boundaries

EPA Pesticide Factsheets

This EnviroAtlas web service supports research and online mapping activities related to EnviroAtlas (https://www.epa.gov/enviroatlas). This web service includes the State and County boundaries from the TIGER shapefiles compiled into a single national coverage for each layer. The TIGER/Line Files are shapefiles and related database files (.dbf) that are an extract of selected geographic and cartographic information from the U.S. Census Bureau's Master Address File / Topologically Integrated Geographic Encoding and Referencing (MAF/TIGER) Database (MTDB).

High-fat diet induced insulin resistance in pregnant rats through pancreatic pax6 signaling pathway.

PubMed

Wu, Hao; Liu, Yunyun; Wang, Hongkun; Xu, Xianming

2015-01-01

To explore the changes in pancreas islet function of pregnant rats after consumption of high-fat diet and the underlying mechanism. Thirty pregnant Wistar rats were randomly divided into two groups: high-fat diet group and normal control group. Twenty days after gestation, fasting blood glucose concentration (FBG) and fasting serum insulin concentration (FINS) were measured. Then, oral glucose tolerance test (OGTT) and insulin release test (IRT) were performed. Finally, all the rats were sacrificed and pancreas were harvested. Insulin sensitivity index (ISI) and insulin resistance index (HOMA-IR) were calculated according to FBG and FINS. RT-PCR and Real-time PCR were performed to study the expression of paired box 6 transcription factor (Pax6) and its target genes in pancreatic tissues. The body weight was significantly increased in the high-fat diet group compared with that of normal control rats (P<0.05). The fasting plasma glucose of rats in high-fat diet group was significantly increased compared with that of normal control rats (6.62 mmol/L vs. 4.96 mmol/L, P<0.05), however there was no significant difference in fasting serum insulin concentration between the two groups. OGTT and IRT were abnormal in the high-fat diet group. The high-fat diet rats were more prone to impaired glucose tolerance and insulin resistance. The level of the expression of Pax6 transcription factor and its target genes in pancreas, such as pancreatic and duodenal homeobox factor-1 (Pdx1), v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA) and glucose transporter 2 (Glut2) were decreased significantly compared with those of normal control group. High-fat diet feeding during pregnancy may induce insulin resistance in maternal rats by inhibiting pancreatic Pax6 and its target genes expression.

ARABIDOPSIS TRITHORAX-RELATED3/SET DOMAIN GROUP2 is Required for the Winter-Annual Habit of Arabidopsis thaliana

PubMed Central

Yun, Jae-Young; Tamada, Yosuke; Kang, Ye Eun; Amasino, Richard M.

2012-01-01

The winter-annual habit of Arabidopsis thaliana requires active alleles of FLOWERING LOCUS C (FLC), which encodes a potent flowering repressor, and FRIGIDA (FRI), an activator of FLC. FLC activation by FRI is accompanied by an increase in specific histone modifications, such as tri-methylation of histone H3 at lysine 4 (H3K4me3), and requires three H3K4 methyltransferases, the Drosophila Trithorax-class ARABIDOPSIS TRITHORAX1 (ATX1) and ATX2, and yeast Set1-class ATX-RELATED7/SET DOMAIN GROUP25 (ATXR7/SDG25). However, lesions in all of these genes failed to suppress the enhanced FLC expression caused by FRI completely, suggesting that another H3K4 methyltransferase may participate in the FLC activation. Here, we show that ATXR3/SDG2, which is a member of a novel class of H3K4 methyltransferases, also contributes to FLC activation. An ATXR3 lesion suppressed the enhanced FLC expression and delayed flowering caused by an active allele of FRI in non-vernalized plants. The decrease in FLC expression in atxr3 mutants was accompanied by reduced H3K4me3 levels at FLC chromatin. We also found that the rapid flowering of atxr3 was epistatic to that of atxr7, suggesting that ATXR3 functions in FLC activation in sequence with ATXR7. Our results indicate that the novel-class H3K4 methyltransferase, ATXR3, is a transcriptional activator that plays a role in the FLC activation and establishing the winter-annual habit. In addition, ATXR3 also contributes to the activation of other FLC clade members, such as FLOWERING LOCUS M/MADS AFFECTING FLOWERING1 (FLM/MAF1) and MAF5, at least partially explaining the ATXR3 function in delayed flowering caused by non-inductive photoperiods. PMID:22378382

TIGER 2010 Boundaries

EPA Pesticide Factsheets

This EnviroAtlas web service supports research and online mapping activities related to EnviroAtlas (https://www.epa.gov/enviroatlas). This web service includes the State, County, and Census Block Groups boundaries from the TIGER shapefiles compiled into a single national coverage for each layer. The TIGER/Line Files are shapefiles and related database files (.dbf) that are an extract of selected geographic and cartographic information from the U.S. Census Bureau's Master Address File / Topologically Integrated Geographic Encoding and Referencing (MAF/TIGER) Database (MTDB).

Future water demand in California under a broad range of land use scenarios

NASA Astrophysics Data System (ADS)

Wilson, T. S.; Sleeter, B. M.; Cameron, D. R.

2016-12-01

California continues to be gripped by the most severe drought on record. Most general circulation models agree the state will continue to warm this century and research suggests persistent, long-term droughts may become the new normal, exacerbating an already uncertain water supply future. Population increases and agricultural intensification will likely stress existing, highly variable inter-annual water supplies even further in coming decades. Using the Land Use and Carbon Scenario Simulator (LUCAS) model, we explore a wide range of potential water demand futures from 2012 to 2062 based on 8 alternative, spatially-explicit (1 km) land use scenarios and land-use related water demand. Scenarios include low and high rates for urbanization, agricultural expansion, and agricultural contraction as well as lowest and highest rates for the combined suite of anthropogenic land uses. Land change values were sampled from county-level historical (1991-2012) land change data and county-level average water use data for urban areas (i.e. municipal and industrial) and annual and perennial cropland. We modeled 100 Monte Carlo simulations for each scenario to better characterize and capture model uncertainty and a range of potential future outcomes. Results show water demand in Mediterranean California was lowest in the low anthropogenic change scenario, dropping an average 2.7 million acre feet (MAF) by 2062. The highest water demand was seen in the high urbanization (+3.2 MAF), high agricultural expansion (+4.1 MAF), and the high anthropogenic (+4.3 MAF) scenarios. Results provide water managers and policy makers with information on diverging land use and water use futures, based on observed land change and water use trends, helping better inform land and resource management decisions.

Along-the-net reconstruction of hydropower potential with consideration of anthropic alterations

NASA Astrophysics Data System (ADS)

Masoero, A.; Claps, P.; Gallo, E.; Ganora, D.; Laio, F.

2014-09-01

Even in regions with mature hydropower development, requirements for stable renewable power sources suggest revision of plans of exploitation of water resources, while taking care of the environmental regulations. Mean Annual Flow (MAF) is a key parameter when trying to represent water availability for hydropower purposes. MAF is usually determined in ungauged basins by means of regional statistical analysis. For this study a regional estimation method consistent along-the-river network has been developed for MAF estimation; the method uses a multi-regressive approach based on geomorphoclimatic descriptors, and it is applied on 100 gauged basins located in NW Italy. The method has been designed to keep the estimates of mean annual flow congruent at the confluences, by considering only raster-summable explanatory variables. Also, the influence of human alterations in the regional analysis of MAF has been studied: impact due to the presence of existing hydropower plants has been taken into account, restoring the "natural" value of runoff through analytical corrections. To exemplify the representation of the assessment of residual hydropower potential, the model has been applied extensively to two specific mountain watersheds by mapping the estimated mean flow for the basins draining into each pixel of a the DEM-derived river network. Spatial algorithms were developed using the OpenSource Software GRASS GIS and PostgreSQL/PostGIS. Spatial representation of the hydropower potential was obtained using different mean flow vs hydraulic-head relations for each pixel. Final potential indices have been represented and mapped through the Google Earth platform, providing a complete and interactive picture of the available potential, useful for planning and regulation purposes.

Effects of flavonoids from Martynia annua and Tephrosia purpurea on cutaneous wound healing

PubMed Central

Lodhi, Santram; Jain, Avijeet; Jain, Alok Pal; Pawar, Rajesh Singh; Singhai, Abhay Kumar

2016-01-01

Objective: Martynia annua L. (M. annua), (Martyniaccae) has been traditionally used in the treatment of epilepsy, sore throat and inflammatory disorders. The leaf paste is used topically on Tuberculosis of the lymphatic glands and wounds of domestic animals. Tephrosia purpurea (T. purpurea), (Fabaceae) has been used traditionally as a remedy for asthma, gonorrhea, rheumatism and ulcers. This study aimed to evaluate the potential wound healing effects of different fractions ofethanol extract of M. annua leaves and aerial parts of T. purpurea. Materials and Methods: Methanol fraction of M. annua (MAF-C) and ethyl acetate fraction of T. purpurea (TPF-A) were evaluated for healing potential in dead-space and burn wound models. An ointment (5% w/w) of MAF-C and TPF-A, pongamol (0.2 and 0.5% w/w) and luteolin (0.2 and 0.5% w/w) was applied topically twice a day. The effects were compared with Povidone Iodine ointment with respect to protein, collagen content, enzymatic assay and histopathological finding of granuloma tissues. Results: Ethanol extracts of M. annua and T. purpureawere exhibited total flavonoid contents of 126.2 ± 4.69 and 171.6 ± 6.38 mg (quercetin equivalent), respectively. HPLC fingerprinting confirmed the presence of luteolin in M. annua and quercetin in T. purpurea. TPF-A and MAF-C ointments (5% w/w) significantly increases the hydroxyproline and protein contents. Luteolin and pongamol ointments were also found to be effective in both wound models. Conclusion: Our findings suggested that 5% w/w ointment of TPF-A and MAF-C fractions were more effective than isolated flavonoids in wound healing which may be due to synergistic interactions between the flavonoids and other constituents. PMID:27761428

Common CYP2D6 polymorphisms affecting alternative splicing and transcription: long-range haplotypes with two regulatory variants modulate CYP2D6 activity

PubMed Central

Wang, Danxin; Poi, Ming J.; Sun, Xiaochun; Gaedigk, Andrea; Leeder, J. Steven; Sadee, Wolfgang

2014-01-01

Cytochrome P450 2D6 (CYP2D6) is involved in the metabolism of 25% of clinically used drugs. Genetic polymorphisms cause substantial variation in CYP2D6 activity and serve as biomarkers guiding drug therapy. However, genotype–phenotype relationships remain ambiguous except for poor metabolizers carrying null alleles, suggesting the presence of yet unknown genetic variants. Searching for regulatory CYP2D6 polymorphisms, we find that a SNP defining the CYP2D6*2 allele, rs16947 [R296C, 17–60% minor allele frequency (MAF)], previously thought to convey normal activity, alters exon 6 splicing, thereby reducing CYP2D6 expression at least 2-fold. In addition, two completely linked SNPs (rs5758550/rs133333, MAF 13–42%) increase CYP2D6 transcription more than 2-fold, located in a distant downstream enhancer region (>100 kb) that interacts with the CYP2D6 promoter. In high linkage disequilibrium (LD) with each other, rs16947 and the enhancer SNPs form haplotypes that affect CYP2D6 enzyme activity in vivo. In a pediatric cohort of 164 individuals, rs16947 alone (minor haplotype frequency 28%) was associated with reduced CYP2D6 metabolic activity (measured as dextromethorphan/metabolite ratios), whereas rs5758550/rs133333 alone (frequency 3%) resulted in increased CYP2D6 activity, while haplotypes containing both rs16947 and rs5758550/rs133333 were similar to the wild-type. Other alleles used in biomarker panels carrying these variants such as CYP2D6*41 require re-evaluation of independent effects on CYP2D6 activity. The occurrence of two regulatory variants of high frequency and in high LD, residing on a long haplotype, highlights the importance of gene architecture, likely shaped by evolutionary selection pressures, in determining activity of encoded proteins. PMID:23985325

Psychometric properties of the Multidimensional Assessment of Fatigue scale in traumatic brain injury: an NIDRR Traumatic Brain Injury Model Systems study.

PubMed

Lequerica, Anthony; Bushnik, Tamara; Wright, Jerry; Kolakowsky-Hayner, Stephanie A; Hammond, Flora M; Dijkers, Marcel P; Cantor, Joshua

2012-01-01

To investigate the psychometric properties of the Multidimensional Assessment of Fatigue (MAF) scale in a traumatic brain injury (TBI) sample. Prospective survey study. Community. One hundred sixty-seven individuals with TBI admitted for inpatient rehabilitation, enrolled into the TBI Model Systems national database, and followed up at either the first or second year postinjury. Not applicable. Multidimensional Assessment of Fatigue. The initial analysis, using items 1 to 14, which are based on a 10-point rating scale, found that only 1 item ("walking") misfit the overall construct of fatigue in this TBI population. However, this 10-point rating scale was found to have disordered thresholds. When ratings were collapsed into 4 response categories, all MAF items used to calculate the Global Fatigue Index formed a unidimensional scale. Findings generally support the unidimensionality of the MAF when used in a TBI population but call into question the use of a 10-point rating scale for items 1 to 14. Further study is needed to investigate the use of a 4-category rating scale across all items and the fit of the "walking" item for a measure of fatigue among individuals with TBI.

Mediation of glucolipotoxicity in INS-1 rat insulinoma cells by small heterodimer partner interacting leucine zipper protein (SMILE).

PubMed

Lee, Kyeong-Min; Seo, Ye Jin; Kim, Mi-Kyung; Seo, Hyun-Ae; Jeong, Ji-Yun; Choi, Hueng-Sik; Lee, In-Kyu; Park, Keun-Gyu

2012-03-23

Sustained elevations of glucose and free fatty acid concentration have deleterious effects on pancreatic beta cell function. One of the hallmarks of such glucolipotoxicity is a reduction in insulin gene expression, resulting from decreased insulin promoter activity. Sterol regulatory element binding protein-1c (SREBP-1c), a lipogenic transcription factor, is related to the development of beta cell dysfunction caused by elevated concentrations of glucose and free fatty acid. Small heterodimer partner (SHP) interacting leucine zipper protein (SMILE), also known as Zhangfei, is a novel protein which interacts with SHP that mediates glucotoxicity in INS-1 rat insulinoma cells. Treatment of INS-1 cells with high concentrations of glucose and palmitate increased SREBP-1c and SMILE expression, and decreased insulin gene expression. Adenovirus-mediated overexpression of SREBP-1c in INS-1 cells induced SMILE expression. Moreover, adenovirus-mediated overexpression of SMILE (Ad-SMILE) in INS-1 cells impaired glucose-stimulated insulin secretion as well as insulin gene expression. Ad-SMILE overexpression also inhibited the expression of beta-cell enriched transcription factors including pancreatic duodenal homeobox factor-1, beta cell E box transactivator 2 and RIPE3b1/MafA, in INS-1 cells. Finally, in COS-1 cells, expression of SMILE inhibited the insulin promoter activity induced by these same beta-cell enriched transcription factors. These results collectively suggest that SMILE plays an important role in the development of beta cell dysfunction induced by glucolipotoxicity. Copyright © 2012 Elsevier Inc. All rights reserved.

Mercury Atomic Frequency Standards for Space Based Navigation and Timekeeping

NASA Technical Reports Server (NTRS)

Tjoelker, R. L.; Burt, E. A.; Chung, S.; Hamell, R. L.; Prestage, J. D.; Tucker, B.; Cash, P.; Lutwak, R.

2012-01-01

A low power Mercury Atomic Frequency Standard (MAFS) has been developed and demonstrated on the path towards future space clock applications. A self contained mercury ion breadboard clock: emulating flight clock interfaces, steering a USO local oscillator, and consuming approx 40 Watts has been operating at JPL for more than a year. This complete, modular ion clock instrument demonstrates that key GNSS size, weight, and power (SWaP) requirements can be achieved while still maintaining short and long term performance demonstrated in previous ground ion clocks. The MAFS breadboard serves as a flexible platform for optimizing further space clock development and guides engineering model design trades towards fabrication of an ion clock for space flight.

Resequencing and Analysis of Variation in the TCF7L2 Gene in African Americans Suggests That SNP rs7903146 Is the Causal Diabetes Susceptibility Variant

PubMed Central

Palmer, Nicholette D.; Hester, Jessica M.; An, S. Sandy; Adeyemo, Adebowale; Rotimi, Charles; Langefeld, Carl D.; Freedman, Barry I.; Ng, Maggie C.Y.; Bowden, Donald W.

2011-01-01

OBJECTIVE Variation in the transcription factor 7-like 2 (TCF7L2) locus is associated with type 2 diabetes across multiple ethnicities. The aim of this study was to elucidate which variant in TCF7L2 confers diabetes susceptibility in African Americans. RESEARCH DESIGN AND METHODS Through the evaluation of tagging single nucleotide polymorphisms (SNPs), type 2 diabetes susceptibility was limited to a 4.3-kb interval, which contains the YRI (African) linkage disequilibrium (LD) block containing rs7903146. To better define the relationship between type 2 diabetes risk and genetic variation we resequenced this 4.3-kb region in 96 African American DNAs. Thirty-three novel and 13 known SNPs were identified: 20 with minor allele frequencies (MAF) >0.05 and 12 with MAF >0.10. These polymorphisms and the previously identified DG10S478 microsatellite were evaluated in African American type 2 diabetic cases (n = 1,033) and controls (n = 1,106). RESULTS Variants identified from direct sequencing and databases were genotyped or imputed. Fifteen SNPs showed association with type 2 diabetes (P < 0.05) with rs7903146 being the most significant (P = 6.32 × 10−6). Results of imputation, haplotype, and conditional analysis of SNPs were consistent with rs7903146 being the trait-defining SNP. Analysis of the DG10S478 microsatellite, which is outside the 4.3-kb LD block, revealed consistent association of risk allele 8 with type 2 diabetes (odds ratio [OR] = 1.33; P = 0.022) as reported in European populations; however, allele 16 (MAF = 0.016 cases and 0.032 controls) was strongly associated with reduced risk (OR = 0.39; P = 5.02 × 10−5) in contrast with previous studies. CONCLUSIONS In African Americans, these observations suggest that rs7903146 is the trait-defining polymorphism associated with type 2 diabetes risk. Collectively, these results support ethnic differences in type 2 diabetes associations. PMID:20980453

Copper exposure induces oxidative injury, disturbs the antioxidant system and changes the Nrf2/ARE (CuZnSOD) signaling in the fish brain: protective effects of myo-inositol.

PubMed

Jiang, Wei-Dan; Liu, Yang; Hu, Kai; Jiang, Jun; Li, Shu-Hong; Feng, Lin; Zhou, Xiao-Qiu

2014-10-01

The brain is the center of the nervous system in all vertebrates, and homeostasis of the brain is crucial for fish survival. Copper (Cu) is essential for normal cellular processes in most eukaryotic organisms but is toxic in excess. Although Cu is indicated as a potent neurotoxicant, information regarding its threat to fish brain and underlying mechanisms is still scarce. In accordance, the objective of this study was to assess the effects and the potential mechanism of Cu toxicity by evaluating brain oxidative status, the enzymatic and mRNA levels of antioxidant genes, as well as the Nrf2/ARE signaling in the brain of fish after Cu exposure. The protective effects of myo-inositol (MI) against subsequent Cu exposure were also investigated. The results indicate that induction of oxidative stress by Cu is shown by increases in brain ROS production, lipid peroxidation and protein oxidation, which are accompanied by depletions of antioxidants, including total superoxide dismutase (T-SOD), CuZnSOD, glutathione-S-transferase (GST) and glutathione reductase (GR) activities and glutathione (GSH) content. Cu exposure increased the catalase (CAT) and glutathione peroxidase (GPx) activities. Further molecular results showed that Cu exposure up-regulated CuZnSOD, GPx1a and GR mRNA levels, suggesting an adaptive mechanism against stress. Moreover, Cu exposure increased fish brain Nrf2 nuclear accumulation and increased its ability of binding to ARE (CuZnSOD), which supported the increased CuZnSOD mRNA levels. In addition, Cu exposure caused increases of the expression of the Nrf2, Maf G1 (rather than Maf G2 gene) and PKCd genes, suggesting that de novo synthesis of those factors is required for the protracted induction of such antioxidant genes. However, the modulation of Keap1a (rather than Keap1b) of fish brain under Cu exposure might be used to turn off of the signaling cascade and avoid harmful effects. Interestingly, pre-treatment of fish with MI prevented the fish brain from Cu-induced oxidative damages mainly by increasing the GSH content and CuZnSOD and GST activities. Summarily, this study indicates that although Cu stimulates adaptive increases in the expression of some antioxidant enzyme genes through Nrf2/ARE signaling, it also induces oxidation and the depletion of most of antioxidant enzyme activities and GSH content due to the increase of ROS production, and MI protects the fish brain against Cu toxicity. Copyright © 2014 Elsevier B.V. All rights reserved.

Limiting glioma development by photodynamic therapy-generated macrophage vaccine and allo-stimulation: an in vivo histological study in rats

NASA Astrophysics Data System (ADS)

Madsen, Steen J.; Christie, Catherine; Huynh, Khoi; Peng, Qian; Uzal, Francisco A.; Krasieva, Tatiana B.; Hirschberg, Henry

2018-02-01

Immunotherapy of brain tumors involves the stimulation of an antitumor immune response. This type of therapy can be targeted specifically to tumor cells thus sparing surrounding normal brain. Due to the presence of the blood-brain barrier, the brain is relatively isolated from the systemic circulation and, as such, the initiation of significant immune responses is more limited than other types of cancers. The purpose of this study was to show that the efficacy of tumor primed antigen presenting macrophage (MaF98) vaccines can be increased by: (1) photodynamic therapy (PDT) of the priming tumor cells and (2) intracranial injection of allogeneic glioma cells directly into the tumor site. Experiments were conducted in an in vivo brain tumor development model using Fischer rats and F98 (syngeneic) and BT4C (allogeneic) glioma cells. The results showed that immunization with Ma (acting as antigen-presenting cells), primed with PDT-treated tumor cells (MaF98), significantly slowed but did not prevent the growth of F98-induced tumors in the brain. Complete suppression of tumor development was obtained via MaF98 inoculation combined with direct intracranial injection of allogeneic glioma cells. No deleterious effects were noted in any of the animals during the 14-day observation period.

Auditory Masking Effects on Speech Fluency in Apraxia of Speech and Aphasia: Comparison to Altered Auditory Feedback

PubMed Central

Haley, Katarina L.

2015-01-01

Purpose To study the effects of masked auditory feedback (MAF) on speech fluency in adults with aphasia and/or apraxia of speech (APH/AOS). We hypothesized that adults with AOS would increase speech fluency when speaking with noise. Altered auditory feedback (AAF; i.e., delayed/frequency-shifted feedback) was included as a control condition not expected to improve speech fluency. Method Ten participants with APH/AOS and 10 neurologically healthy (NH) participants were studied under both feedback conditions. To allow examination of individual responses, we used an ABACA design. Effects were examined on syllable rate, disfluency duration, and vocal intensity. Results Seven of 10 APH/AOS participants increased fluency with masking by increasing rate, decreasing disfluency duration, or both. In contrast, none of the NH participants increased speaking rate with MAF. In the AAF condition, only 1 APH/AOS participant increased fluency. Four APH/AOS participants and 8 NH participants slowed their rate with AAF. Conclusions Speaking with MAF appears to increase fluency in a subset of individuals with APH/AOS, indicating that overreliance on auditory feedback monitoring may contribute to their disorder presentation. The distinction between responders and nonresponders was not linked to AOS diagnosis, so additional work is needed to develop hypotheses for candidacy and underlying control mechanisms. PMID:26363508

Association of TNF-α rs1799964 and IL-1β rs16944 polymorphisms with multiple system atrophy in Chinese Han population.

PubMed

Zhou, Xin; Wang, Chunrong; Chen, Zhao; Peng, Yun; Peng, Huirong; Hou, Xuan; Ye, Wei; Qiu, Rong; Xia, Kun; Tang, Beisha; Jiang, Hong

2018-01-07

Recent evidence suggested that several single nucleotide polymorphisms (SNPs) of inflammation-related genes (TNF-α rs1799964, IL-1α rs1800587, IL-1β rs16944, IL-8 rs4073, ICAM-1 rs5498) were associated with multiple system atrophy (MSA). Herein, we conducted this case-control study to evaluate the possible correlation between the five SNPs related to inflammation and MSA in Chinese Han population. We recruited 154 sporadic patients with MSA and 223 health controls in this study. All subjects were genotyped for the five SNPs using polymerase chain reaction amplification and Sanger sequencing. TNF-α rs1799964, genotype distribution and minor allele frequency (MAF) showed significant differences between patients and controls, which might illustrate the minor allele C may increase the risk for MSA (genotype, P = 0.006, OR = 1.245, 95% CI = [1.066-1.455]; allele, P = 0.001, OR = 1.887, 95% CI = [1.303-2.733]). For rs16944, patients carrying AA genotype showed a nearly 5-year early age at onset (AAO) than GG genotype (50.52 ± 7.45 years vs. 54.90 ± 7.21 years, P = 0.037). No differences were found in genotype distribution and MAF of the five SNPs between patients with MSA with predominant cerebellar ataxia (MSA-C) and with predominant Parkinsonism (MSA-P). Our study suggests that rs1799964 of TNF-α may act as a risk factor for MSA and the IL-1β rs16944 might be a genetic factor that modifies the AAO in MSA. Moreover, the exact mechanism of neuroinflammatory response in MSA deserves further exploration.

Genetic variation underlying renal uric acid excretion in Hispanic children: the Viva La Familia Study.

PubMed

Chittoor, Geetha; Haack, Karin; Mehta, Nitesh R; Laston, Sandra; Cole, Shelley A; Comuzzie, Anthony G; Butte, Nancy F; Voruganti, V Saroja

2017-01-17

Reduced renal excretion of uric acid plays a significant role in the development of hyperuricemia and gout in adults. Hyperuricemia has been associated with chronic kidney disease and cardiovascular disease in children and adults. There are limited genome-wide association studies associating genetic polymorphisms with renal urate excretion measures. Therefore, we investigated the genetic factors that influence the excretion of uric acid and related indices in 768 Hispanic children of the Viva La Familia Study. We performed a genome-wide association analysis for 24-h urinary excretion measures such as urinary uric acid/urinary creatinine ratio, uric acid clearance, fractional excretion of uric acid, and glomerular load of uric acid in SOLAR, while accounting for non-independence among family members. All renal urate excretion measures were significantly heritable (p <2 × 10 -6 ) and ranged from 0.41 to 0.74. Empirical threshold for genome-wide significance was set at p <1 × 10 -7 . We observed a strong association (p < 8 × 10 -8 ) of uric acid clearance with a single nucleotide polymorphism (SNP) in zinc finger protein 446 (ZNF446) (rs2033711 (A/G), MAF: 0.30). The minor allele (G) was associated with increased uric acid clearance. Also, we found suggestive associations of uric acid clearance with SNPs in ZNF324, ZNF584, and ZNF132 (in a 72 kb region of 19q13; p <1 × 10 -6 , MAFs: 0.28-0.31). For the first time, we showed the importance of 19q13 region in the regulation of renal urate excretion in Hispanic children. Our findings indicate differences in inherent genetic architecture and shared environmental risk factors between our cohort and other pediatric and adult populations.

Exome Array Analysis of Nuclear Lens Opacity.

PubMed

Loomis, Stephanie J; Klein, Alison P; Lee, Kristine E; Chen, Fei; Bomotti, Samantha; Truitt, Barbara; Iyengar, Sudha K; Klein, Ronald; Klein, Barbara E K; Duggal, Priya

2018-06-01

Nuclear cataract is the most common subtype of age-related cataract, the leading cause of blindness worldwide. It results from advanced nuclear sclerosis, or opacity in the center of the optic lens, and is affected by both genetic and environmental risk factors, including smoking. We sought to understand the genetic factors associated with nuclear sclerosis through interrogation of rare and low frequency coding variants using exome array data. We analyzed Illumina Human Exome Array data for 1,488 participants of European ancestry in the Beaver Dam Eye Study who were without cataract surgery for association with nuclear sclerosis grade, controlling for age and sex. We performed single-variant regression analysis for 32,138 variants with minor allele frequency (MAF) ≥0.003. In addition, gene-based analysis of 11,844 genes containing at least two variants with MAF < 0.05 was performed using a gene-based unified burden and non-burden sequence kernel association test (SKAT-O). Additionally, both single-variant and gene-based analyses were analyzed stratified by smoking status. No single-variant test was statistically significant after Bonferroni correction (p < 1.6 × 10 -6 ; top single nucleotide polymorphism (SNP): rs144458991, p = 2.83 × 10 -5 ). Gene-based tests were suggestively associated with the gene RNF149 overall (p = 8.29 × 10 -6 ) and among never smokers (N = 790, p = 2.67 × 10 -6 ). This study did not find a significant genetic association with nuclear sclerosis, the possible association with the RNF149 gene highlights a potential candidate gene for future studies that aim to understand the genetic architecture of nuclear sclerosis.

Impact of the Mycobaterium africanum West Africa 2 Lineage on TB Diagnostics in West Africa: Decreased Sensitivity of Rapid Identification Tests in The Gambia.

PubMed

Ofori-Anyinam, Boatema; Kanuteh, Fatoumatta; Agbla, Schadrac C; Adetifa, Ifedayo; Okoi, Catherine; Dolganov, Gregory; Schoolnik, Gary; Secka, Ousman; Antonio, Martin; de Jong, Bouke C; Gehre, Florian

2016-07-01

MPT64 rapid speciation tests are increasingly being used in diagnosis of tuberculosis (TB). Mycobacterium africanum West Africa 2 (Maf 2) remains an important cause of TB in West Africa and causes one third of disease in The Gambia. Since the introduction of MPT64 antigen tests, a higher than expected rate of suspected non-tuberculous mycobacteria (NTM) was seen among AFB smear positive TB suspects, which led us to prospectively assess sensitivity of the MPT64 antigen test in our setting. We compared the abundance of mRNA encoded by the mpt64 gene in sputa of patients with untreated pulmonary TB caused by Maf 2 and Mycobacterium tuberculosis (Mtb). Subsequently, prospectively collected sputum samples from presumptive TB patients were inoculated in the BACTEC MGIT 960 System. One hundred and seventy-three acid fast bacilli (AFB)-positive and blood agar negative MGIT cultures were included in the study. Cultures were tested on the day of MGIT positivity with the BD MGIT TBc Identification Test. A random set of positives and all negatives were additionally tested with the SD Bioline Ag MPT64 Rapid. MPT64 negative cultures were further incubated at 37°C and retested until positive. Bacteria were spoligotyped and assigned to different lineages. Maf 2 isolates were 2.52-fold less likely to produce a positive test result and sensitivity ranged from 78.4% to 84.3% at the beginning and end of the recommended 10 day testing window, respectively. There was no significant difference between the tests. We further showed that the decreased rapid test sensitivity was attributable to variations in mycobacterial growth behavior and the smear grades of the patient. In areas where Maf 2 is endemic MPT64 tests should be cautiously used and MPT64 negative results confirmed by a second technique, such as nucleic acid amplification tests, to avoid their misclassification as NTMs.

Lifestyle habits and fatigue among people with systemic lupus erythematosus and matched population controls.

PubMed

Pettersson, S; Boström, C; Eriksson, K; Svenungsson, E; Gunnarsson, I; Henriksson, E Welin

2015-08-01

The objective of this paper is to identify clusters of fatigue in patients with systemic lupus erythematosus (SLE) and matched controls, and to analyze these clusters with respect to lifestyle habits, health-related quality of life (HRQoL), anxiety and depression. Patients with SLE (n = 305) and age- and gender-matched population controls (n = 311) were included. Three measurements of fatigue (Fatigue Severity Scale (FSS), Vitality (VT, from SF-36) and Multidimensional Assessment of Fatigue scale (MAF) and hierarchic cluster analysis were used to define clusters with different degrees of fatigue. Lifestyle habits were investigated through questionnaires. HRQoL was assessed with the SF-36 and anxiety/depression with the Hospital Anxiety and Depression Scale. Three clusters, denominated "High," "Intermediate" and "Low" fatigue clusters, were identified. The "High" contained 80% patients, and 20% controls (median; VT 25, FSS 5.8, MAF 37.4). These had the most symptoms of depression (51%) and anxiety (34%), lowest HRQoL (p < 0.001) and they exercised least frequently. The "Intermediate" (48% patients and 52% controls) (median; VT 55, FSS 4.1, MAF 23.5) had similarities with the "Low" regarding sleep/rest whereas social status and smoking were closer to the "High." The"Low" contained 22% patients and 78% controls (median; VT 80, FSS 2.3, MAF 10.9). They had the highest perceived HRQoL (p < 0.001), least symptoms of anxiety (10%), no depression, smoked least (13%) and reported the highest percentage (24%) of exercising ≥ 3 times/week. Fatigue is common, but not a general feature of SLE. It is associated with depression, anxiety, low HRQoL and less physical exercise. Patients with SLE and population controls with a healthy lifestyle reported lower levels of fatigue. Whether lifestyle changes can reduce fatigue, which is a major problem for a majority of SLE patients, needs to be further explored. © The Author(s) 2015.

Spatio-Temporal Distribution of Mycobacterium tuberculosis Complex Strains in Ghana.

PubMed

Yeboah-Manu, Dorothy; Asare, P; Asante-Poku, A; Otchere, I D; Osei-Wusu, S; Danso, E; Forson, A; Koram, K A; Gagneux, Sebastien

2016-01-01

There is a perception that genomic differences in the species/lineages of the nine species making the Mycobacterium tuberculosis complex (MTBC) may affect the efficacy of distinct control tools in certain geographical areas. We therefore analyzed the prevalence and spatial distribution of MTBC species and lineages among isolates from pulmonary TB cases over an 8-year period, 2007-2014. Mycobacterial species isolated by culture from consecutively recruited pulmonary tuberculosis patients presenting at selected district/sub-district health facilities were confirmed as MTBC by IS6110 and rpoß PCR and further assigned lineages and sub lineages by spoligotyping and large sequence polymorphism PCR (RDs 4, 9, 12, 702, 711) assays. Patient characteristics, residency, and risks were obtained with a structured questionnaire. We used SaTScan and ArcMap analyses to identify significantly clustered MTBC lineages within selected districts and spatial display, respectively. Among 2,551 isolates, 2,019 (79.1%), 516 (20.2%) and 16 (0.6%) were identified as M. tuberculosis sensu stricto (MTBss), M. africanum (Maf), 15 M. bovis and 1 M. caprae, respectively. The proportions of MTBss and Maf were fairly constant within the study period. Maf spoligotypes were dominated by Spoligotype International Type (SIT) 331 (25.42%), SIT 326 (15.25%) and SIT 181 (14.12%). We found M. bovis to be significantly higher in Northern Ghana (1.9% of 212) than Southern Ghana (0.5% of 2339) (p = 0.020). Using the purely spatial and space-time analysis, seven significant MTBC lineage clusters (p< 0.05) were identified. Notable among the clusters were Ghana and Cameroon sub-lineages found to be associated with north and south, respectively. This study demonstrated that overall, 79.1% of TB in Ghana is caused by MTBss and 20% by M. africanum. Unlike some West African Countries, we did not observe a decline of Maf prevalence in Ghana.

Application of the diffusive gradients in thin films technique for available potassium measurement in agricultural soils: effects of competing cations on potassium uptake by the resin gel.

PubMed

Zhang, Yulin; Mason, Sean; McNeill, Ann; McLaughlin, Michael J

2014-09-09

The utilization of Amberlite (IRP-69 ion-exchange resin, 100-500 wet mesh) as the binding phase in the diffusive gradients in thin films (DGT) technique has shown potential to improve the assessment of plant-available K in soils. The binding phase has recently been optimized by using a mixed Amberlite and ferrihydrite (MAF) gel which results in linear K uptake over extended deployment periods and in solutions with higher K concentrations. As restriction of K uptake by Ca on the Amberlite based resin gel has been previously proposed, potential competing effects of Ca(2+), Mg(2+) and NH(4+) on K uptake by the MAF gel were investigated. These cations had no effect on K elution efficiency which was 85%. However, K uptake by the MAF gel was restricted in the presence of competing cations in solution. Consequently, the diffusion coefficient of K decreased in the presence of cations compared to previous studies but was stable at 1.12×10(-5)cm(2)s(-1) at 25°C regardless of cation concentrations. Uptake of K by the DGT device was affected by the presence of excessive Ca in more than 30% of twenty typical Australian agricultural soils. However, this problem could be circumvented by using a shorter deployment time than the normal 24 h. Moderate correlation of concentrations of K extracted by DGT with Colwell K (extracted by NaHCO(3), R(2)=0.69) and NH4OAc K (R(2)=0.61) indicates that DGT measures a different pool of K in soils than that measured by the standard extractants used. In addition, the MAF gel has the ability to measure Ca and Mg simultaneously. Copyright © 2014 Elsevier B.V. All rights reserved.

High-fat diet induced insulin resistance in pregnant rats through pancreatic pax6 signaling pathway

PubMed Central

Wu, Hao; Liu, Yunyun; Wang, Hongkun; Xu, Xianming

2015-01-01

Objective: To explore the changes in pancreas islet function of pregnant rats after consumption of high-fat diet and the underlying mechanism. Methods: Thirty pregnant Wistar rats were randomly divided into two groups: high-fat diet group and normal control group. Twenty days after gestation, fasting blood glucose concentration (FBG) and fasting serum insulin concentration (FINS) were measured. Then, oral glucose tolerance test (OGTT) and insulin release test (IRT) were performed. Finally, all the rats were sacrificed and pancreas were harvested. Insulin sensitivity index (ISI) and insulin resistance index (HOMA-IR) were calculated according to FBG and FINS. RT-PCR and Real-time PCR were performed to study the expression of paired box 6 transcription factor (Pax6) and its target genes in pancreatic tissues. Results: The body weight was significantly increased in the high-fat diet group compared with that of normal control rats (P<0.05). The fasting plasma glucose of rats in high-fat diet group was significantly increased compared with that of normal control rats (6.62 mmol/L vs. 4.96 mmol/L, P<0.05), however there was no significant difference in fasting serum insulin concentration between the two groups. OGTT and IRT were abnormal in the high-fat diet group. The high-fat diet rats were more prone to impaired glucose tolerance and insulin resistance. The level of the expression of Pax6 transcription factor and its target genes in pancreas, such as pancreatic and duodenal homeobox factor-1 (Pdx1), v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA) and glucose transporter 2 (Glut2) were decreased significantly compared with those of normal control group. Conclusion: High-fat diet feeding during pregnancy may induce insulin resistance in maternal rats by inhibiting pancreatic Pax6 and its target genes expression. PMID:26191217

Hydrogeologic framework and hydrologic budget components of the Columbia Plateau Regional Aquifer System, Washington, Oregon, and Idaho

USGS Publications Warehouse

Kahle, S.C.; Morgan, D.S.; Welch, W.B.; Ely, D.M.; Hinkle, S.R.; Vaccaro, J.J.; Orzol, L.L.

2011-01-01

The Columbia Plateau Regional Aquifer System (CPRAS) covers an area of about 44,000 square miles in a structural and topographic basin within the drainage of the Columbia River in Washington, Oregon, and Idaho. The primary aquifers are basalts of the Columbia River Basalt Group (CRBG) and overlying sediment. Eighty percent of the groundwater use in the study area is for irrigation, in support of a $6 billion per year agricultural economy. Water-resources issues in the Columbia Plateau include competing agricultural, domestic, and environmental demands. Groundwater levels were measured in 470 wells in 1984 and 2009; water levels declined in 83 percent of the wells, and declines greater than 25 feet were measured in 29 percent of the wells. Conceptually, the system is a series of productive basalt aquifers consisting of permeable interflow zones separated by less permeable flow interiors; in places, sedimentary aquifers overly the basalts. The aquifer system of the CPRAS includes seven hydrogeologic units-the overburden aquifer, three aquifer units in the permeable basalt rock, two confining units, and a basement confining unit. The overburden aquifer includes alluvial and colluvial valley-fill deposits; the three basalt units are the Saddle Mountains, Wanapum, and Grande Ronde Basalts and their intercalated sediments. The confining units are equivalent to the Saddle Mountains-Wanapum and Wanapum-Grande Ronde interbeds, referred to in this study as the Mabton and Vantage Interbeds, respectively. The basement confining unit, referred to as Older Bedrock, consists of pre-CRBG rocks that generally have much lower permeabilities than the basalts and are considered the base of the regional flow system. Based on specific-capacity data, median horizontal hydraulic conductivity (Kh) values for the overburden, basalt units, and bedrock are 161, 70, and 6 feet per day, respectively. Analysis of oxygen isotopes in water and carbon isotopes in dissolved inorganic carbon from groundwater samples indicates that groundwater in the CPRAS ranges in age from modern (10,000 years). The oldest groundwater resides in deep, downgradient locations indicating that groundwater movement and replenishment in parts of this regional aquifer system have operated on long timescales under past natural conditions, which is consistent with the length and depth of long flow paths in the system. The mean annual recharge from infiltration of precipitation for the 23-year period 1985-2007 was estimated to be 4.6 inches per year (14,980 cubic feet per second) using a polynomial regression equation based on annual precipitation and the results of recharge modeling done in the 1980s. A regional-scale hydrologic budget was developed using a monthly SOil WATer (SOWAT) Balance model to estimate irrigation-water demand, groundwater flux (recharge or discharge), direct runoff, and soil moisture within irrigated areas. Mean monthly irrigation throughout the study area peaks in July at 1.6 million acre-feet (MAF), of which 0.45 and 1.15 MAF are from groundwater and surface-water sources, respectively. Annual irrigation water use in the study area averaged 5.3 MAF during the period 1985-2007, with 1.4 MAF (or 26 percent) supplied from groundwater and 3.9 MAF supplied from surface water. Mean annual recharge from irrigation return flow in the study area was 4.2 MAF (1985-2007) with 2.1 MAF (50 percent) occurring within the predominately surface-water irrigated regions of the study area. Annual groundwater-use estimates were made for public supply, self-supplied domestic, industrial, and other uses for the period 1984 through 2009. Public supply groundwater use within the study area increased from 200,600 acre-feet per year (acre-ft/yr) in 1984 to 269,100 acre-ft/yr in 2009. Domestic self-supplied groundwater use increased from 54,580 acre-ft/yr in 1984 to 71,160 acre-ft/yr in 2009. Industrial groundwater use decreased from 53,390 acre-ft/yr in 1984 t

Pancreatic carcinogenesis: apoptosis and angiogenesis.

PubMed

Onizuka, Shinya; Kawakami, Shunsuke; Taniguchi, Ken; Fujioka, Hikaru; Miyashita, Kosei

2004-04-01

Apoptosis and angiogenesis are critical biologic processes that are altered during carcinogenesis. Both apoptosis and angiogenesis may play an important role in pancreatic carcinogenesis. Despite numerous advances in the diagnosis and treatment of pancreatic cancer, its prognosis remains dismal and a new therapeutic approach is much needed. Recent research has revealed that apoptosis and angiogenesis are closely interrelated. Several reports show that a tumor suppresser gene that is expressed in pancreatic carcinoma and related to malignant potential can induce apoptosis and also inhibit angiogenesis. At present, it is generally accepted that tumor growth in cancers, including pancreatic cancer, depends on angiogenesis. We have identified 2 new angiogenesis inhibitors from a conditioned medium of human pancreatic carcinoma cell line (BxPC-3): antiangiogenic antithrombin III (aaAT-III) and vitamin D binding protein-macrophage activating factor (DBP-maf). These molecules were able to regress tumors in severe combined immunodeficiency disease (SCID) mice, demonstrating potent inhibition of endothelial cell proliferation. Moreover, the angiogenesis inhibitors induced tumor dormancy in the animal model. These results suggest that antiangiogenic therapy using angiogenesis inhibitors may become a new strategy for treatment of pancreatic cancer in the near future.

Behind the scenes of vitamin D binding protein: more than vitamin D binding.

PubMed

Delanghe, Joris R; Speeckaert, Reinhart; Speeckaert, Marijn M

2015-10-01

Although being discovered in 1959, the number of published papers in recent years reveals that vitamin D binding protein (DBP), a member of the albuminoid superfamily, is a hot research topic. Besides the three major phenotypes (DBP1F, DBP1S and DBP2), more than 120 unique variants have been described of this polymorphic protein. The presence of DBP has been demonstrated in different body fluids (serum, urine, breast milk, ascitic fluid, cerebrospinal fluid, saliva and seminal fluid) and organs (brain, heart, lungs, kidneys, placenta, spleen, testes and uterus). Although the major function is binding, solubilization and transport of vitamin D and its metabolites, the name of this glycoprotein hides numerous other important biological functions. In this review, we will focus on the analytical aspects of the determination of DBP and discuss in detail the multifunctional capacity [actin scavenging, binding of fatty acids, chemotaxis, binding of endotoxins, influence on T cell response and influence of vitamin D binding protein-macrophage activating factor (DBP-MAF) on bone metabolism and cancer] of this abundant plasma protein. Copyright © 2015 Elsevier Ltd. All rights reserved.

A regulatory circuit for piwi by the large Maf gene traffic jam in Drosophila.

PubMed

Saito, Kuniaki; Inagaki, Sachi; Mituyama, Toutai; Kawamura, Yoshinori; Ono, Yukiteru; Sakota, Eri; Kotani, Hazuki; Asai, Kiyoshi; Siomi, Haruhiko; Siomi, Mikiko C

2009-10-29

PIWI-interacting RNAs (piRNAs) silence retrotransposons in Drosophila germ lines by associating with the PIWI proteins Argonaute 3 (AGO3), Aubergine (Aub) and Piwi. piRNAs in Drosophila are produced from intergenic repetitive genes and piRNA clusters by two systems: the primary processing pathway and the amplification loop. The amplification loop occurs in a Dicer-independent, PIWI-Slicer-dependent manner. However, primary piRNA processing remains elusive. Here we analysed piRNA processing in a Drosophila ovarian somatic cell line where Piwi, but not Aub or AGO3, is expressed; thus, only the primary piRNAs exist. In addition to flamenco, a Piwi-specific piRNA cluster, traffic jam (tj), a large Maf gene, was determined as a new piRNA cluster. piRNAs arising from tj correspond to the untranslated regions of tj messenger RNA and are sense-oriented. piRNA loading on to Piwi may occur in the cytoplasm. zucchini, a gene encoding a putative cytoplasmic nuclease, is required for tj-derived piRNA production. In tj and piwi mutant ovaries, somatic cells fail to intermingle with germ cells and Fasciclin III is overexpressed. Loss of tj abolishes Piwi expression in gonadal somatic cells. Thus, in gonadal somatic cells, tj gives rise simultaneously to two different molecules: the TJ protein, which activates Piwi expression, and piRNAs, which define the Piwi targets for silencing.

Transcriptional regulation of xenobiotic detoxification in Drosophila

PubMed Central

Misra, Jyoti R.; Horner, Michael A.; Lam, Geanette; Thummel, Carl S.

2011-01-01

Living organisms, from bacteria to humans, display a coordinated transcriptional response to xenobiotic exposure, inducing enzymes and transporters that facilitate detoxification. Several transcription factors have been identified in vertebrates that contribute to this regulatory response. In contrast, little is known about this pathway in insects. Here we show that the Drosophila Nrf2 (NF-E2-related factor 2) ortholog CncC (cap ‘n’ collar isoform-C) is a central regulator of xenobiotic detoxification responses. A binding site for CncC and its heterodimer partner Maf (muscle aponeurosis fibromatosis) is sufficient and necessary for robust transcriptional responses to three xenobiotic compounds: phenobarbital (PB), chlorpromazine, and caffeine. Genetic manipulations that alter the levels of CncC or its negative regulator, Keap1 (Kelch-like ECH-associated protein 1), lead to predictable changes in xenobiotic-inducible gene expression. Transcriptional profiling studies reveal that more than half of the genes regulated by PB are also controlled by CncC. Consistent with these effects on detoxification gene expression, activation of the CncC/Keap1 pathway in Drosophila is sufficient to confer resistance to the lethal effects of the pesticide malathion. These studies establish a molecular mechanism for the regulation of xenobiotic detoxification in Drosophila and have implications for controlling insect populations and the spread of insect-borne human diseases. PMID:21896655

Psychosocial correlates of fatigue in multiple sclerosis.

PubMed

Schwartz, C E; Coulthard-Morris, L; Zeng, Q

1996-02-01

To explore: (1) the interrelation among the neuropsychological, psychological, and psychosocial factors and fatigue as measured by the Multidimensional Assessment of Fatigue scale, and (2) the impact of fatigue on role performance. Clinical interview with neuropsychological testing and cross-sectional study by mail. Multiple sclerosis (MS) clinic registry of a large Boston teaching hospital. 139 MS patients representing a broad range of disability. The Multidimensional Assessment of Fatigue (MAF) scale, the Extended Disability Status Scale, the Sickness Impact Profile, Rao cognitive battery, the Trailmaking Test, depression, anxiety, and social activity limitations subscales from the Arthritis Impact Measurement Scales, and the Ryff Happiness Scale. Stepwise multiple regression analyses revealed that having a low sense of environmental mastery was the best psychosocial predictor of both global fatigue and fatigue-related distress, after adjusting for sociodemographic and medical factors. Further, people who reported being more depressed tended to report more severe fatigue. Neuropsychological performance was not associated with fatigue. Fatigue was found to limit social, work, and overall role performance, but not physical role performance. People who feel that they can choose or create environments suitable to their psychic or physical conditions report less global fatigue and less fatigue-related distress, and fatigue can have an important impact on role performance. The implications of these findings for designing fatigue management interventions are discussed.

Chain confinement, phase transitions, and lamellar structure in semicrystalline polymers, polymer blends and polymer nanocomposites

NASA Astrophysics Data System (ADS)

Chen, Huipeng

Recent studies suggest that there are three phase fractions in semicrystalline polymers, the crystalline, the mobile amorphous and the rigid amorphous phases. Due to the distinct properties of the rigid amorphous fraction, RAF, it has been investigated for more than twenty years. In this thesis, a general method using quasi-isothermal temperature-modulated differential scaning calorimetry, DSC, is provided for the first time to obtain the temperature dependent RAF and the other two fractions, crystalline fraction and mobile amorphous fraction, MAF. For poly(ethylene terephthalate), PET, our results show RAF was vitrified during quasi-isothermal cooling after crystallization had been completed and became totally devitrified during quasi-isothermal heating before the start of melting. Several years after people initially discovered the existence of RAF, another issue arose relating to the physical location of RAF and mobile amorphous fraction, MAF, within a lamellar stack model. Two very different models to describe the location of RAF were proposed. In the Heterogeneous Stack Model, HET, RAF is located outside the lamellar stacks. In the Homogeneous Stack Model, HSM, RAF was located inside the lamellar stacks. To determine the lamellar structure of semicrystalline polymers comprising three phase, a general method is given in this thesis by using a combination of the DSC and small angle X-ray scattering, SAXS techniques. It has been applied to Nylon 6, isotactic polystyrene, iPS, and PET. It was found for all of these materials, the HSM model is correct to describe the lamellar structure. In addition to the determination of lamellar structures, this method can also provide the exact fraction of MAF inside and outside lamellar stacks for binary polymer blends. For binary polymer blends, MAF, normally is located partially inside and partially outside the lamellar stacks. However, the quantification of the MAF inside and outside the lamellar stacks has now been provided and is applied to the iPS/atactic polystyrene, aPS, blends. The fractions of MAF inside and outside the lamellar stacks were quantified for the first time. For A/B binary polymer blends, it has been reported that if B is already crystalline, the crystalline fraction would serve as a restriction on the subsequent growth of the crystallizable partner A, while amorphous fraction could be diffused from the crystalline growth front of the crystallizing A component. Considering the effect of RAF on binary blends, a new concept is provided: like the crystals, the RAF of one polymer component may inhibit the growth of crystals of the other blend partner. The non-isothermal crystallization of PET/poly(lactic acid), PLA, blends were investigated and the results confirmed the new concept is correct: PET forms a large amount of RAF and inhibits crystal formation in PLA. Then, we broadened the concept of RAF and investigated the RAF in recent 'hot' materials, polymer nanocomposites. It was found the fraction of RAF greatly increased with a small amount of multi-wall carbon nanotubes, MWCNT, loading in PET electrospun, ES, fibers. A general model is given for polymer ES fibers with MWCNTs: the addition of MWCNTs causes polymer chains in the ES fibers to become more extended, (ie, more stretched), resulting in more confinement of PET chains and an increase in the RAF.

Cell-Penetrating Peptide as a Means of Directing the Differentiation of Induced-Pluripotent Stem Cells.

PubMed

Kaitsuka, Taku; Tomizawa, Kazuhito

2015-11-06

Protein transduction using cell-penetrating peptides (CPPs) is useful for the delivery of large protein molecules, including some transcription factors. This method is safer than gene transfection methods with a viral vector because there is no risk of genomic integration of the exogenous DNA. Recently, this method was reported as a means for the induction of induced pluripotent stem (iPS) cells, directing the differentiation into specific cell types and supporting gene editing/correction. Furthermore, we developed a direct differentiation method to obtain a pancreatic lineage from mouse and human pluripotent stem cells via the protein transduction of three transcription factors, Pdx1, NeuroD, and MafA. Here, we discuss the possibility of using CPPs as a means of directing the differentiation of iPS cells and other stem cell technologies.

Estimates of water use and trends in the Colorado River Basin, Southwestern United States, 1985–2010

USGS Publications Warehouse

Maupin, Molly A.; Ivahnenko, Tamara I.; Bruce, Breton

2018-06-26

The Colorado River Basin (CRB) drains 246,000 square miles and includes parts of California, Colorado, Nevada, New Mexico, Utah, and Wyoming, and all of Arizona (Basin States). This report contains water-use estimates by category of use for drainage basins (Hydrologic Unit Code 8; HUC‑8) within the CRB from 1985 to 2010, at 5-year intervals. Estimates for public supply, domestic, commercial, industrial, irrigation, livestock, mining, aquaculture, hydroelectric and thermoelectric power, and wastewater returns are tabulated as (1) water withdrawals from groundwater or surface‑water sources of fresh or saline quality, (2) water delivered for domestic use, (3) wastewater returns and instream use (hydroelectric), and (4) consumptive use, or water that is consumed (USGS definition) and not available for immediate reuse. Water transported outside of the CRB (interbasin transfers) is not included as part of withdrawals and are not accounted for in any category of use within the CRB.Total withdrawals in the CRB (excluding interbasin transfers) averaged about 17 million acre-feet (maf) from 1985 to 2010, peaked at about 17.76 maf in 2000, and reached their lowest levels of 16.43 maf in 1990. Interbasin transfers to serve mostly public-supply and irrigation needs outside of the CRB are reported for 2000, 2005, and 2010 only, and averaged 5.40 maf. More surface water was used in the CRB than groundwater, averaging about 78 percent of total withdrawals, and its use increased less than 2 percent from 1985 to 2010, while groundwater withdrawals decreased about 12 percent. From 1985 to 2010, surface water averaged 98 percent of withdrawals in the upper CRB, and about 59 percent in the lower CRB. Nearly all withdrawals were freshwater, but some saline groundwater was used for mining and self-supplied industrial.Interbasin transfers have a large effect on flows in the Colorado River and are listed in this report separately with no explanation of how the water is used outside of the CRB. There are 34 interbasin transfers that conveyed an estimated 5.83, 5.20, and 5.18 maf out of the CRB in 2000, 2005, and 2010, respectively. The largest interbasin transfers are in the lower CRB and convey surface water (Colorado River water) to southern California; these accounted for 80 to 84 percent of total interbasin transfers in the CRB from 2000 to 2010. Intrabasin transfers are conveyances of surface water that cross drainage basin or State boundaries in the CRB, but the water does not leave the CRB. There are many intrabasin transfers in the CRB, but this report lists 11 that are mostly in the State of Colorado. The largest is the Central Arizona Project (CAP), through which more than 1.00 maf of water was provided to irrigate nearly 1 million acres in Maricopa, Pinal, and Pima Counties, as well as provide municipal water for Phoenix and Tucson, Arizona, during 2000, 2005, and 2010. In 2010, interbasin and intrabasin transfers accounted for 24 and 11 percent of the total water withdrawals in CRB, respectively, with the larger volumes being conveyed out of the lower CRB.Total population in the CRB increased from 4.56 to 9.44 million people from 1985 to 2010. Most of those people were in the lower CRB, with 86 percent of the total in 1985, and 90 percent of the total in 2010. Total public-supply withdrawals in the CRB provided most people with their potable water, and averaged about 1.63 maf from 1985 to 2010, ranging from about 1.07 maf in 1985 to about 2.10 maf in 2010, when it peaked. Most of public-supply withdrawals occurred in the lower CRB, ranging from 87 to 91 percent of total public-supply withdrawals in the CRB over the 25 years. Total domestic use, comprised of public-supply deliveries and self-supply domestic withdrawals, increased more than 90 percent from 1985 to 2010, from about 0.80 maf to about 1.54 maf. Domestic daily per-capita use rates in the CRB ranged from about 144 (1985) to about 121 (2000) gallons (gal) per‑capita between 1985 and 2010. When comparing domestic daily per-capita rates for the upper and lower CRB, people in the lower CRB, on average, used less water for domestic purposes at 128 gal per-capita daily (1985–2010), while those in the upper CRB for the same time period averaged 133 gal per-capita daily. The trend in daily per-capita use rates for the entire CRB fluctuated between the reporting years, but decreased overall, indicating that more people used less water in 2010 than in 1985, likely due to improved infrastructure, conservation, and improvements to water using appliances in homes and businesses.Irrigation accounted for most total withdrawals in the CRB, excluding instream use for hydroelectric power and interbasin transfers, averaging 85 percent from 1985 to 2010. Far more surface water than groundwater was used for irrigation in both the upper and lower CRB, but in the upper CRB, it accounted for an average of more than 98 percent of the total withdrawals (1985–2010), whereas in the lower CRB, surface-water withdrawals for irrigation averaged 61 percent of total withdrawals. On average, the upper CRB accounted for 56 percent of total irrigated acres, and the irrigation systems in the upper CRB trended towards more efficient sprinkler systems from 1985 to 2010. Long-term drought in the CRB substantially decreased the amount of streamflow available for irrigation. Increases in micro-irrigation acres, which can have efficiencies that exceed 90 percent and require 20–50 percent less water than sprinkler systems, likely contributed to reduced withdrawals in the lower CRB.For thermoelectric power, total withdrawals, including the use of reclaimed wastewater, were greater in the upper CRB from 1985 through 2005. In 2010, the lower CRB exceeded the upper by only 11,000 acre-feet. On average, thermoelectric consumptive use accounted for about 80 percent of the total withdrawals; however, consumptive-use data in the upper CRB was incomplete. Surface water was the primary source in the upper CRB and groundwater was the primary source in the lower CRB. In the CRB overall, water withdrawals for thermoelectric generation has decreased since 2000, except for groundwater withdrawals in the lower CRB. Power generation at thermoelectric plants was greater in the upper CRB from 1985 to 2000, and after 2005 the difference in power generation was small; however, the upper CRB continued to have more power generation. In both the upper and lower CRB, power generation increased from 1985 to 2005.

Heritability of Individual Psychotic Experiences Captured by Common Genetic Variants in a Community Sample of Adolescents.

PubMed

Sieradzka, Dominika; Power, Robert A; Freeman, Daniel; Cardno, Alastair G; Dudbridge, Frank; Ronald, Angelica

2015-09-01

Occurrence of psychotic experiences is common amongst adolescents in the general population. Twin studies suggest that a third to a half of variance in adolescent psychotic experiences is explained by genetic influences. Here we test the extent to which common genetic variants account for some of the twin-based heritability. Psychotic experiences were assessed with the Specific Psychotic Experiences Questionnaire in a community sample of 2152 16-year-olds. Self-reported measures of Paranoia, Hallucinations, Cognitive Disorganization, Grandiosity, Anhedonia, and Parent-rated Negative Symptoms were obtained. Estimates of SNP heritability were derived and compared to the twin heritability estimates from the same sample. Three approaches to genome-wide restricted maximum likelihood (GREML) analyses were compared: (1) standard GREML performed on full genome-wide data; (2) GREML stratified by minor allele frequency (MAF); and (3) GREML performed on pruned data. The standard GREML revealed a significant SNP heritability of 20 % for Anhedonia (SE = 0.12; p < 0.046) and an estimate of 19 % for Cognitive Disorganization, which was close to significant (SE = 0.13; p < 0.059). Grandiosity and Paranoia showed modest SNP heritability estimates (17 %; SE = 0.13 and 14 %; SE = 0.13, respectively, both n.s.), and zero estimates were found for Hallucinations and Negative Symptoms. The estimates for Anhedonia, Cognitive Disorganization and Grandiosity accounted for approximately half the previously reported twin heritability. SNP heritability estimates from the MAF-stratified approach were mostly consistent with the standard estimates and offered additional information about the distribution of heritability across the MAF range of the SNPs. In contrast, the estimates derived from the pruned data were for the most part not consistent with the other two approaches. It is likely that the difference seen in the pruned estimates was driven by the loss of tagged causal variants, an issue fundamental to this approach. The current results suggest that common genetic variants play a role in the etiology of some adolescent psychotic experiences, however further research on larger samples is desired and the use of MAF-stratified approach recommended.

Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture

PubMed Central

Zheng, Hou-Feng; Forgetta, Vincenzo; Hsu, Yi-Hsiang; Estrada, Karol; Rosello-Diez, Alberto; Leo, Paul J; Dahia, Chitra L; Park-Min, Kyung Hyun; Tobias, Jonathan H; Kooperberg, Charles; Kleinman, Aaron; Styrkarsdottir, Unnur; Liu, Ching-Ti; Uggla, Charlotta; Evans, Daniel S; Nielson, Carrie M; Walter, Klaudia; Pettersson-Kymmer, Ulrika; McCarthy, Shane; Eriksson, Joel; Kwan, Tony; Jhamai, Mila; Trajanoska, Katerina; Memari, Yasin; Min, Josine; Huang, Jie; Danecek, Petr; Wilmot, Beth; Li, Rui; Chou, Wen-Chi; Mokry, Lauren E; Moayyeri, Alireza; Claussnitzer, Melina; Cheng, Chia-Ho; Cheung, Warren; Medina-Gómez, Carolina; Ge, Bing; Chen, Shu-Huang; Choi, Kwangbom; Oei, Ling; Fraser, James; Kraaij, Robert; Hibbs, Matthew A; Gregson, Celia L; Paquette, Denis; Hofman, Albert; Wibom, Carl; Tranah, Gregory J; Marshall, Mhairi; Gardiner, Brooke B; Cremin, Katie; Auer, Paul; Hsu, Li; Ring, Sue; Tung, Joyce Y; Thorleifsson, Gudmar; Enneman, Anke W; van Schoor, Natasja M; de Groot, Lisette C.P.G.M.; van der Velde, Nathalie; Melin, Beatrice; Kemp, John P; Christiansen, Claus; Sayers, Adrian; Zhou, Yanhua; Calderari, Sophie; van Rooij, Jeroen; Carlson, Chris; Peters, Ulrike; Berlivet, Soizik; Dostie, Josée; Uitterlinden, Andre G; Williams, Stephen R.; Farber, Charles; Grinberg, Daniel; LaCroix, Andrea Z; Haessler, Jeff; Chasman, Daniel I; Giulianini, Franco; Rose, Lynda M; Ridker, Paul M; Eisman, John A; Nguyen, Tuan V; Center, Jacqueline R; Nogues, Xavier; Garcia-Giralt, Natalia; Launer, Lenore L; Gudnason, Vilmunder; Mellström, Dan; Vandenput, Liesbeth; Karlsson, Magnus K; Ljunggren, Östen; Svensson, Olle; Hallmans, Göran; Rousseau, François; Giroux, Sylvie; Bussière, Johanne; Arp, Pascal P; Koromani, Fjorda; Prince, Richard L; Lewis, Joshua R; Langdahl, Bente L; Hermann, A Pernille; Jensen, Jens-Erik B; Kaptoge, Stephen; Khaw, Kay-Tee; Reeve, Jonathan; Formosa, Melissa M; Xuereb-Anastasi, Angela; Åkesson, Kristina; McGuigan, Fiona E; Garg, Gaurav; Olmos, Jose M; Zarrabeitia, Maria T; Riancho, Jose A; Ralston, Stuart H; Alonso, Nerea; Jiang, Xi; Goltzman, David; Pastinen, Tomi; Grundberg, Elin; Gauguier, Dominique; Orwoll, Eric S; Karasik, David; Davey-Smith, George; Smith, Albert V; Siggeirsdottir, Kristin; Harris, Tamara B; Zillikens, M Carola; van Meurs, Joyce BJ; Thorsteinsdottir, Unnur; Maurano, Matthew T; Timpson, Nicholas J; Soranzo, Nicole; Durbin, Richard; Wilson, Scott G; Ntzani, Evangelia E; Brown, Matthew A; Stefansson, Kari; Hinds, David A; Spector, Tim; Cupples, L Adrienne; Ohlsson, Claes; Greenwood, Celia MT; Jackson, Rebecca D; Rowe, David W; Loomis, Cynthia A; Evans, David M; Ackert-Bicknell, Cheryl L; Joyner, Alexandra L; Duncan, Emma L; Kiel, Douglas P; Rivadeneira, Fernando; Richards, J Brent

2016-01-01

SUMMARY The extent to which low-frequency (minor allele frequency [MAF] between 1–5%) and rare (MAF ≤ 1%) variants contribute to complex traits and disease in the general population is largely unknown. Bone mineral density (BMD) is highly heritable, is a major predictor of osteoporotic fractures and has been previously associated with common genetic variants1–8, and rare, population-specific, coding variants9. Here we identify novel non-coding genetic variants with large effects on BMD (ntotal = 53,236) and fracture (ntotal = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n=2,882 from UK10K), whole-exome sequencing (n= 3,549), deep imputation of genotyped samples using a combined UK10K/1000Genomes reference panel (n=26,534), and de-novo replication genotyping (n= 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size 4-fold larger than the mean of previously reported common variants for lumbar spine BMD8 (rs11692564[T], MAF = 1.7%, replication effect size = +0.20 standard deviations [SD], Pmeta = 2×10−14), which was also associated with a decreased risk of fracture (OR = 0.85; P = 2×10−11; ncases = 98,742 and ncontrols = 409,511). Using an En1Cre/flox mouse model, we observed that conditional loss of En1 results in low bone mass, likely as a consequence of high bone turn-over. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817[T], MAF = 1.1%, replication effect size = +0.39 SD, Pmeta = 1×10−11). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population. PMID:26367794

SU-E-I-25: Performance Evaluation of a Proposed CMOS-Based X-Ray Detector Using Linear Cascade Model Analysis.

PubMed

Jain, A; Bednarek, D; Rudin, S

2012-06-01

The need for high-resolution, dynamic x-ray imaging capability for neurovascular applications has put an ever increasing demand on x-ray detector technology. Present state-of-the-art detectors such as flat panels have limited resolution and noise performance. A linear cascade model analysis was used to estimate the theoretical performance for a proposed CMOS-based detector. The proposed CMOS-based detector was assumed to have a 300-micron thick HL type CsI phosphor, 35-micron pixels, a variable gain light image intensifier (LU), and 400 electron readout noise. The proposed detector has a CMOS sensor coupled to an LII which views the output of the CsI phosphor. For the analysis the whole imaging chain was divided into individual stages characterized by one of the basic processes (stochastic/deterministic blurring, binomial selection, quantum gain, additive noise). Standard linear cascade modeling was used for the propagation of signal and noise through the stages and an RQA5 spectrum was assumed. The gain, blurring or transmission of different stages was either measured or taken from manufacturer's specifications. The theoretically calculated MTF and DQE for the proposed detector were compared with a high-resolution, high-sensitive Micro-Angio Fluoroscope (MAF), predecessor of the proposed detector. Signal and noise for each of the 19 stages in the complete imaging chain were calculated and showed improved performance. For example, at 5 cycles/mm the MTF and DQE were 0.08 and 0.28, respectively, for the CMOS detector compared to 0.05 and 0.07 for the MAF detector. The proposed detector will have improved MTF and DQE and slimmer physical dimension due to the elimination of the large fiber-optic taper used in the MAF. Once operational, the proposed CMOS detector will serve as a further improvement over standard flat panel detectors compared to the MAF which is already receiving a very positive reception by neuro-vascular interventionalists. (Support:NIH-Grant R01EB002873) NIH Grants R01- EB008425, R01-EB002873 and an equipment grant from Toshiba Medical Systems Corp. © 2012 American Association of Physicists in Medicine.

From Common to Rare Variants: The Genetic Component of Alzheimer Disease.

PubMed

Nicolas, Gaël; Charbonnier, Camille; Campion, Dominique

2016-01-01

Alzheimer disease (AD) is a remarkable example of genetic heterogeneity. Extremely rare variants in the APP, PSEN1, or PSEN2 genes, or duplications of the APP gene cause autosomal dominant forms, generally with complete penetrance by the age of 65 years. Nonautosomal dominant forms are considered as a complex disorder with a high genetic component, whatever the age of onset. Although genetically heterogeneous, AD is defined by the same neuropathological criteria in all configurations. According to the amyloid cascade hypothesis, the Aβ peptide, which aggregates in AD brains, is a key player. APP, PSEN1, or PSEN2 gene mutations increase the production of more aggregation-prone forms of the Aβ peptide, triggering the pathological process. Several risk factors identified in association studies hit genes involved in Aβ production/secretion, aggregation, clearance, or toxicity. Among them, the APOE ε4 allele is a rare example of a common allele with a large effect size, the ORs ranging from 4 to 11-14 for heterozygous and homozygous carriers, respectively. In addition, genome-wide association studies have identified more than two dozen loci with a weak but significant association, the OR of the at-risk allele ranging from 1.08 to 1.30. Recently, the use of massive parallel sequencing has enabled the analysis of rare variants in a genome-wide manner. Two rare variants have been nominally associated with AD risk or protection (TREM2 p.R47H, MAF approximately 0.002, OR approximately 4 and APP p.A673T, MAF approximately 0.0005, OR approximately 0.2). Association analyses at the gene level identified rare loss-of-function and missense, predicted damaging, variants (MAF <0.01) in the SORL1 and ABCA7 genes associated with a moderate relative risk (OR approximately 5 and approximately 2.8, respectively). Although the latter analyses revealed association signals with moderately rare variants by collapsing them, the power to detect genes hit by extremely rare variants is still limited. An alternative approach is to consider the de novo paradigm, stating that de novo variants may contribute to AD genetics in sporadic patients. Here, we critically review AD genetics reports with a special focus on rare variants. © 2016 S. Karger AG, Basel.

Diversity and impact of rare variants in genes encoding the platelet G protein-coupled receptors.

PubMed

Jones, Matthew L; Norman, Jane E; Morgan, Neil V; Mundell, Stuart J; Lordkipanidzé, Marie; Lowe, Gillian C; Daly, Martina E; Simpson, Michael A; Drake, Sian; Watson, Steve P; Mumford, Andrew D

2015-04-01

Platelet responses to activating agonists are influenced by common population variants within or near G protein-coupled receptor (GPCR) genes that affect receptor activity. However, the impact of rare GPCR gene variants is unknown. We describe the rare single nucleotide variants (SNVs) in the coding and splice regions of 18 GPCR genes in 7,595 exomes from the 1,000-genomes and Exome Sequencing Project databases and in 31 cases with inherited platelet function disorders (IPFDs). In the population databases, the GPCR gene target regions contained 740 SNVs (318 synonymous, 410 missense, 7 stop gain and 6 splice region) of which 70 % had global minor allele frequency (MAF) < 0.05 %. Functional annotation using six computational algorithms, experimental evidence and structural data identified 156/740 (21 %) SNVs as potentially damaging to GPCR function, most commonly in regions encoding the transmembrane and C-terminal intracellular receptor domains. In 31 index cases with IPFDs (Gi-pathway defect n=15; secretion defect n=11; thromboxane pathway defect n=3 and complex defect n=2) there were 256 SNVs in the target regions of 15 stimulatory platelet GPCRs (34 unique; 12 with MAF< 1 % and 22 with MAF≥ 1 %). These included rare variants predicting R122H, P258T and V207A substitutions in the P2Y12 receptor that were annotated as potentially damaging, but only partially explained the platelet function defects in each case. Our data highlight that potentially damaging variants in platelet GPCR genes have low individual frequencies, but are collectively abundant in the population. Potentially damaging variants are also present in pedigrees with IPFDs and may contribute to complex laboratory phenotypes.

Dlx1&2-Dependent Expression of Zfhx1b (Sip1, Zeb2) Regulates the Fate Switch Between Cortical and Striatal Interneurons

PubMed Central

McKinsey, Gabriel L.; Lindtner, Susan; Trzcinski, Brett; Visel, Axel; Pennacchio, Len A.; Huylebroeck, Danny; Higashi, Yujiro; Rubenstein, John L. R.

2013-01-01

Summary Mammalian pallial (cortical and hippocampal) and striatal interneurons are both generated in the embryonic subpallium, including the medial ganglionic eminence (MGE). Herein we demonstrate that the Zfhx1b (Sip1, Zeb2) zinc finger homeobox gene is required in the MGE, directly downstream of Dlx1&2, to generate cortical interneurons that express Cxcr7, MafB and cMaf. In its absence, Nkx2-1 expression is not repressed, and cells that ordinarily would become cortical interneurons appear to transform towards a subtype of GABAeric striatal interneurons. These results show that Zfhx1b is required to generate cortical interneurons, and suggest a mechanism for the epilepsy observed in humans with Zfhx1b mutations (Mowat-Wilson syndrome). PMID:23312518

Highly effective removal of mercury and lead ions from wastewater by mercaptoamine-functionalised silica-coated magnetic nano-adsorbents: Behaviours and mechanisms

NASA Astrophysics Data System (ADS)

Bao, Shuangyou; Li, Kai; Ning, Ping; Peng, Jinhui; Jin, Xu; Tang, Lihong

2017-01-01

A novel hybrid material was fabricated using mercaptoamine-functionalised silica-coated magnetic nanoparticles (MAF-SCMNPs) and was effective in the extraction and recovery of mercury and lead ions from wastewater. The properties of this new magnetic material were explored using various characterisation and analysis methods. Adsorbent amounts, pH levels and initial concentrations were optimised to improve removal efficiency. Additionally, kinetics, thermodynamics and adsorption isotherms were investigated to determine the mechanism by which the fabricated MAF-SCMNPs adsorb heavy metal ions. The results revealed that MAF-SCMNPs were acid-resistant. Sorption likely occurred by chelation through the amine group and ion exchange between heavy metal ions and thiol functional groups on the nanoadsorbent surface. The equilibrium was attained within 120 min, and the adsorption kinetics showed pseudo-second-order (R2 > 0.99). The mercury and lead adsorption isotherms were in agreement with the Freundlich model, displaying maximum adsorption capacities of 355 and 292 mg/g, respectively. The maximum adsorptions took place at pH 5-6 and 6-7 for Hg(II) and Pb(II), respectively. The maximum adsorptions were observed at 10 mg and 12 mg adsorbent quantities for Hg(II) and Pb(II), respectively. The adsorption process was endothermic and spontaneous within the temperature range of 298-318 K. This work demonstrates a unique magnetic nano-adsorbent for the removal of Hg(II) and Pb(II) from wastewater.

Primary and acquired EGFR T790M-mutant NSCLC patients identified by routine mutation testing show different characteristics but may both respond to osimertinib treatment.

PubMed

Li, Weihua; Qiu, Tian; Guo, Lei; Ling, Yun; Gao, Yibo; Ying, Jianming; He, Jie

2018-06-01

Primary EGFR T790M mutation is occasionally identified by routine mutation testing in tyrosine kinase inhibitor (TKI)-naive patients with non-small cell lung cancer (NSCLC). We herein aimed to compare the characteristics of primary and acquired T790M mutations in NSCLC patients, and their response to osimertinib. Using amplification refractory mutation system (ARMS) detection, primary T790M was identified in 0.5% (46/8723) of TKI-naive patients, whereas acquired T790M was detected in 49.7% (71/143) of TKI-relapsed patients. T790M always coexisted with a sensitizing EGFR mutation. Primary T790M more commonly coexisted with L858R, whereas acquired T790M was more likely to coexist with exon 19 deletions. Moreover, next-generation sequencing (NGS) showed that concomitant sensitizing EGFR and primary T790M mutant allele frequencies (MAFs) were highly concordant, but acquired T790M MAFs were significantly lower than the sensitizing EGFR MAFs. Sixteen acquired T790M-mutant patients received osimertinib. The median progression-free survival (PFS) was 8.1 months. Four primary T790M-mutant patients received osimertinib and the median PFS was 8.0 months. Together, our study demonstrates that primary and acquired T790M-mutant patients show distinct differences in some clinical and molecular characteristics, but may both respond to osimertinib treatment. Copyright © 2018 Elsevier B.V. All rights reserved.

Improving Technology for Vascular Imaging

NASA Astrophysics Data System (ADS)

Rana, Raman

Neuro-endovascular image guided interventions (Neuro-EIGIs) is a minimally invasive procedure that require micro catheters and endovascular devices be inserted into the vasculature via an incision near the femoral artery and guided under low dose fluoroscopy to the vasculature of the head and neck. However, the endovascular devices used for the purpose are of very small size (stents are of the order of 50mum to 100mum) and the success of these EIGIs depends a lot on the accurate placement of these devices. In order to accurately place these devices inside the patient, the interventionalist should be able to see them clearly. Hence, high resolution capabilities are of immense importance in neuro-EIGIs. The high-resolution detectors, MAF-CCD and MAF-CMOS, at the Toshiba Stroke and Vascular Research Center at the University at Buffalo are capable of presenting improved images for better patient care. Focal spot of an x-ray tube plays an important role in performance of these high resolution detectors. The finite size of the focal spot results into the blurriness around the edges of the image of the object resulting in reduced spatial resolution. Hence, knowledge of accurate size of the focal spot of the x-ray tube is very essential for the evaluation of the total system performance. Importance of magnification and image detector blur deconvolution was demonstrated to carry out the more accurate measurement of x-ray focal spot using a pinhole camera. A 30 micron pinhole was used to obtain the focal spot images using flat panel detector (FPD) and different source to image distances (SIDs) were used to achieve different magnifications (3.16, 2.66 and 2.16). These focal spot images were deconvolved with a 2-D modulation transfer function (MTF), obtained using noise response (NR) method, to remove the detector blur present in the images. Using these corrected images, the accurate size of all the three focal spots were obtained and it was also established that effect of detector blur can be reduced significantly by using a higher magnification. As discussed earlier, interventionalist need higher resolution capabilities during EIGIs for more confident and successful treatment of the patient. An experimental MAF-CCD enabled with a Control, Acquisition, Processing, Image Display and Storage (CAPIDS) system was installed and aligned on a detector changer attached to the C-arm of a clinical angiographic unit. The CAPIDS system was developed and implemented using LabVIEW software and provides a user-friendly interface that enables control of several clinical radiographic imaging modes of the MAF including: fluoroscopy, roadmap, radiography, and digital-subtraction-angiography (DSA). Whenever the higher resolution is needed, the MAD-CCD detector can be moved in front of the FPD. A particular set of steps were needed to deploy the MAF in front of the FPD and to transfer the controls to CAPIDS from the Toshiba Systems. In order to minimize any possible negative impact of using two different detectors during a procedure, a well-designed workflow was developed that enables smooth deployment of the MAF at critical stages of clinical procedures. The images obtained using MAF-CCD detector demonstrated the advantages the high resolution imagers have over FPDs. Scatter is inevitable in x-ray imaging as it reduces the image quality. The benefit of removing the scatter is that it improves contrast and also increases the signal-to-Noise (SNR). There are various scatter reduction methods like air-gap techniques, collimation, moving anti-scatter grids, stationary anti-scatter grids. Stationary anti-scatter grids is a preferred choice in dynamic imaging because of its compact design and ease to use. However, when these anti-scatter grids are used with high resolution detector, there will be anti-scatter grid-line pattern present in the image, as structure noise. Because of presence of this anti-scatter grid artifact, the contrast-to-Noise (CNR) of the image decreases when grid is used with high resolution detector. In order to address this issue, grid-line artifact minimization method for high resolution detectors is developed. (Abstract shortened by ProQuest.).

The Effect of Fucoidan from the Brown Alga Fucus evanescence on the Activity of α-N-Acetylgalactosaminidase of Human Colon Carcinoma Cells.

PubMed

Bakunina, Irina; Chadova, Oksana; Malyarenko, Olesya; Ermakova, Svetlana

2018-05-10

α- N -acetylgalactosaminidase (EC 3.2.1.49) (alpha-NaGalase) catalyzes the hydrolysis of N -acetamido-2-deoxy-α-d-galactoside residues from non-reducing ends of various complex carbohydrates and glycoconjugates. It is known that human cancer cells express an alpha-NaGalase, which accumulates in the blood plasma of patients. The enzyme deglycosylates the Gc protein-derived macrophage activating factor (GcMAF) and inhibits macrophage activity acting as an immunosuppressor. The high specific activity 0.033 ± 0.002 μmol mg −1 min −1 of the enzyme was found in human colon carcinoma cells DLD-1. The alpha-NaGalase of DLD-1 cells was isolated and biochemical characterized. The enzyme exhibits maximum activity at pH 5.2 and temperature 55 °C. The K m is 2.15 mM, V max ⁻0.021 μmol min −1 mL −1 , k cat ⁻1.55 min −1 and k cat / K m ⁻0.72 min −1 mM −1 at 37 °C, pH 5.2. The effects of fucoidan from the brown alga Fucus evanescence on the activity of alpha-NaGalase in human colon carcinoma DLD-1 cells and on the biosynthesis of this enzyme were investigated. It was shown that fucoidan did not inhibit free alpha-NaGalase, however, it reduced the expression of the enzyme in the DLD-1 cells at IC 50 73 ± 4 μg mL −1 .

Killing of Leishmania parasites in activated murine macrophages is based on an L-arginine-dependent process that produces nitrogen derivatives

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

Maul, J.R.; Ransijn, A.; Buchmueller-Rouiller, Y.

1991-01-01

The experiments described in this report were aimed at determining whether L-arginine (L-arg)-derived nitrogen oxidation products (nitric oxide, nitrous acid, nitrites) are involved in the intracellular killing of Leishmania parasites by activated murine macrophages in vitro. Peritoneal or bone marrow-derived macrophages were infected with L. enriettii or L. major, then activated by exposure to recombinant murine interferon-gamma or to macrophage activating factor (MAF)-rich media in the presence of lipopolysaccharide. Activation of macrophages in regular (i.e., arginine-containing) culture medium led to complete destruction of the microorganisms within 24 h (L. enriettii) or 48 h (L. major), concomitant with accumulation of nitritesmore » (NO2-) in the culture fluids. When macrophage activation was carried out in L-arg-free medium, however, neither parasite killing nor NO2- production was obtained. A similar inhibition of macrophage leishmanicidal activity and of NO2- release was observed using media treated with arginase (which converts L-arg to urea and ornithine), or supplemented with NG-monomethyl-L-arg or guanidine (which inhibit the conversion of L-arg to nitrogen oxidation products). In all these situations, an excellent correlation between the levels of NO2- production by macrophages and intracellular killing of Leishmania was observed, whereas no strict correlation was detectable between leishmanicidal activity and superoxide production. Intracellular parasite killing by activated macrophages could be prevented by addition of iron salts to the incubation fluids. Incubation of free parasites with NaNO2 at acid pH led to immobilisation, multiplication arrest, and morphological degeneration of the microorganisms. Similarly, exposure of infected cells to NaNO2 led to killing of the intracellular parasite without affecting macrophage viability.« less

Three-dimensional rotational micro-angiography

NASA Astrophysics Data System (ADS)

Patel, Vikas

Computed tomography (CT) is state-of-the-art for 3D imaging in which images are acquired about the patient and are used to reconstruct the data. But the commercial CT systems suffer from low spatial resolution (0.5-2 lp/mm). Micro-CT (microCT) systems have high resolution 3D reconstruction (>10 lp/mm), but are currently limited to small objects, e.g., small animals. To achieve artifact free reconstructions, geometric calibration of the rotating-object cone-beam microCT (CBmicroCT) system is performed using new techniques that use only the projection images of the object, i.e., no calibration objects are required. Translations (up to 0.2 mm) occurring during the acquisition in the horizontal direction are detected, quantified, and corrected based on sinogram analysis. The parameters describing the physical axis of rotation determined using our image-based method (aligning anti-posed images) agree well (within 0.1 mm and 0.3 degrees) with those determined using other techniques that use calibration objects. Geometric calibrations of the rotational angiography (RA) systems (clinical cone-beam CT systems with fluoroscopic capabilities provided by flat-panel detectors (FPD)) are performed using a simple single projection technique (SPT), which aligns a known 3D model of a calibration phantom with the projection data. The calibration parameters obtained by the SPT are found to be reproducible (angles within 0.2° and x- and y-translations less than 2 mm) for over 7 months. The spatial resolution of the RA systems is found to be virtually unaffected by such small geometric variations. Finally, using our understanding of the geometric calibrations, we have developed methods to combine relatively low-resolution RA acquisitions (2-3 lp/mm) with high resolution microCT acquisitions (using a high-resolution micro-angiographic fluoroscope (MAF) attached to the RA gantry) to produce the first-ever 3D rotational micro-angiography (3D-RmicroA) system on a clinical gantry. Images of a rabbit with a coronary stent placed in an artery were obtained and reconstructed. To eliminate artifacts due to image truncation, lower-dose (compared to the MAF acquisition) full-FOV (FFOV) FPD RA sequences are also obtained. To ensure high-quality high-resolution reconstruction, the high-resolution images from the MAF are aligned spatially with the lower-dose FPD images (average correlation coefficient before and after alignment: 0.65 and 0.97 respectively), and the pixel values in the FPD image data are scaled (using linear regression) to match those of the MAF. Greater details without any visible truncation artifacts are seen in 3D RmicroA (MAF-FPD) images than in those of the FPD alone. The FWHM of line profiles of stent struts (100 micron diameter) are approximately 192 +/- 21 and 313 +/- 38 microns for the 3D RmicroA and FPD data, respectively. Thus, with the RmicroA system, we have essentially developed a high resolution CBmicroCT system for clinical use.

Primary Sjögren's syndrome in Moroccan patients: characteristics, fatigue and quality of life.

PubMed

Ibn Yacoub, Yousra; Rostom, Samira; Laatiris, Assia; Hajjaj-Hassouni, Najia

2012-09-01

Our aim was to evaluate fatigue and quality of life (QoL) in Moroccan patients with primary Sjögren's syndrome (PSS) and determine their correlates with disease-related parameters. Fifty-seven consecutive patients with PSS according to the American-European Consensus group (AEGG) criteria were included. Demographic, clinical, biological and immunological characteristics for all patients were collected. Xerostomia was demonstrated by histological grading of lower lip glandular biopsy. A Schirmer test was performed to measure lachrymal flow. Oral, ocular, skin, vaginal and tracheal dryness were evaluated by using a visual analogue scale (VAS). Fatigue was assessed by the Multidimensional assessment of fatigue (MAF) and the QoL by using the generic instrument: SF-36. 90% of our patients were women. The mean age of patients was 53.73 ± 7.69 years, and the mean disease duration was 5.38 ± 4.11 years. The mean oral dryness was 68.38 ± 20.29, and the mean ocular dryness was 51.91 ± 14.03. The mean total score of the MAF was 26.73 ± 8.33, and 87.5% of our patients experienced severe fatigue. Also, physical and mental domains of QoL were altered in a significant way, and the severity of fatigue had a negative impact on SF-36 scores. MAF and SF-36 scores were correlated with the delay of diagnosis, the intensity of xerostomia and the activity of joint involvement. A low socioeconomic and educational level had a negative impact on fatigue scores and QoL. Histological grading of lower lip glandular biopsy, immunological status and the severity of systemic involvement had no correlations with fatigue scores or the alteration of QoL. Patients receiving antidepressant have lesser fatigue and those receiving Methotrexate have better SF-36 scores. In our data, there was a high prevalence of fatigue in Moroccan patients with PSS associated with altered QoL. Severe fatigue and reduced QoL seem to be related to the severity of joint involvement, xerostomia and both educational and socioeconomic levels. Also, treatment with methotrexate and antidepressant seems to improve patients' living and QoL. An appropriate therapeutic intervention for depression and articular manifestations in PSS should be applied to improve patients' living.

A functional splice variant associated with decreased asthma risk abolishes the ability of gasdermin B to induce epithelial cell pyroptosis.

PubMed

Panganiban, Ronald A; Sun, Maoyun; Dahlin, Amber; Park, Hae-Ryung; Kan, Mengyuan; Himes, Blanca E; Mitchel, Jennifer A; Iribarren, Carlos; Jorgenson, Eric; Randell, Scott H; Israel, Elliot; Tantisira, Kelan; Shore, Stephanie; Park, Jin-Ah; Weiss, Scott T; Wu, Ann Chen; Lu, Quan

2018-01-09

Genetic variants in the chromosomal region 17q21 are consistently associated with asthma. However, mechanistic studies have not yet linked any of the associated variants to a function that could influence asthma, and as a result, the identity of the asthma gene(s) remains elusive. We sought to identify and characterize functional variants in the 17q21 locus. We used the Exome Aggregation Consortium browser to identify coding (amino acid-changing) variants in the 17q21 locus. We obtained asthma association measures for these variants in both the Genetic Epidemiology Research in Adult Health and Aging (GERA) cohort (16,274 cases and 38,269 matched controls) and the EVE Consortium study (5,303 asthma cases and 12,560 individuals). Gene expression and protein localization were determined by quantitative RT-PCR and fluorescence immunostaining, respectively. Molecular and cellular studies were performed to determine the functional effects of coding variants. Two coding variants (rs2305480 and rs11078928) of the gasdermin B (GSDMB) gene in the 17q21 locus were associated with lower asthma risk in both GERA (odds ratio, 0.92; P = 1.01 × 10 -6 ) and EVE (odds ratio, 0.85; joint P EVE  = 1.31 × 10 -13 ). In GERA, rs11078928 had a minor allele frequency (MAF) of 0.45 in unaffected (nonasthmatic) controls and 0.43 in asthma cases. For European Americans in EVE, the MAF of rs2305480 was 0.45 for controls and 0.39 for cases; for all EVE subjects, the MAF was 0.32 for controls and 0.27 for cases. GSDMB is highly expressed in differentiated airway epithelial cells, including the ciliated cells. We found that, when the GSDMB protein is cleaved by inflammatory caspase-1 to release its N-terminal fragment, potent pyroptotic cell death is induced. The splice variant rs11078928 deletes the entire exon 6, which encodes 13 amino acids in the critical N-terminus, and abolishes the pyroptotic activity of the GSDMB protein. Our study identified a functional asthma variant in the GSDMB gene of the 17q21 locus and implicates GSDMB-mediated epithelial cell pyroptosis in pathogenesis. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

STS-114: Crew Training Clip from JSC

NASA Technical Reports Server (NTRS)

2003-01-01

STS-114 Discovery crew is shown in various training exercises at Johnson Space Center. The crew consists of Eileen Collins, Commander; James Kelley, Pilot; Charles Camarda, Mission Specialist; Wendy Lawrence, Mission Specialist; Soichi Noguchi, Mission Specialist; Steve Robinson, Mission Specialist; and Andy Thomas, Mission Specialist. The exercises include: 1) EVA training in the VR lab; 2) Neutral Buoyancy Laboratory (NBL) EVA Training; 3) Walk to Motion Base Simulator; 4) EVA Preparations in ISS Airlock; and 7) Emergency Egress from Crew Compartment Trainer (CCT). A crew photo session is also presented. Footage of The Space Shuttle Atlantis inside the Kennedy Space Center Vehicle Assembly Building (VAB) after its demating from the Solid Rocket Booster and External Tank is shown. The video ends with techniques for inspecting and repairing Thermal Protection System tiles, a video of external tank production at the Michoud Assembly Facility (MAF) and redesign of the foam from the bipod ramp at Michoud Assembly Facility (MAF).

Defining the Molecular Character of the Developing and Adult Kidney Podocyte

PubMed Central

Brunskill, Eric W.; Georgas, Kylie; Rumballe, Bree; Little, Melissa H.; Potter, S. Steven

2011-01-01

Background The podocyte is a remarkable cell type, which encases the capillaries of the kidney glomerulus. Although mesodermal in origin it sends out axonal like projections that wrap around the capillaries. These extend yet finer projections, the foot processes, which interdigitate, leaving between them the slit diaphragms, through which the glomerular filtrate must pass. The podocytes are a subject of keen interest because of their key roles in kidney development and disease. Methodology/Principal Findings In this report we identified and characterized a novel transgenic mouse line, MafB-GFP, which specifically marked the kidney podocytes from a very early stage of development. These mice were then used to facilitate the fluorescent activated cell sorting based purification of podocytes from embryos at E13.5 and E15.5, as well as adults. Microarrays were then used to globally define the gene expression states of podocytes at these different developmental stages. A remarkable picture emerged, identifying the multiple sets of genes that establish the neuronal, muscle, and phagocytic properties of podocytes. The complete combinatorial code of transcription factors that create the podocyte was characterized, and the global lists of growth factors and receptors they express were defined. Conclusions/Significance The complete molecular character of the in vivo podocyte is established for the first time. The active molecular functions and biological processes further define their unique combination of features. The results provide a resource atlas of gene expression patterns of developing and adult podocytes that will help to guide further research of these incredible cells. PMID:21931791

A fluorescent bimolecular complementation screen reveals MAF1, RNF7 and SETD3 as PCNA-associated proteins in human cells

PubMed Central

Cooper, Simon E; Hodimont, Elsie; Green, Catherine M

2015-01-01

The proliferating cell nuclear antigen (PCNA) is a conserved component of DNA replication factories, and interactions with PCNA mediate the recruitment of many essential DNA replication enzymes to these sites of DNA synthesis. A complete description of the structure and composition of these factories remains elusive, and a better knowledge of them will improve our understanding of how the maintenance of genome and epigenetic stability is achieved. To fully characterize the set of proteins that interact with PCNA we developed a bimolecular fluorescence complementation (BiFC) screen for PCNA-interactors in human cells. This 2-hybrid type screen for interactors from a human cDNA library is rapid and efficient. The fluorescent read-out for protein interaction enables facile selection of interacting clones, and we combined this with next generation sequencing to identify the cDNAs encoding the interacting proteins. This method was able to reproducibly identify previously characterized PCNA-interactors but importantly also identified RNF7, Maf1 and SetD3 as PCNA-interacting proteins. We validated these interactions by co-immunoprecipitation from human cell extracts and by interaction analyses using recombinant proteins. These results show that the BiFC screen is a valuable method for the identification of protein-protein interactions in living mammalian cells. This approach has potentially wide application as it is high throughput and readily automated. We suggest that, given this interaction with PCNA, Maf1, RNF7, and SetD3 are potentially involved in DNA replication, DNA repair, or associated processes. PMID:26030842

Postzygotic single-nucleotide mosaicisms contribute to the etiology of autism spectrum disorder and autistic traits and the origin of mutations.

PubMed

Dou, Yanmei; Yang, Xiaoxu; Li, Ziyi; Wang, Sheng; Zhang, Zheng; Ye, Adam Yongxin; Yan, Linlin; Yang, Changhong; Wu, Qixi; Li, Jiarui; Zhao, Boxun; Huang, August Yue; Wei, Liping

2017-08-01

The roles and characteristics of postzygotic single-nucleotide mosaicisms (pSNMs) in autism spectrum disorders (ASDs) remain unclear. In this study of the whole exomes of 2,361 families in the Simons Simplex Collection, we identified 1,248 putative pSNMs in children and 285 de novo SNPs in children with detectable parental mosaicism. Ultra-deep amplicon resequencing suggested a validation rate of 51%. Analyses of validated pSNMs revealed that missense/loss-of-function (LoF) pSNMs with a high mutant allele fraction (MAF≥ 0.2) contributed to ASD diagnoses (P = 0.022, odds ratio [OR] = 5.25), whereas missense/LoF pSNMs with a low MAF (MAF<0.2) contributed to autistic traits in male non-ASD siblings (P = 0.033). LoF pSNMs in parents were less likely to be transmitted to offspring than neutral pSNMs (P = 0.037), and missense/LoF pSNMs in parents with a low MAF were transmitted more to probands than to siblings (P = 0.016, OR = 1.45). We estimated that pSNMs in probands or de novo mutations inherited from parental pSNMs increased the risk of ASD by approximately 6%. Adding pSNMs into the transmission and de novo association test model revealed 13 new ASD risk genes. These results expand the existing repertoire of genes involved in ASD and shed new light on the contribution of genomic mosaicisms to ASD diagnoses and autistic traits. © 2017 The Authors. Human Mutation published by Wiley Periodicals, Inc.

The index-flood and the GRADEX methods combination for flood frequency analysis.

NASA Astrophysics Data System (ADS)

Fuentes, Diana; Di Baldassarre, Giuliano; Quesada, Beatriz; Xu, Chong-Yu; Halldin, Sven; Beven, Keith

2017-04-01

Flood frequency analysis is used in many applications, including flood risk management, design of hydraulic structures, and urban planning. However, such analysis requires of long series of observed discharge data which are often not available in many basins around the world. In this study, we tested the usefulness of combining regional discharge and local precipitation data to estimate the event flood volume frequency curve for 63 catchments in Mexico, Central America and the Caribbean. This was achieved by combining two existing flood frequency analysis methods, the regionalization index-flood approach with the GRADEX method. For up to 10-years return period, similar shape of the scaled flood frequency curve for catchments with similar flood behaviour was assumed from the index-flood approach. For return periods larger than 10-years the probability distribution of rainfall and discharge volumes were assumed to be asymptotically and exponential-type functions with the same scale parameter from the GRADEX method. Results showed that if the mean annual flood (MAF), used as index-flood, is known, the index-flood approach performed well for up to 10 years return periods, resulting in 25% mean relative error in prediction. For larger return periods the prediction capability decreased but could be improved by the use of the GRADEX method. As the MAF is unknown at ungauged and short-period measured basins, we tested predicting the MAF using catchments climate-physical characteristics, and discharge statistics, the latter when observations were available for only 8 years. Only the use of discharge statistics resulted in acceptable predictions.

A comparison of cataloged variation between International HapMap Consortium and 1000 Genomes Project data.

PubMed

Buchanan, Carrie C; Torstenson, Eric S; Bush, William S; Ritchie, Marylyn D

2012-01-01

Since publication of the human genome in 2003, geneticists have been interested in risk variant associations to resolve the etiology of traits and complex diseases. The International HapMap Consortium undertook an effort to catalog all common variation across the genome (variants with a minor allele frequency (MAF) of at least 5% in one or more ethnic groups). HapMap along with advances in genotyping technology led to genome-wide association studies which have identified common variants associated with many traits and diseases. In 2008 the 1000 Genomes Project aimed to sequence 2500 individuals and identify rare variants and 99% of variants with a MAF of <1%. To determine whether the 1000 Genomes Project includes all the variants in HapMap, we examined the overlap between single nucleotide polymorphisms (SNPs) genotyped in the two resources using merged phase II/III HapMap data and low coverage pilot data from 1000 Genomes. Comparison of the two data sets showed that approximately 72% of HapMap SNPs were also found in 1000 Genomes Project pilot data. After filtering out HapMap variants with a MAF of <5% (separately for each population), 99% of HapMap SNPs were found in 1000 Genomes data. Not all variants cataloged in HapMap are also cataloged in 1000 Genomes. This could affect decisions about which resource to use for SNP queries, rare variant validation, or imputation. Both the HapMap and 1000 Genomes Project databases are useful resources for human genetics, but it is important to understand the assumptions made and filtering strategies employed by these projects.

Genetic Variation in TLR Genes in Ugandan and South African Populations and Comparison with HapMap Data

PubMed Central

Randhawa, April Kaur; Horne, David J.; Adams, Mark D.; Shey, Muki; Barnholtz-Sloan, Jill; Mayanja-Kizza, Harriet; Kaplan, Gilla; Hanekom, Willem A.; Boom, W. Henry; Hawn, Thomas R.; Stein, Catherine M.

2012-01-01

Genetic epidemiological studies of complex diseases often rely on data from the International HapMap Consortium for identification of single nucleotide polymorphisms (SNPs), particularly those that tag haplotypes. However, little is known about the relevance of the African populations used to collect HapMap data for study populations conducted elsewhere in Africa. Toll-like receptor (TLR) genes play a key role in susceptibility to various infectious diseases, including tuberculosis. We conducted full-exon sequencing in samples obtained from Uganda (n = 48) and South Africa (n = 48), in four genes in the TLR pathway: TLR2, TLR4, TLR6, and TIRAP. We identified one novel TIRAP SNP (with minor allele frequency [MAF] 3.2%) and a novel TLR6 SNP (MAF 8%) in the Ugandan population, and a TLR6 SNP that is unique to the South African population (MAF 14%). These SNPs were also not present in the 1000 Genomes data. Genotype and haplotype frequencies and linkage disequilibrium patterns in Uganda and South Africa were similar to African populations in the HapMap datasets. Multidimensional scaling analysis of polymorphisms in all four genes suggested broad overlap of all of the examined African populations. Based on these data, we propose that there is enough similarity among African populations represented in the HapMap database to justify initial SNP selection for genetic epidemiological studies in Uganda and South Africa. We also discovered three novel polymorphisms that appear to be population-specific and would only be detected by sequencing efforts. PMID:23112821

Metabolic Stress and Compromised Identity of Pancreatic Beta Cells

PubMed Central

Swisa, Avital; Glaser, Benjamin; Dor, Yuval

2017-01-01

Beta cell failure is a central feature of type 2 diabetes (T2D), but the molecular underpinnings of the process remain only partly understood. It has been suggested that beta cell failure in T2D involves massive cell death. Other studies ascribe beta cell failure to cell exhaustion, due to chronic oxidative or endoplasmic reticulum stress leading to cellular dysfunction. More recently it was proposed that beta cells in T2D may lose their differentiated identity, possibly even gaining features of other islet cell types. The loss of beta cell identity appears to be driven by glucotoxicity inhibiting the activity of key beta cell transcription factors including Pdx1, Nkx6.1, MafA and Pax6, thereby silencing beta cell genes and derepressing alternative islet cell genes. The loss of beta cell identity is at least partly reversible upon normalization of glycemia, with implications for the reversibility of T2D, although it is not known if beta cell failure reaches eventually a point of no return. In this review we discuss current evidence for metabolism-driven compromised beta cell identity, key knowledge gaps and opportunities for utility in the treatment of T2D. PMID:28270834

Metabolic Stress and Compromised Identity of Pancreatic Beta Cells.

PubMed

Swisa, Avital; Glaser, Benjamin; Dor, Yuval

2017-01-01

Beta cell failure is a central feature of type 2 diabetes (T2D), but the molecular underpinnings of the process remain only partly understood. It has been suggested that beta cell failure in T2D involves massive cell death. Other studies ascribe beta cell failure to cell exhaustion, due to chronic oxidative or endoplasmic reticulum stress leading to cellular dysfunction. More recently it was proposed that beta cells in T2D may lose their differentiated identity, possibly even gaining features of other islet cell types. The loss of beta cell identity appears to be driven by glucotoxicity inhibiting the activity of key beta cell transcription factors including Pdx1, Nkx6.1, MafA and Pax6, thereby silencing beta cell genes and derepressing alternative islet cell genes. The loss of beta cell identity is at least partly reversible upon normalization of glycemia, with implications for the reversibility of T2D, although it is not known if beta cell failure reaches eventually a point of no return. In this review we discuss current evidence for metabolism-driven compromised beta cell identity, key knowledge gaps and opportunities for utility in the treatment of T2D.

Investigation of Caucasian rheumatoid arthritis susceptibility loci in African patients with the same disease

PubMed Central

2012-01-01

Introduction The largest genetic risk to develop rheumatoid arthritis (RA) arises from a group of alleles of the HLA DRB1 locus ('shared epitope', SE). Over 30 non-HLA single nucleotide polymorphisms (SNPs) predisposing to disease have been identified in Caucasians, but they have never been investigated in West/Central Africa. We previously reported a lower prevalence of the SE in RA patients in Cameroon compared to European patients and aimed in the present study to investigate the contribution of Caucasian non-HLA RA SNPs to disease susceptibility in Black Africans. Methods RA cases and controls from Cameroon were genotyped for Caucasian RA susceptibility SNPs using Sequenom MassArray technology. Genotype data were also available for 5024 UK cases and 4281 UK controls and for 119 Yoruba individuals in Ibadan, Nigeria (YRI, HapMap). A Caucasian aggregate genetic-risk score (GRS) was calculated as the sum of the weighted risk-allele counts. Results After genotyping quality control procedures were performed, data on 28 Caucasian non-HLA susceptibility SNPs were available in 43 Cameroonian RA cases and 44 controls. The minor allele frequencies (MAF) were tightly correlated between Cameroonian controls and YRI individuals (correlation coefficient 93.8%, p = 1.7E-13), and they were pooled together. There was no correlation between MAF of UK and African controls; 13 markers differed by more than 20%. The MAF for markers at PTPN22, IL2RA, FCGR2A and IL2/IL21 was below 2% in Africans. The GRS showed a strong association with RA in the UK. However, the GRS did not predict RA in Africans (OR = 0.71, 95% CI 0.29 - 1.74, p = 0.456). Random sampling from the UK cohort showed that this difference in association is unlikely to be explained by small sample size or chance, but is statistically significant with p<0.001. Conclusions The MAFs of non-HLA Caucasian RA susceptibility SNPs are different between Caucasians and Africans, and several polymorphisms are barely detectable in West/Central Africa. The genetic risk of developing RA conferred by a set of 28 Caucasian susceptibility SNPs is significantly different between the UK and Africa with p<0.001. Taken together, these observations strengthen the hypothesis that the genetic architecture of RA susceptibility is different in different ethnic backgrounds. PMID:23121884

Genome-Wide Study of Percent Emphysema on Computed Tomography in the General Population. The Multi-Ethnic Study of Atherosclerosis Lung/SNP Health Association Resource Study

PubMed Central

Manichaikul, Ani; Hoffman, Eric A.; Smolonska, Joanna; Gao, Wei; Cho, Michael H.; Baumhauer, Heather; Budoff, Matthew; Austin, John H. M.; Washko, George R.; Carr, J. Jeffrey; Kaufman, Joel D.; Pottinger, Tess; Powell, Charles A.; Wijmenga, Cisca; Zanen, Pieter; Groen, Harry J. M.; Postma, Dirkje S.; Wanner, Adam; Rouhani, Farshid N.; Brantly, Mark L.; Powell, Rhea; Smith, Benjamin M.; Rabinowitz, Dan; Raffel, Leslie J.; Hinckley Stukovsky, Karen D.; Crapo, James D.; Beaty, Terri H.; Hokanson, John E.; Silverman, Edwin K.; Dupuis, Josée; O’Connor, George T.; Boezen, H. Marike; Rich, Stephen S.

2014-01-01

Rationale: Pulmonary emphysema overlaps partially with spirometrically defined chronic obstructive pulmonary disease and is heritable, with moderately high familial clustering. Objectives: To complete a genome-wide association study (GWAS) for the percentage of emphysema-like lung on computed tomography in the Multi-Ethnic Study of Atherosclerosis (MESA) Lung/SNP Health Association Resource (SHARe) Study, a large, population-based cohort in the United States. Methods: We determined percent emphysema and upper-lower lobe ratio in emphysema defined by lung regions less than −950 HU on cardiac scans. Genetic analyses were reported combined across four race/ethnic groups: non-Hispanic white (n = 2,587), African American (n = 2,510), Hispanic (n = 2,113), and Chinese (n = 704) and stratified by race and ethnicity. Measurements and Main Results: Among 7,914 participants, we identified regions at genome-wide significance for percent emphysema in or near SNRPF (rs7957346; P = 2.2 × 10−8) and PPT2 (rs10947233; P = 3.2 × 10−8), both of which replicated in an additional 6,023 individuals of European ancestry. Both single-nucleotide polymorphisms were previously implicated as genes influencing lung function, and analyses including lung function revealed independent associations for percent emphysema. Among Hispanics, we identified a genetic locus for upper-lower lobe ratio near the α-mannosidase–related gene MAN2B1 (rs10411619; P = 1.1 × 10−9; minor allele frequency [MAF], 4.4%). Among Chinese, we identified single-nucleotide polymorphisms associated with upper-lower lobe ratio near DHX15 (rs7698250; P = 1.8 × 10−10; MAF, 2.7%) and MGAT5B (rs7221059; P = 2.7 × 10−8; MAF, 2.6%), which acts on α-linked mannose. Among African Americans, a locus near a third α-mannosidase–related gene, MAN1C1 (rs12130495; P = 9.9 × 10−6; MAF, 13.3%) was associated with percent emphysema. Conclusions: Our results suggest that some genes previously identified as influencing lung function are independently associated with emphysema rather than lung function, and that genes related to α-mannosidase may influence risk of emphysema. PMID:24383474

Investigation of Caucasian rheumatoid arthritis susceptibility loci in African patients with the same disease.

PubMed

Viatte, Sebastien; Flynn, Edward; Lunt, Mark; Barnes, Joanne; Singwe-Ngandeu, Madeleine; Bas, Sylvette; Barton, Anne; Gabay, Cem

2012-11-03

The largest genetic risk to develop rheumatoid arthritis (RA) arises from a group of alleles of the HLA DRB1 locus ('shared epitope', SE). Over 30 non-HLA single nucleotide polymorphisms (SNPs) predisposing to disease have been identified in Caucasians, but they have never been investigated in West/Central Africa. We previously reported a lower prevalence of the SE in RA patients in Cameroon compared to European patients and aimed in the present study to investigate the contribution of Caucasian non-HLA RA SNPs to disease susceptibility in Black Africans. RA cases and controls from Cameroon were genotyped for Caucasian RA susceptibility SNPs using Sequenom MassArray technology. Genotype data were also available for 5024 UK cases and 4281 UK controls and for 119 Yoruba individuals in Ibadan, Nigeria (YRI, HapMap). A Caucasian aggregate genetic-risk score (GRS) was calculated as the sum of the weighted risk-allele counts. After genotyping quality control procedures were performed, data on 28 Caucasian non-HLA susceptibility SNPs were available in 43 Cameroonian RA cases and 44 controls. The minor allele frequencies (MAF) were tightly correlated between Cameroonian controls and YRI individuals (correlation coefficient 93.8%, p = 1.7E-13), and they were pooled together. There was no correlation between MAF of UK and African controls; 13 markers differed by more than 20%. The MAF for markers at PTPN22, IL2RA, FCGR2A and IL2/IL21 was below 2% in Africans. The GRS showed a strong association with RA in the UK. However, the GRS did not predict RA in Africans (OR = 0.71, 95% CI 0.29 - 1.74, p = 0.456). Random sampling from the UK cohort showed that this difference in association is unlikely to be explained by small sample size or chance, but is statistically significant with p<0.001. The MAFs of non-HLA Caucasian RA susceptibility SNPs are different between Caucasians and Africans, and several polymorphisms are barely detectable in West/Central Africa. The genetic risk of developing RA conferred by a set of 28 Caucasian susceptibility SNPs is significantly different between the UK and Africa with p<0.001. Taken together, these observations strengthen the hypothesis that the genetic architecture of RA susceptibility is different in different ethnic backgrounds.

Optimization of the diffusive gradients in thin films (DGT) method for simultaneous assay of potassium and plant-available phosphorus in soils.

PubMed

Zhang, Yulin; Mason, Sean; McNeill, Ann; McLaughlin, Michael J

2013-09-15

Potassium (K) and phosphorus (P) are two important macronutrients for crops, and are usually applied to soils as granular fertilizer before seeding. Therefore, accurate soil tests prior to planting to predict crop response to fertilizers are important in optimizing crop yields. Traditional methods used for testing both available K and P in soils, which are based on chemical extraction procedures, are to be soil-type dependent, and the predictive relationships across a broad range of soils are generally poor. The diffusive gradients in thin films (DGT) technique, based on diffusion theory, is extensively used to measure the diffusive supply of trace elements, metals and some nutrients in soils and water. When DGT is used to assess plant-available P in soils, a good relationship is found between crop response to P fertilizer and concentrations of P in soil measured by DGT, and therefore the DGT method provides a more precise recommendation of P fertilizer requirements. Adaptation of the DGT method to measure plant-available K in soils has already been attempted [1], but limitations were reported due to the non-uniform size of the resin gel, decreased K binding rate of the gel at long deployment times and a limited ability to measure a wide range of K concentrations. To eliminate these problems, a new resin gel has been developed by combining Amberlite and ferrihydrite. This mixed Amberlite and ferrihydrite (MAF) gel has improved properties in terms of handling and even distribution of Amberlite in the gel. The elution efficiencies of the MAF gel for K and P were 90% and 96%, respectively. The diffusion coefficient of K through the diffusive gel was 1.30 × 10(-5)cm(2)s(-1) at 22 ± 1°C and was stable through time. Since ferrihydrite is already used in DGT P testing, the ability of the MAF gel to assess available P simultaneously was also assessed. The MAF gel performed the same as the traditional ferrihydrite gel for available P assessment in a wide variety of agricultural soils. This means that the newly developed gel has the potential to measure K and plant-available P in soils simultaneously. Copyright © 2013 Elsevier B.V. All rights reserved.

NF-E2 p45 Is Important for Establishing Normal Function of Platelets

PubMed Central

Fujita, Rie; Takayama-Tsujimoto, Mariko; Satoh, Hironori; Gutiérrez, Laura; Aburatani, Hiroyuki; Fujii, Satoshi; Sarai, Akinori; Bresnick, Emery H.

2013-01-01

NF-E2 is a heterodimeric transcription factor consisting of p45 and small Maf subunits. Since p45−/− mice display severe thrombocytopenia, p45 is recognized as a critical regulator of platelet production from megakaryocytes. To identify direct p45 target genes in megakaryocytes, we used chromatin immunoprecipitation (ChIP) sequencing to analyze the genome-wide chromatin occupancy of p45 in primary megakaryocytes. p45 target gene candidates obtained from the analysis are implicated in the production and function of platelets. Two of these genes, Selp and Myl9, were verified as direct p45 targets through multiple approaches. Since P-selectin, encoded by Selp, plays a critical role in platelet function during thrombogenesis, we tested whether p45 determines the intrinsic reactivity and potency of platelets generated from megakaryocytes. Mice expressing a hypomorphic p45 mutant instead of wild-type p45 in megakaryocytes (p45−/−:ΔNTD-Tg mice) displayed platelet hypofunction accompanied by mild thrombocytopenia. Furthermore, lung metastasis of melanoma cells, which requires platelet activation, was repressed in p45−/−:ΔNTD-Tg mice compared to control mice, validating the impaired function of platelets produced from p45−/−:ΔNTD-Tg megakaryocytes. By activating genes in megakaryocytes that mediate platelet production and function, p45 determines the quantity and quality of platelets. PMID:23648484

The Contribution of Common UGT2B10 and CYP2A6 Alleles to Variation in Nicotine Glucuronidation among European Americans

PubMed Central

Bloom, A. Joseph; von Weymarn, Linda B.; Martinez, Maribel; Bierut, Laura J.; Goate, Alison; Murphy, Sharon E.

2014-01-01

UDP-glucuronosytransferase-2B10 (UGT2B10) is the primary catalyst of nicotine glucuronidation. To develop a predictive genetic model of nicotine metabolism, the conversion of deuterated (D2)-nicotine to D2-nicotine-glucuronide, D2-cotinine, D2-cotinine-glucuronide, and D2-trans-3'-hydroxycotinine were quantified in 188 European Americans, and the contribution of UGT2B10 genotype to variability in first-pass nicotine glucuronidation assessed, following a procedure previously applied to nicotine C-oxidation. The proportion of total nicotine converted to nicotine-glucuronide (D2-nicotine-glucuronide/ (D2-nicotine +D2-nicotine-glucuronide +D2-cotinine +D2-cotinine-glucuronide +D2-trans-3'-hydroxycotinine)) was the primary phenotype. The variant, rs61750900T (D67Y) (minor allele frequency (MAF) = 10%), is confirmed to abolish nicotine glucuronidation activity. Another variant, rs112561475G (N397D) (MAF = 2%), is significantly associated with enhanced glucuronidation. rs112561475G is the ancestral allele of a well-conserved amino acid, indicating that the majority of human UGT2B10 alleles are derived hypomorphic alleles. CYP2A6 and UGT2B10 genotype explain 53% of the variance in oral nicotine glucuronidation in this sample. CYP2A6 and UGT2B10 genetic variants are also significantly associated with un-deuterated (D0) nicotine glucuronidation in subjects smoking ad libitum. We find no evidence for further common variation markedly influencing hepatic UGT2B10 expression in European Americans. PMID:24192532

An exome-wide analysis of low frequency and rare variants in relation to risk of breast cancer in African American Women: the AMBER Consortium

PubMed Central

Haddad, Stephen A.; Ruiz-Narváez, Edward A.; Haiman, Christopher A.; Sucheston-Campbell, Lara E.; Bensen, Jeannette T.; Zhu, Qianqian; Liu, Song; Yao, Song; Bandera, Elisa V.; Rosenberg, Lynn; Olshan, Andrew F.; Ambrosone, Christine B.; Palmer, Julie R.; Lunetta, Kathryn L.

2016-01-01

A large percentage of breast cancer heritability remains unaccounted for, and most of the known susceptibility loci have been established in European and Asian populations. Rare variants may contribute to the unexplained heritability of this disease, including in women of African ancestry (AA). We conducted an exome-wide analysis of rare variants in relation to risk of overall and subtype-specific breast cancer in the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium, which includes data from four large studies of AA women. Genotyping on the Illumina Human Exome Beadchip yielded data for 170 812 SNPs and 8287 subjects: 3629 cases (1093 estrogen receptor negative (ER−), 1968 ER+, 568 ER unknown) and 4658 controls, the largest exome chip study to date for AA breast cancer. Pooled gene-based association analyses were performed using the unified optimal sequence kernel association test (SKAT-O) for variants with minor allele frequency (MAF) ≤ 5%. In addition, each variant with MAF >0.5% was tested for association using logistic regression. There were no significant associations with overall breast cancer. However, a novel gene, FBXL22 (P = 8.2×10–6), and a gene previously identified in GWAS of European ancestry populations, PDE4D (P = 1.2×10–6), were significantly associated with ER− breast cancer after correction for multiple testing. Cases with the associated rare variants were also negative for progesterone and human epidermal growth factor receptors—thus, triple-negative cancer. Replication is required to confirm these gene-level associations, which are based on very small counts at extremely rare SNPs. PMID:27267999

The BTB and CNC homology 1 (BACH1) target genes are involved in the oxidative stress response and in control of the cell cycle.

PubMed

Warnatz, Hans-Jörg; Schmidt, Dominic; Manke, Thomas; Piccini, Ilaria; Sultan, Marc; Borodina, Tatiana; Balzereit, Daniela; Wruck, Wasco; Soldatov, Alexey; Vingron, Martin; Lehrach, Hans; Yaspo, Marie-Laure

2011-07-01

The regulation of gene expression in response to environmental signals and metabolic imbalances is a key step in maintaining cellular homeostasis. BTB and CNC homology 1 (BACH1) is a heme-binding transcription factor repressing the transcription from a subset of MAF recognition elements at low intracellular heme levels. Upon heme binding, BACH1 is released from the MAF recognition elements, resulting in increased expression of antioxidant response genes. To systematically address the gene regulatory networks involving BACH1, we combined chromatin immunoprecipitation sequencing analysis of BACH1 target genes in HEK 293 cells with knockdown of BACH1 using three independent types of small interfering RNAs followed by transcriptome profiling using microarrays. The 59 BACH1 target genes identified by chromatin immunoprecipitation sequencing were found highly enriched in genes showing expression changes after BACH1 knockdown, demonstrating the impact of BACH1 repression on transcription. In addition to known and new BACH1 targets involved in heme degradation (HMOX1, FTL, FTH1, ME1, and SLC48A1) and redox regulation (GCLC, GCLM, and SLC7A11), we also discovered BACH1 target genes affecting cell cycle and apoptosis pathways (ITPR2, CALM1, SQSTM1, TFE3, EWSR1, CDK6, BCL2L11, and MAFG) as well as subcellular transport processes (CLSTN1, PSAP, MAPT, and vault RNA). The newly identified impact of BACH1 on genes involved in neurodegenerative processes and proliferation provides an interesting basis for future dissection of BACH1-mediated gene repression in neurodegeneration and virus-induced cancerogenesis.

Common and rare genetic markers of lipid variation in subjects with type 2 diabetes from the ACCORD clinical trial.

PubMed

Marvel, Skylar W; Rotroff, Daniel M; Wagner, Michael J; Buse, John B; Havener, Tammy M; McLeod, Howard L; Motsinger-Reif, Alison A

2017-01-01

Individuals with type 2 diabetes are at an increased risk of cardiovascular disease. Alterations in circulating lipid levels, total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides (TG) are heritable risk factors for cardiovascular disease. Here we conduct a genome-wide association study (GWAS) of common and rare variants to investigate associations with baseline lipid levels in 7,844 individuals with type 2 diabetes from the ACCORD clinical trial. DNA extracted from stored blood samples from ACCORD participants were genotyped using the Affymetrix Axiom Biobank 1 Genotyping Array. After quality control and genotype imputation, association of common genetic variants (CV), defined as minor allele frequency (MAF) ≥ 3%, with baseline levels of TC, LDL, HDL, and TG was tested using a linear model. Rare variant (RV) associations (MAF < 3%) were conducted using a suite of methods that collapse multiple RV within individual genes. Many statistically significant CV ( p  < 1 × 10 -8 ) replicate findings in large meta-analyses in non-diabetic subjects. RV analyses also confirmed findings in other studies, whereas significant RV associations with CNOT2 , HPN-AS1 , and SIRPD appear to be novel ( q  < 0.1). Here we present findings for the largest GWAS of lipid levels in people with type 2 diabetes to date. We identified 17 statistically significant ( p  < 1 × 10 -8 ) associations of CV with lipid levels in 11 genes or chromosomal regions, all of which were previously identified in meta-analyses of mostly non-diabetic cohorts. We also identified 13 associations in 11 genes based on RV, several of which represent novel findings.

Common and rare genetic markers of lipid variation in subjects with type 2 diabetes from the ACCORD clinical trial

PubMed Central

Wagner, Michael J.; Buse, John B.; Havener, Tammy M.; McLeod, Howard L.

2017-01-01

Background Individuals with type 2 diabetes are at an increased risk of cardiovascular disease. Alterations in circulating lipid levels, total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides (TG) are heritable risk factors for cardiovascular disease. Here we conduct a genome-wide association study (GWAS) of common and rare variants to investigate associations with baseline lipid levels in 7,844 individuals with type 2 diabetes from the ACCORD clinical trial. Methods DNA extracted from stored blood samples from ACCORD participants were genotyped using the Affymetrix Axiom Biobank 1 Genotyping Array. After quality control and genotype imputation, association of common genetic variants (CV), defined as minor allele frequency (MAF) ≥ 3%, with baseline levels of TC, LDL, HDL, and TG was tested using a linear model. Rare variant (RV) associations (MAF < 3%) were conducted using a suite of methods that collapse multiple RV within individual genes. Results Many statistically significant CV (p < 1 × 10−8) replicate findings in large meta-analyses in non-diabetic subjects. RV analyses also confirmed findings in other studies, whereas significant RV associations with CNOT2, HPN-AS1, and SIRPD appear to be novel (q < 0.1). Discussion Here we present findings for the largest GWAS of lipid levels in people with type 2 diabetes to date. We identified 17 statistically significant (p < 1 × 10−8) associations of CV with lipid levels in 11 genes or chromosomal regions, all of which were previously identified in meta-analyses of mostly non-diabetic cohorts. We also identified 13 associations in 11 genes based on RV, several of which represent novel findings. PMID:28480134

Frequency of convergence and accommodative disorders in a clinical population of Mashhad, Iran.

PubMed

Hoseini-Yazdi, Seyed Hosein; Yekta, AbbasAli; Nouri, Hosein; Heravian, Javad; Ostadimoghaddam, Hadi; Khabazkhoob, Mehdi

2015-01-01

To investigate the frequency of convergence and accommodation anomalies in an optometric clinical setting in Mashhad, Iran, and to determine tests with highest accuracy in diagnosing these anomalies. From 261 patients who came to the optometric clinics of Mashhad University of Medical Sciences during a month, 83 of them were included in the study based on the inclusion criteria. Near point of convergence (NPC), near and distance heterophoria, monocular and binocular accommodative facility (MAF and BAF, respectively), lag of accommodation, positive and negative fusional vergences (PFV and NFV, respectively), AC/A ratio, relative accommodation, and amplitude of accommodation (AA) were measured to diagnose the convergence and accommodation anomalies. The results were also compared between symptomatic and asymptomatic patients. The accuracy of these tests was explored using sensitivity (S), specificity (Sp), and positive and negative likelihood ratios (LR+, LR-). Mean age of the patients was 21.3 ± 3.5 years and 14.5% of them had specific binocular and accommodative symptoms. Convergence and accommodative anomalies were found in 19.3% of the patients; accommodative excess (4.8%) and convergence insufficiency (3.6%) were the most common accommodative and convergence disorders, respectively. Symptomatic patients showed lower values for BAF (p = .003), MAF (p = .001), as well as AA (p = .001) compared with asymptomatic patients. Moreover, BAF (S = 75%, Sp = 62%) and MAF (S = 62%, Sp = 89%) were the most accurate tests for detecting accommodative and convergence disorders in terms of both sensitivity and specificity. Convergence and accommodative anomalies are the most common binocular disorders in optometric patients. Including tests of monocular and binocular accommodative facility in routine eye examinations as accurate tests to diagnose these anomalies requires further investigation.

Breast Cancer Clinical Trial of Chemotherapy and Trastuzumab: Potential Tool to Identify Cardiac Modifying Variants of Dilated Cardiomyopathy

PubMed Central

Serie, Daniel J.; Crook, Julia E.; Necela, Brian M.; Axenfeld, Bianca C.; Dockter, Travis J.; Colon-Otero, Gerardo; Perez, Edith A.; Thompson, E. Aubrey; Norton, Nadine

2017-01-01

Doxorubicin and the ERBB2 targeted therapy, trastuzumab, are routinely used in the treatment of HER2+ breast cancer. In mouse models, doxorubicin is known to cause cardiomyopathy and conditional cardiac knock out of Erbb2 results in dilated cardiomyopathy and increased sensitivity to doxorubicin-induced cell death. In humans, these drugs also result in cardiac phenotypes, but severity and reversibility is highly variable. We examined the association of decline in left ventricular ejection fraction (LVEF) at 15,204 single nucleotide polymorphisms (SNPs) spanning 72 cardiomyopathy genes, in 800 breast cancer patients who received doxorubicin and trastuzumab. For 7033 common SNPs (minor allele frequency (MAF) > 0.01) we performed single marker linear regression. For all SNPs, we performed gene-based testing with SNP-set (Sequence) Kernel Association Tests: SKAT, SKAT-O and SKAT-common/rare under rare variant non-burden; rare variant optimized burden and non-burden tests; and a combination of rare and common variants respectively. Single marker analyses identified seven missense variants in OBSCN (p = 0.0045–0.0009, MAF = 0.18–0.50) and two in TTN (both p = 0.04, MAF = 0.22). Gene-based rare variant analyses, SKAT and SKAT-O, performed very similarly (ILK, TCAP, DSC2, VCL, FXN, DSP and KCNQ1, p = 0.042–0.006). Gene-based tests of rare/common variants were significant at the nominal 5% level for OBSCN as well as TCAP, DSC2, VCL, NEXN, KCNJ2 and DMD (p = 0.044–0.008). Our results suggest that rare and common variants in OBSCN, as well as in other genes, could have modifying effects in cardiomyopathy. PMID:29367538

Performance of genotype imputation for low frequency and rare variants from the 1000 genomes.

PubMed

Zheng, Hou-Feng; Rong, Jing-Jing; Liu, Ming; Han, Fang; Zhang, Xing-Wei; Richards, J Brent; Wang, Li

2015-01-01

Genotype imputation is now routinely applied in genome-wide association studies (GWAS) and meta-analyses. However, most of the imputations have been run using HapMap samples as reference, imputation of low frequency and rare variants (minor allele frequency (MAF) < 5%) are not systemically assessed. With the emergence of next-generation sequencing, large reference panels (such as the 1000 Genomes panel) are available to facilitate imputation of these variants. Therefore, in order to estimate the performance of low frequency and rare variants imputation, we imputed 153 individuals, each of whom had 3 different genotype array data including 317k, 610k and 1 million SNPs, to three different reference panels: the 1000 Genomes pilot March 2010 release (1KGpilot), the 1000 Genomes interim August 2010 release (1KGinterim), and the 1000 Genomes phase1 November 2010 and May 2011 release (1KGphase1) by using IMPUTE version 2. The differences between these three releases of the 1000 Genomes data are the sample size, ancestry diversity, number of variants and their frequency spectrum. We found that both reference panel and GWAS chip density affect the imputation of low frequency and rare variants. 1KGphase1 outperformed the other 2 panels, at higher concordance rate, higher proportion of well-imputed variants (info>0.4) and higher mean info score in each MAF bin. Similarly, 1M chip array outperformed 610K and 317K. However for very rare variants (MAF ≤ 0.3%), only 0-1% of the variants were well imputed. We conclude that the imputation of low frequency and rare variants improves with larger reference panels and higher density of genome-wide genotyping arrays. Yet, despite a large reference panel size and dense genotyping density, very rare variants remain difficult to impute.

A comparison of cataloged variation between International HapMap Consortium and 1000 Genomes Project data

PubMed Central

Buchanan, Carrie C; Torstenson, Eric S; Bush, William S

2012-01-01

Background Since publication of the human genome in 2003, geneticists have been interested in risk variant associations to resolve the etiology of traits and complex diseases. The International HapMap Consortium undertook an effort to catalog all common variation across the genome (variants with a minor allele frequency (MAF) of at least 5% in one or more ethnic groups). HapMap along with advances in genotyping technology led to genome-wide association studies which have identified common variants associated with many traits and diseases. In 2008 the 1000 Genomes Project aimed to sequence 2500 individuals and identify rare variants and 99% of variants with a MAF of <1%. Methods To determine whether the 1000 Genomes Project includes all the variants in HapMap, we examined the overlap between single nucleotide polymorphisms (SNPs) genotyped in the two resources using merged phase II/III HapMap data and low coverage pilot data from 1000 Genomes. Results Comparison of the two data sets showed that approximately 72% of HapMap SNPs were also found in 1000 Genomes Project pilot data. After filtering out HapMap variants with a MAF of <5% (separately for each population), 99% of HapMap SNPs were found in 1000 Genomes data. Conclusions Not all variants cataloged in HapMap are also cataloged in 1000 Genomes. This could affect decisions about which resource to use for SNP queries, rare variant validation, or imputation. Both the HapMap and 1000 Genomes Project databases are useful resources for human genetics, but it is important to understand the assumptions made and filtering strategies employed by these projects. PMID:22319179

A genome-wide association study of asthma symptoms in Latin American children.

PubMed

Costa, Gustavo N O; Dudbridge, Frank; Fiaccone, Rosemeire L; da Silva, Thiago M; Conceição, Jackson S; Strina, Agostino; Figueiredo, Camila A; Magalhães, Wagner C S; Rodrigues, Maira R; Gouveia, Mateus H; Kehdy, Fernanda S G; Horimoto, Andrea R V R; Horta, Bernardo; Burchard, Esteban G; Pino-Yanes, Maria; Del Rio Navarro, Blanca; Romieu, Isabelle; Hancock, Dana B; London, Stephanie; Lima-Costa, Maria Fernanda; Pereira, Alexandre C; Tarazona, Eduardo; Rodrigues, Laura C; Barreto, Mauricio L

2015-12-03

Asthma is a chronic disease of the airways and, despite the advances in the knowledge of associated genetic regions in recent years, their mechanisms have yet to be explored. Several genome-wide association studies have been carried out in recent years, but none of these have involved Latin American populations with a high level of miscegenation, as is seen in the Brazilian population. 1246 children were recruited from a longitudinal cohort study in Salvador, Brazil. Asthma symptoms were identified in accordance with an International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire. Following quality control, 1,877,526 autosomal SNPs were tested for association with childhood asthma symptoms by logistic regression using an additive genetic model. We complemented the analysis with an estimate of the phenotypic variance explained by common genetic variants. Replications were investigated in independent Mexican and US Latino samples. Two chromosomal regions reached genome-wide significance level for childhood asthma symptoms: the 14q11 region flanking the DAD1 and OXA1L genes (rs1999071, MAF 0.32, OR 1.78, 95% CI 1.45-2.18, p-value 2.83 × 10(-8)) and 15q22 region flanking the FOXB1 gene (rs10519031, MAF 0.04, OR 3.0, 95% CI 2.02-4.49, p-value 6.68 × 10(-8) and rs8029377, MAF 0.03, OR 2.49, 95% CI 1.76-3.53, p-value 2.45 × 10(-7)). eQTL analysis suggests that rs1999071 regulates the expression of OXA1L gene. However, the original findings were not replicated in the Mexican or US Latino samples. We conclude that the 14q11 and 15q22 regions may be associated with asthma symptoms in childhood.

Rare versus common variants in pharmacogenetics: SLCO1B1 variation and methotrexate disposition

PubMed Central

Ramsey, Laura B.; Bruun, Gitte H.; Yang, Wenjian; Treviño, Lisa R.; Vattathil, Selina; Scheet, Paul; Cheng, Cheng; Rosner, Gary L.; Giacomini, Kathleen M.; Fan, Yiping; Sparreboom, Alex; Mikkelsen, Torben S.; Corydon, Thomas J.; Pui, Ching-Hon; Evans, William E.; Relling, Mary V.

2012-01-01

Methotrexate is used to treat autoimmune diseases and malignancies, including acute lymphoblastic leukemia (ALL). Inter-individual variation in clearance of methotrexate results in heterogeneous systemic exposure, clinical efficacy, and toxicity. In a genome-wide association study of children with ALL, we identified SLCO1B1 as harboring multiple common polymorphisms associated with methotrexate clearance. The extent of influence of rare versus common variants on pharmacogenomic phenotypes remains largely unexplored. We tested the hypothesis that rare variants in SLCO1B1 could affect methotrexate clearance and compared the influence of common versus rare variants in addition to clinical covariates on clearance. From deep resequencing of SLCO1B1 exons in 699 children, we identified 93 SNPs, 15 of which were non-synonymous (NS). Three of these NS SNPs were common, with a minor allele frequency (MAF) >5%, one had low frequency (MAF 1%–5%), and 11 were rare (MAF <1%). NS SNPs (common or rare) predicted to be functionally damaging were more likely to be found among patients with the lowest methotrexate clearance than patients with high clearance. We verified lower function in vitro of four SLCO1B1 haplotypes that were associated with reduced methotrexate clearance. In a multivariate stepwise regression analysis adjusting for other genetic and non-genetic covariates, SLCO1B1 variants accounted for 10.7% of the population variability in clearance. Of that variability, common NS variants accounted for the majority, but rare damaging NS variants constituted 17.8% of SLCO1B1's effects (1.9% of total variation) and had larger effect sizes than common NS variants. Our results show that rare variants are likely to have an important effect on pharmacogenetic phenotypes. PMID:22147369

Generalized two-dimensional (2D) linear system analysis metrics (GMTF, GDQE) for digital radiography systems including the effect of focal spot, magnification, scatter, and detector characteristics.

PubMed

Jain, Amit; Kuhls-Gilcrist, Andrew T; Gupta, Sandesh K; Bednarek, Daniel R; Rudin, Stephen

2010-03-01

The MTF, NNPS, and DQE are standard linear system metrics used to characterize intrinsic detector performance. To evaluate total system performance for actual clinical conditions, generalized linear system metrics (GMTF, GNNPS and GDQE) that include the effect of the focal spot distribution, scattered radiation, and geometric unsharpness are more meaningful and appropriate. In this study, a two-dimensional (2D) generalized linear system analysis was carried out for a standard flat panel detector (FPD) (194-micron pixel pitch and 600-micron thick CsI) and a newly-developed, high-resolution, micro-angiographic fluoroscope (MAF) (35-micron pixel pitch and 300-micron thick CsI). Realistic clinical parameters and x-ray spectra were used. The 2D detector MTFs were calculated using the new Noise Response method and slanted edge method and 2D focal spot distribution measurements were done using a pin-hole assembly. The scatter fraction, generated for a uniform head equivalent phantom, was measured and the scatter MTF was simulated with a theoretical model. Different magnifications and scatter fractions were used to estimate the 2D GMTF, GNNPS and GDQE for both detectors. Results show spatial non-isotropy for the 2D generalized metrics which provide a quantitative description of the performance of the complete imaging system for both detectors. This generalized analysis demonstrated that the MAF and FPD have similar capabilities at lower spatial frequencies, but that the MAF has superior performance over the FPD at higher frequencies even when considering focal spot blurring and scatter. This 2D generalized performance analysis is a valuable tool to evaluate total system capabilities and to enable optimized design for specific imaging tasks.

A comprehensive 1,000 Genomes-based genome-wide association meta-analysis of coronary artery disease.

PubMed

Nikpay, Majid; Goel, Anuj; Won, Hong-Hee; Hall, Leanne M; Willenborg, Christina; Kanoni, Stavroula; Saleheen, Danish; Kyriakou, Theodosios; Nelson, Christopher P; Hopewell, Jemma C; Webb, Thomas R; Zeng, Lingyao; Dehghan, Abbas; Alver, Maris; Armasu, Sebastian M; Auro, Kirsi; Bjonnes, Andrew; Chasman, Daniel I; Chen, Shufeng; Ford, Ian; Franceschini, Nora; Gieger, Christian; Grace, Christopher; Gustafsson, Stefan; Huang, Jie; Hwang, Shih-Jen; Kim, Yun Kyoung; Kleber, Marcus E; Lau, King Wai; Lu, Xiangfeng; Lu, Yingchang; Lyytikäinen, Leo-Pekka; Mihailov, Evelin; Morrison, Alanna C; Pervjakova, Natalia; Qu, Liming; Rose, Lynda M; Salfati, Elias; Saxena, Richa; Scholz, Markus; Smith, Albert V; Tikkanen, Emmi; Uitterlinden, Andre; Yang, Xueli; Zhang, Weihua; Zhao, Wei; de Andrade, Mariza; de Vries, Paul S; van Zuydam, Natalie R; Anand, Sonia S; Bertram, Lars; Beutner, Frank; Dedoussis, George; Frossard, Philippe; Gauguier, Dominique; Goodall, Alison H; Gottesman, Omri; Haber, Marc; Han, Bok-Ghee; Huang, Jianfeng; Jalilzadeh, Shapour; Kessler, Thorsten; König, Inke R; Lannfelt, Lars; Lieb, Wolfgang; Lind, Lars; Lindgren, Cecilia M; Lokki, Marja-Liisa; Magnusson, Patrik K; Mallick, Nadeem H; Mehra, Narinder; Meitinger, Thomas; Memon, Fazal-Ur-Rehman; Morris, Andrew P; Nieminen, Markku S; Pedersen, Nancy L; Peters, Annette; Rallidis, Loukianos S; Rasheed, Asif; Samuel, Maria; Shah, Svati H; Sinisalo, Juha; Stirrups, Kathleen E; Trompet, Stella; Wang, Laiyuan; Zaman, Khan S; Ardissino, Diego; Boerwinkle, Eric; Borecki, Ingrid B; Bottinger, Erwin P; Buring, Julie E; Chambers, John C; Collins, Rory; Cupples, L Adrienne; Danesh, John; Demuth, Ilja; Elosua, Roberto; Epstein, Stephen E; Esko, Tõnu; Feitosa, Mary F; Franco, Oscar H; Franzosi, Maria Grazia; Granger, Christopher B; Gu, Dongfeng; Gudnason, Vilmundur; Hall, Alistair S; Hamsten, Anders; Harris, Tamara B; Hazen, Stanley L; Hengstenberg, Christian; Hofman, Albert; Ingelsson, Erik; Iribarren, Carlos; Jukema, J Wouter; Karhunen, Pekka J; Kim, Bong-Jo; Kooner, Jaspal S; Kullo, Iftikhar J; Lehtimäki, Terho; Loos, Ruth J F; Melander, Olle; Metspalu, Andres; März, Winfried; Palmer, Colin N; Perola, Markus; Quertermous, Thomas; Rader, Daniel J; Ridker, Paul M; Ripatti, Samuli; Roberts, Robert; Salomaa, Veikko; Sanghera, Dharambir K; Schwartz, Stephen M; Seedorf, Udo; Stewart, Alexandre F; Stott, David J; Thiery, Joachim; Zalloua, Pierre A; O'Donnell, Christopher J; Reilly, Muredach P; Assimes, Themistocles L; Thompson, John R; Erdmann, Jeanette; Clarke, Robert; Watkins, Hugh; Kathiresan, Sekar; McPherson, Ruth; Deloukas, Panos; Schunkert, Heribert; Samani, Nilesh J; Farrall, Martin

2015-10-01

Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of ∼185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.

Using ancestry-informative markers to identify fine structure across 15 populations of European origin.

PubMed

Huckins, Laura M; Boraska, Vesna; Franklin, Christopher S; Floyd, James A B; Southam, Lorraine; Sullivan, Patrick F; Bulik, Cynthia M; Collier, David A; Tyler-Smith, Chris; Zeggini, Eleftheria; Tachmazidou, Ioanna

2014-10-01

The Wellcome Trust Case Control Consortium 3 anorexia nervosa genome-wide association scan includes 2907 cases from 15 different populations of European origin genotyped on the Illumina 670K chip. We compared methods for identifying population stratification, and suggest list of markers that may help to counter this problem. It is usual to identify population structure in such studies using only common variants with minor allele frequency (MAF) >5%; we find that this may result in highly informative SNPs being discarded, and suggest that instead all SNPs with MAF >1% may be used. We established informative axes of variation identified via principal component analysis and highlight important features of the genetic structure of diverse European-descent populations, some studied for the first time at this scale. Finally, we investigated the substructure within each of these 15 populations and identified SNPs that help capture hidden stratification. This work can provide information regarding the designing and interpretation of association results in the International Consortia.

Fibroblast growth factor receptor signaling is essential for lens fiber cell differentiation.

PubMed

Zhao, Haotian; Yang, Tianyu; Madakashira, Bhavani P; Thiels, Cornelius A; Bechtle, Chad A; Garcia, Claudia M; Zhang, Huiming; Yu, Kai; Ornitz, David M; Beebe, David C; Robinson, Michael L

2008-06-15

The vertebrate lens provides an excellent model to study the mechanisms that regulate terminal differentiation. Although fibroblast growth factors (FGFs) are thought to be important for lens cell differentiation, it is unclear which FGF receptors mediate these processes during different stages of lens development. Deletion of three FGF receptors (Fgfr1-3) early in lens development demonstrated that expression of only a single allele of Fgfr2 or Fgfr3 was sufficient for grossly normal lens development, while mice possessing only a single Fgfr1 allele developed cataracts and microphthalmia. Profound defects were observed in lenses lacking all three Fgfrs. These included lack of fiber cell elongation, abnormal proliferation in prospective lens fiber cells, reduced expression of the cell cycle inhibitors p27(kip1) and p57(kip2), increased apoptosis and aberrant or reduced expression of Prox1, Pax6, c-Maf, E-cadherin and alpha-, beta- and gamma-crystallins. Therefore, while signaling by FGF receptors is essential for lens fiber differentiation, different FGF receptors function redundantly.

Variation in PTCHD2, CRISP3, NAP1L4, FSCB, and AP3B2 associated with spherical equivalent.

PubMed

Chen, Fei; Duggal, Priya; Klein, Barbara E K; Lee, Kristine E; Truitt, Barbara; Klein, Ronald; Iyengar, Sudha K; Klein, Alison P

2016-01-01

Ocular refraction is measured in spherical equivalent as the power of the external lens required to focus images on the retina. Myopia (nearsightedness) and hyperopia (farsightedness) are the most common refractive errors, and the leading causes of visual impairment and blindness in the world. The goal of this study is to identify rare and low-frequency variants that influence spherical equivalent. We conducted variant-level and gene-level quantitative trait association analyses for mean spherical equivalent, using data from 1,560 individuals in the Beaver Dam Eye Study. Genotyping was conducted using the Illumina exome array. We analyzed 34,976 single nucleotide variants and 11,571 autosomal genes across the genome, using single-variant tests as well as gene-based tests. Spherical equivalent was significantly associated with five genes in gene-based analysis: PTCHD2 at 1p36.22 (p = 3.6 × 10(-7)), CRISP3 at 6p12.3 (p = 4.3 × 10(-6)), NAP1L4 at 11p15.5 (p = 3.6 × 10(-6)), FSCB at 14q21.2 (p = 1.5 × 10(-7)), and AP3B2 at 15q25.2 (p = 1.6 × 10(-7)). The variant-based tests identified evidence suggestive of association with two novel variants in linkage disequilibrium (pairwise r(2) = 0.80) in the TCTE1 gene region at 6p21.1 (rs2297336, minor allele frequency (MAF) = 14.1%, β = -0.62 p = 3.7 × 10(-6); rs324146, MAF = 16.9%, β = -0.55, p = 1.4 × 10(-5)). In addition to these novel findings, we successfully replicated a previously reported association with rs634990 near GJD2 at 15q14 (MAF = 47%, β = -0.29, p=1.8 × 10(-3)). We also found evidence of association with spherical equivalent on 2q37.1 in PRSS56 at rs1550094 (MAF = 31%, β = -0.33, p = 1.7 × 10(-3)), a region previously associated with myopia. We identified several novel candidate genes that may play a role in the control of spherical equivalent. However, further studies are needed to replicate these findings. In addition, our results contribute to the increasing evidence that variation in the GJD2 and PRSS56 genes influence the development of refractive errors. Identifying that variation in these genes is associated with spherical equivalent may provide further insight into the etiology of myopia and consequent vision loss.

Distributed and dynamic intracellular organization of extracellular information.

PubMed

Granados, Alejandro A; Pietsch, Julian M J; Cepeda-Humerez, Sarah A; Farquhar, Iseabail L; Tkačik, Gašper; Swain, Peter S

2018-06-05

Although cells respond specifically to environments, how environmental identity is encoded intracellularly is not understood. Here, we study this organization of information in budding yeast by estimating the mutual information between environmental transitions and the dynamics of nuclear translocation for 10 transcription factors. Our method of estimation is general, scalable, and based on decoding from single cells. The dynamics of the transcription factors are necessary to encode the highest amounts of extracellular information, and we show that information is transduced through two channels: Generalists (Msn2/4, Tod6 and Dot6, Maf1, and Sfp1) can encode the nature of multiple stresses, but only if stress is high; specialists (Hog1, Yap1, and Mig1/2) encode one particular stress, but do so more quickly and for a wider range of magnitudes. In particular, Dot6 encodes almost as much information as Msn2, the master regulator of the environmental stress response. Each transcription factor reports differently, and it is only their collective behavior that distinguishes between multiple environmental states. Changes in the dynamics of the localization of transcription factors thus constitute a precise, distributed internal representation of extracellular change. We predict that such multidimensional representations are common in cellular decision-making.

Sangivamycin-Like Molecule 6 (SLM6) exhibits potent anti-multiple myeloma activity through inhibition of cyclin-dependent kinase-9 (CDK9)

PubMed Central

Dolloff, Nathan G.; Allen, Joshua E.; Dicker, David T.; Aqui, Nicole; Vogl, Dan; Malysz, Jozef; Talamo, Giampaolo; El-Deiry, Wafik S.

2012-01-01

Despite significant treatment advances over the past decade, multiple myeloma (MM) remains largely incurable. In this study we found that MM cells were remarkably sensitive to the death-inducing effects of a new class of sangivamycin-like molecules (SLMs). A panel of structurally related SLMs selectively induced apoptosis in MM cells but not other tumor or non-malignant cell lines at sub-micromolar concentrations. SLM6 was the most active compound in vivo, where it was well-tolerated and significantly inhibited growth and induced apoptosis of MM tumors. We determined that the anti-MM activity of SLM6 was mediated by direct inhibition of cyclin-dependent kinase 9 (CDK9), which resulted in transcriptional repression of oncogenes that are known to drive MM progression (c-Maf, cyclin D1, and c-Myc). Furthermore, SLM6 demonstrated superior in vivo anti-MM activity over the CDK inhibitor flavopiridol, which is currently in clinical trials for MM. These findings demonstrate that SLM6 is a novel CDK9 inhibitor with promising preclinical activity as an anti-MM agent. PMID:22964485

Issues in HRD. Symposium.

ERIC Educational Resources Information Center

2002

This document contains four papers on issues in human resource development (HRD). "Employability By Sector of Industry: Taking Account of Supply and Demand Characteristics (Andries de Grip, Jasper B. van Loo, Jos M.A.F. Sanders) reports on development of an Industry Employability Index that integrates both supply and demand determinants of…

43 CFR 414.2 - Definitions of terms used in this part.

Code of Federal Regulations, 2012 CFR

2012-10-01

... by the Secretary of the Interior, to satisfy 7.5 million acre-feet (maf) of annual consumptive use in... reservation of water from the Secretary. Intentionally created unused apportionment or ICUA means unused... have been pumped and consumed. Secretary means the Secretary of the Interior or an authorized...

43 CFR 414.2 - Definitions of terms used in this part.

Code of Federal Regulations, 2013 CFR

2013-10-01

... by the Secretary of the Interior, to satisfy 7.5 million acre-feet (maf) of annual consumptive use in... reservation of water from the Secretary. Intentionally created unused apportionment or ICUA means unused... have been pumped and consumed. Secretary means the Secretary of the Interior or an authorized...

75 FR 2850 - Submission for OMB Review; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2010-01-19

... Referencing (TIGER) database of address ranges and associated geographic information. The Census Bureau plans... areas with high concentrations of noncity- style addresses, and to provide a rural counterpart to the update of city-style addresses the MAF receives from the U.S. Postal Services's Delivery Sequence File...

The organoid-initiating cells in mouse pancreas and liver are phenotypically and functionally similar

PubMed Central

Dorrell, Craig; Tarlow, Branden; Wang, Yuhan; Canaday, Pamela S; Haft, Annelise; Schug, Jonathan; Streeter, Philip R; Finegold, Milton J; Shenje, Lincoln T; Kaestner, Klaus H; Grompe, Markus

2014-01-01

Pancreatic Lgr5 expression has been associated with organoid-forming epithelial progenitor populations but the identity of the organoid-initiating epithelial cell subpopulation has remained elusive. Injury causes the emergence of an Lgr5+ organoid-forming epithelial progenitor population in the adult mouse liver and pancreas. Here, we define the origin of organoid-initiating cells from mouse pancreas and liver prior to Lgr5 activation. This clonogenic population was defined as MIC1-1C3+/CD133+/CD26− in both tissues and the frequency of organoid initiation within this population was approximately 5% in each case. The transcriptomes of these populations overlapped extensively and showed enrichment of epithelial progenitor-associated regulatory genes such as Sox9 and FoxJ1. Surprisingly, pancreatic organoid cells also had the capacity to generate hepatocyte-like cells upon transplantation to Fah-/- mice, indicating a differentiation capacity similar to hepatic organoids. Although spontaneous endocrine differentiation of pancreatic progenitors was not observed in culture, adenoviral delivery of fate-specifying factors Pdx1, Neurog3 and MafA induced insulin expression without glucagon or somatostatin. Pancreatic organoid cultures therefore preserve many key attributes of progenitor cells while allowing unlimited expansion, facilitating the study of fate determination. PMID:25151611

78 FR 22511 - Submission for OMB Review; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2013-04-16

... evaluation. In years past, the Census Bureau collected the long-form data only once every ten years and it... methodology to collect and update demographic, social, economic, and housing data every year that are... File (MAF) from the decennial census, which is updated each year, we select a sample of addresses and...

Coal liquefaction process

DOEpatents

Carr, Norman L.; Moon, William G.; Prudich, Michael E.

1983-01-01

A C.sub.5 -900.degree. F. (C.sub.5 -482.degree. C.) liquid yield greater than 50 weight percent MAF feed coal is obtained in a coal liquefaction process wherein a selected combination of higher hydrogen partial pressure, longer slurry residence time and increased recycle ash content of the feed slurry are controlled within defined ranges.

Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure underpinning obesity

PubMed Central

Turcot, Valérie; Lu, Yingchang; Highland, Heather M; Schurmann, Claudia; Justice, Anne E; Fine, Rebecca S; Bradfield, Jonathan P; Esko, Tõnu; Giri, Ayush; Graff, Mariaelisa; Guo, Xiuqing; Hendricks, Audrey E; Karaderi, Tugce; Lempradl, Adelheid; Locke, Adam E; Mahajan, Anubha; Marouli, Eirini; Sivapalaratnam, Suthesh; Young, Kristin L; Alfred, Tamuno; Feitosa, Mary F; Masca, Nicholas GD; Manning, Alisa K; Medina-Gomez, Carolina; Mudgal, Poorva; Ng, Maggie CY; Reiner, Alex P; Vedantam, Sailaja; Willems, Sara M; Winkler, Thomas W; Abecasis, Goncalo; Aben, Katja K; Alam, Dewan S; Alharthi, Sameer E; Allison, Matthew; Amouyel, Philippe; Asselbergs, Folkert W; Auer, Paul L; Balkau, Beverley; Bang, Lia E; Barroso, Inês; Bastarache, Lisa; Benn, Marianne; Bergmann, Sven; Bielak, Lawrence F; Blüher, Matthias; Boehnke, Michael; Boeing, Heiner; Boerwinkle, Eric; Böger, Carsten A; Bork-Jensen, Jette; Bots, Michiel L; Bottinger, Erwin P; Bowden, Donald W; Brandslund, Ivan; Breen, Gerome; Brilliant, Murray H; Broer, Linda; Brumat, Marco; Burt, Amber A; Butterworth, Adam S; Campbell, Peter T; Cappellani, Stefania; Carey, David J; Catamo, Eulalia; Caulfield, Mark J; Chambers, John C; Chasman, Daniel I; Chen, Yii-Der Ida; Chowdhury, Rajiv; Christensen, Cramer; Chu, Audrey Y; Cocca, Massimiliano; Collins, Francis S; Cook, James P; Corley, Janie; Galbany, Jordi Corominas; Cox, Amanda J; Crosslin, David S; Cuellar-Partida, Gabriel; D'Eustacchio, Angela; Danesh, John; Davies, Gail; de Bakker, Paul IW; de Groot, Mark CH; de Mutsert, Renée; Deary, Ian J; Dedoussis, George; Demerath, Ellen W; den Heijer, Martin; den Hollander, Anneke I; den Ruijter, Hester M; Dennis, Joe G; Denny, Josh C; Di Angelantonio, Emanuele; Drenos, Fotios; Du, Mengmeng; Dubé, Marie-Pierre; Dunning, Alison M; Easton, Douglas F; Edwards, Todd L; Ellinghaus, David; Ellinor, Patrick T; Elliott, Paul; Evangelou, Evangelos; Farmaki, Aliki-Eleni; Farooqi, I. Sadaf; Faul, Jessica D; Fauser, Sascha; Feng, Shuang; Ferrannini, Ele; Ferrieres, Jean; Florez, Jose C; Ford, Ian; Fornage, Myriam; Franco, Oscar H; Franke, Andre; Franks, Paul W; Friedrich, Nele; Frikke-Schmidt, Ruth; Galesloot, Tessel E.; Gan, Wei; Gandin, Ilaria; Gasparini, Paolo; Gibson, Jane; Giedraitis, Vilmantas; Gjesing, Anette P; Gordon-Larsen, Penny; Gorski, Mathias; Grabe, Hans-Jörgen; Grant, Struan FA; Grarup, Niels; Griffiths, Helen L; Grove, Megan L; Gudnason, Vilmundur; Gustafsson, Stefan; Haessler, Jeff; Hakonarson, Hakon; Hammerschlag, Anke R; Hansen, Torben; Harris, Kathleen Mullan; Harris, Tamara B; Hattersley, Andrew T; Have, Christian T; Hayward, Caroline; He, Liang; Heard-Costa, Nancy L; Heath, Andrew C; Heid, Iris M; Helgeland, Øyvind; Hernesniemi, Jussi; Hewitt, Alex W; Holmen, Oddgeir L; Hovingh, G Kees; Howson, Joanna MM; Hu, Yao; Huang, Paul L; Huffman, Jennifer E; Ikram, M Arfan; Ingelsson, Erik; Jackson, Anne U; Jansson, Jan-Håkan; Jarvik, Gail P; Jensen, Gorm B; Jia, Yucheng; Johansson, Stefan; Jørgensen, Marit E; Jørgensen, Torben; Jukema, J Wouter; Kahali, Bratati; Kahn, René S; Kähönen, Mika; Kamstrup, Pia R; Kanoni, Stavroula; Kaprio, Jaakko; Karaleftheri, Maria; Kardia, Sharon LR; Karpe, Fredrik; Kathiresan, Sekar; Kee, Frank; Kiemeney, Lambertus A; Kim, Eric; Kitajima, Hidetoshi; Komulainen, Pirjo; Kooner, Jaspal S; Kooperberg, Charles; Korhonen, Tellervo; Kovacs, Peter; Kuivaniemi, Helena; Kutalik, Zoltán; Kuulasmaa, Kari; Kuusisto, Johanna; Laakso, Markku; Lakka, Timo A; Lamparter, David; Lange, Ethan M; Lange, Leslie A; Langenberg, Claudia; Larson, Eric B; Lee, Nanette R; Lehtimäki, Terho; Lewis, Cora E; Li, Huaixing; Li, Jin; Li-Gao, Ruifang; Lin, Honghuang; Lin, Keng-Hung; Lin, Li-An; Lin, Xu; Lind, Lars; Lindström, Jaana; Linneberg, Allan; Liu, Ching-Ti; Liu, Dajiang J; Liu, Yongmei; Lo, Ken Sin; Lophatananon, Artitaya; Lotery, Andrew J; Loukola, Anu; Luan, Jian'an; Lubitz, Steven A; Lyytikäinen, Leo-Pekka; Männistö, Satu; Marenne, Gaëlle; Mazul, Angela L; McCarthy, Mark I; McKean-Cowdin, Roberta; Medland, Sarah E; Meidtner, Karina; Milani, Lili; Mistry, Vanisha; Mitchell, Paul; Mohlke, Karen L; Moilanen, Leena; Moitry, Marie; Montgomery, Grant W; Mook-Kanamori, Dennis O; Moore, Carmel; Mori, Trevor A; Morris, Andrew D; Morris, Andrew P; Müller-Nurasyid, Martina; Munroe, Patricia B; Nalls, Mike A; Narisu, Narisu; Nelson, Christopher P; Neville, Matt; Nielsen, Sune F; Nikus, Kjell; Njølstad, Pål R; Nordestgaard, Børge G; Nyholt, Dale R; O'Connel, Jeffrey R; O’Donoghue, Michelle L.; Olde Loohuis, Loes M; Ophoff, Roel A; Owen, Katharine R; Packard, Chris J; Padmanabhan, Sandosh; Palmer, Colin NA; Palmer, Nicholette D; Pasterkamp, Gerard; Patel, Aniruddh P; Pattie, Alison; Pedersen, Oluf; Peissig, Peggy L; Peloso, Gina M; Pennell, Craig E; Perola, Markus; Perry, James A; Perry, John RB; Pers, Tune H; Person, Thomas N; Peters, Annette; Petersen, Eva RB; Peyser, Patricia A; Pirie, Ailith; Polasek, Ozren; Polderman, Tinca J; Puolijoki, Hannu; Raitakari, Olli T; Rasheed, Asif; Rauramaa, Rainer; Reilly, Dermot F; Renström, Frida; Rheinberger, Myriam; Ridker, Paul M; Rioux, John D; Rivas, Manuel A; Roberts, David J; Robertson, Neil R; Robino, Antonietta; Rolandsson, Olov; Rudan, Igor; Ruth, Katherine S; Saleheen, Danish; Salomaa, Veikko; Samani, Nilesh J; Sapkota, Yadav; Sattar, Naveed; Schoen, Robert E; Schreiner, Pamela J; Schulze, Matthias B; Scott, Robert A; Segura-Lepe, Marcelo P; Shah, Svati H; Sheu, Wayne H-H; Sim, Xueling; Slater, Andrew J; Small, Kerrin S; Smith, Albert Vernon; Southam, Lorraine; Spector, Timothy D; Speliotes, Elizabeth K; Starr, John M; Stefansson, Kari; Steinthorsdottir, Valgerdur; Stirrups, Kathleen E; Strauch, Konstantin; Stringham, Heather M; Stumvoll, Michael; Sun, Liang; Surendran, Praveen; Swift, Amy J; Tada, Hayato; Tansey, Katherine E; Tardif, Jean-Claude; Taylor, Kent D; Teumer, Alexander; Thompson, Deborah J; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Thuesen, Betina H; Tönjes, Anke; Tromp, Gerard; Trompet, Stella; Tsafantakis, Emmanouil; Tuomilehto, Jaakko; Tybjaerg-Hansen, Anne; Tyrer, Jonathan P; Uher, Rudolf; Uitterlinden, André G; Uusitupa, Matti; van der Laan, Sander W; van Duijn, Cornelia M; van Leeuwen, Nienke; van Setten, Jessica; Vanhala, Mauno; Varbo, Anette; Varga, Tibor V; Varma, Rohit; Velez Edwards, Digna R; Vermeulen, Sita H; Veronesi, Giovanni; Vestergaard, Henrik; Vitart, Veronique; Vogt, Thomas F; Völker, Uwe; Vuckovic, Dragana; Wagenknecht, Lynne E; Walker, Mark; Wallentin, Lars; Wang, Feijie; Wang, Carol A; Wang, Shuai; Wang, Yiqin; Ware, Erin B; Wareham, Nicholas J; Warren, Helen R; Waterworth, Dawn M; Wessel, Jennifer; White, Harvey D; Willer, Cristen J; Wilson, James G; Witte, Daniel R; Wood, Andrew R; Wu, Ying; Yaghootkar, Hanieh; Yao, Jie; Yao, Pang; Yerges-Armstrong, Laura M; Young, Robin; Zeggini, Eleftheria; Zhan, Xiaowei; Zhang, Weihua; Zhao, Jing Hua; Zhao, Wei; Zhao, Wei; Zhou, Wei; Zondervan, Krina T; Rotter, Jerome I; Pospisilik, John A; Rivadeneira, Fernando; Borecki, Ingrid B; Deloukas, Panos; Frayling, Timothy M; Lettre, Guillaume; North, Kari E; Lindgren, Cecilia M; Hirschhorn, Joel N; Loos, Ruth JF

2018-01-01

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, non-coding variants from which pinpointing causal genes remains challenging. Here, we combined data from 718,734 individuals to discover rare and low-frequency (MAF<5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which eight in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2, ZNF169) newly implicated in human obesity, two (MC4R, KSR2) previously observed in extreme obesity, and two variants in GIPR. Effect sizes of rare variants are ~10 times larger than of common variants, with the largest effect observed in carriers of an MC4R stop-codon (p.Tyr35Ter, MAF=0.01%), weighing ~7kg more than non-carriers. Pathway analyses confirmed enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically-supported therapeutic targets to treat obesity. PMID:29273807

Efficacy of sodium hypochlorite, ethylenediaminetetraacetic acid, citric acid and phosphoric acid in calcium hydroxide removal from the root canal: a microscopic cleanliness evaluation.

PubMed

da Silva, Juliana Melo; Silveira, Amanda; Santos, Elizandra; Prado, Laiìs; Pessoa, Oscar F

2011-12-01

Rooted molars were subjected to standardized canal instrumentation to a master apical file (MAF). The samples were dressed with Ca(OH)(2), and after 7 days, teeth were reopened and Ca(OH)(2) medication was removed by 1 of 4 different experimental procedures: 2.5% sodium hypochlorite (NaOCl) (n = 10); 17% EDTA-T (n = 10); 10% citric acid (n = 10); or 37% phosphoric acid (n = 10). This was followed by reinstrumentation with MAF plus 15 mL saline solution. The roots were prepared for scanning electron microscopic analysis of the cervical, middle, and apical thirds. Statistical analysis was performed with the Kruskal-Wallis test. EDTA-T and phosphoric acid gave the best results in the apical third, with significant statistical differences compared with other groups. NaOCl gave the worst results. Irrigation with 17% EDTA-T and 37% phosphoric acid is more effective than sodium hypochlorite and citric acid in the removal of calcium hydroxide from the apical third. Copyright © 2011 Mosby, Inc. All rights reserved.

Cancer genes mutation profiling in calcifying epithelial odontogenic tumour.

PubMed

de Sousa, Sílvia Ferreira; Diniz, Marina Gonçalves; França, Josiane Alves; Fontes Pereira, Thaís Dos Santos; Moreira, Rennan Garcias; Santos, Jean Nunes Dos; Gomez, Ricardo Santiago; Gomes, Carolina Cavalieri

2018-03-01

To identify calcifying epithelial odontogenic tumour (CEOT) mutations in oncogenes and tumour suppressor genes. A panel of 50 genes commonly mutated in cancer was sequenced in CEOT by next-generation sequencing. Sanger sequencing was used to cover the region of the frameshift deletion identified in one sample. Missense single nucleotide variants (SNVs) with minor allele frequency (MAF) <1% were detected in PTEN , MET and JAK3 . A frameshift deletion in CDKN2A occurred in association with a missense mutation in the same gene region, suggesting a second hit in the inactivation of this gene. APC, KDR, KIT, PIK3CA and TP53 missense SNVs were identified; however, these are common SNVs, showing MAF >1%. CEOT harbours mutations in the tumour suppressor PTEN and CDKN2A and in the oncogenes JAK3 and MET . As these mutations occurred in only one case each, they are probably not driver mutations for these tumours. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Effect of variable soil texture, metal saturation of soil organic matter (SOM) and tree species composition on spatial distribution of SOM in forest soils in Poland.

PubMed

Gruba, Piotr; Socha, Jarosław; Błońska, Ewa; Lasota, Jarosław

2015-07-15

In this study we investigated the effect of fine (ϕ<0.05mm) fraction, i.e., silt+clay (FF) content in soils, site moisture, metal (Al and Fe) of soil organic matter (SOM) and forest species composition on the spatial distribution of carbon (C) pools in forest soils at the landscape scale. We established 275 plots in regular 200×200m grid in a forested area of 14.4km(2). Fieldwork included soil sampling of the organic horizon, mineral topsoil and subsoil down to 40cm deep. We analysed the vertical and horizontal distribution of soil organic carbon (SOC) stocks, as well as the quantity of physically separated fractions including the free light (fLF), occluded light (oLF) and mineral associated fractions (MAF) in the mineral topsoil (A, AE) horizons. Distribution of C in soils was predominantly affected by the variation in the FF content. In soils richer in the FF more SOC was accumulated in mineral horizons and less in the organic horizons. Accumulation of SOC in mineral soil was also positively affected by the degree of saturation of SOM with Al and Fe. The increasing share of beech influenced the distribution of C stock in soil profiles by reducing the depth of O horizon and increasing C stored in mineral soil. The content of FF was positively correlated with the content of C in MAF and fLF fractions. The content of oLF and MAF fractions was also positively influenced by a higher degree of metal saturation, particularly Al. Our results confirmed that Al plays an important role in the stabilization of SOM inside aggregates (CoLF) and as in CMAF fractions. We also found a significant, positive effect of beech on the CfLF and fir on the CoLF content. Copyright © 2015 Elsevier B.V. All rights reserved.

Self-management of fatigue in rheumatoid arthritis: a randomised controlled trial of group cognitive-behavioural therapy

PubMed Central

Hewlett, Sarah; Ambler, Nick; Almeida, Celia; Cliss, Alena; Hammond, Alison; Kitchen, Karen; Knops, Bev; Pope, Denise; Spears, Melissa; Swinkels, Annette; Pollock, Jon

2011-01-01

Objectives To investigate the effect of group cognitive behavioural therapy (CBT) for fatigue self-management, compared with groups receiving fatigue information alone, on fatigue impact among people with rheumatoid arthritis (RA). Methods Two-arm, parallel randomised controlled trial in adults with RA, fatigue ≥6/10 (Visual Analogue Scale (VAS) 0–10, high bad) and no recent change in RA medication. Group CBT for fatigue self-management comprised six (weekly) 2 h sessions, and consolidation session (week 14). Control participants received fatigue self-management information in a 1 h didactic group session. Primary outcome at 18 weeks was the impact of fatigue measured using two methods (Multi-dimensional Assessment of Fatigue (MAF) 0–50; VAS 0–10), analysed using intention-to-treat analysis of covariance with multivariable regression models. Results Of 168 participants randomised, 41 withdrew before entry and 127 participated. There were no major baseline differences between the 65 CBT and 62 control participants. At 18 weeks CBT participants reported better scores than control participants for fatigue impact: MAF 28.99 versus 23.99 (adjusted difference −5.48, 95% CI −9.50 to −1.46, p=0.008); VAS 5.99 versus 4.26 (adjusted difference −1.95, 95% CI −2.99 to −0.90, p<0.001). Standardised effect sizes for fatigue impact were MAF 0.59 (95% CI 0.15 to 1.03) and VAS 0.77 (95% CI 0.33 to 1.21), both in favour of CBT. Secondary outcomes of perceived fatigue severity, coping, disability, depression, helplessness, self-efficacy and sleep were also better in CBT participants. Conclusions Group CBT for fatigue self-management in RA improves fatigue impact, coping and perceived severity, and well-being. Trial registration: ISRCTN 32195100 PMID:21540202

Extremely hypomorphic and severe deep intronic variants in the ABCA4 locus result in varying Stargardt disease phenotypes.

PubMed

Zernant, Jana; Lee, Winston; Nagasaki, Takayuki; Collison, Frederick T; Fishman, Gerald A; Bertelsen, Mette; Rosenberg, Thomas; Gouras, Peter; Tsang, Stephen H; Allikmets, Rando

2018-05-30

Autosomal recessive Stargardt disease (STGD1, MIM 248200) is caused by mutations in the ABCA4 gene. Complete sequencing of the ABCA4 locus in STGD1 patients identifies two expected disease-causing alleles in ~75% of patients and only one mutation in ~15% of patients. Recently, many possibly pathogenic variants in deep intronic sequences of ABCA4 have been identified in the latter group. We extended our analyses of deep intronic ABCA4 variants and determined that one of these, c.4253+43G>A (rs61754045), is present in 29/1155 (2.6%) of STGD1 patients. The variant is found at statistically significantly higher frequency in patients with only one pathogenic ABCA4 allele, 23/160 (14.38%), MAF=0.072, compared to MAF=0.013 in all STGD1 cases and MAF=0.006 in the matching general population (P<1x10-7). The variant, which is not predicted to have any effect on splicing, is the first reported intronic "extremely hypomorphic allele" in the ABCA4 locus; i.e., it is pathogenic only when in trans with a loss-of-function ABCA4 allele. It results in a distinct clinical phenotype characterized by late-onset of symptoms and foveal sparing. In ~70% of cases the variant was allelic with the c.6006-609T>A (rs575968112) variant, which was deemed non-pathogenic. Another rare deep intronic variant, c.5196+1056A>G (rs886044749), found in 5/834 (0.6%) of STGD1 cases is, conversely, a severe allele. This study determines pathogenicity for three non-coding variants in STGD1 patients of European descent accounting for ~3% of the disease. Defining disease-associated alleles in the non-coding sequences of the ABCA4 locus can be accomplished by integrated clinical and genetic analyses. Cold Spring Harbor Laboratory Press.

Meta-genome-wide association studies identify a locus on chromosome 1 and multiple variants in the MHC region for serum C-peptide in type 1 diabetes.

PubMed

Roshandel, Delnaz; Gubitosi-Klug, Rose; Bull, Shelley B; Canty, Angelo J; Pezzolesi, Marcus G; King, George L; Keenan, Hillary A; Snell-Bergeon, Janet K; Maahs, David M; Klein, Ronald; Klein, Barbara E K; Orchard, Trevor J; Costacou, Tina; Weedon, Michael N; Oram, Richard A; Paterson, Andrew D

2018-05-01

The aim of this study was to identify genetic variants associated with beta cell function in type 1 diabetes, as measured by serum C-peptide levels, through meta-genome-wide association studies (meta-GWAS). We performed a meta-GWAS to combine the results from five studies in type 1 diabetes with cross-sectionally measured stimulated, fasting or random C-peptide levels, including 3479 European participants. The p values across studies were combined, taking into account sample size and direction of effect. We also performed separate meta-GWAS for stimulated (n = 1303), fasting (n = 2019) and random (n = 1497) C-peptide levels. In the meta-GWAS for stimulated/fasting/random C-peptide levels, a SNP on chromosome 1, rs559047 (Chr1:238753916, T>A, minor allele frequency [MAF] 0.24-0.26), was associated with C-peptide (p = 4.13 × 10 -8 ), meeting the genome-wide significance threshold (p < 5 × 10 -8 ). In the same meta-GWAS, a locus in the MHC region (rs9260151) was close to the genome-wide significance threshold (Chr6:29911030, C>T, MAF 0.07-0.10, p = 8.43 × 10 -8 ). In the stimulated C-peptide meta-GWAS, rs61211515 (Chr6:30100975, T/-, MAF 0.17-0.19) in the MHC region was associated with stimulated C-peptide (β [SE] = - 0.39 [0.07], p = 9.72 × 10 -8 ). rs61211515 was also associated with the rate of stimulated C-peptide decline over time in a subset of individuals (n = 258) with annual repeated measures for up to 6 years (p = 0.02). In the meta-GWAS of random C-peptide, another MHC region, SNP rs3135002 (Chr6:32668439, C>A, MAF 0.02-0.06), was associated with C-peptide (p = 3.49 × 10 -8 ). Conditional analyses suggested that the three identified variants in the MHC region were independent of each other. rs9260151 and rs3135002 have been associated with type 1 diabetes, whereas rs559047 and rs61211515 have not been associated with a risk of developing type 1 diabetes. We identified a locus on chromosome 1 and multiple variants in the MHC region, at least some of which were distinct from type 1 diabetes risk loci, that were associated with C-peptide, suggesting partly non-overlapping mechanisms for the development and progression of type 1 diabetes. These associations need to be validated in independent populations. Further investigations could provide insights into mechanisms of beta cell loss and opportunities to preserve beta cell function.

Variation in PTCHD2, CRISP3, NAP1L4, FSCB, and AP3B2 associated with spherical equivalent

PubMed Central

Chen, Fei; Duggal, Priya; Klein, Barbara E.K.; Lee, Kristine E.; Truitt, Barbara; Klein, Ronald; Iyengar, Sudha K.

2016-01-01

Purpose Ocular refraction is measured in spherical equivalent as the power of the external lens required to focus images on the retina. Myopia (nearsightedness) and hyperopia (farsightedness) are the most common refractive errors, and the leading causes of visual impairment and blindness in the world. The goal of this study is to identify rare and low-frequency variants that influence spherical equivalent. Methods We conducted variant-level and gene-level quantitative trait association analyses for mean spherical equivalent, using data from 1,560 individuals in the Beaver Dam Eye Study. Genotyping was conducted using the Illumina exome array. We analyzed 34,976 single nucleotide variants and 11,571 autosomal genes across the genome, using single-variant tests as well as gene-based tests. Results Spherical equivalent was significantly associated with five genes in gene-based analysis: PTCHD2 at 1p36.22 (p = 3.6 × 10−7), CRISP3 at 6p12.3 (p = 4.3 × 10−6), NAP1L4 at 11p15.5 (p = 3.6 × 10−6), FSCB at 14q21.2 (p = 1.5 × 10−7), and AP3B2 at 15q25.2 (p = 1.6 × 10−7). The variant-based tests identified evidence suggestive of association with two novel variants in linkage disequilibrium (pairwise r2 = 0.80) in the TCTE1 gene region at 6p21.1 (rs2297336, minor allele frequency (MAF) = 14.1%, β = –0.62 p = 3.7 × 10−6; rs324146, MAF = 16.9%, β = –0.55, p = 1.4 × 10−5). In addition to these novel findings, we successfully replicated a previously reported association with rs634990 near GJD2 at 15q14 (MAF = 47%, β = –0.29, p=1.8 × 10−3). We also found evidence of association with spherical equivalent on 2q37.1 in PRSS56 at rs1550094 (MAF = 31%, β = –0.33, p = 1.7 × 10−3), a region previously associated with myopia. Conclusions We identified several novel candidate genes that may play a role in the control of spherical equivalent. However, further studies are needed to replicate these findings. In addition, our results contribute to the increasing evidence that variation in the GJD2 and PRSS56 genes influence the development of refractive errors. Identifying that variation in these genes is associated with spherical equivalent may provide further insight into the etiology of myopia and consequent vision loss. PMID:27440996

Design of a Family Study Among High-Risk Caribbean Hispanics: The Northern Manhattan Family Study

PubMed Central

Sacco, Ralph L.; Sabala, Edison A.; Rundek, Tanja; Juo, Suh-Hang Hank; Huang, Jinaping Sam; DiTullio, Marco; Homma, Shunichi; Almonte, Katihurka; Lithgow, Carlos García; Boden-Albala, Bernadette

2008-01-01

Stroke continues to kill disproportionately more Blacks and Hispanics than Whites in the United States. Racial/ethnic variations in the incidence of stroke and prevalence of stroke risk factors are probably explained by both genetic and environmental influences. Family studies can help identify genetic predisposition to stroke and potential stroke precursors. Few studies have evaluated the heritability of these stroke risk factors among non-White populations, and none have focused on Caribbean Hispanic populations. The aim of the Northern Manhattan Family Study (NOMAFS) is to investigate the gene-environment interaction of stroke risk factors among Caribbean Hispanics. The unique recruitment and methodologic approaches used in this study are relevant to the design and conduct of genetic aggregation studies to investigate complex genetic disorders in non-White populations. The aim of this paper is to describe the NOMAFS and report enrollment and characteristics of the participants. The NO-MAFS will provide a data resource for the exploration of the genetic determinants of highly heritable stroke precursor phenotypes that are less complex than the stroke phenotype. Understanding the gene environment interaction is the critical next step toward the development of new and unique approaches to disease prevention and interventions. PMID:17682370

An Experimental Investigation of the Effect of Altered Auditory Feedback on the Conversational Speech of Adults Who Stutter

ERIC Educational Resources Information Center

Lincoln, Michelle; Packman, Ann; Onslow, Mark; Jones, Mark

2010-01-01

Purpose: To investigate the impact on percentage of syllables stuttered of various durations of delayed auditory feedback (DAF), levels of frequency-altered feedback (FAF), and masking auditory feedback (MAF) during conversational speech. Method: Eleven adults who stuttered produced 10-min conversational speech samples during a control condition…

Dehydration-induced endodormancy in crown buds of leafy spurge highlights involvement of MAF3- and RVE1-like homologs, and hormone signaling cross-talk

USDA-ARS?s Scientific Manuscript database

Vegetative shoot growth from underground adventitious buds of leafy spurge is critical for survival of this invasive perennial weed after episodes of severe abiotic stress. To determine the impact that dehydration-stress has on molecular mechanisms associated with vegetative reproduction of leafy sp...

Simulation of introgression of the polled allele into the Holstein breed via conventional breeding versus gene editing

USDA-ARS?s Scientific Manuscript database

The objective of this study was to simulate the introgression of the polled allele into a dairy cattle population and compare the impact of using the methods of conventional breeding versus gene editing to increase the frequency of the polled allele. The rate of minor allele frequency (MAF) change, ...

A DRDC Management Accountability Framework

DTIC Science & Technology

2009-09-01

51 A.2 Cultural Theory: Risk, Blame and Good Governance ................................................. 53 A.3...the MAF. These elements guide good management, enclosing the elements required to make good decisions. 18 In essence, the elements focus on the...of these areas.20 As a guide to good management practices, the elements focus on organizational capacity and capability within a department 21

An Analysis of the Special Landing Force during the Vietnam War from 1965 to 1969

DTIC Science & Technology

2008-01-01

CONSIDERATIONS Extended Operations Ashore 24 Status Quo 26 1969: RETURN TO THE SEA AND OPERATIONAL ASSESSMENTS Deja vu : ; 27 . Varying Opinions .’ 29...THE SEA AND OPERATIONAL ASSESSMENTS Deja vu On the ground, 1969 looked to be yet another year of intense fighting and high operational tempo. III MAF

Saturn Apollo Program

NASA Image and Video Library

1960-01-01

Workers at the Michoud Assembly Facility near New Orleans, Louisiana install the H-1 engines into the S-IB stage, the Saturn IB launch vehicle's first stage. Developed by the Marshall Space Flight Center and built by the Chrysler Corporation at MAF, the 90,000-pound booster utilized eight H-1 engines to produce a combined thrust of 1,600,000 pounds.

Heme Oxygenase-1 Influences Satellite Cells and Progression of Duchenne Muscular Dystrophy in Mice.

PubMed

Pietraszek-Gremplewicz, Katarzyna; Kozakowska, Magdalena; Bronisz-Budzynska, Iwona; Ciesla, Maciej; Mucha, Olga; Podkalicka, Paulina; Madej, Magdalena; Glowniak, Urszula; Szade, Krzysztof; Stepniewski, Jacek; Jez, Mateusz; Andrysiak, Kalina; Bukowska-Strakova, Karolina; Kaminska, Anna; Kostera-Pruszczyk, Anna; Jozkowicz, Alicja; Loboda, Agnieszka; Dulak, Jozef

2018-07-10

Muscle damage in Duchenne muscular dystrophy (DMD) caused by the lack of dystrophin is strongly linked to inflammation. Heme oxygenase-1 (HO-1; Hmox1) is an anti-inflammatory and cytoprotective enzyme affecting myoblast differentiation by inhibiting myomiRs. The role of HO-1 has not been so far well addressed in DMD. In dystrophin-deficient mdx mice, expression of Hmox1 in limb skeletal muscles and diaphragm is higher than in wild-type animals, being consistently elevated from 8 up to 52 weeks, both in myofibers and inflammatory leukocytes. Accordingly, HO-1 expression is induced in muscles of DMD patients. Pharmacological inhibition of HO-1 activity or genetic ablation of Hmox1 aggravates muscle damage and inflammation in mdx mice. Double knockout animals (Hmox1 -/- mdx) demonstrate impaired exercise capacity in comparison with mdx mice. Interestingly, in contrast to the effect observed in muscle fibers, in dystrophin-deficient muscle satellite cells (SCs) expression of Hmox1 is decreased, while MyoD, myogenin, and miR-206 are upregulated compared with wild-type counterparts. Mdx SCs demonstrate disturbed and enhanced differentiation, which is further intensified by Hmox1 deficiency. RNA sequencing revealed downregulation of Atf3, MafK, Foxo1, and Klf2 transcription factors, known to activate Hmox1 expression, as well as attenuation of nitric oxide-mediated cGMP-dependent signaling in mdx SCs. Accordingly, treatment with NO-donor induces Hmox1 expression and inhibits differentiation. Finally, differentiation of mdx SCs was normalized by CO, a product of HO-1 activity. Innovation and Conclusions: HO-1 is induced in DMD, and HO-1 inhibition aggravates DMD pathology. Therefore, HO-1 can be considered a therapeutic target to alleviate this disease. Antioxid. Redox Signal. 00, 000-000.

Regulation of Bach2 by the aryl hydrocarbon receptor as a mechanism for suppression of B-cell differentiation by 2,3,7,8-tetrachlorodibenzo-p-dioxin

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

De Abrew, K. Nadira; Phadnis, Ashwini S.; Genetics Program, Michigan State University, East Lansing, MI 48824

2011-04-15

Exposure to the aryl hydrocarbon receptor (AHR) agonist, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters B-cell differentiation and suppresses antibody production. Previous genomic studies in mouse B cells identified Bach2 as a direct target of the AHR. Bach2 is known to repress expression of Prdm1, a key transcription factor involved in B-cell differentiation, by binding to Maf elements (MAREs) in the regulatory regions of the gene. Chromatin immunoprecipitation followed by quantitative PCR in TCDD-treated lipopolysaccharide (LPS)-activated B cells showed increased binding of the AHR within the first intron in the Bach2 gene. The binding was further confirmed by electrophoretic mobility shift assay (EMSA). TCDDmore » also induced expression of Bach2 in activated as well as resting B cells from 2 to 24 h post-treatment in a time- and concentration-dependent manner. Expression of Prdm1 was decreased by TCDD at 24 h and was consistent with repression by Bach2. Increased DNA binding activity to the intron 5 MARE with increasing TCDD concentrations was observed by EMSA. Supershifts identified the presence of Bach2 in the DNA binding complex associated with the intron 5 MARE of Prdm1. Functional validation of the role of Bach2 in the suppression of B-cell differentiation by TCDD was performed using RNA interference (RNAi). Knockdown of Bach2 showed approximately 40% reversal in the TCDD-induced suppression of IgM secretion when compared to controls. The results suggest that the transcriptional regulation of Bach2 by the AHR is one of the mechanisms involved in the suppression of B-cell differentiation by TCDD.« less

Regulation of Bach2 by the Aryl-hydrocarbon Receptor as a Mechanism for Suppression of B-cell Differentiation by 2,3,7,8-Tetrachlorodibenzo-p-dioxin

PubMed Central

De Abrew, K. Nadira; Phadnis, Ashwini S.; Crawford, Robert B.; Kaminski, Norbert E.; Thomas, Russell S.

2011-01-01

Exposure to the aryl hydrocarbon receptor (AHR) agonist, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), alters B cell differentiation and suppresses antibody production. Previous genomic studies in mouse B cells identified Bach2 as a direct target of the AHR. Bach2 is known to repress expression of Prdm1, a key transcription factor involved in B cell differentiation, by binding to Maf elements (MAREs) in the regulatory regions of the gene. Chromatin immunopreciptiation followed by quantitative PCR in TCDD-treated lipopolysaccharide (LPS)-activated B cells showed increased binding of the AHR within the first intron in the Bach2 gene. The binding was further confirmed by electrophoretic mobility shift assay (EMSA). TCDD also induced expression of Bach2 in activated as well as resting B cells from 2 to 24 h post-treatment in a time and concentration-dependent manner. Expression of Prdm1 was decreased by TCDD at 24 h and was consistent with repression by Bach2. Increased DNA binding activity to the intron 5 MARE with increasing TCDD concentration was observed by EMSA. Supershifts identified the presence of Bach2 in the DNA binding complex associated with the intron5 MARE of Prdm1. Functional validation of the role of Bach2 in the suppression of B-cell differentiation by TCDD was performed using RNAi. Knockdown of Bach2 showed approximately 40% reversal in the TCDD-induced suppression of IgM secretion when compared to controls. The results suggest that the transcriptional regulation of Bach2 by the AHR is one of the mechanisms involved in the suppression of B-cell differentiation by TCDD. PMID:21296099

Minor Allele Frequency Changes the Nature of Genotype by Environment Interactions.

PubMed

Verhulst, Brad; Neale, Michael C

2016-09-01

In the classical twin study, phenotypic variation is often partitioned into additive genetic (A), common (C) and specific environment (E) components. From genetical theory, the outcome of genotype by environment interaction is expected to inflate A when the interacting factor is shared (i.e., C) between the members of a twin pair. We show that estimates of both A and C can be inflated. When the shared interacting factor changes the size of the difference between homozygotes' means, the expected sibling or DZ twin correlation is .5 if and only if the minor allele frequency (MAF) is .5; otherwise the expected DZ correlation is greater than this value, consistent (and confounded) with some additional effect of C. This result is considered in the light of the distribution of minor allele frequencies for polygenic traits. Also discussed is whether such interactions take place at the locus level or affect an aggregated biological structure or system. Interactions with structures or endophenotypes that result from the aggregated effects of many loci will generally emerge as part of the A estimate.

Rare, low frequency and common coding variants in CHRNA5 and their contribution to nicotine dependence in European and African Americans.

PubMed

Olfson, E; Saccone, N L; Johnson, E O; Chen, L-S; Culverhouse, R; Doheny, K; Foltz, S M; Fox, L; Gogarten, S M; Hartz, S; Hetrick, K; Laurie, C C; Marosy, B; Amin, N; Arnett, D; Barr, R G; Bartz, T M; Bertelsen, S; Borecki, I B; Brown, M R; Chasman, D I; van Duijn, C M; Feitosa, M F; Fox, E R; Franceschini, N; Franco, O H; Grove, M L; Guo, X; Hofman, A; Kardia, S L R; Morrison, A C; Musani, S K; Psaty, B M; Rao, D C; Reiner, A P; Rice, K; Ridker, P M; Rose, L M; Schick, U M; Schwander, K; Uitterlinden, A G; Vojinovic, D; Wang, J-C; Ware, E B; Wilson, G; Yao, J; Zhao, W; Breslau, N; Hatsukami, D; Stitzel, J A; Rice, J; Goate, A; Bierut, L J

2016-05-01

The common nonsynonymous variant rs16969968 in the α5 nicotinic receptor subunit gene (CHRNA5) is the strongest genetic risk factor for nicotine dependence in European Americans and contributes to risk in African Americans. To comprehensively examine whether other CHRNA5 coding variation influences nicotine dependence risk, we performed targeted sequencing on 1582 nicotine-dependent cases (Fagerström Test for Nicotine Dependence score⩾4) and 1238 non-dependent controls, with independent replication of common and low frequency variants using 12 studies with exome chip data. Nicotine dependence was examined using logistic regression with individual common variants (minor allele frequency (MAF)⩾0.05), aggregate low frequency variants (0.05>MAF⩾0.005) and aggregate rare variants (MAF<0.005). Meta-analysis of primary results was performed with replication studies containing 12 174 heavy and 11 290 light smokers. Next-generation sequencing with 180 × coverage identified 24 nonsynonymous variants and 2 frameshift deletions in CHRNA5, including 9 novel variants in the 2820 subjects. Meta-analysis confirmed the risk effect of the only common variant (rs16969968, European ancestry: odds ratio (OR)=1.3, P=3.5 × 10(-11); African ancestry: OR=1.3, P=0.01) and demonstrated that three low frequency variants contributed an independent risk (aggregate term, European ancestry: OR=1.3, P=0.005; African ancestry: OR=1.4, P=0.0006). The remaining 22 rare coding variants were associated with increased risk of nicotine dependence in the European American primary sample (OR=12.9, P=0.01) and in the same risk direction in African Americans (OR=1.5, P=0.37). Our results indicate that common, low frequency and rare CHRNA5 coding variants are independently associated with nicotine dependence risk. These newly identified variants likely influence the risk for smoking-related diseases such as lung cancer.

SCREENING LOW FREQUENCY SNPS FROM GENOME WIDE ASSOCIATION STUDY REVEALS A NEW RISK ALLELE FOR PROGRESSION TO AIDS

PubMed Central

Le Clerc, Sigrid; Coulonges, Cédric; Delaneau, Olivier; Van Manen, Danielle; Herbeck, Joshua T.; Limou, Sophie; An, Ping; Martinson, Jeremy J.; Spadoni, Jean-Louis; Therwath, Amu; Veldink, Jan H.; van den Berg, Leonard H.; Taing, Lieng; Labib, Taoufik; Mellak, Safa; Montes, Matthieu; Delfraissy, Jean-François; Schächter, François; Winkler, Cheryl; Froguel, Philippe; Mullins, James I.; Schuitemaker, Hanneke; Zagury, Jean-François

2011-01-01

Background Seven genome-wide association studies (GWAS) have been published in AIDS and only associations in the HLA region on chromosome 6 and CXCR6 have passed genome-wide significance. Methods We reanalyzed the data from three previously published GWAS, targeting specifically low frequency SNPs (minor allele frequency (MAF)<5%). Two groups composed of 365 slow progressors (SP) and 147 rapid progressors (RP) from Europe and the US were compared with a control group of 1394 seronegative individuals using Eigenstrat corrections. Results Of the 8584 SNPs with MAF<5% in cases and controls (Bonferroni threshold=5.8×10−6), four SNPs showed statistical evidence of association with the SP phenotype. The best result was for HCP5 rs2395029 (p=8.54×10−15, OR=3.41) in the HLA locus, in partial linkage disequilibrium with two additional chromosome 6 associations in C6orf48 (p=3.03×10−10, OR=2.9) and NOTCH4 (9.08×10−07, OR=2.32). The fourth association corresponded to rs2072255 located in RICH2 (p=3.30×10−06, OR=0.43) in chromosome 17. Using HCP5 rs2395029 as a covariate, the C6orf48 and NOTCH4 signals disappeared, but the RICH2 signal still remained significant. Conclusion Besides the already known chromosome 6 associations, the analysis of low frequency SNPs brought up a new association in the RICH2 gene. Interestingly, RICH2 interacts with BST-2 known to be a major restriction factor for HIV-1 infection. Our study has thus identified a new candidate gene for AIDS molecular etiology and confirms the interest of singling out low frequency SNPs in order to exploit GWAS data. PMID:21107268

Association Analysis of WNT10B With Bone Mass and Structure Among Individuals of African Ancestry

PubMed Central

Zmuda, Joseph M; Yerges, Laura M; Kammerer, Candace M; Cauley, Jane A; Wang, Xiaojing; Nestlerode, Cara S; Wheeler, Victor W; Patrick, Alan L; Bunker, ClareAnn H; Moffett, Susan P; Ferrell, Robert E

2009-01-01

Wnts comprise a family of secreted growth factors that regulate the development and maintenance of many organs. Recently, Wnt10b was shown to stimulate osteoblastogenesis and bone formation in mice. To evaluate further the role of Wnt10b in bone health in humans, we performed bidirectional sequencing of ∼8 kb of the WNT10B gene region in 192 individuals (96 African, 96 white) to identify single nucleotide polymorphisms (SNPs). We identified 19 SNPs with minor allele frequency (MAF) ≥0.01. Ten of these SNPs were not present in the NCBI dbSNP database (build 127), whereas 10 of the 20 SNPs (50%) reported in dbSNP were not verified. We initially genotyped seven tagging SNPs that captured common (MAF ≥ 0.05) variation in the region with r 2 > 0.80 and a potentially functional SNP in exon 5 in 1035 Afro-Caribbean men ≥40 yr of age. Association analysis showed three SNPs in a 3′ region of linkage disequilibrium that were associated with DXA measures of hip BMD. Associations between two of these three SNPs (rs1051886, rs3741627) with hip BMD were replicated in an additional 980 Afro-Caribbean men (p < 0.05), in the combined sample of 2015 men (p ≤ 0.006), and in 416 individuals ≥18 yr of age (mean, 44 yr) belonging to eight extended, multigenerational Afro-Caribbean families with mean family size >50 (3535 relative pairs; p < 0.05). Further analysis showed that rs1051886 and rs3741627 were associated with cortical cross-sectional area, periosteal circumference, and BMC in the radius, such that individuals with the minor alleles had lower biomechanical indices of long-bone bending strength. This analysis implicates the WNT10B locus as a genetic element in the regulation of bone mass and structural geometry. PMID:19016593

Association analysis of WNT10B with bone mass and structure among individuals of African ancestry.

PubMed

Zmuda, Joseph M; Yerges, Laura M; Kammerer, Candace M; Cauley, Jane A; Wang, Xiaojing; Nestlerode, Cara S; Wheeler, Victor W; Patrick, Alan L; Bunker, ClareAnn H; Moffett, Susan P; Ferrell, Robert E

2009-03-01

Wnts comprise a family of secreted growth factors that regulate the development and maintenance of many organs. Recently, Wnt10b was shown to stimulate osteoblastogenesis and bone formation in mice. To evaluate further the role of Wnt10b in bone health in humans, we performed bidirectional sequencing of approximately 8 kb of the WNT10B gene region in 192 individuals (96 African, 96 white) to identify single nucleotide polymorphisms (SNPs). We identified 19 SNPs with minor allele frequency (MAF) > or =0.01. Ten of these SNPs were not present in the NCBI dbSNP database (build 127), whereas 10 of the 20 SNPs (50%) reported in dbSNP were not verified. We initially genotyped seven tagging SNPs that captured common (MAF > or = 0.05) variation in the region with r (2) > 0.80 and a potentially functional SNP in exon 5 in 1035 Afro-Caribbean men > or =40 yr of age. Association analysis showed three SNPs in a 3' region of linkage disequilibrium that were associated with DXA measures of hip BMD. Associations between two of these three SNPs (rs1051886, rs3741627) with hip BMD were replicated in an additional 980 Afro-Caribbean men (p < 0.05), in the combined sample of 2015 men (p < or = 0.006), and in 416 individuals > or =18 yr of age (mean, 44 yr) belonging to eight extended, multigenerational Afro-Caribbean families with mean family size >50 (3535 relative pairs; p < 0.05). Further analysis showed that rs1051886 and rs3741627 were associated with cortical cross-sectional area, periosteal circumference, and BMC in the radius, such that individuals with the minor alleles had lower biomechanical indices of long-bone bending strength. This analysis implicates the WNT10B locus as a genetic element in the regulation of bone mass and structural geometry.

Formulaic expert method to integrate evaluation and valuation of heritage trees in compact city.

PubMed

Jim, C Y

2006-05-01

Urban trees serve important environmental, social and economic functions, but similar to other natural endowments they are not customarily depicted in monetary terms. The needs to augment protection, funding and community support for urban greening call for proper valuation. Heritage trees (HTs), the cream of urban-tree stock, deserve special attention. Existing assessment methods do not give justice to outstanding trees in compact cities deficient in high-caliber greenery, and to their social-cultural-historical importance. They artificially separate evaluation from valuation, which should be a natural progression from the former. Review of tree valuation methods suggested the formula approach to be more suitable than contingent valuation and hedonic pricing, and provided hints on their strengths and weaknesses. This study develops an alternative formulaic expert method (FEM) that integrates evaluation and valuation, maximizes objectivity, broadly encompasses the key tree, tree-environment and tree-human traits, and accords realistic monetary value to HTs. Six primary criteria (dimension, species, tree, condition, location, and outstanding consideration) branched into 45 secondary criteria, each allocated numerical marks. Each primary criterion was standardized to carry equal weight, and a tree's maximum aggregate score is capped at 100. A Monetary Assignment Factor (MAF) to consign dollar value to each score unit was derived from three-year average per m(2) sale price of medium-sized residential flats. The applicability of FEM was tested on selected HTs in compact Hong Kong. The aggregate score of a tree multiplied by MAF yielded monetary value, which was on average 66 times higher than the result from the commonly-adopted Council of Tree and Landscape Appraisers method. The computed tree values could be publicized together with multiple tree benefits to raise understanding and awareness and rally support to protect HTs. The property-linked FEM could be flexibly applied to other cities, especially to assess HTs in compact developing cities.

Climate change and managing water crisis: Pakistan's perspective.

PubMed

Hussain, Mumtaz; Mumtaz, Saniea

2014-01-01

Climate change is a global phenomenon manifested mainly through global warming. The International Panel on Climate Change (IPCC) has reported its negative consequences on natural resources, anthropogenic activities, and natural disasters. The El Nino and La Nina have affected hydrologic regimes and ecosystems. It has been observed that the average temperature in 1995 was 0.4°C higher than that in 1895. By the end of the 21st century, 10% of the area of Bangladesh is likely to be submerged by the sea. Most of the islands of Pacific Ocean will disappear. A major part of Maldives will be submerged. The sea level is expected to rise by 30-150 cm. Extreme events such as floods, cyclones, tsunamis, and droughts have become regular phenomena in many parts of the world. Other adverse impacts are proliferation of water-borne diseases, sea water intrusion, salinization of coastal areas, loss of biodiversity, eco-degradation of watersheds and global glacial decline, and haphazard snow melts/thaws. In turn, these factors have serious effect on water resources. Pakistan is confronting similar climate change. Meteorological data reveal that winter temperatures are rising and summers are getting cooler. Temperature is expected to increase by 0.9°C and 1.5°C by years 2020 and 2050, respectively. Water resources in Pakistan are affected by climate change as it impacts the behavior of glaciers, rainfall patterns, greenhouse gas emissions, recurrence of extreme events such as floods and droughts. Severe floods have occurred in the years 1950, 1956, 1957, 1973, 1976, 1978, 1988, 1992, 2010, 2011, and 2012. Pakistan has faced the worst-ever droughts during the period from 1998 to 2004. Pakistan has surface water potential of 140 million acre feet (MAF) and underground water reserve of 56 MAF. It is one of the most water-stressed countries in the world. The per capita annual availability of water has reduced from 5140 m3 in 1950 to 1000 m3 now. It is fast approaching towards water scarcity. To minimize adverse impacts of climate change on the water crisis in Pakistan, the preparation of integrated national, provincial, and local level master plans encompassing technical, social, environmental, administrative, and financial considerations is necessary. It is imperative to implement two simultaneous approaches of adaptation (living with climate change) and mitigation (addressing negativities of climate change). Salient features are integrated management of watersheds/catchments/water bodies, optimum exploitation of present sources, development of new sources, water conservation, adequate drainage, efficient design of water storage, conveyance, distribution and supply systems, utilization of waste water, and regulation of water quality.

The Adenylate Cyclase Toxins of Bacillus anthracis and Bordetella pertussis Promote Th2 Cell Development by Shaping T Cell Antigen Receptor Signaling

PubMed Central

Rossi Paccani, Silvia; Benagiano, Marisa; Capitani, Nagaja; Zornetta, Irene; Ladant, Daniel; Montecucco, Cesare; D'Elios, Mario M.; Baldari, Cosima T.

2009-01-01

The adjuvanticity of bacterial adenylate cyclase toxins has been ascribed to their capacity, largely mediated by cAMP, to modulate APC activation, resulting in the expression of Th2–driving cytokines. On the other hand, cAMP has been demonstrated to induce a Th2 bias when present during T cell priming, suggesting that bacterial cAMP elevating toxins may directly affect the Th1/Th2 balance. Here we have investigated the effects on human CD4+ T cell differentiation of two adenylate cyclase toxins, Bacillus anthracis edema toxin (ET) and Bordetella pertussis CyaA, which differ in structure, mode of cell entry, and subcellular localization. We show that low concentrations of ET and CyaA, but not of their genetically detoxified adenylate cyclase defective counterparts, potently promote Th2 cell differentiation by inducing expression of the master Th2 transcription factors, c-maf and GATA-3. We also present evidence that the Th2–polarizing concentrations of ET and CyaA selectively inhibit TCR–dependent activation of Akt1, which is required for Th1 cell differentiation, while enhancing the activation of two TCR–signaling mediators, Vav1 and p38, implicated in Th2 cell differentiation. This is at variance from the immunosuppressive toxin concentrations, which interfere with the earliest step in TCR signaling, activation of the tyrosine kinase Lck, resulting in impaired CD3ζ phosphorylation and inhibition of TCR coupling to ZAP-70 and Erk activation. These results demonstrate that, notwithstanding their differences in their intracellular localization, which result in focalized cAMP production, both toxins directly affect the Th1/Th2 balance by interfering with the same steps in TCR signaling, and suggest that their adjuvanticity is likely to result from their combined effects on APC and CD4+ T cells. Furthermore, our results strongly support the key role of cAMP in the adjuvanticity of these toxins. PMID:19266022

National Center for Advanced Manufacturing Overview

NASA Technical Reports Server (NTRS)

Vickers, John H.

2000-01-01

This paper presents a general overview of the National Center for Advanced Manufacturing, with an emphasis on Aerospace Materials, Processes and Environmental Technology. The topics include: 1) Background; 2) Mission; 3) Technology Development Approach; 4) Space Transportation Significance; 5) Partnering; 6) NCAM MAF Project; 7) NASA & Calhoun Community College; 8) Educational Development; and 9) Intelligent Synthesis Environment. This paper is presented in viewgraph form.

Psychometric Evaluation of the Multidimensional Assessment of Fatigue Scale for Use with Pregnant and Postpartum Women

ERIC Educational Resources Information Center

Fairbrother, Nichole; Hutton, Eileen K.; Stoll, Kathrin; Hall, Wendy; Kluka, Sandy

2008-01-01

Although fatigue is a common experience for pregnant women and new mothers, few measures of fatigue have been validated for use with this population. To address this gap, the authors assessed psychometric properties of the Multidimensional Assessment of Fatigue (MAF) scale, which was used in 2 independent samples of pregnant women. Results…

Rise of the Functionals?: Mobility Air Force Developmental Teams and their Impact on Officer Education and Advancement

DTIC Science & Technology

2014-06-01

Specialists (43X/44X/45X) Chaplain (52R) Civil Engineer (32E) Combat Air Force Contracting (64P) Cyber Operations (17D) Dental (47X) Finance (65 F...assume the principal has a perfect decision making calculus . The MAF DT may actually have asymmetric information, and given the opportunity, they could

Strength Testing in the Air Force: Current Processes and Suggestions for Improvements

DTIC Science & Technology

2014-01-01

Electrical Power Production 4Y0X1 Dental Assistant 3E1X1 Heating, Ventilation, AC, & Refrigeration 4Y0X2 Dental Laboratory 3E2X1 Pavements and...MAFS AFE SF AFU-AS EOD Push 29 -- 22 -- 113 72 111 62 Pull 22 -- 21 -- -- -- 82 -- Cary 19 57 20 -- 188 120 77 -- Hold -- -- -- -- -- -- 64

Awareness of financial skills in dementia.

PubMed

Van Wielingen, L E; Tuokko, H A; Cramer, K; Mateer, C A; Hultsch, D F

2004-07-01

The present study examined the relations among levels of cognitive functioning, executive dysfunction, and awareness of financial management capabilities among a sample of 42 community-dwelling persons with dementia. Financial tasks on the Measure of Awareness of Financial Skills (MAFS) were dichotomized as simple or complex based on Piaget's operational levels of childhood cognitive development. Severity of global cognitive impairment and executive dysfunction were significantly related to awareness of financial abilities as measured by informant-participant discrepancy scores on the MAFS. For persons with mild and moderate/severe dementia, and persons with and without executive dysfunction, proportions of awareness within simple and complex financial task categories were tabulated. Significantly less awareness of financial abilities occurred on complex compared with simple tasks. Individuals with mild dementia were significantly less aware of abilities on complex items, whereas persons with moderate/severe dementia were less aware of abilities, regardless of task complexity. Similar patterns of awareness were observed for individuals with and without executive dysfunction. These findings support literature suggesting that deficits associated with dementia first occur for complex cognitive tasks involving inductive reasoning or decision-making in novel situations, and identify where loss of function in the financial domain may first be expected. Copyright Taylor & Francis Ltd

Ground target geolocation based on digital elevation model for airborne wide-area reconnaissance system

NASA Astrophysics Data System (ADS)

Qiao, Chuan; Ding, Yalin; Xu, Yongsen; Xiu, Jihong

2018-01-01

To obtain the geographical position of the ground target accurately, a geolocation algorithm based on the digital elevation model (DEM) is developed for an airborne wide-area reconnaissance system. According to the platform position and attitude information measured by the airborne position and orientation system and the gimbal angles information from the encoder, the line-of-sight pointing vector in the Earth-centered Earth-fixed coordinate frame is solved by the homogeneous coordinate transformation. The target longitude and latitude can be solved with the elliptical Earth model and the global DEM. The influences of the systematic error and measurement error on ground target geolocation calculation accuracy are analyzed by the Monte Carlo method. The simulation results show that this algorithm can improve the geolocation accuracy of ground target in rough terrain area obviously. The geolocation accuracy of moving ground target can be improved by moving average filtering (MAF). The validity of the geolocation algorithm is verified by the flight test in which the plane flies at a geodetic height of 15,000 m and the outer gimbal angle is <47°. The geolocation root mean square error of the target trajectory is <45 and <7 m after MAF.

Advanced direct coal liquefaction concepts. Quarterly report, January 1, 1994--March 31, 1994

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

Berger, D.J.; Parker, R.J.; Simpson, P.L.

A detailed evaluation of the bench unit data on Black Thunder feedstocks was completed. The results show that in a once-through operation using counterflow, reactor technology coal conversions in excess of 90% could be obtained, giving distillable oil yields in the range 60--65 wt % on MAF coal. The remaining non-distillable oil fraction which represents 20--25 wt % on MAF coal is a source of additional distillable oil in further processing, for example, bottoms recycle operation. C{sub 1}-C{sub 3} gas yields were generally in the order of 6--8 wt %. In autoclave studies, Illinois No. 6 coal was found tomore » be much less reactive than Black Thunder coal, and did not respond well to solubilization with carbon monoxide/steam. Process severity was, therefore, increased for bench unit operations on Illinois No. 6 coal, and work has concentrated on the use of hydrogen rather than carbon monoxide for solubilization. Preliminary coking studies on the resid from bench unit runs on Black Thunder coal were also carried out. Distillable liquid yields of 55--60 wt % were obtained. The technical and economic study to be carried out by Kilborn Engineering Company has been initiated.« less

Ex vivo imaging and quantification of liver fibrosis using second-harmonic generation microscopy

NASA Astrophysics Data System (ADS)

Sun, Tzu-Lin; Liu, Yuan; Sung, Ming-Chin; Chen, Hsiao-Ching; Yang, Chun-Hui; Hovhannisyan, Vladimir; Lin, Wei-Chou; Jeng, Yung-Ming; Chen, Wei-Liang; Chiou, Ling-Ling; Huang, Guan-Tarn; Kim, Ki-Hean; So, Peter T. C.; Chen, Yang-Fang; Lee, Hsuan-Shu; Dong, Chen-Yuan

2010-05-01

Conventionally, liver fibrosis is diagnosed using histopathological techniques. The traditional method is time-consuming in that the specimen preparation procedure requires sample fixation, slicing, and labeling. Our goal is to apply multiphoton microscopy to efficiently image and quantitatively analyze liver fibrosis specimens bypassing steps required in histological preparation. In this work, the combined imaging modality of multiphoton autofluorescence (MAF) and second-harmonic generation (SHG) was used for the qualitative imaging of liver fibrosis of different METAVIR grades under label-free, ex vivo conditions. We found that while MAF is effective in identifying cellular architecture in the liver specimens, it is the spectrally distinct SHG signal that allows the characterization of the extent of fibrosis. We found that qualitative SHG imaging can be used for the effective identification of the associated features of liver fibrosis specimens graded METAVIR 0 to 4. In addition, we attempted to associate quantitative SHG signal to the different METAVIR grades and found that an objective determination of the extent of disease progression can be made. Our approach demonstrates the potential of using multiphoton imaging in rapid classification of ex vivo liver fibrosis in the clinical setting and investigation of liver fibrosis-associated physiopathology in animal models in vivo.

Ex vivo imaging and quantification of liver fibrosis using second-harmonic generation microscopy.

PubMed

Sun, Tzu-Lin; Liu, Yuan; Sung, Ming-Chin; Chen, Hsiao-Ching; Yang, Chun-Hui; Hovhannisyan, Vladimir; Lin, Wei-Chou; Jeng, Yung-Ming; Chen, Wei-Liang; Chiou, Ling-Ling; Huang, Guan-Tarn; Kim, Ki-Hean; So, Peter T C; Chen, Yang-Fang; Lee, Hsuan-Shu; Dong, Chen-Yuan

2010-01-01

Conventionally, liver fibrosis is diagnosed using histopathological techniques. The traditional method is time-consuming in that the specimen preparation procedure requires sample fixation, slicing, and labeling. Our goal is to apply multiphoton microscopy to efficiently image and quantitatively analyze liver fibrosis specimens bypassing steps required in histological preparation. In this work, the combined imaging modality of multiphoton autofluorescence (MAF) and second-harmonic generation (SHG) was used for the qualitative imaging of liver fibrosis of different METAVIR grades under label-free, ex vivo conditions. We found that while MAF is effective in identifying cellular architecture in the liver specimens, it is the spectrally distinct SHG signal that allows the characterization of the extent of fibrosis. We found that qualitative SHG imaging can be used for the effective identification of the associated features of liver fibrosis specimens graded METAVIR 0 to 4. In addition, we attempted to associate quantitative SHG signal to the different METAVIR grades and found that an objective determination of the extent of disease progression can be made. Our approach demonstrates the potential of using multiphoton imaging in rapid classification of ex vivo liver fibrosis in the clinical setting and investigation of liver fibrosis-associated physiopathology in animal models in vivo.

Alpha-synuclein mRNA isoform formation and translation affected by polymorphism in the human SNCA 3'UTR.

PubMed

Barrie, Elizabeth S; Lee, Sung-Ha; Frater, John T; Kataki, Maria; Scharre, Douglas W; Sadee, Wolfgang

2018-05-06

Multiple variants in SNCA, encoding alpha-synuclein, a main component of Lewy bodies, are implicated in Parkinson's disease. We searched for cis-acting SNCA variants using allelic mRNA ratios in human brain tissues. In a SNCA 3'UTR (2,520 bp) luciferase reporter gene assay, translation in SH-SY5Y cells in the presence of the rs17016074 G/A alleles was measured. To assess clinical impact, we queried neurocognitive genome-wide association studies. Allelic ratios deviated up to twofold, measured at a marker SNP in the middle of a long 3' untranslated region (3'UTR), but not at a marker at its start, suggesting regulation of 3'UTR processing. 3'UTR SNP rs17016074 G/A, minor allele frequency (MAF) <1% in Caucasians, 13% in Africans, strongly associates with large allelic mRNA expression imbalance (AEI), resulting in reduced expression of long 3'UTR isoforms. A second 3'UTR SNP (rs356165) associates with moderate AEI and enhances SNCA mRNA expression. The rs17016074 A allele reduces overall 3'UTR expression in luciferase reporter gene assays but supports more efficient translation, resolving previous contradictory results. We failed to detect significant genome-wide associations for rs17016074, possibly a result of low MAF in Caucasians or its absence from most genotyping panels. In the "Genome Wide Association Study of Yoruba in Nigeria," rs356165 was associated with reduced memory performance. Here, we identify two cis-acting regulatory variants affecting SNCA mRNA expression, measured by allelic ratios in the 3'UTR. The rs17016074 minor A allele is associated with higher expression of luciferase protein activity. Resolving the genetic influence of SNCA polymorphisms requires study of the interactions between multiple regulatory variants with distinct frequencies among populations. © 2018 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.

Lower frequency of TLR9 variant associated with protection from breast cancer among African Americans

PubMed Central

Tuomela, Johanna M.; Forero-Torres, Andres; Desmond, Renee; Vuopala, Katri S.; Harris, Kevin W.; Merner, Nancy D.

2017-01-01

Introduction Toll-like receptor 9 (TLR9) is an innate immune system DNA-receptor that regulates tumor invasion and immunity in vitro. Low tumor TLR9 expression has been associated with poor survival in Caucasian patients with triple negative breast cancer (TNBC). African American (AA) patients with TNBC have worse prognosis than Caucasians but whether this is due to differences in tumor biology remains controversial. We studied the prognostic significance of tumor Toll like receptor-9 (TLR9) protein expression among African American (AA) triple negative breast cancer (TNBC) patients. Germline TLR9 variants in European Americans (EAs) and AAs were investigated, to determine their contribution to AA breast cancer risk. Methods TLR9 expression was studied with immunohistochemistry in archival tumors. Exome Variant Server and The Cancer Genome Atlas were used to determine the genetic variation in the general EA and AA populations, and AA breast cancer cases. Minor allele frequencies (MAFs) were compared between EAs (n = 4300), AAs (n = 2203), and/or AA breast cancer cases (n = 131). Results Thirty-two TLR9 variants had a statistically significant MAF difference between general EAs and AAs. Twenty-one of them affect a CpG site. Rs352140, a variant previously associated with protection from breast cancer, is more common in EAs than AAs (p = 2.20E-16). EAs had more synonymous alleles, while AAs had more rare coding alleles. Similar analyses comparing AA breast cancer cases with AA controls did not reveal any variant class differences; however, three previously unreported TLR9 variants were associated with late onset breast cancer. Although not statistically significant, rs352140 was observed less frequently in AA cases compared to controls. Tumor TLR9 protein expression was not associated with prognosis. Conclusions Tumor TLR9 expression is not associated with prognosis in AA TNBC. Significant differences were detected in TLR9 variant MAFs between EAs and AAs. They may affect TLR9 expression and function. Rs352140, which may protect from breast cancer, is 1.6 X more common among EAs. These findings call for a detailed analysis of the contribution of TLR9 to breast cancer pathophysiology and health disparities. PMID:28886076

Can the Gila River reduce risk in the Colorado River Basin?

NASA Astrophysics Data System (ADS)

Wade, L. C.; Rajagopalan, B.; Lukas, J.; Kanzer, D.

2012-12-01

The Colorado River is the most important source of water in the southwest United States and Northern Mexico, providing water to approximately 35 million people and 4-5 million acres of irrigated lands. To manage the water resources of the basin, estimated to be about 17 million acre-feet (MAF) of undepleted supplies per year, managers use reservoir facilities that can store more than 60 MAF. As the demands on the water resources of the basin approach or exceed the average annual supply, and with average flow projected to decrease due to climate change, smart water management is vital for its sustainability. To quantify the future risk of depleting reservoir storage, Rajagopalan et al. (2009) developed a water-balance model and ran it under scenarios based on historical, paleo-reconstructed and future projections of flows, and different management alternatives. That study did not consider the impact of the Gila River, which enters the Colorado River below all major reservoirs and U.S. diversions. Due to intensive use in Central Arizona, the Gila only has significant inflows to the Colorado in wet years. However, these irregular inflows could beneficially influence system reliability in the US by helping to meet a portion of the 1.5 MAF delivery obligations to Mexico. To help quantify the potential system reliability benefit of the Gila River, we modify the Rajagopalan et al (2009) model to incorporate simulated Gila River inflows. These new data inputs to the water balance model are based on historical flows and tree-ring reconstructions of flow in the Upper Colorado River Basin (at Lee's Ferry), the Lower Colorado River Basin (tributary inflows), and the intermittent flows from the Gila River which are generated using extreme value analysis methods. Incorporating Gila River inflows, although they are highly variable and intermittent, reduces the modeled cumulative risk of reservoir depletion by 4 to 11% by 2057, depending on the demand schedule, reservoir operation guidelines, and climate change scenario assumptions. This potential risk mitigation could be at least partly realized through enhancements to current management practices, possibly in the Gila River, that could improve the water supply reliability for all stakeholders in the Colorado River Basin.

Lower frequency of TLR9 variant associated with protection from breast cancer among African Americans.

PubMed

Chandler, Madison R; Keene, Kimberly S; Tuomela, Johanna M; Forero-Torres, Andres; Desmond, Renee; Vuopala, Katri S; Harris, Kevin W; Merner, Nancy D; Selander, Katri S

2017-01-01

Toll-like receptor 9 (TLR9) is an innate immune system DNA-receptor that regulates tumor invasion and immunity in vitro. Low tumor TLR9 expression has been associated with poor survival in Caucasian patients with triple negative breast cancer (TNBC). African American (AA) patients with TNBC have worse prognosis than Caucasians but whether this is due to differences in tumor biology remains controversial. We studied the prognostic significance of tumor Toll like receptor-9 (TLR9) protein expression among African American (AA) triple negative breast cancer (TNBC) patients. Germline TLR9 variants in European Americans (EAs) and AAs were investigated, to determine their contribution to AA breast cancer risk. TLR9 expression was studied with immunohistochemistry in archival tumors. Exome Variant Server and The Cancer Genome Atlas were used to determine the genetic variation in the general EA and AA populations, and AA breast cancer cases. Minor allele frequencies (MAFs) were compared between EAs (n = 4300), AAs (n = 2203), and/or AA breast cancer cases (n = 131). Thirty-two TLR9 variants had a statistically significant MAF difference between general EAs and AAs. Twenty-one of them affect a CpG site. Rs352140, a variant previously associated with protection from breast cancer, is more common in EAs than AAs (p = 2.20E-16). EAs had more synonymous alleles, while AAs had more rare coding alleles. Similar analyses comparing AA breast cancer cases with AA controls did not reveal any variant class differences; however, three previously unreported TLR9 variants were associated with late onset breast cancer. Although not statistically significant, rs352140 was observed less frequently in AA cases compared to controls. Tumor TLR9 protein expression was not associated with prognosis. Tumor TLR9 expression is not associated with prognosis in AA TNBC. Significant differences were detected in TLR9 variant MAFs between EAs and AAs. They may affect TLR9 expression and function. Rs352140, which may protect from breast cancer, is 1.6 X more common among EAs. These findings call for a detailed analysis of the contribution of TLR9 to breast cancer pathophysiology and health disparities.

Hyperglycaemia attenuates in vivo reprogramming of pancreatic exocrine cells to beta cells in mice

PubMed Central

Cavelti-Weder, Claudia; Li, Weida; Zumsteg, Adrian; Stemann-Andersen, Marianne; Zhang, Yuemei; Yamada, Takatsugu; Wang, Max; Lu, Jiaqi; Jermendy, Agnes; Bee, Yong Mong; Bonner-Weir, Susan; Weir, Gordon C.; Zhou, Qiao

2016-01-01

Aims/hypothesis Reprogramming of pancreatic exocrine to insulin-producing cells by viral delivery of the genes encoding transcription factors neurogenin-3 (Ngn3), pancreas/duodenum homeobox protein 1 (Pdx1) and MafA is an efficient method for reversing diabetes in murine models. The variables that modulate reprogramming success are currently ill-defined. Methods Here, we assess the impact of glycaemia on in vivo reprogramming in a mouse model of streptozotocin-induced beta cell ablation, using subsequent islet transplantation or insulin pellet implantation for creation of groups with differing levels of glycaemia before viral delivery of transcription factors. Results We observed that hyperglycaemia significantly impaired reprogramming of exocrine to insulin-producing cells in their quantity, differentiation status and function. With hyperglycaemia, the reprogramming of acinar towards beta cells was less complete. Moreover, inflammatory tissue changes within the exocrine pancreas including macrophage accumulation were found, which may represent the tissue’s response to clear the pancreas from insufficiently reprogrammed cells. Conclusions/interpretation Our findings shed light on normoglycaemia as a prerequisite for optimal reprogramming success in a diabetes model, which might be important in other tissue engineering approaches and disease models, potentially facilitating their translational applications. PMID:26693711

Hyperglycaemia attenuates in vivo reprogramming of pancreatic exocrine cells to beta cells in mice.

PubMed

Cavelti-Weder, Claudia; Li, Weida; Zumsteg, Adrian; Stemann-Andersen, Marianne; Zhang, Yuemei; Yamada, Takatsugu; Wang, Max; Lu, Jiaqi; Jermendy, Agnes; Bee, Yong Mong; Bonner-Weir, Susan; Weir, Gordon C; Zhou, Qiao

2016-03-01

Reprogramming of pancreatic exocrine to insulin-producing cells by viral delivery of the genes encoding transcription factors neurogenin-3 (Ngn3), pancreas/duodenum homeobox protein 1 (Pdx1) and MafA is an efficient method for reversing diabetes in murine models. The variables that modulate reprogramming success are currently ill-defined. Here, we assess the impact of glycaemia on in vivo reprogramming in a mouse model of streptozotocin-induced beta cell ablation, using subsequent islet transplantation or insulin pellet implantation for creation of groups with differing levels of glycaemia before viral delivery of transcription factors. We observed that hyperglycaemia significantly impaired reprogramming of exocrine to insulin-producing cells in their quantity, differentiation status and function. With hyperglycaemia, the reprogramming of acinar towards beta cells was less complete. Moreover, inflammatory tissue changes within the exocrine pancreas including macrophage accumulation were found, which may represent the tissue's response to clear the pancreas from insufficiently reprogrammed cells. Our findings shed light on normoglycaemia as a prerequisite for optimal reprogramming success in a diabetes model, which might be important in other tissue engineering approaches and disease models, potentially facilitating their translational applications.

Transcriptional regulation of podocyte specification and differentiation.

PubMed

Quaggin, Susan E

2002-05-15

Glomerular visceral epithelial cells (podocytes) are highly specialized cells found in the vertebrate and invertebrate kidney and make up a major portion of the filtration barrier between blood and urinary spaces. During development, specification and differentiation of the podocyte lineage must be tightly orchestrated to produce highly specialized characteristics such as foot processes and slit diaphragms. Furthermore, podocytes are poised to direct incoming endothelial and mesangial cells during glomerular development. They express a number of growth factors that likely play a major role in these processes. Recent findings from transgenic and knockout mouse models and the identification of genes responsible for human podocyte disease have provided insight into transcriptional regulation of some of these processes. These transcription factors include Pax2, WT1 (the Wilms tumor suppressor gene), Pod1 (capsulin, epicardin), Kreisler (maf-1), lmx1b, and mf2. Furthermore, regulatory regions from a podocyte-restricted gene, NPHS1 (nephrin) that are required to direct podocyte-specific expression have been identified from both human and murine genes and provide a tool to further dissect the transcriptional regulation of podocyte-specific gene expression. This article reviews the present state of knowledge regarding transcriptional regulation of podocyte specification and differentiation. Copyright 2002 Wiley-Liss, Inc.

Impact of North Carolina's Early Childhood Programs and Policies on Educational Outcomes in Elementary School

ERIC Educational Resources Information Center

Dodge, Kenneth A.; Bai, Yu; Ladd, Helen F.; Muschkin, Clara G.

2017-01-01

North Carolina's Smart Start and More at Four (MAF) early childhood programs were evaluated through the end of elementary school (age 11) by estimating the impact of state funding allocations to programs in each of 100 counties across 13 consecutive years on outcomes for all children in each county-year group (n = 1,004,571; 49% female; 61%…

Demonstration of Sensor Data Integration Across Naval Aviation Maintenance

DTIC Science & Technology

2018-02-01

With expedited fault detection, fewer unnecessary parts would need to be ordered, saving time and money . Recommendations Based on our findings...level maintainer. These notes were included in every MAF in the “corrective action” block and were unformatted free -text. Out of the 70 repairs, only...translates to fewer unnecessary parts ordered, a reduction in the money spent on unnecessary parts, and a reduction of unnecessary logistic delays

A One-Dimensional, Noniterative Trajectory Model (With a C++ Implementation)

DTIC Science & Technology

2014-03-01

maF = (6) 2 2 1 AvC m a Dρ−=⇒ (7) Next, the definitions of speed and acceleration can be used to find acceleration as a function of speed and...position: dt dxv ≡ (8) and dt dx dx dv dt dva =≡ (9) dx dvva =⇒ (10) Combining equations 7 and 10, AvC mdx dv Dρ2 1 −= (11) Next

Saturn Apollo Program

NASA Image and Video Library

1965-03-01

S-IB-1, the first flight version of the Saturn IB launch vehicle's first stage (S-IB stage), sat in the Marshall Space Flight Center (MSFC) Saturn IB static test stand on March 15, 1965. Developed by the MSFC and built by the Chrysler Corporation at the Michoud Assembly Facility (MAF) in New Orleans, Louisiana, the 90,000-pound booster utilized eight H-1 engines to produce a combined thrust of 1,600,000 pounds.

Effect of apical clearing technique on the treatment outcome of teeth with asymptomatic apical periodontitis: A randomized clinical trial

PubMed Central

Mittal, Priya; Logani, Ajay; Shah, Naseem; Pandey, R. M.

2016-01-01

Aim: This study aims to compare the periapical healing of teeth with asymptomatic apical periodontitis treated either by conventional apical preparation (CAP) or apical clearing technique (ACT). Materials and Methods: Twenty subjects with bilateral nonvital similar teeth exhibiting comparable periapical index (PAI) score were enrolled and randomly allocated. Group I (CAP, n = 20): Apical preparation three sizes greater (master apical file [MAF]) than the first binding file at the established working length. Group II (ACT, n = 20): Apical preparation three sizes greater than the MAF that was followed by dry reaming. Root canal therapy was accomplished in single-visit for all the teeth. They were pursued radiographically at 3, 6, 9 and 12 months. Pre- and post-treatment PAI scores were compared. To ascertain the proportion of healed teeth between the two groups, McNemar Chi-square test was applied. Results: At 3, 6, and 9 months’ time interval the proportion of healed teeth for Group II (ACT) was greater in comparison to Group I (CAP) (P < 0.05). However, at 12 months follow-up period this difference was not significant (P = 0.08). Conclusion: ACT enhanced the healing kinetics. However, the long-term (12 months) radiographic outcome was similar for either technique. PMID:27656054

Effect of apical clearing technique on the treatment outcome of teeth with asymptomatic apical periodontitis: A randomized clinical trial.

PubMed

Mittal, Priya; Logani, Ajay; Shah, Naseem; Pandey, R M

2016-01-01

This study aims to compare the periapical healing of teeth with asymptomatic apical periodontitis treated either by conventional apical preparation (CAP) or apical clearing technique (ACT). Twenty subjects with bilateral nonvital similar teeth exhibiting comparable periapical index (PAI) score were enrolled and randomly allocated. Group I (CAP, n = 20): Apical preparation three sizes greater (master apical file [MAF]) than the first binding file at the established working length. Group II (ACT, n = 20): Apical preparation three sizes greater than the MAF that was followed by dry reaming. Root canal therapy was accomplished in single-visit for all the teeth. They were pursued radiographically at 3, 6, 9 and 12 months. Pre- and post-treatment PAI scores were compared. To ascertain the proportion of healed teeth between the two groups, McNemar Chi-square test was applied. At 3, 6, and 9 months' time interval the proportion of healed teeth for Group II (ACT) was greater in comparison to Group I (CAP) (P < 0.05). However, at 12 months follow-up period this difference was not significant (P = 0.08). ACT enhanced the healing kinetics. However, the long-term (12 months) radiographic outcome was similar for either technique.

Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.

PubMed

Turcot, Valérie; Lu, Yingchang; Highland, Heather M; Schurmann, Claudia; Justice, Anne E; Fine, Rebecca S; Bradfield, Jonathan P; Esko, Tõnu; Giri, Ayush; Graff, Mariaelisa; Guo, Xiuqing; Hendricks, Audrey E; Karaderi, Tugce; Lempradl, Adelheid; Locke, Adam E; Mahajan, Anubha; Marouli, Eirini; Sivapalaratnam, Suthesh; Young, Kristin L; Alfred, Tamuno; Feitosa, Mary F; Masca, Nicholas G D; Manning, Alisa K; Medina-Gomez, Carolina; Mudgal, Poorva; Ng, Maggie C Y; Reiner, Alex P; Vedantam, Sailaja; Willems, Sara M; Winkler, Thomas W; Abecasis, Gonçalo; Aben, Katja K; Alam, Dewan S; Alharthi, Sameer E; Allison, Matthew; Amouyel, Philippe; Asselbergs, Folkert W; Auer, Paul L; Balkau, Beverley; Bang, Lia E; Barroso, Inês; Bastarache, Lisa; Benn, Marianne; Bergmann, Sven; Bielak, Lawrence F; Blüher, Matthias; Boehnke, Michael; Boeing, Heiner; Boerwinkle, Eric; Böger, Carsten A; Bork-Jensen, Jette; Bots, Michiel L; Bottinger, Erwin P; Bowden, Donald W; Brandslund, Ivan; Breen, Gerome; Brilliant, Murray H; Broer, Linda; Brumat, Marco; Burt, Amber A; Butterworth, Adam S; Campbell, Peter T; Cappellani, Stefania; Carey, David J; Catamo, Eulalia; Caulfield, Mark J; Chambers, John C; Chasman, Daniel I; Chen, Yii-Der I; Chowdhury, Rajiv; Christensen, Cramer; Chu, Audrey Y; Cocca, Massimiliano; Collins, Francis S; Cook, James P; Corley, Janie; Corominas Galbany, Jordi; Cox, Amanda J; Crosslin, David S; Cuellar-Partida, Gabriel; D'Eustacchio, Angela; Danesh, John; Davies, Gail; Bakker, Paul I W; Groot, Mark C H; Mutsert, Renée; Deary, Ian J; Dedoussis, George; Demerath, Ellen W; Heijer, Martin; Hollander, Anneke I; Ruijter, Hester M; Dennis, Joe G; Denny, Josh C; Di Angelantonio, Emanuele; Drenos, Fotios; Du, Mengmeng; Dubé, Marie-Pierre; Dunning, Alison M; Easton, Douglas F; Edwards, Todd L; Ellinghaus, David; Ellinor, Patrick T; Elliott, Paul; Evangelou, Evangelos; Farmaki, Aliki-Eleni; Farooqi, I Sadaf; Faul, Jessica D; Fauser, Sascha; Feng, Shuang; Ferrannini, Ele; Ferrieres, Jean; Florez, Jose C; Ford, Ian; Fornage, Myriam; Franco, Oscar H; Franke, Andre; Franks, Paul W; Friedrich, Nele; Frikke-Schmidt, Ruth; Galesloot, Tessel E; Gan, Wei; Gandin, Ilaria; Gasparini, Paolo; Gibson, Jane; Giedraitis, Vilmantas; Gjesing, Anette P; Gordon-Larsen, Penny; Gorski, Mathias; Grabe, Hans-Jörgen; Grant, Struan F A; Grarup, Niels; Griffiths, Helen L; Grove, Megan L; Gudnason, Vilmundur; Gustafsson, Stefan; Haessler, Jeff; Hakonarson, Hakon; Hammerschlag, Anke R; Hansen, Torben; Harris, Kathleen Mullan; Harris, Tamara B; Hattersley, Andrew T; Have, Christian T; Hayward, Caroline; He, Liang; Heard-Costa, Nancy L; Heath, Andrew C; Heid, Iris M; Helgeland, Øyvind; Hernesniemi, Jussi; Hewitt, Alex W; Holmen, Oddgeir L; Hovingh, G Kees; Howson, Joanna M M; Hu, Yao; Huang, Paul L; Huffman, Jennifer E; Ikram, M Arfan; Ingelsson, Erik; Jackson, Anne U; Jansson, Jan-Håkan; Jarvik, Gail P; Jensen, Gorm B; Jia, Yucheng; Johansson, Stefan; Jørgensen, Marit E; Jørgensen, Torben; Jukema, J Wouter; Kahali, Bratati; Kahn, René S; Kähönen, Mika; Kamstrup, Pia R; Kanoni, Stavroula; Kaprio, Jaakko; Karaleftheri, Maria; Kardia, Sharon L R; Karpe, Fredrik; Kathiresan, Sekar; Kee, Frank; Kiemeney, Lambertus A; Kim, Eric; Kitajima, Hidetoshi; Komulainen, Pirjo; Kooner, Jaspal S; Kooperberg, Charles; Korhonen, Tellervo; Kovacs, Peter; Kuivaniemi, Helena; Kutalik, Zoltán; Kuulasmaa, Kari; Kuusisto, Johanna; Laakso, Markku; Lakka, Timo A; Lamparter, David; Lange, Ethan M; Lange, Leslie A; Langenberg, Claudia; Larson, Eric B; Lee, Nanette R; Lehtimäki, Terho; Lewis, Cora E; Li, Huaixing; Li, Jin; Li-Gao, Ruifang; Lin, Honghuang; Lin, Keng-Hung; Lin, Li-An; Lin, Xu; Lind, Lars; Lindström, Jaana; Linneberg, Allan; Liu, Ching-Ti; Liu, Dajiang J; Liu, Yongmei; Lo, Ken S; Lophatananon, Artitaya; Lotery, Andrew J; Loukola, Anu; Luan, Jian'an; Lubitz, Steven A; Lyytikäinen, Leo-Pekka; Männistö, Satu; Marenne, Gaëlle; Mazul, Angela L; McCarthy, Mark I; McKean-Cowdin, Roberta; Medland, Sarah E; Meidtner, Karina; Milani, Lili; Mistry, Vanisha; Mitchell, Paul; Mohlke, Karen L; Moilanen, Leena; Moitry, Marie; Montgomery, Grant W; Mook-Kanamori, Dennis O; Moore, Carmel; Mori, Trevor A; Morris, Andrew D; Morris, Andrew P; Müller-Nurasyid, Martina; Munroe, Patricia B; Nalls, Mike A; Narisu, Narisu; Nelson, Christopher P; Neville, Matt; Nielsen, Sune F; Nikus, Kjell; Njølstad, Pål R; Nordestgaard, Børge G; Nyholt, Dale R; O'Connel, Jeffrey R; O'Donoghue, Michelle L; Olde Loohuis, Loes M; Ophoff, Roel A; Owen, Katharine R; Packard, Chris J; Padmanabhan, Sandosh; Palmer, Colin N A; Palmer, Nicholette D; Pasterkamp, Gerard; Patel, Aniruddh P; Pattie, Alison; Pedersen, Oluf; Peissig, Peggy L; Peloso, Gina M; Pennell, Craig E; Perola, Markus; Perry, James A; Perry, John R B; Pers, Tune H; Person, Thomas N; Peters, Annette; Petersen, Eva R B; Peyser, Patricia A; Pirie, Ailith; Polasek, Ozren; Polderman, Tinca J; Puolijoki, Hannu; Raitakari, Olli T; Rasheed, Asif; Rauramaa, Rainer; Reilly, Dermot F; Renström, Frida; Rheinberger, Myriam; Ridker, Paul M; Rioux, John D; Rivas, Manuel A; Roberts, David J; Robertson, Neil R; Robino, Antonietta; Rolandsson, Olov; Rudan, Igor; Ruth, Katherine S; Saleheen, Danish; Salomaa, Veikko; Samani, Nilesh J; Sapkota, Yadav; Sattar, Naveed; Schoen, Robert E; Schreiner, Pamela J; Schulze, Matthias B; Scott, Robert A; Segura-Lepe, Marcelo P; Shah, Svati H; Sheu, Wayne H-H; Sim, Xueling; Slater, Andrew J; Small, Kerrin S; Smith, Albert V; Southam, Lorraine; Spector, Timothy D; Speliotes, Elizabeth K; Starr, John M; Stefansson, Kari; Steinthorsdottir, Valgerdur; Stirrups, Kathleen E; Strauch, Konstantin; Stringham, Heather M; Stumvoll, Michael; Sun, Liang; Surendran, Praveen; Swift, Amy J; Tada, Hayato; Tansey, Katherine E; Tardif, Jean-Claude; Taylor, Kent D; Teumer, Alexander; Thompson, Deborah J; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Thuesen, Betina H; Tönjes, Anke; Tromp, Gerard; Trompet, Stella; Tsafantakis, Emmanouil; Tuomilehto, Jaakko; Tybjaerg-Hansen, Anne; Tyrer, Jonathan P; Uher, Rudolf; Uitterlinden, André G; Uusitupa, Matti; Laan, Sander W; Duijn, Cornelia M; Leeuwen, Nienke; van Setten, Jessica; Vanhala, Mauno; Varbo, Anette; Varga, Tibor V; Varma, Rohit; Velez Edwards, Digna R; Vermeulen, Sita H; Veronesi, Giovanni; Vestergaard, Henrik; Vitart, Veronique; Vogt, Thomas F; Völker, Uwe; Vuckovic, Dragana; Wagenknecht, Lynne E; Walker, Mark; Wallentin, Lars; Wang, Feijie; Wang, Carol A; Wang, Shuai; Wang, Yiqin; Ware, Erin B; Wareham, Nicholas J; Warren, Helen R; Waterworth, Dawn M; Wessel, Jennifer; White, Harvey D; Willer, Cristen J; Wilson, James G; Witte, Daniel R; Wood, Andrew R; Wu, Ying; Yaghootkar, Hanieh; Yao, Jie; Yao, Pang; Yerges-Armstrong, Laura M; Young, Robin; Zeggini, Eleftheria; Zhan, Xiaowei; Zhang, Weihua; Zhao, Jing Hua; Zhao, Wei; Zhao, Wei; Zhou, Wei; Zondervan, Krina T; Rotter, Jerome I; Pospisilik, John A; Rivadeneira, Fernando; Borecki, Ingrid B; Deloukas, Panos; Frayling, Timothy M; Lettre, Guillaume; North, Kari E; Lindgren, Cecilia M; Hirschhorn, Joel N; Loos, Ruth J F

2018-01-01

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.

Meta-analysis of genome-wide association studies of adult height in East Asians identifies 17 novel loci.

PubMed

He, Meian; Xu, Min; Zhang, Ben; Liang, Jun; Chen, Peng; Lee, Jong-Young; Johnson, Todd A; Li, Huaixing; Yang, Xiaobo; Dai, Juncheng; Liang, Liming; Gui, Lixuan; Qi, Qibin; Huang, Jinyan; Li, Yanping; Adair, Linda S; Aung, Tin; Cai, Qiuyin; Cheng, Ching-Yu; Cho, Myeong-Chan; Cho, Yoon Shin; Chu, Minjie; Cui, Bin; Gao, Yu-Tang; Go, Min Jin; Gu, Dongfeng; Gu, Weiqiong; Guo, Huan; Hao, Yongchen; Hong, Jie; Hu, Zhibin; Hu, Yanling; Huang, Jianfeng; Hwang, Joo-Yeon; Ikram, Mohammad Kamran; Jin, Guangfu; Kang, Dae-Hee; Khor, Chiea Chuen; Kim, Bong-Jo; Kim, Hung Tae; Kubo, Michiaki; Lee, Jeannette; Lee, Juyoung; Lee, Nanette R; Li, Ruoying; Li, Jun; Liu, JianJun; Longe, Jirong; Lu, Wei; Lu, Xiangfeng; Miao, Xiaoping; Okada, Yukinori; Ong, Rick Twee-Hee; Qiu, Gaokun; Seielstad, Mark; Sim, Xueling; Song, Huaidong; Takeuchi, Fumihiko; Tanaka, Toshihiro; Taylor, Phil R; Wang, Laiyuan; Wang, Weiqing; Wang, Yiqin; Wu, Chen; Wu, Ying; Xiang, Yong-Bing; Yamamoto, Ken; Yang, Handong; Liao, Ming; Yokota, Mitsuhiro; Young, Terri; Zhang, Xiaomin; Kato, Norihiro; Wang, Qing K; Zheng, Wei; Hu, Frank B; Lin, Dongxin; Shen, Hongbing; Teo, Yik Ying; Mo, Zengnan; Wong, Tien Yin; Lin, Xu; Mohlke, Karen L; Ning, Guang; Tsunoda, Tatsuhiko; Han, Bok-Ghee; Shu, Xiao-Ou; Tai, E Shyong; Wu, Tangchun; Qi, Lu

2015-03-15

Human height is associated with risk of multiple diseases and is profoundly determined by an individual's genetic makeup and shows a high degree of ethnic heterogeneity. Large-scale genome-wide association (GWA) analyses of adult height in Europeans have identified nearly 180 genetic loci. A recent study showed high replicability of results from Europeans-based GWA studies in Asians; however, population-specific loci may exist due to distinct linkage disequilibrium patterns. We carried out a GWA meta-analysis in 93 926 individuals from East Asia. We identified 98 loci, including 17 novel and 81 previously reported loci, associated with height at P < 5 × 10(-8), together explaining 8.89% of phenotypic variance. Among the newly identified variants, 10 are commonly distributed (minor allele frequency, MAF > 5%) in Europeans, with comparable frequencies with in Asians, and 7 single-nucleotide polymorphisms are with low frequency (MAF < 5%) in Europeans. In addition, our data suggest that novel biological pathway such as the protein tyrosine phosphatase family is involved in regulation of height. The findings from this study considerably expand our knowledge of the genetic architecture of human height in Asians. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

The identification of the relationship between the perceived social support, fatigue levels and maternal attachment during the postpartum period.

PubMed

Yesilcinar, Ilknur; Yavan, Tulay; Karasahin, Kazim Emre; Yenen, Mufit Cemal

2017-05-01

This study aims to determinate the relationship between social support perceived by women, fatigue levels and maternal attachment in postpartum period. The sample of this descriptive study consists of 181 women who gave birth in the study period. The data was collected by the socio-demographic characteristics forms; "Multidimensional Scale of Perceived Social Support" (MSPSS); "Multidimensional Assessment of Fatigue Scale" (MAFS) and "Maternal Attachment Scale" (MAS) on the postpartum first days and 30-40th days. MSPSS scores of women who had university or higher education, employed, had their first pregnancy, have 12 months or less between two pregnancies, were found to be significantly higher than others. MAS scores of women at the end of the postpartum first month were significantly increased. MAFS scores of women at the end of the postpartum first month were significantly decreased. The correlation between the fatigue levels and maternal attachment levels at the end of the postpartum first month was found to be negative and significant. In the postpartum period, the care of the mother should include social support, maternal attachment and fatigue assessment. Mothers should be encouraged to use social support resources. The continuity of social support systems should be provided.

Controls on Water Use for Thermoelectric Generation: Case Study Texas, U.S.

PubMed Central

2013-01-01

Large-scale U.S. dependence on thermoelectric (steam electric) generation requiring water for cooling underscores the need to understand controls on this water use. The study objective was to quantify water consumption and withdrawal for thermoelectric generation, identifying controls, using Texas as a case study. Water consumption for thermoelectricity in Texas in 2010 totaled ∼0.43 million acre feet (maf; 0.53 km3), accounting for ∼4% of total state water consumption. High water withdrawals (26.2 maf, 32.3 km3) mostly reflect circulation between ponds and power plants, with only two-thirds of this water required for cooling. Controls on water consumption include (1) generator technology/thermal efficiency and (2) cooling system, resulting in statewide consumption intensity for natural gas combined cycle generators with mostly cooling towers (0.19 gal/kWh) being 63% lower than that of traditional coal, nuclear, or natural gas steam turbine generators with mostly cooling ponds (0.52 gal/kWh). The primary control on water withdrawals is cooling system, with ∼2 orders of magnitude lower withdrawals for cooling towers relative to once-through ponds statewide. Increases in natural gas combined cycle plants with cooling towers in response to high production of low-cost natural gas has greatly reduced water demand for thermoelectric cooling since 2000. PMID:23937226

Controls on water use for thermoelectric generation: case study Texas, US.

PubMed

Scanlon, Bridget R; Reedy, Robert C; Duncan, Ian; Mullican, William F; Young, Michael

2013-10-01

Large-scale U.S. dependence on thermoelectric (steam electric) generation requiring water for cooling underscores the need to understand controls on this water use. The study objective was to quantify water consumption and withdrawal for thermoelectric generation, identifying controls, using Texas as a case study. Water consumption for thermoelectricity in Texas in 2010 totaled ∼0.43 million acre feet (maf; 0.53 km(3)), accounting for ∼4% of total state water consumption. High water withdrawals (26.2 maf, 32.3 km(3)) mostly reflect circulation between ponds and power plants, with only two-thirds of this water required for cooling. Controls on water consumption include (1) generator technology/thermal efficiency and (2) cooling system, resulting in statewide consumption intensity for natural gas combined cycle generators with mostly cooling towers (0.19 gal/kWh) being 63% lower than that of traditional coal, nuclear, or natural gas steam turbine generators with mostly cooling ponds (0.52 gal/kWh). The primary control on water withdrawals is cooling system, with ∼2 orders of magnitude lower withdrawals for cooling towers relative to once-through ponds statewide. Increases in natural gas combined cycle plants with cooling towers in response to high production of low-cost natural gas has greatly reduced water demand for thermoelectric cooling since 2000.

Characterization of Nrf2 activation and heme oxygenase-1 expression in NIH3T3 cells exposed to aqueous extracts of cigarette smoke.

PubMed

Knörr-Wittmann, Constanze; Hengstermann, Arnd; Gebel, Stephan; Alam, Jawed; Müller, Thomas

2005-12-01

Cigarette smoke (CS) is a complex chemical mixture estimated to be composed of up to 5000 different chemicals, many of which are prooxidant. Here we show that, at least in vitro, the cellular response designed to combat oxidative stress resulting from CS exposure is primarily controlled by the transcription factor Nrf2, a principal inducer of antioxidant and phase II-related genes. The prominent role of Nrf2 in the cellular response to CS is substantiated by the following observations: In NIH3T3 cells exposed to aqueous extracts of CS (i) Nrf2 is strongly stabilized and becomes detectable in nuclear extracts. (ii) Nuclear localization of Nrf2 coincides with increased DNA binding of a putative Nrf2/MafK heterodimer to its cognate cis-regulatory site, i.e., the antioxidant-responsive element (ARE). (iii) Studies on the regulatory elements of the oxidative stress-inducible gene heme oxygenase-1 (hmox1) using various hmox1 promoter/luciferase reporter constructs revealed that the strong CS-dependent expression of this gene is primarily governed by the distal enhancers 1 ("E1") and 2 ("E2"), which both contain three canonical ARE-like stress-responsive elements (StREs). Notably, depletion of Nrf2 levels caused by RNA interference significantly compromised CS-induced hmox1 promoter activation, based on the distinct Nrf2 sensitivity exhibited by E1 and E2. Finally, (iv) siRNA-dependent knock-down of Nrf2 completely abrogated CS-induced expression of phase II-related genes. Taken together, these results confirm the outstanding role of Nrf2 both in sensing (oxidant) stress and in orchestrating an efficient transcriptional response aimed at resolving the stressing conditions.

Sensitive and Specific Fluorescent Probes for Functional Analysis of the Three Major Types of Mammalian ABC Transporters

PubMed Central

Lebedeva, Irina V.; Pande, Praveen; Patton, Wayne F.

2011-01-01

An underlying mechanism for multi drug resistance (MDR) is up-regulation of the transmembrane ATP-binding cassette (ABC) transporter proteins. ABC transporters also determine the general fate and effect of pharmaceutical agents in the body. The three major types of ABC transporters are MDR1 (P-gp, P-glycoprotein, ABCB1), MRP1/2 (ABCC1/2) and BCRP/MXR (ABCG2) proteins. Flow cytometry (FCM) allows determination of the functional expression levels of ABC transporters in live cells, but most dyes used as indicators (rhodamine 123, DiOC2(3), calcein-AM) have limited applicability as they do not detect all three major types of ABC transporters. Dyes with broad coverage (such as doxorubicin, daunorubicin and mitoxantrone) lack sensitivity due to overall dimness and thus may yield a significant percentage of false negative results. We describe two novel fluorescent probes that are substrates for all three common types of ABC transporters and can serve as indicators of MDR in flow cytometry assays using live cells. The probes exhibit fast internalization, favorable uptake/efflux kinetics and high sensitivity of MDR detection, as established by multidrug resistance activity factor (MAF) values and Kolmogorov-Smirnov statistical analysis. Used in combination with general or specific inhibitors of ABC transporters, both dyes readily identify functional efflux and are capable of detecting small levels of efflux as well as defining the type of multidrug resistance. The assay can be applied to the screening of putative modulators of ABC transporters, facilitating rapid, reproducible, specific and relatively simple functional detection of ABC transporter activity, and ready implementation on widely available instruments. PMID:21799851

Advanced Manufacturing at the Marshall Space Flight Center and Application to Ares I and Ares V Launch Vehicles

NASA Technical Reports Server (NTRS)

Carruth, Ralph

2008-01-01

There are various aspects of advanced manufacturing technology development at the field centers of the National Aeronautics and Space Administration (NASA). The Marshall Space Flight Center (MSFC) has been given the assignment to lead the National Center for Advanced Manufacturing (NCAM) at MSFC and pursue advanced development and coordination with other federal agencies for NASA. There are significant activities at the Marshall Center as well as at the Michoud Assembly Facility (MAF) in New Orleans which we operate in conjunction with the University of New Orleans. New manufacturing processes in metals processing, component development, welding operations, composite manufacturing and thermal protection system material and process development will be utilized in the manufacturing of the United States two new launch vehicles, the Ares I and the Ares V. An overview of NCAM will be presented as well as some of the development activities and manufacturing that are ongoing in Ares Upper Stage development. Some of the tools and equipment produced by Italian owned companies and their application in this work will be mentioned.

Expansion and conversion of human pancreatic ductal cells into insulin-secreting endocrine cells

PubMed Central

Lee, Jonghyeob; Sugiyama, Takuya; Liu, Yinghua; Wang, Jing; Gu, Xueying; Lei, Ji; Markmann, James F; Miyazaki, Satsuki; Miyazaki, Jun-ichi; Szot, Gregory L; Bottino, Rita; Kim, Seung K

2013-01-01

Pancreatic islet β-cell insufficiency underlies pathogenesis of diabetes mellitus; thus, functional β-cell replacement from renewable sources is the focus of intensive worldwide effort. However, in vitro production of progeny that secrete insulin in response to physiological cues from primary human cells has proven elusive. Here we describe fractionation, expansion and conversion of primary adult human pancreatic ductal cells into progeny resembling native β-cells. FACS-sorted adult human ductal cells clonally expanded as spheres in culture, while retaining ductal characteristics. Expression of the cardinal islet developmental regulators Neurog3, MafA, Pdx1 and Pax6 converted exocrine duct cells into endocrine progeny with hallmark β-cell properties, including the ability to synthesize, process and store insulin, and secrete it in response to glucose or other depolarizing stimuli. These studies provide evidence that genetic reprogramming of expandable human pancreatic cells with defined factors may serve as a general strategy for islet replacement in diabetes. DOI: http://dx.doi.org/10.7554/eLife.00940.001 PMID:24252877

Expansion and conversion of human pancreatic ductal cells into insulin-secreting endocrine cells.

PubMed

Lee, Jonghyeob; Sugiyama, Takuya; Liu, Yinghua; Wang, Jing; Gu, Xueying; Lei, Ji; Markmann, James F; Miyazaki, Satsuki; Miyazaki, Jun-Ichi; Szot, Gregory L; Bottino, Rita; Kim, Seung K

2013-11-19

Pancreatic islet β-cell insufficiency underlies pathogenesis of diabetes mellitus; thus, functional β-cell replacement from renewable sources is the focus of intensive worldwide effort. However, in vitro production of progeny that secrete insulin in response to physiological cues from primary human cells has proven elusive. Here we describe fractionation, expansion and conversion of primary adult human pancreatic ductal cells into progeny resembling native β-cells. FACS-sorted adult human ductal cells clonally expanded as spheres in culture, while retaining ductal characteristics. Expression of the cardinal islet developmental regulators Neurog3, MafA, Pdx1 and Pax6 converted exocrine duct cells into endocrine progeny with hallmark β-cell properties, including the ability to synthesize, process and store insulin, and secrete it in response to glucose or other depolarizing stimuli. These studies provide evidence that genetic reprogramming of expandable human pancreatic cells with defined factors may serve as a general strategy for islet replacement in diabetes. DOI: http://dx.doi.org/10.7554/eLife.00940.001.

Mapping hard magnetic recording disks by TOF-SIMS

NASA Astrophysics Data System (ADS)

Spool, A.; Forrest, J.

2008-12-01

Mapping of hard magnetic recording disks by TOF-SIMS was performed both to produce significant analytical results for the understanding of the disk surface and the head disk interface in hard disk drives, and as an example of a macroscopic non-rectangular mapping problem for the technique. In this study, maps were obtained by taking discrete samples of the disk surface at set intervals in R and Θ. Because both in manufacturing, and in the disk drive, processes that may affect the disk surface are typically circumferential in nature, changes in the surface are likely to be blurred in the Θ direction. An algorithm was developed to determine the optimum relative sampling ratio in R and Θ. The results confirm what the experience of the analysts suggested, that changes occur more rapidly on disks in the radial direction, and that more sampling in the radial direction is desired. The subsequent use of statistical methods principle component analysis (PCA), maximum auto-correlation factors (MAF), and the algorithm inverse distance weighting (IDW) are explored.

Noninvasive Prenatal Paternity Testing (NIPAT) through Maternal Plasma DNA Sequencing: A Pilot Study.

PubMed

Jiang, Haojun; Xie, Yifan; Li, Xuchao; Ge, Huijuan; Deng, Yongqiang; Mu, Haofang; Feng, Xiaoli; Yin, Lu; Du, Zhou; Chen, Fang; He, Nongyue

2016-01-01

Short tandem repeats (STRs) and single nucleotide polymorphisms (SNPs) have been already used to perform noninvasive prenatal paternity testing from maternal plasma DNA. The frequently used technologies were PCR followed by capillary electrophoresis and SNP typing array, respectively. Here, we developed a noninvasive prenatal paternity testing (NIPAT) based on SNP typing with maternal plasma DNA sequencing. We evaluated the influence factors (minor allele frequency (MAF), the number of total SNP, fetal fraction and effective sequencing depth) and designed three different selective SNP panels in order to verify the performance in clinical cases. Combining targeted deep sequencing of selective SNP and informative bioinformatics pipeline, we calculated the combined paternity index (CPI) of 17 cases to determine paternity. Sequencing-based NIPAT results fully agreed with invasive prenatal paternity test using STR multiplex system. Our study here proved that the maternal plasma DNA sequencing-based technology is feasible and accurate in determining paternity, which may provide an alternative in forensic application in the future.

Recruitment of Rod Photoreceptors from Short-Wavelength-Sensitive Cones during the Evolution of Nocturnal Vision in Mammals.

PubMed

Kim, Jung-Woong; Yang, Hyun-Jin; Oel, Adam Phillip; Brooks, Matthew John; Jia, Li; Plachetzki, David Charles; Li, Wei; Allison, William Ted; Swaroop, Anand

2016-06-20

Vertebrate ancestors had only cone-like photoreceptors. The duplex retina evolved in jawless vertebrates with the advent of highly photosensitive rod-like photoreceptors. Despite cones being the arbiters of high-resolution color vision, rods emerged as the dominant photoreceptor in mammals during a nocturnal phase early in their evolution. We investigated the evolutionary and developmental origins of rods in two divergent vertebrate retinas. In mice, we discovered genetic and epigenetic vestiges of short-wavelength cones in developing rods, and cell-lineage tracing validated the genesis of rods from S cones. Curiously, rods did not derive from S cones in zebrafish. Our study illuminates several questions regarding the evolution of duplex retina and supports the hypothesis that, in mammals, the S-cone lineage was recruited via the Maf-family transcription factor NRL to augment rod photoreceptors. We propose that this developmental mechanism allowed the adaptive exploitation of scotopic niches during the nocturnal bottleneck early in mammalian evolution. Published by Elsevier Inc.

Seismic Regionalization of Michoacan, Mexico and Recurrence Periods for Earthquakes

NASA Astrophysics Data System (ADS)

Magaña García, N.; Figueroa-Soto, Á.; Garduño-Monroy, V. H.; Zúñiga, R.

2017-12-01

Michoacán is one of the states with the highest occurrence of earthquakes in Mexico and it is a limit of convergence triggered by the subduction of Cocos plate over the North American plate, located in the zone of the Pacific Ocean of our country, in addition to the existence of active faults inside of the state like the Morelia-Acambay Fault System (MAFS).It is important to make a combination of seismic, paleosismological and geological studies to have good planning and development of urban complexes to mitigate disasters if destructive earthquakes appear. With statistical seismology it is possible to characterize the degree of seismic activity as well as to estimate the recurrence periods for earthquakes. For this work, seismicity catalog of Michoacán was compiled and homogenized in time and magnitude. This information was obtained from world and national agencies (SSN, CMT, etc), some data published by Mendoza and Martínez-López (2016) and starting from the seismic catalog homogenized by F. R. Zúñiga (Personal communication). From the analysis of the different focal mechanisms reported in the literature and geological studies, the seismic regionalization of the state of Michoacán complemented the one presented by Vázquez-Rosas (2012) and the recurrence periods for earthquakes within the four different seismotectonic regions. In addition, stable periods were determined for the b value of the Gutenberg-Richter (1944) using the Maximum Curvature and EMR (Entire Magnitude Range Method, 2005) techniques, which allowed us to determine recurrence periods: years for earthquakes upper to 7.5 for the subduction zone (A zone) with EMR technique and years with MAXC technique for the same years for earthquakes upper to 5 for B1 zone with EMR technique and years with MAXC technique; years for earthquakes upper to 7.0 for B2 zone with EMR technique and years with MAXC technique; and the last one, the Morelia-Acambay Fault Sistem zone (C zone) years for earthquakes upper to 5 with EMR technique and years with MAXC technique. This recurrence periods are very similar to periods calculated by Garduño-Monroy (2009) and Sunye-Puchol (2015) using paleoseismological methods. If we consider that the MAFS cross Zacapu, Pátzcuaro, Morelia, Cuitzeo, Maravatío and Acambay, the affected population would be around 1132807 habitants.

Early Loss of Splenic Tfh Cells in SIV-Infected Rhesus Macaques

PubMed Central

Moukambi, Félicien; Rabezanahary, Henintsoa; Rodrigues, Vasco; Racine, Gina; Robitaille, Lynda; Krust, Bernard; Andreani, Guadalupe; Soundaramourty, Calayselvy; Silvestre, Ricardo; Laforge, Mireille; Estaquier, Jérôme

2015-01-01

Follicular T helper cells (Tfh), a subset of CD4 T lymphocytes, provide crucial help to B cells in the production of antigen-specific antibodies. Although several studies have analyzed the dynamics of Tfh cells in peripheral blood and lymph nodes (LNs) during Aids, none has yet addressed the impact of SIV infection on the dynamics of Tfh cells in the spleen, the primary organ of B cell activation. We show here a significant decrease in splenic Tfh cells in SIVmac251-infected rhesus macaques (RMs) during the acute phase of infection, which persists thereafter. This profound loss is associated with lack of sustained expression of the Tfh-defining transcription factors, Bcl-6 and c-Maf but with higher expression of the repressors KLF2 and Foxo1. In this context of Tfh abortive differentiation and loss, we found decreased percentages of memory B cell subsets and lower titers of SIV-specific IgG. We further demonstrate a drastic remodeling of the lymphoid architecture of the spleen and LNs, which disrupts the crucial cell-cell interactions necessary to maintain memory B cells and Tfh cells. Finally, our data demonstrated the early infection of Tfh cells. Paradoxically, the frequencies of SIV DNA were higher in splenic Tfh cells of RMs progressing more slowly suggesting sanctuaries for SIV in the spleen. Our findings provide important information regarding the impact of HIV/SIV infection on Tfh cells, and provide new clues for future vaccine strategies. PMID:26640894

Follicular helper T cell in immunity and autoimmunity.

PubMed

Mesquita, D; Cruvinel, W M; Resende, L S; Mesquita, F V; Silva, N P; Câmara, N O S; Andrade, L E C

2016-01-01

The traditional concept that effector T helper (Th) responses are mediated by Th1/Th2 cell subtypes has been broadened by the recent demonstration of two new effector T helper cells, the IL-17 producing cells (Th17) and the follicular helper T cells (Tfh). These new subsets have many features in common, such as the ability to produce IL-21 and to express the IL-23 receptor (IL23R), the inducible co-stimulatory molecule ICOS, and the transcription factor c-Maf, all of them essential for expansion and establishment of the final pool of both subsets. Tfh cells differ from Th17 by their ability to home to B cell areas in secondary lymphoid tissue through interactions mediated by the chemokine receptor CXCR5 and its ligand CXCL13. These CXCR5+ CD4+ T cells are considered an effector T cell type specialized in B cell help, with a transcriptional profile distinct from Th1 and Th2 cells. The role of Tfh cells and its primary product, IL-21, on B-cell activation and differentiation is essential for humoral immunity against infectious agents. However, when deregulated, Tfh cells could represent an important mechanism contributing to exacerbated humoral response and autoantibody production in autoimmune diseases. This review highlights the importance of Tfh cells by focusing on their biology and differentiation processes in the context of normal immune response to infectious microorganisms and their role in the pathogenesis of autoimmune diseases.

NAMPT-Mediated Salvage Synthesis of NAD+ Controls Morphofunctional Changes of Macrophages

PubMed Central

Venter, Gerda; Oerlemans, Frank T. J. J.; Willemse, Marieke; Wijers, Mietske; Fransen, Jack A. M.; Wieringa, Bé

2014-01-01

Functional morphodynamic behavior of differentiated macrophages is strongly controlled by actin cytoskeleton rearrangements, a process in which also metabolic cofactors ATP and NAD(H) (i.e. NAD+ and NADH) and NADP(H) (i.e. NADP+ and NADPH) play an essential role. Whereas the link to intracellular ATP availability has been studied extensively, much less is known about the relationship between actin cytoskeleton dynamics and intracellular redox state and NAD+-supply. Here, we focus on the role of nicotinamide phosphoribosyltransferase (NAMPT), found in extracellular form as a cytokine and growth factor, and in intracellular form as one of the key enzymes for the production of NAD+ in macrophages. Inhibition of NAD+ salvage synthesis by the NAMPT-specific drug FK866 caused a decrease in cytosolic NAD+ levels in RAW 264.7 and Maf-DKO macrophages and led to significant downregulation of the glycolytic flux without directly affecting cell viability, proliferation, ATP production capacity or mitochondrial respiratory activity. Concomitant with these differential metabolic changes, the capacity for phagocytic ingestion of particles and also substrate adhesion of macrophages were altered. Depletion of cytoplasmic NAD+ induced cell-morphological changes and impaired early adhesion in phagocytosis of zymosan particles as well as spreading performance. Restoration of NAD+ levels by NAD+, NMN, or NADP+ supplementation reversed the inhibitory effects of FK866. We conclude that direct coupling to local, actin-based, cytoskeletal dynamics is an important aspect of NAD+’s cytosolic role in the regulation of morphofunctional characteristics of macrophages. PMID:24824795

Strict adherence to malaria rapid test results might lead to a neglect of other dangerous diseases: a cost benefit analysis from Burkina Faso.

PubMed

Bisoffi, Zeno; Sirima, Sodiomon B; Meheus, Filip; Lodesani, Claudia; Gobbi, Federico; Angheben, Andrea; Tinto, Halidou; Neya, Bouma; Van den Ende, Klara; Romeo, Annalisa; Van den Ende, Jef

2011-08-04

Malaria rapid diagnostic tests (RDTs) have generally been found reliable and cost-effective. In Burkina Faso, the adherence of prescribers to the negative test result was found to be poor. Moreover, the test accuracy for malaria-attributable fever (MAF) is not the same as for malaria infection. This paper aims at determining the costs and benefits of two competing strategies for the management of MAF: presumptive treatment for all or use of RDTs. A cost benefit analysis was carried out using a decision tree, based on data previously obtained, including a randomized controlled trial (RCT) recruiting 852 febrile patients during the dry season and 1,317 in the rainy season. Cost and benefit were calculated using both the real adherence found by the RCT and assuming an ideal adherence of 90% with the negative result. The main parameters were submitted to sensitivity analysis. At real adherence, the test-based strategy was dominated. Assuming ideal adherence, at the value of 525 € for a death averted, the total cost of managing 1,000 febrile children was 1,747 vs. 1,862 € in the dry season and 1,372 vs. 2,138 in the rainy season for the presumptive vs. the test-based strategy. For adults it was 2,728 vs. 1,983 and 2,604 vs. 2,225, respectively. At the subsidized policy adopted locally, assuming ideal adherence, the RDT would be the winning strategy for adults in both seasons and for children in the dry season.At sensitivity analysis, the factors most influencing the choice of the better strategy were the value assigned to a death averted and the proportion of potentially severe NMFI treated with antibiotics in patients with false positive RDT results. The test-based strategy appears advantageous for adults if a satisfactory adherence could be achieved. For children the presumptive strategy remains the best choice for a wide range of scenarios. For RDTs to be preferred, a positive result should not influence the decision to treat a potentially severe NMFI with antibiotics. In the rainy season the presumptive strategy always remains the better choice for children.

Saturn Apollo Program

NASA Image and Video Library

1965-03-15

Workers at the Marshall Space Flight Center (MSFC) hoist S-IB-1, the first flight version of the Saturn IB launch vehicle's first stage (S-IB stage), into the Saturn IB static test stand on March 15, 1965. Developed by the MSFC and built by the Chrysler Corporation at the Michoud Assembly Facility (MAF) in New Orleans, Louisiana, the 90,000-pound booster utilized eight H-1 engines to produce a combined thrust of 1,600,000 pounds.

Welcome to Methods and Applications in Fluorescence

NASA Astrophysics Data System (ADS)

Birch, David; Mély, Yves; Wolfbeis, Otto S.

2013-03-01

On behalf of the Editorial Board of Methods and Applications in Fluorescence and IOP Publishing we are delighted to invite you to read the first articles in our new journal. Methods and Applications in Fluorescence is forged out of the renowned MAF conference series of the same name and we fully expect the natural synergy between the two to provide the ideal platform for moving the field of fluorescence forward. Our aim is for this new journal to reflect the truly global and diverse impact fluorescence is having across many disciplines and help fluorescence achieve its full potential. Just as MAF is the leading conference in fluorescence we are confident of the high impact of this new journal. Methods and Applications in Fluorescence has a distinguished Editorial Board that is drawn from the MAF conference Permanent Steering Committee. Together with the Editorial Board and the rest of the community, the journal will closely track the very latest developments in fluorescence while delivering a fair and constructive review process. We are very pleased that this journal is backed by the Institute of Physics, one of the world's premier learned societies. IOP Publishing has a wealth of experience in science publishing that dates back to 1874. It is a not-for-profit organization that publishes over 60 journals, many on multidisciplinary topics and many including seminal contributions from Nobel Laureates. Any funding surplus generated by IOP Publishing goes directly back into science through the Institute of Physics, thus helping to nurture science for future generations. We invite submissions as regular articles, review articles and technical notes within the scope of the journal, which includes all the major aspects of fluorescence. This covers both theory and experiment across spectroscopy, imaging, materials, labels, probes and sensors. The applications of fluorescence to emerging areas in bionanotechnology, nanotechnology and medicine are very much part of the vision for the journal. Methods and Applications in Fluorescence is a journal for the whole community, so do please join us in helping to give the field of fluorescence the standing it deserves by submitting your latest and most exciting work. The success of the journal depends on all of us in the field and we look forward to working with you on this exciting project. David Birch, Yves Mély and Otto S WolfbeisEditors in Chief

Welcome to Methods and Applications in Fluorescence.

PubMed

Birch, David; Mély, Yves; Wolfbeis, Otto S

2013-01-28

On behalf of the Editorial Board of Methods and Applications in Fluorescence and IOP Publishing we are delighted to invite you to read the first articles in our new journal. Methods and Applications in Fluorescence is forged out of the renowned MAF conference series of the same name and we fully expect the natural synergy between the two to provide the ideal platform for moving the field of fluorescence forward. Our aim is for this new journal to reflect the truly global and diverse impact fluorescence is having across many disciplines and help fluorescence achieve its full potential. Just as MAF is the leading conference in fluorescence we are confident of the high impact of this new journal. Methods and Applications in Fluorescence has a distinguished Editorial Board that is drawn from the MAF conference Permanent Steering Committee. Together with the Editorial Board and the rest of the community, the journal will closely track the very latest developments in fluorescence while delivering a fair and constructive review process. We are very pleased that this journal is backed by the Institute of Physics, one of the world's premier learned societies. IOP Publishing has a wealth of experience in science publishing that dates back to 1874. It is a not-for-profit organization that publishes over 60 journals, many on multidisciplinary topics and many including seminal contributions from Nobel Laureates. Any funding surplus generated by IOP Publishing goes directly back into science through the Institute of Physics, thus helping to nurture science for future generations. We invite submissions as regular articles, review articles and technical notes within the scope of the journal, which includes all the major aspects of fluorescence. This covers both theory and experiment across spectroscopy, imaging, materials, labels, probes and sensors. The applications of fluorescence to emerging areas in bionanotechnology, nanotechnology and medicine are very much part of the vision for the journal. Methods and Applications in Fluorescence is a journal for the whole community, so do please join us in helping to give the field of fluorescence the standing it deserves by submitting your latest and most exciting work. The success of the journal depends on all of us in the field and we look forward to working with you on this exciting project. David Birch, Yves Mély and Otto S WolfbeisEditors in Chief.

Water extract of the fruits of Alpinia oxyphylla inhibits osteoclast differentiation and bone loss.

PubMed

Ha, Hyunil; Shim, Ki-Shuk; Kim, Taesoo; Lee, Chung-Jo; Park, Ji Hyung; Kim, Han Sung; Ma, Jin Yeul

2014-09-23

Excessive bone resorption by osteoclasts causes pathological bone destruction, seen in various bone diseases. There is accumulating evidence that certain herbal extracts have beneficial effects on bone metabolism. The fruits of Alpinia oxyphylla has been traditionally used for the treatment of diarrhea and enuresis. In this study, we investigated the effects of water extract of the fruits of Alpinia oxyphylla (WEAO) on osteoclast differentiation and osteoclast-mediated bone destruction. For osteoclast differentiation assay, mouse bone marrow-derived macrophages (BMMs) were cultured in the presence of RANKL and M-CSF. RANKL signaling pathways and gene expression of transcription factors regulating osteoclast differentiation were investigated by real-time PCR and Western blotting. A constitutively active form of NFATc1 was retrovirally transduced into BMMs. Bone resorbing activity of mature osteoclast was examined on a plate coated with an inorganic crystalline calcium phosphate. The in vivo effect against bone destruction was assessed in a murine model of RANKL-induced osteoporosis by micro-computed tomography and bone metabolism marker analyses. WEAO dose-dependently inhibited RANKL-induced osteoclast differentiation from BMMs by targeting the early stages of osteoclast differentiation. WEAO inhibited RANKL-induced expression of NFATc1, the master regulator of osteoclast differentiation. Overexpression of a constitutively active form of NFATc1 blunted the inhibitory effect of WEAO on osteoclast differentiation, suggesting that NFATc1 is a critical target of the inhibitory action of WEAO. WEAO inhibited RANKL-induced expression of c-Fos, an upstream activator of NFATc1, by suppressing the classical NF-κB signaling pathway. WEAO also inhibited RANKL-induced down-regulation of Id2 and MafB, negative regulators of NFATc1. WEAO does not directly affect bone resorbing activity of mature osteoclasts. In accordance with the in vitro results, WEAO attenuated RANKL-induced bone destruction in mice by inhibiting osteoclast differentiation. This study demonstrates that WEAO exhibits a protective effect against bone loss by inhibiting RANKL-induced osteoclast differentiation. These findings suggest that WEAO might be useful for the prevention and treatment of bone diseases associated with excessive bone resorption.

MAF Resource Reel August 2016

NASA Image and Video Library

2016-08-01

Edited b-roll video of NASA's Michoud Assembly Facility, which is managed by the Marshall Space Flight Center in Huntsville, Alabama. This B-roll shows various projects including manufacturing of the Space Launch System core stage and the Orion spacecraft pressure vessel. It includes interior and exterior views of the facility. For more information and more detailed footage, please contact the center's Public & Employee Communications Office. PAO Name:Tracy McMahan Phone Number:256-544-0034 Email Address: tracy.mcmahan@nasa.gov

Myeloid transformation of plasma cell myeloma: molecular evidence of clonal evolution revealed by next generation sequencing.

PubMed

Gralewski, Jonathon H; Post, Ginell R; van Rhee, Frits; Yuan, Youzhong

2018-02-20

Plasma cell myeloma (PCM) is a neoplasm of terminally differentiated B lymphocytes with molecular heterogeneity. Although therapy-related myeloid neoplasms are common in plasma cell myeloma patients after chemotherapy, transdifferentiation of plasma cell myeloma into myeloid neoplasms has not been reported in literature. Here we report a very rare case of myeloid neoplasm transformed from plasma cell myeloma. A 60-year-old man with a history of plasma cell myeloma with IGH-MAF gene rearrangement and RAS/RAF mutations developed multiple soft tissue lesions one year following melphalan-based chemotherapy and autologous stem cell transplant. Morphological and immunohistochemical characterization of the extramedullary disease demonstrated that the tumor cells were derived from the monocyte-macrophage lineage. Next generation sequencing (NGS) studies detected similar clonal aberrations in the diagnostic plasma cell population and post-therapy neoplastic cells, including IGH-MAF rearrangement, multiple genetic mutations in RAS signaling pathway proteins, and loss of tumor suppressor genes. Molecular genetic analysis also revealed unique genomic alterations in the transformed tumor cells, including gain of NF1 and loss of TRAF3. To our knowledge, this is the first case of myeloid sarcoma transdifferentiated from plasma cell neoplasm. Our findings in this unique case suggest clonal evolution of plasma cell myeloma to myeloma neoplasm and the potential roles of abnormal RAS/RAF signaling pathway in lineage switch or transdifferentiation.

Graphics Processing Unit (GPU) implementation of image processing algorithms to improve system performance of the Control, Acquisition, Processing, and Image Display System (CAPIDS) of the Micro-Angiographic Fluoroscope (MAF).

PubMed

Vasan, S N Swetadri; Ionita, Ciprian N; Titus, A H; Cartwright, A N; Bednarek, D R; Rudin, S

2012-02-23

We present the image processing upgrades implemented on a Graphics Processing Unit (GPU) in the Control, Acquisition, Processing, and Image Display System (CAPIDS) for the custom Micro-Angiographic Fluoroscope (MAF) detector. Most of the image processing currently implemented in the CAPIDS system is pixel independent; that is, the operation on each pixel is the same and the operation on one does not depend upon the result from the operation on the other, allowing the entire image to be processed in parallel. GPU hardware was developed for this kind of massive parallel processing implementation. Thus for an algorithm which has a high amount of parallelism, a GPU implementation is much faster than a CPU implementation. The image processing algorithm upgrades implemented on the CAPIDS system include flat field correction, temporal filtering, image subtraction, roadmap mask generation and display window and leveling. A comparison between the previous and the upgraded version of CAPIDS has been presented, to demonstrate how the improvement is achieved. By performing the image processing on a GPU, significant improvements (with respect to timing or frame rate) have been achieved, including stable operation of the system at 30 fps during a fluoroscopy run, a DSA run, a roadmap procedure and automatic image windowing and leveling during each frame.

A Convenient Cas9-based Conditional Knockout Strategy for Simultaneously Targeting Multiple Genes in Mouse.

PubMed

Chen, Jiang; Du, Yinan; He, Xueyan; Huang, Xingxu; Shi, Yun S

2017-03-31

The most powerful way to probe protein function is to characterize the consequence of its deletion. Compared to conventional gene knockout (KO), conditional knockout (cKO) provides an advanced gene targeting strategy with which gene deletion can be performed in a spatially and temporally restricted manner. However, for most species that are amphiploid, the widely used Cre-flox conditional KO (cKO) system would need targeting loci in both alleles to be loxP flanked, which in practice, requires time and labor consuming breeding. This is considerably significant when one is dealing with multiple genes. CRISPR/Cas9 genome modulation system is advantaged in its capability in targeting multiple sites simultaneously. Here we propose a strategy that could achieve conditional KO of multiple genes in mouse with Cre recombinase dependent Cas9 expression. By transgenic construction of loxP-stop-loxP (LSL) controlled Cas9 (LSL-Cas9) together with sgRNAs targeting EGFP, we showed that the fluorescence molecule could be eliminated in a Cre-dependent manner. We further verified the efficacy of this novel strategy to target multiple sites by deleting c-Maf and MafB simultaneously in macrophages specifically. Compared to the traditional Cre-flox cKO strategy, this sgRNAs-LSL-Cas9 cKO system is simpler and faster, and would make conditional manipulation of multiple genes feasible.

Shapefile for Coastal Zone Management Program counties of the United States and its territories, 2009 (CZMP_counties_2009.shp)

USGS Publications Warehouse

Hartwell, Stephen R.; Wingfield, Dana K.; Allwardt, Alan O.; Wong, Florence L.; Lightsom, Frances L.

2013-01-01

A shapefile of 492 Coastal Zone Management Program counties of the United States and its territories, current for the ground condition in 2009, has been extracted from the U.S. Census Bureau MAF/TIGER database. Geospatial information systems with the capability to search user-defined, polygonal geographic areas will be able to utilize this shapefile or secondary products derived from it, such as well-known text representations of the individual polygons within the shapefile.

Visual Approach and Landing Aids for Aircraft. A Theoretical Analysis of Some Fundamental Aspects of the Problem by Means of Perspective Diagrams

DTIC Science & Technology

1947-01-01

mm one) THAN TNI «umom») HCU<H.»OM OWA—U rowappw or TM» oocmpff. iv ~»^^»K.iMouA»iMiMAf.TOor.TMPii»tMN»iiA«« «it> Aamt.» A natto EIAAUCTE urrm...noted that the pilot is not tied to an ideal approach path fixed in space. 6.5 An important advantage of this pattern is that it resolves the

Optimizing the Weapons Officer in the Mobility Air Forces

DTIC Science & Technology

2015-06-19

terms of professional development, what should the progression of a Weapons Officer in the MAF look like after graduation from the USAF Weapons School...appropriately. Many KC-135 commanders have openly admitted that they do not know what to do with their WOs at the unit level on a daily basis, and many...UCLA professor, and it relates to the Delphic oracle from ancient Greece whose prophetess would reveal the divine purpose of the gods in order to shape

Frequency Based Continuation Training (FBCT): A Concept for use in the Mobility Air Forces (MAF)

DTIC Science & Technology

2014-06-13

allowed the researcher to predict the impact of training period changes upon the completion percentage for a given event. These changes were then...before sunrise, … (c) Instrument experience. Except as provided in paragraph (e) of this section, a person may act as pilot in command under IFR or...be required in order to determine the real-world impact of a FBCT system on aircrew readiness. The author recommends AMC conduct a small-group

IL-6-mediated environmental conditioning of defective Th1 differentiation dampens antitumour immune responses in old age.

PubMed

Tsukamoto, Hirotake; Senju, Satoru; Matsumura, Keiko; Swain, Susan L; Nishimura, Yasuharu

2015-04-07

Decline in immune function and inflammation concomitantly develop with ageing. Here we focus on the impact of this inflammatory environment on T cells, and demonstrate that in contrast to successful tumour elimination in young mice, replenishment of tumour-specific CD4(+) T cells fails to induce tumour regression in aged hosts. The impaired antitumour effect of CD4(+) T cells with their defective Th1 differentiation in an aged environment is restored by interleukin (IL)-6 blockade or IL-6 deficiency. IL-6 blockade also restores the impaired ability of CD4(+) T cells to promote CD8(+) T-cell-dependent tumour elimination in aged mice, which requires IFN-γ. Furthermore, IL-6-stimulated production of IL-4/IL-21 through c-Maf induction is responsible for impaired Th1 differentiation. IL-6 also contributes to IL-10 production from CD4(+) T cells in aged mice, causing attenuated responses of CD8(+) T cells. These findings suggest that IL-6 serves as an extrinsic factor counteracting CD4(+) T-cell-mediated immunity against tumour in old age.

Clinical Relevant Polymorphisms Affecting Clopidogrel Pharmacokinetics and Pharmacodynamics: Insights from the Puerto Rico Newborn Screening Program.

PubMed

Hernandez-Suarez, Dagmar F; Tomassini-Fernandini, Jonnalie C; Cuevas, Angelica; Rosario-Berrios, Anyelis N; Nuñez-Medina, Héctor J; Padilla-Arroyo, Dariana; Rivera, Nannette; Liriano, Jennifer; Vega-Roman, Rocio K; Renta, Jessicca Y; Melin, Kyle; Duconge, Jorge

2018-05-30

Background: Variations in several clopidogrel-pharmacogenes have been linked to clopidogrel response variability and clinical outcomes. We aimed to determine the frequency distribution of major polymorphisms on CYP2C19 , PON1 , ABCB1 and P2RY12 pharmacogenes in Puerto Ricans. Methods : This was a cross-sectional, population-based study of 200 unrelated "Guthrie" cards specimens from newborns registered in the Puerto Rican newborn screening program (PRNSP) between 2004 and 2014. Taqman ® SNP assay techniques were used for genotyping. Results: Minor allele frequencies (MAF) were 46% for PON1 (rs662), 41% for ABCB1 (rs1045642), 14% for CYP2C19 *17, 13% for CYP2C19 *2, 12% for P2RY12 -H2 and 0.3% for CYP2C19 *4. No carriers of the CYP2C19 *3 variants were detected. All alleles and genotype proportions were found to be in Hardy⁻Weinberg equilibrium (HWE). Overall, there were no significant differences between MAFs of these variants in Puerto Ricans and the general population ( n = 453) of the 1000 Genome project, except when comparisons to each individual parental group were performed (i.e., Africans, Europeans and East-Asians; p < 0.05). As expected, the prevalence of these markers in Puerto Ricans most resembled those in the 181 subjects from reference populations of the Americas. Conclusions: These prevalence data provide a necessary groundwork for future clinical studies of clopidogrel pharmacogenetics in Caribbean Hispanics.

Linkage Disequilibrium and Inversion-Typing of the Drosophila melanogaster Genome Reference Panel

PubMed Central

Houle, David; Márquez, Eladio J.

2015-01-01

We calculated the linkage disequilibrium between all pairs of variants in the Drosophila Genome Reference Panel with minor allele count ≥5. We used r2 ≥ 0.5 as the cutoff for a highly correlated SNP. We make available the list of all highly correlated SNPs for use in association studies. Seventy-six percent of variant SNPs are highly correlated with at least one other SNP, and the mean number of highly correlated SNPs per variant over the whole genome is 83.9. Disequilibrium between distant SNPs is also common when minor allele frequency (MAF) is low: 37% of SNPs with MAF < 0.1 are highly correlated with SNPs more than 100 kb distant. Although SNPs within regions with polymorphic inversions are highly correlated with somewhat larger numbers of SNPs, and these correlated SNPs are on average farther away, the probability that a SNP in such regions is highly correlated with at least one other SNP is very similar to SNPs outside inversions. Previous karyotyping of the DGRP lines has been inconsistent, and we used LD and genotype to investigate these discrepancies. When previous studies agreed on inversion karyotype, our analysis was almost perfectly concordant with those assignments. In discordant cases, and for inversion heterozygotes, our results suggest errors in two previous analyses or discordance between genotype and karyotype. Heterozygosities of chromosome arms are, in many cases, surprisingly highly correlated, suggesting strong epsistatic selection during the inbreeding and maintenance of the DGRP lines. PMID:26068573

A geopressured-geothermal, solar conversion system to produce potable water

NASA Astrophysics Data System (ADS)

Nitschke, George Samuel

A design is presented for recovering Geopressured-Geothermal (GPGT) reservoir brines for conversion into solar ponds to renewably power coastal seawater desalination. The hot, gas-cut, high-pressure GPGT brine is flowed through a well-bore to surface systems which concentrate the brine in multi-effect evaporators and recover the gas. The gas and distilled water are used for thermal enhanced oil recovery, and the concentrated brine is used to construct solar ponds. The thermal energy from the solar ponds is used to produce electricity, which is then used to renewably power coastal desalination plants for large-scale potable water production from the sea. The design is proposed for deployment in California and Texas, where the two largest U.S. GPGT basins exist. Projections show that the design fully deployed in California could provide 5 MAF/y (million acre-ft per year) while yielding a 45% Rate of Return (combined oil and water revenues); the California municipal water load is 10 MAF/y. The dissertation contains a feasibility study of the design approach, supported by engineering analyses and simulation models, included in the appendices. A range of systems configurations and GPGT flow conditions are modeled to illustrate how the approach lends itself to modular implementation, i.e., incrementally installing a single system, tens of systems, up to 1000 systems, which corresponds to full deployment in California for the scenario analyzed. The dissertation includes a method for launching and piloting the approach, starting from a single system installation.

Evaluation of Bovine High-Density SNP Genotyping Array in Indigenous Dairy Cattle Breeds.

PubMed

Dash, S; Singh, A; Bhatia, A K; Jayakumar, S; Sharma, A; Singh, S; Ganguly, I; Dixit, S P

2018-04-03

In total 52 samples of Sahiwal ( 19 ), Tharparkar ( 17 ), and Gir ( 16 ) were genotyped by using BovineHD SNP chip to analyze minor allele frequency (MAF), genetic diversity, and linkage disequilibrium among these cattle. The common SNPs of BovineHD and 54K SNP Chips were also extracted and evaluated for their performance. Only 40%-50% SNPs of these arrays was found informative for genetic analysis in these cattle breeds. The overall mean of MAF for SNPs of BovineHD SNPChip was 0.248 ± 0.006, 0.241 ± 0.007, and 0.242 ± 0.009 in Sahiwal, Tharparkar and Gir, respectively, while that for 54K SNPs was on lower side. The average Reynold's genetic distance between breeds ranged from 0.042 to 0.055 based on BovineHD Beadchip, and from 0.052 to 0.084 based on 54K SNP Chip. The estimates of genetic diversity based on HD and 54K chips were almost same and, hence, low density chip seems to be good enough to decipher genetic diversity of these cattle breeds. The linkage disequilibrium started decaying (r 2  < 0.2) at 140 kb inter-marker distance and, hence, a 20K low density customized SNP array from HD chip could be designed for genomic selection in these cattle else the 54K Bead Chip as such will be useful.

Linkage Disequilibrium and Inversion-Typing of the Drosophila melanogaster Genome Reference Panel.

PubMed

Houle, David; Márquez, Eladio J

2015-06-10

We calculated the linkage disequilibrium between all pairs of variants in the Drosophila Genome Reference Panel with minor allele count ≥5. We used r(2) ≥ 0.5 as the cutoff for a highly correlated SNP. We make available the list of all highly correlated SNPs for use in association studies. Seventy-six percent of variant SNPs are highly correlated with at least one other SNP, and the mean number of highly correlated SNPs per variant over the whole genome is 83.9. Disequilibrium between distant SNPs is also common when minor allele frequency (MAF) is low: 37% of SNPs with MAF < 0.1 are highly correlated with SNPs more than 100 kb distant. Although SNPs within regions with polymorphic inversions are highly correlated with somewhat larger numbers of SNPs, and these correlated SNPs are on average farther away, the probability that a SNP in such regions is highly correlated with at least one other SNP is very similar to SNPs outside inversions. Previous karyotyping of the DGRP lines has been inconsistent, and we used LD and genotype to investigate these discrepancies. When previous studies agreed on inversion karyotype, our analysis was almost perfectly concordant with those assignments. In discordant cases, and for inversion heterozygotes, our results suggest errors in two previous analyses or discordance between genotype and karyotype. Heterozygosities of chromosome arms are, in many cases, surprisingly highly correlated, suggesting strong epsistatic selection during the inbreeding and maintenance of the DGRP lines. Copyright © 2015 Houle and Márquez.

Cooperative function of Pdx1 and Oc1 in multipotent pancreatic progenitors impacts postnatal islet maturation and adaptability.

PubMed

Kropp, Peter A; Dunn, Jennifer C; Carboneau, Bethany A; Stoffers, Doris A; Gannon, Maureen

2018-04-01

The transcription factors pancreatic and duodenal homeobox 1 (Pdx1) and onecut1 (Oc1) are coexpressed in multipotent pancreatic progenitors (MPCs), but their expression patterns diverge in hormone-expressing cells, with Oc1 expression being extinguished in the endocrine lineage and Pdx1 being maintained at high levels in β-cells. We previously demonstrated that cooperative function of these two factors in MPCs is necessary for proper specification and differentiation of pancreatic endocrine cells. In those studies, we observed a persistent decrease in expression of the β-cell maturity factor MafA. We therefore hypothesized that Pdx1 and Oc1 cooperativity in MPCs impacts postnatal β-cell maturation and function. Here our model of Pdx1-Oc1 double heterozygosity was used to investigate the impact of haploinsufficiency for both of these factors on postnatal β-cell maturation, function, and adaptability. Examining mice at postnatal day (P) 14, we observed alterations in pancreatic insulin content in both Pdx1 heterozygotes and double heterozygotes. Gene expression analysis at this age revealed significantly decreased expression of many genes important for glucose-stimulated insulin secretion (e.g., Glut2, Pcsk1/2, Abcc8) exclusively in double heterozygotes. Analysis of P14 islets revealed an increase in the number of mixed islets in double heterozygotes. We predicted that double-heterozygous β-cells would have an impaired ability to respond to stress. Indeed, we observed that β-cell proliferation fails to increase in double heterozygotes in response to either high-fat diet or placental lactogen. We thus report here the importance of cooperation between regulatory factors early in development for postnatal islet maturation and adaptability.

Topical Bibliography of Published Works Regarding the Health of Veterans of the Persian Gulf War

DTIC Science & Technology

1995-08-01

strain). Modern Pathology. 1991;6:750-754. Lubani MM, Lulu AR, Araj GF, Khateeb MI, Qurtom MAF, Dudin KI. Pulmonary brucellosis. Q JMed. 1989;71:319-324...Hyg. 1985;88:319-322. Molan AL, Saida LA. Echinococcosis in Iraq: prevalence of Echinococcus granulosus in stray dogs in Arbil Province. Jpn J Med Sci...in the western region of Saudi Arabia. Trans R Soc Trop Med Hyg. 1987;81:219- 221. Shweiki HM, Hira PR, Behbehani K. Cystic hydatid disease: aspects of

Saturn Apollo Program

NASA Image and Video Library

1968-03-01

The Saturn 1B first stage (S-IB) enters the NASA barge Point Barrow, in March 1968. The Marshall Space Flight Center (MSFC) utilized a number of water transportation craft to transport the Saturn stages to-and-from the manufacturing facilities and test sites, as well as delivery to the Kennedy Space Center for launch. Developed by the Marshall Space Flight Center and built by the Chrysler Corporation at Michoud Assembly Facility (MAF), the S-IB utilized the eight H-1 engines and each produced 200,000 pounds of thrust, a combined thrust of 1,600,000 pounds.

Saturn Apollo Program

NASA Image and Video Library

1965-04-01

S-IB-1, the first flight version of the Saturn IB launch vehicle's first stage (S-IB stage), undergoes a full-duration static firing in Saturn IB static test stand at the Marshall Space Flight Center (MSFC) on April 13, 1965. Developed by the MSFC and built by the Chrysler Corporation at the Michoud Assembly Facility (MAF) in New Orleans, Louisiana, the 90,000-pound booster utilized eight H-1 engines to produce a combined thrust of 1,600,000 pounds. Between April 1965 and July 1968, MSFC performed thirty-two static tests on twelve different S-IB stages.

Enhanced GITR/GITRL interactions augment IL-27 expression and induce IL-10-producing Tr-1 like cells.

PubMed

Carrier, Yijun; Whitters, Matthew J; Miyashiro, Joy S; LaBranche, Timothy P; Ramon, Hilda E; Benoit, Stephen E; Ryan, Mark S; Keegan, Sean P; Guay, Heath; Douhan, John; Collins, Mary; Dunussi-Joannopoulos, Kyri; Medley, Quintus G

2012-06-01

The glucocorticoid-induced TNFR-related (GITR) protein is a coactivating receptor that is constitutively expressed on Treg cells and induced on activated T cells. To better under-stand the role of long-term GITR signaling, we generated a mouse that constitutively expresses GITR ligand (GITRL) on APCs that mimics the physiological distribution of GITRL in vivo. Despite a five-fold expansion of the Treg-cell pool, there is increased activation and depletion of naive T cells in the transgenic (Tg) mice, suggesting that the increased number of Treg cells cannot fully suppress T-cell activation. Interestingly, GITRL Tg mice have multiorgan lymphocytic infiltrates yet display no overt autoimmunity, indicating the existence of a compensatory immunoregulatory mechanism(s). In the spleens and tissue infiltrates ofGITRL Tg mice, we found increased numbers of Foxp3(-) IL-10-producing type 1 regulatory T (Tr-1)-like cells that suppress naïve T-cell proliferation in an IL-10-dependent fashion. Increased IL-27 production from Tg APCs and activation of c-Maf in the Tr1-like cells suggest a possible mechanism for their induction. Our results demonstrate that enhanced GITR/GITRL interactions have a pleiotropic role on the regulation of T-cell responses, which includes promoting the differentiation of Tr-1-like cells, which contribute to the maintenance of peripheral T-cell tolerance. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Association between TPMT*3C and decreased thiopurine S-methyltransferase activity in patients with neuromyelitis optica spectrum disorders in China.

PubMed

Gong, Xiaoqing; Mei, Shenghui; Li, Xindi; Li, Xingang; Zhou, Heng; Liu, Yonghong; Zhou, Anna; Yang, Li; Zhao, Zhigang; Zhang, Xinghu

2018-06-01

Thiopurines are effective drugs in treating neuromyelitis optica spectrum disorders and other diseases. Thiopurines' toxicity is mainly imputed to thiopurine S-methyltransferase activity. In Chinese population, the most common and important variation of thiopurine S-methyltransferase is TPMT*3C (rs1142345). This study aims to reveal the association between thiopurine S-methyltransferase activity and genetic polymorphisms of thiopurine S-methyltransferase in patients with neuromyelitis optica spectrum disorders in China. A liquid chromatography tandem mass/mass method was used to evaluate the thiopurine S-methyltransferase activity by using 6-mercapthioprine as the substrate in human erythrocyte haemolysate via 1 h incubation at 37 °C to form its methylated product 6-methylmercaptopurine. The amount of 6-methylmercaptopurine was adjusted by haematocrit and normalized to 8 × 10 8 erythrocytes. The selected polymorphisms of thiopurine S-methyltransferase were identified using MassARRAY system (Sequenom) and multiple SNaPshot technique. In 69 patients with neuromyelitis optica spectrum disorders, thiopurine S-methyltransferase activity was 80.29-154.53 (127.51 ± 16.83) pmol/h/8 × 10 8 erythrocytes. TPMT*3C (rs1142345) was associated with lower thiopurine S-methyltransferase activity (BETA = -25.37, P = 0.011). Other selected variants were not associated with thiopurine S-methyltransferase activity. TPMT*3C affects TPMT activity in Chinese patients with neuromyelitis optica spectrum disorders. Further studies are warranted to confirm the results. TPRs = thiopurines; NMOSD = neuromyelitis optica spectrum disorders; TPMT = thiopurine S-methyltransferase; LC-MS/MS = liquid chromatography tandem mass/mass; 6-MMP = 6-methylmercaptopurine; IS = internal standard; SNP = single nucleotide polymorphism; MAF = minor allele frequency; HWE = Hardy-Weinberg equilibrium; BETA = regression coefficients; UTR-3 = untranslated region 3.

Design considerations for a new, high resolution Micro-Angiographic Fluoroscope based on a CMOS sensor (MAF-CMOS).

PubMed

Loughran, Brendan; Swetadri Vasan, S N; Singh, Vivek; Ionita, Ciprian N; Jain, Amit; Bednarek, Daniel R; Titus, Albert; Rudin, Stephen

2013-03-06

The detectors that are used for endovascular image-guided interventions (EIGI), particularly for neurovascular interventions, do not provide clinicians with adequate visualization to ensure the best possible treatment outcomes. Developing an improved x-ray imaging detector requires the determination of estimated clinical x-ray entrance exposures to the detector. The range of exposures to the detector in clinical studies was found for the three modes of operation: fluoroscopic mode, high frame-rate digital angiographic mode (HD fluoroscopic mode), and DSA mode. Using these estimated detector exposure ranges and available CMOS detector technical specifications, design requirements were developed to pursue a quantum limited, high resolution, dynamic x-ray detector based on a CMOS sensor with 50 μm pixel size. For the proposed MAF-CMOS, the estimated charge collected within the full exposure range was found to be within the estimated full well capacity of the pixels. Expected instrumentation noise for the proposed detector was estimated to be 50-1,300 electrons. Adding a gain stage such as a light image intensifier would minimize the effect of the estimated instrumentation noise on total image noise but may not be necessary to ensure quantum limited detector operation at low exposure levels. A recursive temporal filter may decrease the effective total noise by 2 to 3 times, allowing for the improved signal to noise ratios at the lowest estimated exposures despite consequent loss in temporal resolution. This work can serve as a guide for further development of dynamic x-ray imaging prototypes or improvements for existing dynamic x-ray imaging systems.

ANGPTL4 E40K and T266M: effects on plasma triglyceride and HDL levels, postprandial responses, and CHD risk.

PubMed

Talmud, Philippa J; Smart, Melissa; Presswood, Edward; Cooper, Jackie A; Nicaud, Viviane; Drenos, Fotios; Palmen, Jutta; Marmot, Michael G; Boekholdt, S Matthijs; Wareham, Nicholas J; Khaw, Kay-Tee; Kumari, Meena; Humphries, Steve E

2008-12-01

Angiopoietin-like 4 is a dual-function protein: an inhibitor of LPL, influencing plasma triglycerides (TGs), with angiogenic properties. We examined the association of common ANGPTL4 variants with CHD traits and risk in 5 studies (13,527 individuals). The effects on plasma lipids of 6 tagging SNPs and the recently identified E40K were examined in a study of 2772 men. Only T266M (rs1044250, MAF=30%) and E40K (MAF=2%) were significantly associated with TG-lowering (-10.4%, P<0.004 and -20.4%, P<0.0001), respectively. T266M no longer showed significant associations when K40 carriers (K40+) were excluded (P=0.2). Combining data from 5 studies confirmed the TG-lowering effect of K40+ (weighted mean difference: -0.12 [95% CI -0.18, -0.05] mmol/L TG P=0.0001). Surprisingly, in the 3 prospective studies, the combined OR for CHD was 1.48 (1.11 to 1.96, P=0.007), independent of TG. In individuals with a paternal history of MI (n=332) T266M, but not E40K, showed effects on postprandial AUC TG and glucose (P=0.009 and P=0.017, respectively) compared to controls (n=370). Although associated with an atheroprotective lipid profile, E40K was associated with increased CHD risk, suggesting Angptl4 influences parameters beyond lipid levels. T266M showed effects only under conditions of postprandial stress. The functionality of these potential "loss-of-function" variants needs validation.

Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility

PubMed Central

Wessel, Jennifer; Chu, Audrey Y; Willems, Sara M; Wang, Shuai; Yaghootkar, Hanieh; Brody, Jennifer A; Dauriz, Marco; Hivert, Marie-France; Raghavan, Sridharan; Lipovich, Leonard; Hidalgo, Bertha; Fox, Keolu; Huffman, Jennifer E; An, Ping; Lu, Yingchang; Rasmussen-Torvik, Laura J; Grarup, Niels; Ehm, Margaret G; Li, Li; Baldridge, Abigail S; Stančáková, Alena; Abrol, Ravinder; Besse, Céline; Boland, Anne; Bork-Jensen, Jette; Fornage, Myriam; Freitag, Daniel F; Garcia, Melissa E; Guo, Xiuqing; Hara, Kazuo; Isaacs, Aaron; Jakobsdottir, Johanna; Lange, Leslie A; Layton, Jill C; Li, Man; Hua Zhao, Jing; Meidtner, Karina; Morrison, Alanna C; Nalls, Mike A; Peters, Marjolein J; Sabater-Lleal, Maria; Schurmann, Claudia; Silveira, Angela; Smith, Albert V; Southam, Lorraine; Stoiber, Marcus H; Strawbridge, Rona J; Taylor, Kent D; Varga, Tibor V; Allin, Kristine H; Amin, Najaf; Aponte, Jennifer L; Aung, Tin; Barbieri, Caterina; Bihlmeyer, Nathan A; Boehnke, Michael; Bombieri, Cristina; Bowden, Donald W; Burns, Sean M; Chen, Yuning; Chen, Yii-DerI; Cheng, Ching-Yu; Correa, Adolfo; Czajkowski, Jacek; Dehghan, Abbas; Ehret, Georg B; Eiriksdottir, Gudny; Escher, Stefan A; Farmaki, Aliki-Eleni; Frånberg, Mattias; Gambaro, Giovanni; Giulianini, Franco; Goddard, William A; Goel, Anuj; Gottesman, Omri; Grove, Megan L; Gustafsson, Stefan; Hai, Yang; Hallmans, Göran; Heo, Jiyoung; Hoffmann, Per; Ikram, Mohammad K; Jensen, Richard A; Jørgensen, Marit E; Jørgensen, Torben; Karaleftheri, Maria; Khor, Chiea C; Kirkpatrick, Andrea; Kraja, Aldi T; Kuusisto, Johanna; Lange, Ethan M; Lee, I T; Lee, Wen-Jane; Leong, Aaron; Liao, Jiemin; Liu, Chunyu; Liu, Yongmei; Lindgren, Cecilia M; Linneberg, Allan; Malerba, Giovanni; Mamakou, Vasiliki; Marouli, Eirini; Maruthur, Nisa M; Matchan, Angela; McKean-Cowdin, Roberta; McLeod, Olga; Metcalf, Ginger A; Mohlke, Karen L; Muzny, Donna M; Ntalla, Ioanna; Palmer, Nicholette D; Pasko, Dorota; Peter, Andreas; Rayner, Nigel W; Renström, Frida; Rice, Ken; Sala, Cinzia F; Sennblad, Bengt; Serafetinidis, Ioannis; Smith, Jennifer A; Soranzo, Nicole; Speliotes, Elizabeth K; Stahl, Eli A; Stirrups, Kathleen; Tentolouris, Nikos; Thanopoulou, Anastasia; Torres, Mina; Traglia, Michela; Tsafantakis, Emmanouil; Javad, Sundas; Yanek, Lisa R; Zengini, Eleni; Becker, Diane M; Bis, Joshua C; Brown, James B; Adrienne Cupples, L; Hansen, Torben; Ingelsson, Erik; Karter, Andrew J; Lorenzo, Carlos; Mathias, Rasika A; Norris, Jill M; Peloso, Gina M; Sheu, Wayne H.-H.; Toniolo, Daniela; Vaidya, Dhananjay; Varma, Rohit; Wagenknecht, Lynne E; Boeing, Heiner; Bottinger, Erwin P; Dedoussis, George; Deloukas, Panos; Ferrannini, Ele; Franco, Oscar H; Franks, Paul W; Gibbs, Richard A; Gudnason, Vilmundur; Hamsten, Anders; Harris, Tamara B; Hattersley, Andrew T; Hayward, Caroline; Hofman, Albert; Jansson, Jan-Håkan; Langenberg, Claudia; Launer, Lenore J; Levy, Daniel; Oostra, Ben A; O'Donnell, Christopher J; O'Rahilly, Stephen; Padmanabhan, Sandosh; Pankow, James S; Polasek, Ozren; Province, Michael A; Rich, Stephen S; Ridker, Paul M; Rudan, Igor; Schulze, Matthias B; Smith, Blair H; Uitterlinden, André G; Walker, Mark; Watkins, Hugh; Wong, Tien Y; Zeggini, Eleftheria; Sharp, Stephen J; Forouhi, Nita G; Kerrison, Nicola D; Lucarelli, Debora ME; Sims, Matt; Barroso, Inês; McCarthy, Mark I; Arriola, Larraitz; Balkau, Beverley; Barricarte, Aurelio; Gonzalez, Carlos; Grioni, Sara; Kaaks, Rudolf; Key, Timothy J; Navarro, Carmen; Nilsson, Peter M; Overvad, Kim; Palli, Domenico; Panico, Salvatore; Quirós, J. Ramón; Rolandsson, Olov; Sacerdote, Carlotta; Sánchez, María–José; Slimani, Nadia; Tjonneland, Anne; Tumino, Rosario; van der A, Daphne L; van der Schouw, Yvonne T; Riboli, Elio; Laakso, Markku; Borecki, Ingrid B; Chasman, Daniel I; Pedersen, Oluf; Psaty, Bruce M; Shyong Tai, E; van Duijn, Cornelia M; Wareham, Nicholas J; Waterworth, Dawn M; Boerwinkle, Eric; Linda Kao, W H; Florez, Jose C; Loos, Ruth J.F.; Wilson, James G; Frayling, Timothy M; Siscovick, David S; Dupuis, Josée; Rotter, Jerome I; Meigs, James B; Scott, Robert A; Goodarzi, Mark O

2015-01-01

Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=−0.09±0.01 mmol l−1, P=3.4 × 10−12), T2D risk (OR[95%CI]=0.86[0.76–0.96], P=0.010), early insulin secretion (β=−0.07±0.035 pmolinsulin mmolglucose−1, P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l−1, P=4.3 × 10−4). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10−6) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol l−1, P=1.3 × 10−8). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility. PMID:25631608

A domain unique to plant RanGAP is responsible for its targeting to the plant nuclear rim

PubMed Central

Rose, Annkatrin; Meier, Iris

2001-01-01

Ran is a small signaling GTPase that is involved in nucleocytoplasmic transport. Two additional functions of animal Ran in the formation of spindle asters and the reassembly of the nuclear envelope in mitotic cells have been recently reported. In contrast to Ras or Rho, Ran is not associated with membranes. Instead, the spatial sequestering of its accessory proteins, the Ran GTPase-activating protein RanGAP and the nucleotide exchange factor RCC1, appears to define the local concentration of RanGTP vs. RanGDP involved in signaling. Mammalian RanGAP is bound to the nuclear pore by a mechanism involving the attachment of small ubiquitin-related modifier protein (SUMO) to its C terminus and the subsequent binding of the SUMOylated domain to the nucleoporin Nup358. Here we show that plant RanGAP utilizes a different mechanism for nuclear envelope association, involving a novel targeting domain that appears to be unique to plants. The N-terminal WPP domain is highly conserved among plant RanGAPs and the small, plant-specific nuclear envelope-associated protein MAF1, but not present in yeast or animal RanGAP. Confocal laser scanning microscopy of green fluorescent protein (GFP) fusion proteins showed that it is necessary for RanGAP targeting and sufficient to target the heterologous protein GFP to the plant nuclear rim. The highly conserved tryptophan and proline residues of the WPP motif are necessary for its function. The 110-aa WPP domain is the first nuclear-envelope targeting domain identified in plants. Its fundamental difference to its mammalian counterpart implies that different mechanisms have evolved in plants and animals to anchor RanGAP at the nuclear surface. PMID:11752475

Regulation of Insulin Synthesis and Secretion and Pancreatic Beta-Cell Dysfunction in Diabetes

PubMed Central

Fu, Zhuo; Gilbert, Elizabeth R.; Liu, Dongmin

2014-01-01

Pancreatic β-cell dysfunction plays an important role in the pathogenesis of both type 1 and type 2 diabetes. Insulin, which is produced in β-cells, is a critical regulator of metabolism. Insulin is synthesized as preproinsulin and processed to proinsulin. Proinsulin is then converted to insulin and C-peptide and stored in secretary granules awaiting release on demand. Insulin synthesis is regulated at both the transcriptional and translational level. The cis-acting sequences within the 5′ flanking region and trans-activators including paired box gene 6 (PAX6), pancreatic and duodenal homeobox-1(PDX-1), MafA, and B-2/Neurogenic differentiation 1 (NeuroD1) regulate insulin transcription, while the stability of preproinsulin mRNA and its untranslated regions control protein translation. Insulin secretion involves a sequence of events in β-cells that lead to fusion of secretory granules with the plasma membrane. Insulin is secreted primarily in response to glucose, while other nutrients such as free fatty acids and amino acids can augment glucose-induced insulin secretion. In addition, various hormones, such as melatonin, estrogen, leptin, growth hormone, and glucagon like peptide-1 also regulate insulin secretion. Thus, the β-cell is a metabolic hub in the body, connecting nutrient metabolism and the endocrine system. Although an increase in intracellular [Ca2+] is the primary insulin secretary signal, cAMP signaling-dependent mechanisms are also critical in the regulation of insulin secretion. This article reviews current knowledge on how β-cells synthesize and secrete insulin. In addition, this review presents evidence that genetic and environmental factors can lead to hyperglycemia, dyslipidemia, inflammation, and autoimmunity, resulting in β-cell dysfunction, thereby triggering the pathogenesis of diabetes. PMID:22974359

Clinical and experimental advances in congenital and paediatric cataracts

PubMed Central

Churchill, Amanda; Graw, Jochen

2011-01-01

Cataracts (opacities of the lens) are frequent in the elderly, but rare in paediatric practice. Congenital cataracts (in industrialized countries) are mainly caused by mutations affecting lens development. Much of our knowledge about the underlying mechanisms of cataractogenesis has come from the genetic analysis of affected families: there are contributions from genes coding for transcription factors (such as FoxE3, Maf, Pitx3) and structural proteins such as crystallins or connexins. In addition, there are contributions from enzymes affecting sugar pathways (particularly the galactose pathway) and from a quite unexpected area: axon guidance molecules like ephrins and their receptors. Cataractous mouse lenses can be identified easily by visual inspection, and a remarkable number of mutant lines have now been characterized. Generally, most of the mouse mutants show a similar phenotype to their human counterparts; however, there are some remarkable differences. It should be noted that many mutations affect genes that are expressed not only in the lens, but also in tissues and organs outside the eye. There is increasing evidence for pleiotropic effects of these genes, and increasing consideration that cataracts may act as early and readily detectable biomarkers for a number of systemic syndromes. PMID:21402583

SUMOylated MAFB promotes colorectal cancer tumorigenesis

PubMed Central

Xie, Yin-Yin; Sun, Xiao-Jian; Zhao, Ren; Huang, Qiu-Hua

2016-01-01

The transcription factor, v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB), promotes tumorigenesis in some cancers. In this study, we found that MAFB levels were increased in clinical colorectal cancer (CRC) samples, and higher expression correlated with more advanced TNM stage. We identified MAFB amplifications in a majority of tumor types in an assessment of The Cancer Genome Atlas database. Altered MAFB levels due to gene amplification, deletion, mutation, or transcription upregulation occurred in 9% of CRC cases within the database. shRNA knockdown experiments demonstrated that MAFB deficiency blocked CRC cell proliferation by arresting the cell cycle at G0/G1 phase in vitro. We found that MAFB could be SUMOylated by SUMO1 at lysine 32, and this modification was critical for cell cycle regulation by MAFB in CRC cells. SUMOylated MAFB directly regulated cyclin-dependent kinase 6 transcription by binding to its promoter. MAFB knockdown CRC cell xenograft tumors in mice grew more slowly than controls, and wild-type MAFB-overexpressing tumors grew more quickly than tumors overexpressing MAFB mutated at lysine 32. These data suggest that SUMOylated MAFB promotes CRC tumorigenesis through cell cycle regulation. MAFB and its SUMOylation process may serve as novel therapeutic targets for CRC treatment. PMID:27829226

External Tank Program Legacy of Success

NASA Technical Reports Server (NTRS)

Welzyn, Ken; Pilet, Jeff

2010-01-01

I.Goal: a) Extensive TPS damage caused by extreme hail storm. b) Repair plan required to restore TPS to minimize program manifest impacts. II. Challenges: a) Skeptical technical community - Concerned about interactions of damage with known/unknown failure modes. b) Schedule pressure to accommodate ISS program- Next tank still at MAF c)Limited ET resources. III. How d We Do It?: a) Developed unique engineering requirements and tooling to minimize repairs. b) Performed large amount of performance testing to demonstrate understanding of repairs and residual conditions. c) Effectively communicated results to technical community and management to instill confidence in expected performance.

Essentiality Weighting Models for Wholesale Level Inventory Management

DTIC Science & Technology

1988-12-01

Collection System (MDCS) and the VIDS/MAF (Visual Identification Display System/Maintenance Action Form, OPNAV 4790/ 60 ) to obtain Equipment Operation...4-) oI C. oo >, U r09 09 L C IC d - E- 0 .l . C .P UH 4- 3 0 r r-1 U 4- 0000 0U H Uu) 𔃾-) > 4-) ri Ol U- 0f 01l U >/ a U)) ODL U . t .1 Z 11 U0...the definition in reference (b). The remaining 60 percent, although not all MEC 3 items, must currently be assigned that MEC since none other exists

Coagulation factor XII genetic variation, ex vivo thrombin generation, and stroke risk in the elderly: results from the Cardiovascular Health Study.

PubMed

Olson, N C; Butenas, S; Lange, L A; Lange, E M; Cushman, M; Jenny, N S; Walston, J; Souto, J C; Soria, J M; Chauhan, G; Debette, S; Longstreth, W T; Seshadri, S; Reiner, A P; Tracy, R P

2015-10-01

The relationships of thrombin generation (TG) with cardiovascular disease risk are underevaluated in population-based cohorts. To evaluate the relationships of TG influenced by the contact and tissue factor coagulation pathways ex vivo with common single-nucleotide polymorphisms (SNPs) and incident cardiovascular disease and stroke. We measured peak TG (pTG) in baseline plasma samples of Cardiovascular Health Study participants (n = 5411), both with and without inhibitory anti-factor XIa antibody (pTG/FXIa(-) ). We evaluated their associations with ~ 50 000 SNPs by using the IBCv2 genotyping array, and with incident cardiovascular disease and stroke events over a median follow-up of 13.2 years. The minor allele for an SNP in the FXII gene (F12), rs1801020, was associated with lower pTG in European-Americans (β = - 34.2 ± 3.5 nm; P = 3.3 × 10(-22) ; minor allele frequency [MAF] = 0.23) and African-Americans (β = - 31.1 ± 7.9 nm; P = 9.0 × 10(-5) ; MAF = 0.42). Lower FXIa-independent pTG (pTG/FXIa(-) ) was associated with the F12 rs1801020 minor allele, and higher pTG/FXIa(-) was associated with the ABO SNP rs657152 minor allele (β = 16.3 nm; P = 4.3 × 10(-9) ; MAF = 0.37). The risk factor-adjusted ischemic stroke hazard ratios were 1.09 (95% confidence interval CI 1.01-1.17; P = 0.03) for pTG, 1.06 (95% CI 0.98-1.15; P = 0.17) for pTG/FXIa(-) , and 1.11 (95% CI 1.02-1.21; P = 0.02) for FXIa-dependent pTG (pTG/FXIa(+) ), per one standard deviation increment (n = 834 ischemic strokes). In a multicohort candidate gene analysis, rs1801020 was not associated with incident ischemic stroke (β = - 0.02; standard error = 0.08; P = 0.81). These results support the importance of contact activation pathway-dependent TG as a risk factor for ischemic stroke, and indicate the importance of F12 SNPs for TG ex vivo and in vivo. © 2015 International Society on Thrombosis and Haemostasis.

A serine/threonine kinase, Cot/Tpl2, modulates bacterial DNA-induced IL-12 production and Th cell differentiation.

PubMed

Sugimoto, Kenji; Ohata, Mutsuhiro; Miyoshi, Jun; Ishizaki, Hiroyoshi; Tsuboi, Naotake; Masuda, Akio; Yoshikai, Yasunobu; Takamoto, Masaya; Sugane, Kazuo; Matsuo, Seiichi; Shimada, Yasuhiro; Matsuguchi, Tetsuya

2004-09-01

A serine/threonine protein kinase, Cot/Tpl2, is indispensable for extracellular signal-regulated kinase (ERK) activation and production of TNF-alpha and PGE2 in LPS-stimulated macrophages. We show here that Cot/Tpl2 is also activated by other Toll-like receptor (TLR) ligands. Bacterial DNA rich in the dinucleotide CG (CpG-DNA), unlike LPS or synthetic lipopeptide, activated ERK in a Cot/Tpl2-independent manner. Peritoneal macrophages and bone marrow-derived DCs from Cot/Tpl2-/- mice produced significantly more IL-12 in response to CpG-DNA than those from WT mice. Enhanced IL-12 production in Cot/Tpl2-/- macrophages is, at least partly, regulated at the transcriptional level, and the elevated IL-12 mRNA level in Cot/Tpl2-/- macrophages is accompanied by decreased amounts of IL-12 repressors, such as c-musculoaponeurotic fibrosarcoma (c-Maf) and GATA sequence in the IL-12 promoter-binding protein (GA-12-binding protein; GAP-12) in the nucleus. Consistently, Cot/Tpl2-/- mice showed Th1-skewed antigen-specific immune responses upon OVA immunization and Leishmania major infection in vivo. These results indicate that Cot/Tpl2 is an important negative regulator of Th1-type adaptive immunity, that it achieves this regulation by inhibiting IL-12 production from accessory cells, and that it might be a potential target molecule in CpG-DNA-guided vaccination.

Characterization of pathogenic SORL1 genetic variants for association with Alzheimer’s disease: a clinical interpretation strategy

PubMed Central

Holstege, Henne; van der Lee, Sven J; Hulsman, Marc; Wong, Tsz Hang; van Rooij, Jeroen GJ; Weiss, Marjan; Louwersheimer, Eva; Wolters, Frank J; Amin, Najaf; Uitterlinden, André G; Hofman, Albert; Ikram, M Arfan; van Swieten, John C; Meijers-Heijboer, Hanne; van der Flier, Wiesje M; Reinders, Marcel JT; van Duijn, Cornelia M; Scheltens, Philip

2017-01-01

Accumulating evidence suggests that genetic variants in the SORL1 gene are associated with Alzheimer disease (AD), but a strategy to identify which variants are pathogenic is lacking. In a discovery sample of 115 SORL1 variants detected in 1908 Dutch AD cases and controls, we identified the variant characteristics associated with SORL1 variant pathogenicity. Findings were replicated in an independent sample of 103 SORL1 variants detected in 3193 AD cases and controls. In a combined sample of the discovery and replication samples, comprising 181 unique SORL1 variants, we developed a strategy to classify SORL1 variants into five subtypes ranging from pathogenic to benign. We tested this pathogenicity screen in SORL1 variants reported in two independent published studies. SORL1 variant pathogenicity is defined by the Combined Annotation Dependent Depletion (CADD) score and the minor allele frequency (MAF) reported by the Exome Aggregation Consortium (ExAC) database. Variants predicted strongly damaging (CADD score >30), which are extremely rare (ExAC-MAF <1 × 10−5) increased AD risk by 12-fold (95% CI 4.2–34.3; P=5 × 10−9). Protein-truncating SORL1 mutations were all unknown to ExAC and occurred exclusively in AD cases. More common SORL1 variants (ExAC-MAF≥1 × 10−5) were not associated with increased AD risk, even when predicted strongly damaging. Findings were independent of gender and the APOE-ε4 allele. High-risk SORL1 variants were observed in a substantial proportion of the AD cases analyzed (2%). Based on their effect size, we propose to consider high-risk SORL1 variants next to variants in APOE, PSEN1, PSEN2 and APP for personalized risk assessments in clinical practice. PMID:28537274

Genome-wide association studies identified novel loci for non-high-density lipoprotein cholesterol and its postprandial lipemic response.

PubMed

An, Ping; Straka, Robert J; Pollin, Toni I; Feitosa, Mary F; Wojczynski, Mary K; Daw, E Warwick; O'Connell, Jeffrey R; Gibson, Quince; Ryan, Kathleen A; Hopkins, Paul N; Tsai, Michael Y; Lai, Chao-Qiang; Province, Michael A; Ordovas, Jose M; Shuldiner, Alan R; Arnett, Donna K; Borecki, Ingrid B

2014-07-01

Non-high-density lipoprotein cholesterol(NHDL) is an independent and superior predictor of CVD risk as compared to low-density lipoprotein alone. It represents a spectrum of atherogenic lipid fractions with possibly a distinct genomic signature. We performed genome-wide association studies (GWAS) to identify loci influencing baseline NHDL and its postprandial lipemic (PPL) response. We carried out GWAS in 4,241 participants of European descent. Our discovery cohort included 928 subjects from the Genetics of Lipid-Lowering Drugs and Diet Network Study. Our replication cohorts included 3,313 subjects from the Heredity and Phenotype Intervention Heart Study and Family Heart Study. A linear mixed model using the kinship matrix was used for association tests. The best association signal was found in a tri-genic region at RHOQ-PIGF-CRIPT for baseline NHDL (lead SNP rs6544903, discovery p = 7e-7, MAF = 2 %; validation p = 6e-4 at 0.1 kb upstream neighboring SNP rs3768725, and 5e-4 at 0.7 kb downstream neighboring SNP rs6733143, MAF = 10 %). The lead and neighboring SNPs were not perfect surrogate proxies to each other (D' = 1, r (2) = 0.003) but they seemed to be partially dependent (likelihood ration test p = 0.04). Other suggestive loci (discovery p < 1e-6) included LOC100419812 and LOC100288337 for baseline NHDL, and LOC100420502 and CDH13 for NHDL PPL response that were not replicated (p > 0.01). The current and first GWAS of NHDL yielded an interesting common variant in RHOQ-PIGF-CRIPT influencing baseline NHDL levels. Another common variant in CDH13 for NHDL response to dietary high-fat intake challenge was also suggested. Further validations for both loci from large independent studies, especially interventional studies, are warranted.

Cluster formation of network-modifier cations in cesium silicate glasses

NASA Astrophysics Data System (ADS)

Jardón-Álvarez, Daniel; Sanders, Kevin J.; Phyo, Pyae; Baltisberger, Jay H.; Grandinetti, Philip J.

2018-03-01

Natural abundance 29Si two-dimensional magic-angle flipping (2D MAF) NMR spectra were measured in a series of ten cesium silicate glass compositions xCs2O.(1 - x)SiO2, where x is 0.067, 0.113, 0.175, 0.179, 0.218, 0.234, 0.263, 0.298, 0.31, and 0.36. The Q3 shielding anisotropy decreases with increasing Cs content—interpreted as an increase in the non-bridging oxygen (NBO) bond length from increasing Cs coordination (clustering) around the NBO. The 29Si 2D MAF spectra for four glass compositions x = 0.218, 0.234, 0.263, 0.298 exhibit a second co-existing and distinctly smaller shielding anisotropy corresponding to a significantly longer Si-NBO length arising from a higher degree of Cs clustering around the NBO. This second Q3 site appears at a Cs2O mole fraction close to the critical mole fraction of x = 0.24 associated with the percolation threshold of non-bridging oxygen in random close packing of oxygen, thus suggesting that the longer Si-NBO length is associated with an infinite size spanning cluster while the sites with larger anisotropies are associated with shorter Si-NBO lengths and belong to finite size clusters. The equilibrium constant of the Q3 disproportionation reaction was determined as k3 = 0.005, indicating a Qn anionic species distribution close to a binary model as expected for a low field strength modifier such as cesium. It is also found that evolution of the isotropic Q4 and line shapes with increasing Cs content are consistent with a random connectivity model between Qn of differing number of bridging oxygen, n.

Subjecting appropriate lung adenocarcinoma samples to next-generation sequencing-based molecular testing: challenges and possible solutions.

PubMed

Li, Weihua; Qiu, Tian; Ling, Yun; Gao, Shugeng; Ying, Jianming

2018-05-01

Next-generation sequencing (NGS) has recently been rapidly adopted in the molecular diagnosis of cancer, but it still faces some obstacles. In this study, 665 lung adenocarcinoma samples (558 TKI-naive and 107 TKI-relapsed samples) were interrogated using NGS, and the challenges and possible solutions of subjecting appropriate tissue samples to NGS testing were explored. The results showed that lower frequencies of HER2/BRAF/PIK3CA and acquired EGFR T790M mutations were observed in biopsy samples with <20% tumor cellularity than in those with ≥20%, but there were no significant differences in the frequencies of EGFR or KRAS mutations. Moreover, tumor heterogeneity was assessed by heterogeneity score (HS), which was calculated through multiplying by 2 the mutant allele frequency (MAF) of tumor cells. In TKI-naive samples, intratumor heterogeneity could occur in EGFR, KRAS, HER2, BRAF, and PIK3CA mutant tumors, but the degree was variable. Higher EGFR, but lower BRAF and PIK3CA HS values were observed compared with KRAS HS. In TKI-relapsed samples, analysis of concomitant sensitizing EGFR and T790M MAFs showed that intratumor heterogeneity was common in acquired EGFR T790M mutant tumors. The mutational status between primary and metastatic tumors was usually concordant, but KRAS, HER2, and PIK3CA HS were significantly higher in metastatic tumors than in primary tumors. Additionally, the discordance rate of mutational status in multifocal lung adenocarcinomas diagnosed as equivocal or multiple primary tumors was high. Together, our findings demonstrate that a comprehensive quality assessment is necessary during tissue process to mitigate the challenges of poor tumor cellularity, tumor heterogeneity, and multifocal clonally independent tumors. © 2018 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

Comparison of high resolution x-ray detectors with conventional FPDs using experimental MTFs and apodized aperture pixel design for reduced aliasing

NASA Astrophysics Data System (ADS)

Shankar, A.; Russ, M.; Vijayan, S.; Bednarek, D. R.; Rudin, S.

2017-03-01

Apodized Aperture Pixel (AAP) design, proposed by Ismailova et.al, is an alternative to the conventional pixel design. The advantages of AAP processing with a sinc filter in comparison with using other filters include non-degradation of MTF values and elimination of signal and noise aliasing, resulting in an increased performance at higher frequencies, approaching the Nyquist frequency. If high resolution small field-of-view (FOV) detectors with small pixels used during critical stages of Endovascular Image Guided Interventions (EIGIs) could also be extended to cover a full field-of-view typical of flat panel detectors (FPDs) and made to have larger effective pixels, then methods must be used to preserve the MTF over the frequency range up to the Nyquist frequency of the FPD while minimizing aliasing. In this work, we convolve the experimentally measured MTFs of an Microangiographic Fluoroscope (MAF) detector, (the MAF-CCD with 35μm pixels) and a High Resolution Fluoroscope (HRF) detector (HRF-CMOS50 with 49.5μm pixels) with the AAP filter and show the superiority of the results compared to MTFs resulting from moving average pixel binning and to the MTF of a standard FPD. The effect of using AAP is also shown in the spatial domain, when used to image an infinitely small point object. For detectors in neurovascular interventions, where high resolution is the priority during critical parts of the intervention, but full FOV with larger pixels are needed during less critical parts, AAP design provides an alternative to simple pixel binning while effectively eliminating signal and noise aliasing yet allowing the small FOV high resolution imaging to be maintained during critical parts of the EIGI.

Resequencing of IRS2 reveals rare variants for obesity but not fasting glucose homeostasis in Hispanic children.

PubMed

Butte, Nancy F; Voruganti, V Saroja; Cole, Shelley A; Haack, Karin; Comuzzie, Anthony G; Muzny, Donna M; Wheeler, David A; Chang, Kyle; Hawes, Alicia; Gibbs, Richard A

2011-09-22

Our objective was to resequence insulin receptor substrate 2 (IRS2) to identify variants associated with obesity- and diabetes-related traits in Hispanic children. Exonic and intronic segments, 5' and 3' flanking regions of IRS2 (∼14.5 kb), were bidirectionally sequenced for single nucleotide polymorphism (SNP) discovery in 934 Hispanic children using 3730XL DNA Sequencers. Additionally, 15 SNPs derived from Illumina HumanOmni1-Quad BeadChips were analyzed. Measured genotype analysis tested associations between SNPs and obesity and diabetes-related traits. Bayesian quantitative trait nucleotide analysis was used to statistically infer the most likely functional polymorphisms. A total of 140 SNPs were identified with minor allele frequencies (MAF) ranging from 0.001 to 0.47. Forty-two of the 70 coding SNPs result in nonsynonymous amino acid substitutions relative to the consensus sequence; 28 SNPs were detected in the promoter, 12 in introns, 28 in the 3'-UTR, and 2 in the 5'-UTR. Two insertion/deletions (indels) were detected. Ten independent rare SNPs (MAF = 0.001-0.009) were associated with obesity-related traits (P = 0.01-0.00002). SNP 10510452_139 in the promoter region was shown to have a high posterior probability (P = 0.77-0.86) of influencing BMI, fat mass, and waist circumference in Hispanic children. SNP 10510452_139 contributed between 2 and 4% of the population variance in body weight and composition. None of the SNPs or indels were associated with diabetes-related traits or accounted for a previously identified quantitative trait locus on chromosome 13 for fasting serum glucose. Rare but not common IRS2 variants may play a role in the regulation of body weight but not an essential role in fasting glucose homeostasis in Hispanic children.

Direct liquefaction proof-of-concept program. Finaltopical report, Bench Run 4 (227-95)

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

Comolli, A.G.; Pradhan, V.R.; Lee, T.L.K.

This report presents the results of bench-scale work, Bench Run PB-04, conducted under the DOE Proof of Concept-Bench Option Program in direct coal liquefaction at Hydrocarbon Technologies, Inc. in Lawrenceville, New Jersey. The Bench Run PB-04 was the fifth of the nine runs planned in the POC Bench Option Contract between the U.S. DOE and Hydrocarbon Technologies, Inc. Bench Run PB-04 had multiple goals. These included the evaluation of the effects of dispersed slurry catalyst system on the performance of direct liquefaction of a subbituminous Wyoming Black Thunder mine coal under extinction recycle (454{degrees}C+ recycle) condition; another goal was tomore » investigate the effects of the combined processing of automobile shredder residue (auto-fluff) with coal and other organic waste materials. PB-04 employed a two-stage, back-mixed, slurry reactor system with an interstage V/L separator and an in-line fixed-bed hydrotreater. The HTI`s newly modified P/Fe catalyst was very effective for direct liquefaction and coprocessing of Black Thunder mine subbituminous coal with Hondo resid and auto-fluff; during `coal-only` liquefaction mode, over 93% maf coal conversion was obtained with about 90% residuum conversion and as high as 67% light distillate (C{sub 4}-975 F) yield, while during `coprocessing` mode of operation, distillate yields varied between 58 and 69%; the residuum conversions varied between 74 and 89% maf. Overall, it is concluded, based upon the yield data available from PB-04, that auto-effective as MSW plastics in improving coal hydroconversion process performance. Auto-fluff did not increase light distillate yields nor decrease light gas make and chemical hydrogen consumption in coal liquefaction, as was observed to occur with MSW plastics.« less

Microglia immunophenotyping in gliomas

PubMed Central

Annovazzi, Laura; Mellai, Marta; Bovio, Enrica; Mazzetti, Samanta; Pollo, Bianca; Schiffer, Davide

2018-01-01

Microglia, once assimilated to peripheral macrophages, in gliomas has long been discussed and currently it is hypothesized to play a pro-tumor role in tumor progression. Uncertain between M1 and M2 polarization, it exchanges signals with glioma cells to create an immunosuppressive microenvironment and stimulates cell proliferation and migration. Four antibodies are currently used for microglia/macrophage identification in tissues that exhibit different cell forms and cell localization. The aim of the present work was to describe the distribution of the different cell forms and to deduce their significance on the basis of what is known on their function from the literature. Normal resting microglia, reactive microglia, intermediate and bumpy forms and macrophage-like cells can be distinguished by Iba1, CD68, CD16 and CD163 and further categorized by CD11b, CD45, c-MAF and CD98. The number of microglia/macrophages strongly increased from normal cortex and white matter to infiltrating and solid tumors. The ramified microglia accumulated in infiltration areas of both high- and low-grade gliomas, when hypertrophy and hyperplasia occur. In solid tumors, intermediate and bumpy forms prevailed and there is a large increase of macrophage-like cells in glioblastoma. The total number of microglia cells did not vary among the three grades of malignancy, but macrophage-like cells definitely prevailed in high-grade gliomas and frequently expressed CD45 and c-MAF. CD98+ cells were present. Microglia favors tumor progression, but many aspects suggest that the phagocytosing function is maintained. CD98+ cells can be the product of fusion, but also of phagocytosis. Microglia correlated with poorer survival in glioblastoma, when considering CD163+ cells, whereas it did not change prognosis in isocitrate dehydrogenase-mutant low grade gliomas. PMID:29399160

Extended diversity analysis of cultivated grapevine Vitis vinifera with 10K genome-wide SNPs.

PubMed

Laucou, Valérie; Launay, Amandine; Bacilieri, Roberto; Lacombe, Thierry; Adam-Blondon, Anne-Françoise; Bérard, Aurélie; Chauveau, Aurélie; de Andrés, Maria Teresa; Hausmann, Ludger; Ibáñez, Javier; Le Paslier, Marie-Christine; Maghradze, David; Martinez-Zapater, José Miguel; Maul, Erika; Ponnaiah, Maharajah; Töpfer, Reinhard; Péros, Jean-Pierre; Boursiquot, Jean-Michel

2018-01-01

Grapevine is a very important crop species that is mainly cultivated worldwide for fruits, wine and juice. Identification of the genetic bases of performance traits through association mapping studies requires a precise knowledge of the available diversity and how this diversity is structured and varies across the whole genome. An 18k SNP genotyping array was evaluated on a panel of Vitis vinifera cultivars and we obtained a data set with no missing values for a total of 10207 SNPs and 783 different genotypes. The average inter-SNP spacing was ~47 kbp, the mean minor allele frequency (MAF) was 0.23 and the genetic diversity in the sample was high (He = 0.32). Fourteen SNPs, chosen from those with the highest MAF values, were sufficient to identify each genotype in the sample. Parentage analysis revealed 118 full parentages and 490 parent-offspring duos, thus confirming the close pedigree relationships within the cultivated grapevine. Structure analyses also confirmed the main divisions due to an eastern-western gradient and human usage (table vs. wine). Using a multivariate approach, we refined the structure and identified a total of eight clusters. Both the genetic diversity (He, 0.26-0.32) and linkage disequilibrium (LD, 28.8-58.2 kbp) varied between clusters. Despite the short span LD, we also identified some non-recombining haplotype blocks that may complicate association mapping. Finally, we performed a genome-wide association study that confirmed previous works and also identified new regions for important performance traits such as acidity. Taken together, all the results contribute to a better knowledge of the genetics of the cultivated grapevine.

Quantitative comparison using Generalized Relative Object Detectability (G-ROD) metrics of an amorphous selenium detector with high resolution Microangiographic Fluoroscopes (MAF) and standard flat panel detectors (FPD).

PubMed

Russ, M; Shankar, A; Jain, A; Setlur Nagesh, S V; Ionita, C N; Scott, C; Karim, K S; Bednarek, D R; Rudin, S

2016-02-27

A novel amorphous selenium (a-Se) direct detector with CMOS readout has been designed, and relative detector performance investigated. The detector features include a 25 μ m pixel pitch, and 1000 μ m thick a-Se layer operating at 10V/ μ m bias field. A simulated detector DQE was determined, and used in comparative calculations of the Relative Object Detectability (ROD) family of prewhitening matched-filter (PWMF) observer and non-prewhitening matched filter (NPWMF) observer model metrics to gauge a-Se detector performance against existing high resolution micro-angiographic fluoroscopic (MAF) detectors and a standard flat panel detector (FPD). The PWMF-ROD or ROD metric compares two x-ray imaging detectors in their relative abilities in imaging a given object by taking the integral over spatial frequencies of the Fourier transform of the detector DQE weighted by an object function, divided by the comparable integral for a different detector. The generalized-ROD (G-ROD) metric incorporates clinically relevant parameters (focal-spot size, magnification, and scatter) to show the degradation in imaging performance for detectors that are part of an imaging chain. Preliminary ROD calculations using simulated spheres as the object predicted superior imaging performance by the a-Se detector as compared to existing detectors. New PWMF-G-ROD and NPWMF-G-ROD results still indicate better performance by the a-Se detector in an imaging chain over all sphere sizes for various focal spot sizes and magnifications, although a-Se performance advantages were degraded by focal spot blurring. Nevertheless, the a-Se technology has great potential to provide breakthrough abilities such as visualization of fine details including of neuro-vascular perforator vessels and of small vascular devices.

IL-27 triggers IL-10 production in Th17 cells via a c-Maf/RORγt/Blimp-1 signal to promote the progression of endometriosis

PubMed Central

Chang, Kai-Kai; Liu, Li-Bing; Jin, Li-Ping; Zhang, Bing; Mei, Jie; Li, Hui; Wei, Chun-Yan; Zhou, Wen-Jie; Zhu, Xiao-Yong; Shao, Jun; Li, Da-Jin; Li, Ming-Qing

2017-01-01

Endometriosis is an estrogen-dependent inflammatory disease. The anti-inflammatory cytokine IL-10 is also increased in endometriosis. IL-10 production by Th17 cells is critical for limiting autoimmunity and inflammatory responses. However, the mechanism of inducing IL-10-producing Th17 cells is still largely unknown. The present study investigated the differentiation mechanism and role of IL-10-producing Th17 cells in endometriosis. Here, we report that IL-10+Th17 cells are significantly increased in the peritoneal fluid of women with endometriosis, along with an elevation of IL-27, IL-6 and TGF-β. Compared with peripheral CD4+ T cells, endometrial CD4+ T cells highly expressed IL-27 receptors, especially the ectopic endometrium. Under external (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD) and local (estrogen, IL-6 and TGF-β) environmental regulation, IL-27 from macrophages and endometrial stromal cells (ESCs) induces IL-10 production in Th17 cells in vitro and in vivo. This process may be mediated through the interaction between c-musculoaponeurotic fibrosarconna (c-Maf) and retinoic acid-related orphan receptor gamma t (RORγt), and associated with the upregulation of downstream B lymphocyte-induced maturation protein-1 (Blimp-1). IL-10+Th17 cells, in turn, stimulate the proliferation and implantation of ectopic lesions and accelerate the progression of endometriosis. These results suggest that IL-27 is a pivotal regulator in endometriotic immune tolerance by triggering Th17 cells to produce IL-10 and promoting the rapid growth and implantation of ectopic lesions. This finding provides a scientific basis for potential therapeutic strategies aimed at preventing the development of endometriosis, especially for patients with high levels of IL-10+Th17 cells. PMID:28300844

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

Loughran, B; Singh, V; Jain, A

Purpose: Although generalized linear system analytic metrics such as GMTF and GDQE can evaluate performance of the whole imaging system including detector, scatter and focal-spot, a simplified task-specific measured metric may help to better compare detector systems. Methods: Low quantum-noise images of a neuro-vascular stent with a modified ANSI head phantom were obtained from the average of many exposures taken with the high-resolution Micro-Angiographic Fluoroscope (MAF) and with a Flat Panel Detector (FPD). The square of the Fourier Transform of each averaged image, equivalent to the measured product of the system GMTF and the object function in spatial-frequency space, wasmore » then divided by the normalized noise power spectra (NNPS) for each respective system to obtain a task-specific generalized signal-to-noise ratio. A generalized measured relative object detectability (GM-ROD) was obtained by taking the ratio of the integral of the resulting expressions for each detector system to give an overall metric that enables a realistic systems comparison for the given detection task. Results: The GM-ROD provides comparison of relative performance of detector systems from actual measurements of the object function as imaged by those detector systems. This metric includes noise correlations and spatial frequencies relevant to the specific object. Additionally, the integration bounds for the GM-ROD can be selected to emphasis the higher frequency band of each detector if high-resolution image details are to be evaluated. Examples of this new metric are discussed with a comparison of the MAF to the FPD for neuro-vascular interventional imaging. Conclusion: The GM-ROD is a new direct-measured task-specific metric that can provide clinically relevant comparison of the relative performance of imaging systems. Supported by NIH Grant: 2R01EB002873 and an equipment grant from Toshiba Medical Systems Corporation.« less

Extended diversity analysis of cultivated grapevine Vitis vinifera with 10K genome-wide SNPs

PubMed Central

Launay, Amandine; Bacilieri, Roberto; Lacombe, Thierry; Adam-Blondon, Anne-Françoise; Bérard, Aurélie; Chauveau, Aurélie; de Andrés, Maria Teresa; Maghradze, David; Maul, Erika; Ponnaiah, Maharajah; Töpfer, Reinhard; Péros, Jean-Pierre; Boursiquot, Jean-Michel

2018-01-01

Grapevine is a very important crop species that is mainly cultivated worldwide for fruits, wine and juice. Identification of the genetic bases of performance traits through association mapping studies requires a precise knowledge of the available diversity and how this diversity is structured and varies across the whole genome. An 18k SNP genotyping array was evaluated on a panel of Vitis vinifera cultivars and we obtained a data set with no missing values for a total of 10207 SNPs and 783 different genotypes. The average inter-SNP spacing was ~47 kbp, the mean minor allele frequency (MAF) was 0.23 and the genetic diversity in the sample was high (He = 0.32). Fourteen SNPs, chosen from those with the highest MAF values, were sufficient to identify each genotype in the sample. Parentage analysis revealed 118 full parentages and 490 parent-offspring duos, thus confirming the close pedigree relationships within the cultivated grapevine. Structure analyses also confirmed the main divisions due to an eastern-western gradient and human usage (table vs. wine). Using a multivariate approach, we refined the structure and identified a total of eight clusters. Both the genetic diversity (He, 0.26–0.32) and linkage disequilibrium (LD, 28.8–58.2 kbp) varied between clusters. Despite the short span LD, we also identified some non-recombining haplotype blocks that may complicate association mapping. Finally, we performed a genome-wide association study that confirmed previous works and also identified new regions for important performance traits such as acidity. Taken together, all the results contribute to a better knowledge of the genetics of the cultivated grapevine. PMID:29420602

Quantitative comparison using generalized relative object detectability (G-ROD) metrics of an amorphous selenium detector with high resolution microangiographic fluoroscopes (MAF) and standard flat panel detectors (FPD)

NASA Astrophysics Data System (ADS)

Russ, M.; Shankar, A.; Jain, A.; Setlur Nagesh, S. V.; Ionita, C. N.; Scott, C.; Karim, K. S.; Bednarek, D. R.; Rudin, S.

2016-03-01

A novel amorphous selenium (a-Se) direct detector with CMOS readout has been designed, and relative detector performance investigated. The detector features include a 25μm pixel pitch, and 1000μm thick a-Se layer operating at 10V/μm bias field. A simulated detector DQE was determined, and used in comparative calculations of the Relative Object Detectability (ROD) family of prewhitening matched-filter (PWMF) observer and non-pre-whitening matched filter (NPWMF) observer model metrics to gauge a-Se detector performance against existing high resolution micro-angiographic fluoroscopic (MAF) detectors and a standard flat panel detector (FPD). The PWMF-ROD or ROD metric compares two x-ray imaging detectors in their relative abilities in imaging a given object by taking the integral over spatial frequencies of the Fourier transform of the detector DQE weighted by an object function, divided by the comparable integral for a different detector. The generalized-ROD (G-ROD) metric incorporates clinically relevant parameters (focal- spot size, magnification, and scatter) to show the degradation in imaging performance for detectors that are part of an imaging chain. Preliminary ROD calculations using simulated spheres as the object predicted superior imaging performance by the a-Se detector as compared to existing detectors. New PWMF-G-ROD and NPWMF-G-ROD results still indicate better performance by the a-Se detector in an imaging chain over all sphere sizes for various focal spot sizes and magnifications, although a-Se performance advantages were degraded by focal spot blurring. Nevertheless, the a-Se technology has great potential to provide break- through abilities such as visualization of fine details including of neuro-vascular perforator vessels and of small vascular devices.

Quantitative comparison using Generalized Relative Object Detectability (G-ROD) metrics of an amorphous selenium detector with high resolution Microangiographic Fluoroscopes (MAF) and standard flat panel detectors (FPD)

PubMed Central

Russ, M.; Shankar, A.; Jain, A.; Setlur Nagesh, S. V.; Ionita, C. N.; Scott, C.; Karim, K. S.; Bednarek, D. R.; Rudin, S.

2017-01-01

A novel amorphous selenium (a-Se) direct detector with CMOS readout has been designed, and relative detector performance investigated. The detector features include a 25μm pixel pitch, and 1000μm thick a-Se layer operating at 10V/μm bias field. A simulated detector DQE was determined, and used in comparative calculations of the Relative Object Detectability (ROD) family of prewhitening matched-filter (PWMF) observer and non-prewhitening matched filter (NPWMF) observer model metrics to gauge a-Se detector performance against existing high resolution micro-angiographic fluoroscopic (MAF) detectors and a standard flat panel detector (FPD). The PWMF-ROD or ROD metric compares two x-ray imaging detectors in their relative abilities in imaging a given object by taking the integral over spatial frequencies of the Fourier transform of the detector DQE weighted by an object function, divided by the comparable integral for a different detector. The generalized-ROD (G-ROD) metric incorporates clinically relevant parameters (focal-spot size, magnification, and scatter) to show the degradation in imaging performance for detectors that are part of an imaging chain. Preliminary ROD calculations using simulated spheres as the object predicted superior imaging performance by the a-Se detector as compared to existing detectors. New PWMF-G-ROD and NPWMF-G-ROD results still indicate better performance by the a-Se detector in an imaging chain over all sphere sizes for various focal spot sizes and magnifications, although a-Se performance advantages were degraded by focal spot blurring. Nevertheless, the a-Se technology has great potential to provide breakthrough abilities such as visualization of fine details including of neuro-vascular perforator vessels and of small vascular devices. PMID:28615795

Genetic and epigenetic mechanisms of gene regulation during lens development

PubMed Central

Cvekl, Ales; Duncan, Melinda K.

2007-01-01

Recent studies demonstrated a number of links between chromatin structure, gene expression, extracellular signaling and cellular differentiation during lens development. Lens progenitor cells originate from a pool of common progenitor cells, the pre-placodal region (PPR) which is formed due to a complex exchange of extracellular signals between the neural plate, naïve ectoderm and mesendoderm. A specific commitment to the lens program over alternate choices such as the formation of olfactory epithelium or the anterior pituitary is manifested by the formation of a thickened surface ectoderm, the lens placode. Mouse lens progenitor cells are characterized by the expression of a complement of lens lineage-specific transcription factors including Pax6, Six3 and Sox2, controlled by FGF and BMP signaling, followed later by c-Maf, Mab21like1, Prox1 and FoxE3. Proliferation of lens progenitors together with their morphogenetic movements results in the formation of the lens vesicle. This transient structure, comprised of lens precursor cells, is polarized with its anterior cells retaining their epithelial morphology and proliferative capacity, whereas the posterior lens precursor cells initiate terminal differentiation forming the primary lens fibers. Lens differentiation is marked by expression and accumulation of crystallins and other structural proteins. The transcriptional control of crystallin genes is characterized by the reiterative use of transcription factors required for the establishment of lens precursors in combination with more ubiquitously expressed factors (e.g. AP-1, AP-2α, CREB and USF) and recruitment of histone acetyltransferases (HATs) CBP and p300, and chromatin remodeling complexes SWI/SNF and ISWI. These studies have poised the study of lens development at the forefront of efforts to understand the connections between development, cell signaling, gene transcription and chromatin remodeling. PMID:17905638

Small cell lung cancer: Recruitment of macrophages by circulating tumor cells

PubMed Central

Hamilton, Gerhard; Rath, Barbara; Klameth, Lukas; Hochmair, Maximilan J.

2016-01-01

ABSTRACT Tumor-associated macrophages (TAMs) play an important role in tumor progression, suppression of antitumor immunity and dissemination. Blood monocytes infiltrate the tumor region and are primed by local microenvironmental conditions to promote tumor growth and invasion. Although many of the interacting cytokines and factors are known for the tumor-macrophage interactions, the putative contribution of circulating tumor cells (CTCs) is not known so far. These specialized cells are characterized by increased mobility, ability to degrade the extracellular matrix (ECM) and to enter the blood stream and generate secondary lesions which is a leading cause of death for the majority of tumor patients. The first establishment of two permanent CTC lines, namely BHGc7 and 10, from blood samples of advanced stage small cell lung cancer (SCLC) patients allowed us to investigate the CTC-immune cell interaction. Cocultures of peripheral blood mononuclear cells (PBMNCs) with CTCs or addition of CTC-conditioned medium (CTC-CM) in vitro resulted in monocyte-macrophage differentiation and appearance of CD14+, CD163weak and CD68+ macrophages expressing markers of TAMs. Furthermore, we screened the supernatants of CTC-primed macrophages for presence of approximately 100 cytokines and compared the expression with those induced by the local metastatic SCLC26A cell line. Macrophages recruited by SCLC26A-CM showed expression of osteopontin (OPN), monocyte chemoattractant protein-1 (MCP-1), IL-8, chitinase3-like 1 (CHI3L1), platelet factor (Pf4), IL-1ra and matrix metalloproteinase-9 (MMP-9) among other minor cytokines/chemokines. In contrast, BHGc7-CM induced marked overexpression of complement factor D (CFD)/adipsin and vitamin D-BP (VDBP), as well as increased secretion of OPN, lipocalin-2 (LCN2), CHI3L1, uPAR, MIP-1 and GDF-15/MIC-1. BHGc10, derived independently from relapsed SCLC, revealed an almost identical pattern with added expression of ENA-78/CXCL5. CMs of the non-tumor HEK293 cell line revealed no induction of macrophages, whereas incubation of PBMNCs with recombinant CHI3L1 gave positive results. Thus, the specific contributions of CTCs in SCLC affect CFD/adipsin, possibly involved in immunity/cachexia, VDBP which gives rise to group-specific component protein-derived macrophage-activating factor (GcMAF), GDF-15/MIC-1 which enhances the malignant phenotype of tumor cells and ENA-78/CXCL5 which attracts angiogenic neutrophils. In conclusion, CTCs are competent to specifically manipulate TAMs to increase invasiveness, angiogenesis, immunosuppression and possibly lipid catabolism. PMID:27141354

Small cell lung cancer: Recruitment of macrophages by circulating tumor cells.

PubMed

Hamilton, Gerhard; Rath, Barbara; Klameth, Lukas; Hochmair, Maximilan J

2016-03-01

Tumor-associated macrophages (TAMs) play an important role in tumor progression, suppression of antitumor immunity and dissemination. Blood monocytes infiltrate the tumor region and are primed by local microenvironmental conditions to promote tumor growth and invasion. Although many of the interacting cytokines and factors are known for the tumor-macrophage interactions, the putative contribution of circulating tumor cells (CTCs) is not known so far. These specialized cells are characterized by increased mobility, ability to degrade the extracellular matrix (ECM) and to enter the blood stream and generate secondary lesions which is a leading cause of death for the majority of tumor patients. The first establishment of two permanent CTC lines, namely BHGc7 and 10, from blood samples of advanced stage small cell lung cancer (SCLC) patients allowed us to investigate the CTC-immune cell interaction. Cocultures of peripheral blood mononuclear cells (PBMNCs) with CTCs or addition of CTC-conditioned medium (CTC-CM) in vitro resulted in monocyte-macrophage differentiation and appearance of CD14 + , CD163 weak and CD68 + macrophages expressing markers of TAMs. Furthermore, we screened the supernatants of CTC-primed macrophages for presence of approximately 100 cytokines and compared the expression with those induced by the local metastatic SCLC26A cell line. Macrophages recruited by SCLC26A-CM showed expression of osteopontin (OPN), monocyte chemoattractant protein-1 (MCP-1), IL-8, chitinase3-like 1 (CHI3L1), platelet factor (Pf4), IL-1ra and matrix metalloproteinase-9 (MMP-9) among other minor cytokines/chemokines. In contrast, BHGc7-CM induced marked overexpression of complement factor D (CFD)/adipsin and vitamin D-BP (VDBP), as well as increased secretion of OPN, lipocalin-2 (LCN2), CHI3L1, uPAR, MIP-1 and GDF-15/MIC-1. BHGc10, derived independently from relapsed SCLC, revealed an almost identical pattern with added expression of ENA-78/CXCL5. CMs of the non-tumor HEK293 cell line revealed no induction of macrophages, whereas incubation of PBMNCs with recombinant CHI3L1 gave positive results. Thus, the specific contributions of CTCs in SCLC affect CFD/adipsin, possibly involved in immunity/cachexia, VDBP which gives rise to group-specific component protein-derived macrophage-activating factor (GcMAF), GDF-15/MIC-1 which enhances the malignant phenotype of tumor cells and ENA-78/CXCL5 which attracts angiogenic neutrophils. In conclusion, CTCs are competent to specifically manipulate TAMs to increase invasiveness, angiogenesis, immunosuppression and possibly lipid catabolism.

Embryonic Origins of the Mouse Superior Olivary Complex

PubMed Central

Howell, David M.; Spirou, George A.; Mathers, Peter H.

2014-01-01

Many areas of the central nervous system are organized into clusters of cell groups, with component cell groups exhibiting diverse but related functions. One such cluster, the superior olivary complex (SOC), is located in the ventral auditory brainstem in mammals. The SOC is an obligatory contact point for most projection neurons of the ventral cochlear nucleus and plays central roles in many aspects of monaural and binaural information processing. Despite their important interrelated functions, little is known about the embryonic origins of SOC nuclei, due in part to a paucity of developmental markers to distinguish individual cell groups. In this report, we present a collection of novel markers for the developing SOC nuclei in mice, including the transcription factors FoxP1, MafB, and Sox2, and the lineage-marking transgenic line En1-Cre. We use these definitive markers to examine the rhombic lip and rhombomeric origins of SOC nuclei and demonstrate that they can serve to uniquely identify SOC nuclei and subnuclei in newborn pups. The markers are also useful in identifying distinct nuclear domains within the presumptive SOC as early as embryonic day (E) 14.5, well before morphological distinction of individual nuclei is evident. These findings indicate that the mediolateral and dorsoventral position of SOC nuclei characteristic of the adult brainstem is established during early neurogenesis. PMID:23303740

Activation of the Hedgehog Signaling Pathway in the Developing Lens Stimulates Ectopic FoxE3 Expression and Disruption in Fiber Cell Differentiation

PubMed Central

Kerr, Christine L.; Huang, Jian; Williams, Trevor; West-Mays, Judith A.

2012-01-01

Purpose. The signaling pathways and transcriptional effectors responsible for directing mammalian lens development provide key regulatory molecules that can inform our understanding of human eye defects. The hedgehog genes encode extracellular signaling proteins responsible for patterning and tissue formation during embryogenesis. Signal transduction of this pathway is mediated through activation of the transmembrane proteins smoothened and patched, stimulating downstream signaling resulting in the activation or repression of hedgehog target genes. Hedgehog signaling is implicated in eye development, and defects in hedgehog signaling components have been shown to result in defects of the retina, iris, and lens. Methods. We assessed the consequences of constitutive hedgehog signaling in the developing mouse lens using Cre-LoxP technology to express the conditional M2 smoothened allele in the embryonic head and lens ectoderm. Results. Although initial lens development appeared normal, morphological defects were apparent by E12.5 and became more significant at later stages of embryogenesis. Altered lens morphology correlated with ectopic expression of FoxE3, which encodes a critical gene required for human and mouse lens development. Later, inappropriate expression of the epithelial marker Pax6, and as well as fiber cell markers c-maf and Prox1 also occurred, indicating a failure of appropriate lens fiber cell differentiation accompanied by altered lens cell proliferation and cell death. Conclusions. Our findings demonstrate that the ectopic activation of downstream effectors of the hedgehog signaling pathway in the mouse lens disrupts normal fiber cell differentiation by a mechanism consistent with a sustained epithelial cellular developmental program driven by FoxE3. PMID:22491411

Dissociation of lipotoxicity and glucotoxicity in a mouse model of obesity associated diabetes: role of forkhead box O1 (FOXO1) in glucose-induced beta cell failure.

PubMed

Kluth, O; Mirhashemi, F; Scherneck, S; Kaiser, D; Kluge, R; Neschen, S; Joost, H-G; Schürmann, A

2011-03-01

Carbohydrate-free diet prevents hyperglycaemia and beta cell destruction in the New Zealand Obese (NZO) mouse model. Here we have used a sequential dietary regimen to dissociate the effects of obesity and hyperglycaemia on beta cell function and integrity, and to study glucose-induced alterations of key transcription factors over 16 days. Mice were rendered obese by feeding a carbohydrate-free diet for 18 weeks. Thereafter, a carbohydrate-containing diet was given. Plasma glucose, plasma insulin and total pancreatic insulin were determined, and forkhead box O1 protein (FOXO1) phosphorylation and the transcription factors pancreatic and duodenal homeobox 1 (PDX1), NK6 homeobox 1 protein (NKX6.1) and v-maf musculoaponeurotic fibrosarcoma oncogene family, protein A (avian) (MAFA) were monitored by immunohistochemistry for 16 days. Dietary carbohydrates produced a rapid and continuous increase in plasma glucose in NZO mice between day 2 and 16 after the dietary challenge. Hyperglycaemia caused a dramatic dephosphorylation of FOXO1 at day 2, followed by a progressive depletion of insulin stores. The loss of beta cells was triggered by apoptosis (detectable at day 8), associated with reduction of crucial transcription factors (PDX1, NKX6.1 and MAFA). Incubation of isolated islets from carbohydrate-restricted NZO mice or MIN6 cells with palmitate and glucose for 48 h resulted in a dephosphorylation of FOXO1 and thymoma viral proto-oncogene 1 (AKT) without changing the protein levels of both proteins. The dietary regimen dissociates the effects of obesity (lipotoxicity) from those of hyperglycaemia (glucotoxicity) in NZO mice. Obese NZO mice are unable to compensate for the carbohydrate challenge by increasing insulin secretion or synthesising adequate amounts of insulin. In response to the hyperglycaemia, FOXO1 is dephosphorylated, leading to reduced levels of beta cell-specific transcription factors and to apoptosis of the cells.

Space Shuttle Projects

NASA Image and Video Library

1977-03-01

This photograph shows the liquid hydrogen tank and liquid oxygen tank for the Space Shuttle external tank (ET) being assembled in the weld assembly area of the Michoud Assembly Facility (MAF). The ET provides liquid hydrogen and liquid oxygen to the Shuttle's three main engines during the first eight 8.5 minutes of flight. At 154-feet long and more than 27-feet in diameter, the ET is the largest component of the Space Shuttle, the structural backbone of the entire Shuttle system, and the only part of the vehicle that is not reusable. The ET is manufactured at the Michoud Assembly Facility near New Orleans, Louisiana, by the Martin Marietta Corporation under management of the Marshall Space Flight Center.

Reciprocal patterns of allergen-induced GATA-3 expression in peripheral blood mononuclear cells from atopics vs. non-atopics.

PubMed

Macaubas, C; Lee, P T; Smallacombe, T B; Holt, B J; Wee, C; Sly, P D; Holt, P G

2002-01-01

T helper (Th)2 cytokines are considered to play a central role in the induction and expression of allergic disease. However, the relative importance of individual cytokines is unclear, and overall disease pathogenesis appears to involve the coordinate activities of a range of Th2 cytokines acting in sequence or in parallel. The present study examines an alternative approach to the study of cytokine gene function in atopy, focusing instead upon T cell transcription factors (TFs) which play a role in the regulation of multiple cytokine genes. To investigate the allergen-induced expression of the TF GATA-3 and c-Maf in peripheral blood mononuclear cells (PBMCs) and in cytokine-driven Th polarization. PBMC from house dust mite (HDM)-atopic and non-atopics were stimulated in vitro with allergen or anti-CD3/IL-2. TF expression was analysed by semiquantitative RT-PCR and major findings were validated by real-time PCR. Cell separations were performed to analyse the contribution of CD45RO+ cells. CD4+ cord blood cells were Th1 or Th2 polarized in vitro by exogenous cytokines and TF expression analysed by Northern blot and real-time PCR. Results We demonstrate for the first time that during differentiation of CD4+ CD45RA+ naïve human T cells towards Th2 commitment, and during allergen-specific reactivation of peripheral CD4+ CD45RO+ Th2 memory cells in established atopics, expression of the Th2-associated TF GATA-3 is rapidly up-regulated, whereas T cells from non-atopics display equally rapid GATA-3 down-regulation under identical conditions of allergen stimulation. These findings identify Th2-associated TFs as key determinants of the atopic phenotype, suggesting their unique potential as therapeutic targets for disease control.

Active Center Control of Termination by RNA Polymerase III and tRNA Gene Transcription Levels In Vivo

PubMed Central

Rijal, Keshab; Maraia, Richard J.

2016-01-01

The ability of RNA polymerase (RNAP) III to efficiently recycle from termination to reinitiation is critical for abundant tRNA production during cellular proliferation, development and cancer. Yet understanding of the unique termination mechanisms used by RNAP III is incomplete, as is its link to high transcription output. We used two tRNA-mediated suppression systems to screen for Rpc1 mutants with gain- and loss- of termination phenotypes in S. pombe. 122 point mutation mutants were mapped to a recently solved 3.9 Å structure of yeast RNAP III elongation complex (EC); they cluster in the active center bridge helix and trigger loop, as well as the pore and funnel, the latter of which indicate involvement of the RNA cleavage domain of the C11 subunit in termination. Purified RNAP III from a readthrough (RT) mutant exhibits increased elongation rate. The data strongly support a kinetic coupling model in which elongation rate is inversely related to termination efficiency. The mutants exhibit good correlations of terminator RT in vitro and in vivo, and surprisingly, amounts of transcription in vivo. Because assessing in vivo transcription can be confounded by various parameters, we used a tRNA reporter with a processing defect and a strong terminator. By ruling out differences in RNA decay rates, the data indicate that mutants with the RT phenotype synthesize more RNA than wild type cells, and than can be accounted for by their increased elongation rate. Finally, increased activity by the mutants appears unrelated to the RNAP III repressor, Maf1. The results show that the mobile elements of the RNAP III active center, including C11, are key determinants of termination, and that some of the mutations activate RNAP III for overall transcription. Similar mutations in spontaneous cancer suggest this as an unforeseen mechanism of RNAP III activation in disease. PMID:27518095

Discrete β-adrenergic mechanisms regulate early and late erythropoiesis in erythropoietin-resistant anemia.

PubMed

Hasan, Shirin; Mosier, Michael J; Szilagyi, Andrea; Gamelli, Richard L; Muthumalaiappan, Kuzhali

2017-10-01

Anemia of critical illness is resistant to exogenous erythropoietin. Packed red blood cells transfusions is the only treatment option, and despite related cost and morbidity, there is a need for alternate strategies. Erythrocyte development can be divided into erythropoietin-dependent and erythropoietin-independent stages. We have shown previously that erythropoietin-dependent development is intact in burn patients and the erythropoietin-independent early commitment stage, which is regulated by β1/β2-adrenergic mechanisms, is compromised. Utilizing the scald burn injury model, we studied erythropoietin-independent late maturation stages and the effect of β1/β2, β-2, or β-3 blockade in burn mediated erythropoietin-resistant anemia. Burn mice were randomized to receive daily injections of propranolol (nonselective β1/β2 antagonist), nadolol (long-acting β1/β2 antagonist), butoxamine (selective β2 antagonist), or SR59230A (selective β3 antagonist) for 6 days after burn. Total bone marrow cells were characterized as nonerythroid cells, early and late erythroblasts, nucleated orthochromatic erythroblasts and enucleated reticulocyte subsets using CD71, Ter119, and Syto-16 by flow cytometry. Multipotential progenitors were probed for MafB expressing cells. Although propranolol improved early and late erythroblasts, only butoxamine and selective β3-antagonist administrations were positively reflected in the peripheral blood hemoglobin and red blood cells count. While burn impeded early commitment and late maturation stages, β1/β2 antagonism increased the early erythroblasts through commitment stages via β2 specific MafB regulation. β3 antagonism was more effective in improving overall red blood cells through late maturation stages. The study unfolds novel β2 and β3 adrenergic mechanisms orchestrating erythropoietin resistant anemia after burn, which impedes both the early commitment stage and the late maturation stages, respectively. Copyright © 2017 Elsevier Inc. All rights reserved.

Detailed Investigation of the Role of Common and Low-Frequency WFS1 Variants in Type 2 Diabetes Risk

PubMed Central

Fawcett, Katherine A.; Wheeler, Eleanor; Morris, Andrew P.; Ricketts, Sally L.; Hallmans, Göran; Rolandsson, Olov; Daly, Allan; Wasson, Jon; Permutt, Alan; Hattersley, Andrew T.; Glaser, Benjamin; Franks, Paul W.; McCarthy, Mark I.; Wareham, Nicholas J.; Sandhu, Manjinder S.; Barroso, Inês

2010-01-01

OBJECTIVE Wolfram syndrome 1 (WFS1) single nucleotide polymorphisms (SNPs) are associated with risk of type 2 diabetes. In this study we aimed to refine this association and investigate the role of low-frequency WFS1 variants in type 2 diabetes risk. RESEARCH DESIGN AND METHODS For fine-mapping, we sequenced WFS1 exons, splice junctions, and conserved noncoding sequences in samples from 24 type 2 diabetic case and 68 control subjects, selected tagging SNPs, and genotyped these in 959 U.K. type 2 diabetic case and 1,386 control subjects. The same genomic regions were sequenced in samples from 1,235 type 2 diabetic case and 1,668 control subjects to compare the frequency of rarer variants between case and control subjects. RESULTS Of 31 tagging SNPs, the strongest associated was the previously untested 3′ untranslated region rs1046320 (P = 0.008); odds ratio 0.84 and P = 6.59 × 10−7 on further replication in 3,753 case and 4,198 control subjects. High correlation between rs1046320 and the original strongest SNP (rs10010131) (r2 = 0.92) meant that we could not differentiate between their effects in our samples. There was no difference in the cumulative frequency of 82 rare (minor allele frequency [MAF] <0.01) nonsynonymous variants between type 2 diabetic case and control subjects (P = 0.79). Two intermediate frequency (MAF 0.01–0.05) nonsynonymous changes also showed no statistical association with type 2 diabetes. CONCLUSIONS We identified six highly correlated SNPs that show strong and comparable associations with risk of type 2 diabetes, but further refinement of these associations will require large sample sizes (>100,000) or studies in ethnically diverse populations. Low frequency variants in WFS1 are unlikely to have a large impact on type 2 diabetes risk in white U.K. populations, highlighting the complexities of undertaking association studies with low-frequency variants identified by resequencing. PMID:20028947

Differential association of ESR1 and ESR2 gene variants with the risk of breast cancer and associated features: A case-control study.

PubMed

Ghali, Rabeb M; Al-Mutawa, Maryam A; Al-Ansari, Abrar K; Zaied, Sonia; Bhiri, Hanen; Mahjoub, Touhami; Almawi, Wassim Y

2018-04-20

Estrogen is key to breast cancer pathogenesis, and acts by binding its receptor (ER), which exists as ERα and ERβ, encoded by ESR1 and ESR2 genes, respectively. Studies that investigated the association of ESR1 and ESR2 variants with breast cancer yielded mixed outcome, and ethnic contribution was proposed. We evaluated the association between ESR1 and ESR2 variants and breast cancer and associated features in Tunisian women. Retrospective case-control study involving 207 female breast cancer patients, and 284 control women. Genotyping was done by real-time PCR. Minor allele frequencies (MAF) of tagging SNPs rs2234693 and rs3798577 (ESR1) were significantly higher, while MAF of rs1256049 (ESR2) was significantly lower in breast cancer patients vs. Patients carrying rs3798577 genotypes had higher risk, while rs1256049 genotype carriers had reduced risk of breast cancer. The association of ESR1 and ESR2 gene variants with breast cancer depended on ER and Her-2 status. ESR1 rs3798577 and ESR2 rs1256049 were associated with breast cancer in ER-positive cases, and ESR1 rs2234693, and rs3798577 were associated with breast cancer in Her-2-negative cases, while the association of ESR2 rs1256049 with breast cancer was seen in Her-2 positive cases. Haploview analysis identified 4-locus ESR1 haplotypes that were positively (CGTT, TACC, and TACT), and negatively (CGTC) associated with breast cancer. No ESR2 haplotypes associated with breast cancer were identified. ESR1 alleles and genotypes, and specific 3-locus ESR1 haplotypes are related with increased breast cancer susceptibility in Tunisian women. However, ESR2 variant and specific 1-locus ESR1 haplotype have a protective effect. Copyright © 2018 Elsevier B.V. All rights reserved.

America's Next Great Ship: Space Launch System Core Stage Transitioning from Design to Manufacturing

NASA Technical Reports Server (NTRS)

Birkenstock, Benjamin; Kauer, Roy

2014-01-01

The Space Launch System (SLS) Program is essential to achieving the Nation's and NASA's goal of human exploration and scientific investigation of the solar system. As a multi-element program with emphasis on safety, affordability, and sustainability, SLS is becoming America's next great ship of exploration. The SLS Core Stage includes avionics, main propulsion system, pressure vessels, thrust vector control, and structures. Boeing manufactures and assembles the SLS core stage at the Michoud Assembly Facility (MAF) in New Orleans, LA, a historical production center for Saturn V and Space Shuttle programs. As the transition from design to manufacturing progresses, the importance of a well-executed manufacturing, assembly, and operation (MA&O) plan is crucial to meeting performance objectives. Boeing employs classic techniques such as critical path analysis and facility requirements definition as well as innovative approaches such as Constraint Based Scheduling (CBS) and Cirtical Chain Project Management (CCPM) theory to provide a comprehensive suite of project management tools to manage the health of the baseline plan on both a macro (overall project) and micro level (factory areas). These tools coordinate data from multiple business systems and provide a robust network to support Material & Capacity Requirements Planning (MRP/CRP) and priorities. Coupled with these tools and a highly skilled workforce, Boeing is orchestrating the parallel buildup of five major sub assemblies throughout the factory. Boeing and NASA are transforming MAF to host state of the art processes, equipment and tooling, the most prominent of which is the Vertical Assembly Center (VAC), the largest weld tool in the world. In concert, a global supply chain is delivering a range of structural elements and component parts necessary to enable an on-time delivery of the integrated Core Stage. SLS is on plan to launch humanity into the next phase of space exploration.

Identification and Functional Characterization of G6PC2 Coding Variants Influencing Glycemic Traits Define an Effector Transcript at the G6PC2-ABCB11 Locus

PubMed Central

Mahajan, Anubha; Sim, Xueling; Ng, Hui Jin; Manning, Alisa; Rivas, Manuel A.; Highland, Heather M.; Locke, Adam E.; Grarup, Niels; Im, Hae Kyung; Cingolani, Pablo; Flannick, Jason; Fontanillas, Pierre; Fuchsberger, Christian; Gaulton, Kyle J.; Teslovich, Tanya M.; Rayner, N. William; Robertson, Neil R.; Beer, Nicola L.; Rundle, Jana K.; Bork-Jensen, Jette; Ladenvall, Claes; Blancher, Christine; Buck, David; Buck, Gemma; Burtt, Noël P.; Gabriel, Stacey; Gjesing, Anette P.; Groves, Christopher J.; Hollensted, Mette; Huyghe, Jeroen R.; Jackson, Anne U.; Jun, Goo; Justesen, Johanne Marie; Mangino, Massimo; Murphy, Jacquelyn; Neville, Matt; Onofrio, Robert; Small, Kerrin S.; Stringham, Heather M.; Syvänen, Ann-Christine; Trakalo, Joseph; Abecasis, Goncalo; Bell, Graeme I.; Blangero, John; Cox, Nancy J.; Duggirala, Ravindranath; Hanis, Craig L.; Seielstad, Mark; Wilson, James G.; Christensen, Cramer; Brandslund, Ivan; Rauramaa, Rainer; Surdulescu, Gabriela L.; Doney, Alex S. F.; Lannfelt, Lars; Linneberg, Allan; Isomaa, Bo; Tuomi, Tiinamaija; Jørgensen, Marit E.; Jørgensen, Torben; Kuusisto, Johanna; Uusitupa, Matti; Salomaa, Veikko; Spector, Timothy D.; Morris, Andrew D.; Palmer, Colin N. A.; Collins, Francis S.; Mohlke, Karen L.; Bergman, Richard N.; Ingelsson, Erik; Lind, Lars; Tuomilehto, Jaakko; Hansen, Torben; Watanabe, Richard M.; Prokopenko, Inga; Dupuis, Josee; Karpe, Fredrik; Groop, Leif; Laakso, Markku; Pedersen, Oluf; Florez, Jose C.; Morris, Andrew P.; Altshuler, David; Meigs, James B.; Boehnke, Michael; McCarthy, Mark I.; Lindgren, Cecilia M.; Gloyn, Anna L.

2015-01-01

Genome wide association studies (GWAS) for fasting glucose (FG) and insulin (FI) have identified common variant signals which explain 4.8% and 1.2% of trait variance, respectively. It is hypothesized that low-frequency and rare variants could contribute substantially to unexplained genetic variance. To test this, we analyzed exome-array data from up to 33,231 non-diabetic individuals of European ancestry. We found exome-wide significant (P<5×10-7) evidence for two loci not previously highlighted by common variant GWAS: GLP1R (p.Ala316Thr, minor allele frequency (MAF)=1.5%) influencing FG levels, and URB2 (p.Glu594Val, MAF = 0.1%) influencing FI levels. Coding variant associations can highlight potential effector genes at (non-coding) GWAS signals. At the G6PC2/ABCB11 locus, we identified multiple coding variants in G6PC2 (p.Val219Leu, p.His177Tyr, and p.Tyr207Ser) influencing FG levels, conditionally independent of each other and the non-coding GWAS signal. In vitro assays demonstrate that these associated coding alleles result in reduced protein abundance via proteasomal degradation, establishing G6PC2 as an effector gene at this locus. Reconciliation of single-variant associations and functional effects was only possible when haplotype phase was considered. In contrast to earlier reports suggesting that, paradoxically, glucose-raising alleles at this locus are protective against type 2 diabetes (T2D), the p.Val219Leu G6PC2 variant displayed a modest but directionally consistent association with T2D risk. Coding variant associations for glycemic traits in GWAS signals highlight PCSK1, RREB1, and ZHX3 as likely effector transcripts. These coding variant association signals do not have a major impact on the trait variance explained, but they do provide valuable biological insights. PMID:25625282

Common genetic variants associated with thyroid function may be risk alleles for Hashimoto's disease and Graves' disease.

PubMed

Campbell, Purdey; Brix, Thomas H; Wilson, Scott G; Ward, Lynley C; Hui, Jennie; Beilby, John P; Hegedüs, Laszlo; Walsh, John P

2015-02-14

Recent studies have identified common genetic variants associated with TSH, free T4 and thyroid peroxidase antibodies, but it is unclear whether these differ between patients with Hashimoto's disease and Graves' disease. To examine whether 11 common genetic variants differ between Graves' disease and Hashimoto's disease. We genotyped 11 common variants in a discovery cohort of 203 Australian patients with autoimmune thyroid disease (AITD). Two variants with significant or suggestive associations were analysed in a replication cohort of 384 Danish patients. For rs753760 (PDE10A), the minor allele frequency in Graves' disease and Hashimoto's disease was 0·38 vs. 0·23, respectively, (P = 6·42 × 10 -4 ) in the discovery cohort, 0·29 vs. 0·24 (P = 0·147) in the replication cohort and 0·32 vs. 0·24 in combined analysis (P = 0·0021; all analyses adjusted for sex). In healthy controls from Busselton, the frequency was 0·29, significantly different from Hashimoto's disease but not Graves' disease. For rs4889009 (MAF gene region), the frequency of the minor G-allele in Graves' disease and Hashimoto's disease was 0·48 vs. 0·36 (P = 0·0156) in the discovery cohort, 0·48 vs. 0·34 (P = 1·83 × 10 -4 ) in the replication cohort and 0·48 vs. 0·35 in the combined analysis (P = 7·53 × 10 -6 ); in controls, the frequency was 0·38, significantly different from Graves' disease but not Hashimoto's disease. After further adjustment for smoking, associations with rs4889009 remained significant, whereas those with rs753760 were not. Common variants in PDE10A and MAF gene regions may influence whether patients with AITD develop Graves' disease or Hashimoto's disease. © 2015 John Wiley & Sons Ltd.

αIIbβ3 variants defined by next-generation sequencing: Predicting variants likely to cause Glanzmann thrombasthenia

PubMed Central

Buitrago, Lorena; Rendon, Augusto; Liang, Yupu; Simeoni, Ilenia; Negri, Ana; Filizola, Marta; Ouwehand, Willem H.; Coller, Barry S.; Alessi, Marie-Christine; Ballmaier, Matthias; Bariana, Tadbir; Bellissimo, Daniel; Bertoli, Marta; Bray, Paul; Bury, Loredana; Carrell, Robin; Cattaneo, Marco; Collins, Peter; French, Deborah; Favier, Remi; Freson, Kathleen; Furie, Bruce; Germeshausen, Manuela; Ghevaert, Cedric; Gomez, Keith; Goodeve, Anne; Gresele, Paolo; Guerrero, Jose; Hampshire, Dan J.; Hadinnapola, Charaka; Heemskerk, Johan; Henskens, Yvonne; Hill, Marian; Hogg, Nancy; Johnsen, Jill; Kahr, Walter; Kerr, Ron; Kunishima, Shinji; Laffan, Michael; Natwani, Amit; Neerman-Arbez, Marguerite; Nurden, Paquita; Nurden, Alan; Ormiston, Mark; Othman, Maha; Ouwehand, Willem; Perry, David; Vilk, Shoshana Ravel; Reitsma, Pieter; Rondina, Matthew; Simeoni, Ilenia; Smethurst, Peter; Stephens, Jonathan; Stevenson, William; Szkotak, Artur; Turro, Ernest; Van Geet, Christel; Vries, Minka; Ward, June; Waye, John; Westbury, Sarah; Whiteheart, Sidney; Wilcox, David; Zhang, Bi

2015-01-01

Next-generation sequencing is transforming our understanding of human genetic variation but assessing the functional impact of novel variants presents challenges. We analyzed missense variants in the integrin αIIbβ3 receptor subunit genes ITGA2B and ITGB3 identified by whole-exome or -genome sequencing in the ThromboGenomics project, comprising ∼32,000 alleles from 16,108 individuals. We analyzed the results in comparison with 111 missense variants in these genes previously reported as being associated with Glanzmann thrombasthenia (GT), 20 associated with alloimmune thrombocytopenia, and 5 associated with aniso/macrothrombocytopenia. We identified 114 novel missense variants in ITGA2B (affecting ∼11% of the amino acids) and 68 novel missense variants in ITGB3 (affecting ∼9% of the amino acids). Of the variants, 96% had minor allele frequencies (MAF) < 0.1%, indicating their rarity. Based on sequence conservation, MAF, and location on a complete model of αIIbβ3, we selected three novel variants that affect amino acids previously associated with GT for expression in HEK293 cells. αIIb P176H and β3 C547G severely reduced αIIbβ3 expression, whereas αIIb P943A partially reduced αIIbβ3 expression and had no effect on fibrinogen binding. We used receiver operating characteristic curves of combined annotation-dependent depletion, Polyphen 2-HDIV, and sorting intolerant from tolerant to estimate the percentage of novel variants likely to be deleterious. At optimal cut-off values, which had 69–98% sensitivity in detecting GT mutations, between 27% and 71% of the novel αIIb or β3 missense variants were predicted to be deleterious. Our data have implications for understanding the evolutionary pressure on αIIbβ3 and highlight the challenges in predicting the clinical significance of novel missense variants. PMID:25827233

The present and future organisation of Veterinary Services in Asia: the examples of the Republic of Korea and Japan.

PubMed

Ozawa, Y; Chang, K; Yoshida, K; Michino, H

2003-08-01

The Veterinary Services of the Republic of Korea and Japan are reviewed and summarised. To cope with ever-increasing demands on Veterinary Services, both countries have made continued efforts to expand the services, which currently only have a limited number of government personnel. To overcome some of the problems associated with international trade, e.g. outbreaks of foot and mouth disease and classical swine fever (hog cholera), the authorities of the Republic of Korea are considering strengthening quarantine services by combining the National Veterinary Research and Quarantine Service and the National Plant Quarantine Service of the Ministry of Agriculture and Forestry (MAF). In the field of veterinary public health services, the Republic of Korea and Japan have different organisational structures. All Veterinary Services, including veterinary public health, are kept within the MAF in the Republic of Korea, whereas in Japan, the Ministry of Agriculture, Forestry and Fisheries (MAFF) deals with general animal production and health services and the Ministry of Health, Labour and Welfare (MHLW) deals with the safety of animal products, food poisoning and the prevention/control of zoonoses, such as rabies and Q fever. In Japan, after the occurrence of bovine spongiform encephalopathy in 2001, the authorities undertook a thorough review of the Veterinary Services, focusing particularly on food safety. A reorganisation of the administrative structure was proposed, and will be completed by the end of 2003. Subject to the approval of the Diet (House of Councillors), an independent 'Food Safety Commission' will be created within the cabinet office which will undertake risk analyses related to foods, and risk management will be carried out by the relevant ministry, i.e. the MAFF or the MHLW. The Animal Health Division of the MAFF will also be moved from the Livestock Industry Department to a new 'Consumer Safety Department' of the MAFF, where additional responsibilities in fish health control and feed safety control will be assumed.

Variability of Creatine Metabolism Genes in Children with Autism Spectrum Disorder.

PubMed

Cameron, Jessie M; Levandovskiy, Valeriy; Roberts, Wendy; Anagnostou, Evdokia; Scherer, Stephen; Loh, Alvin; Schulze, Andreas

2017-07-31

Creatine deficiency syndrome (CDS) comprises three separate enzyme deficiencies with overlapping clinical presentations: arginine:glycine amidinotransferase ( GATM gene, glycine amidinotransferase), guanidinoacetate methyltransferase ( GAMT gene), and creatine transporter deficiency ( SLC6A8 gene, solute carrier family 6 member 8). CDS presents with developmental delays/regression, intellectual disability, speech and language impairment, autistic behaviour, epileptic seizures, treatment-refractory epilepsy, and extrapyramidal movement disorders; symptoms that are also evident in children with autism. The objective of the study was to test the hypothesis that genetic variability in creatine metabolism genes is associated with autism. We sequenced GATM , GAMT and SLC6A8 genes in 166 patients with autism (coding sequence, introns and adjacent untranslated regions). A total of 29, 16 and 25 variants were identified in each gene, respectively. Four variants were novel in GATM , and 5 in SLC6A8 (not present in the 1000 Genomes, Exome Sequencing Project (ESP) or Exome Aggregation Consortium (ExAC) databases). A single variant in each gene was identified as non-synonymous, and computationally predicted to be potentially damaging. Nine variants in GATM were shown to have a lower minor allele frequency (MAF) in the autism population than in the 1000 Genomes database, specifically in the East Asian population (Fisher's exact test). Two variants also had lower MAFs in the European population. In summary, there were no apparent associations of variants in GAMT and SLC6A8 genes with autism. The data implying there could be a lower association of some specific GATM gene variants with autism is an observation that would need to be corroborated in a larger group of autism patients, and with sub-populations of Asian ethnicities. Overall, our findings suggest that the genetic variability of creatine synthesis/transport is unlikely to play a part in the pathogenesis of autism spectrum disorder (ASD) in children.

The measurement of fatigue in chronic illness: a systematic review of unidimensional and multidimensional fatigue measures.

PubMed

Whitehead, Lisa

2009-01-01

Fatigue is a common symptom associated with a wide range of chronic diseases. A large number of instruments have been developed to measure fatigue. An assessment regarding the reliability, validity, and utility of fatigue measures is time-consuming for the clinician and researcher, and few reviews exist on which to draw such information. The aim of this article is to present a critical review of fatigue measures, the populations in which the scales have been used, and the extent to which the psychometric properties of each instrument have been evaluated to provide clinicians and researchers with information on which to base decisions. Seven databases were searched for all articles that measured fatigue and offered an insight into the psychometric properties of the scales used over the period 1980-2007. Criteria for judging the "ideal" measure were developed to encompass scale usability, clinical/research utility, and the robustness of psychometric properties. Twenty-two fatigue measures met the inclusion criteria and were evaluated. A further 17 measures met some of the criteria, but have not been tested beyond initial development, and are reviewed briefly at the end of the article. The review did not identify any instrument that met all the criteria of an ideal instrument. However, a small number of short instruments demonstrated good psychometric properties (Fatigue Severity Scale [FSS], Fatigue Impact Scale [FIS], and Brief Fatigue Inventory [BFI]), and three comprehensive instruments demonstrated the same (Fatigue Symptom Inventory [FSI], Multidimensional Assessment of Fatigue [MAF], and Multidimensional Fatigue Symptom Inventory [MFSI]). Only four measures (BFI, FSS, FSI, and MAF) demonstrated the ability to detect change over time. The clinician and researcher also should consider the populations in which the scale has been used previously to assess its validity with their own patient group, and assess the content of a scale to ensure that the key qualitative aspects of fatigue of the population of interest are covered.

Resequencing of IRS2 reveals rare variants for obesity but not fasting glucose homeostasis in Hispanic children

PubMed Central

Voruganti, V. Saroja; Cole, Shelley A.; Haack, Karin; Comuzzie, Anthony G.; Muzny, Donna M.; Wheeler, David A.; Chang, Kyle; Hawes, Alicia; Gibbs, Richard A.

2011-01-01

Our objective was to resequence insulin receptor substrate 2 (IRS2) to identify variants associated with obesity- and diabetes-related traits in Hispanic children. Exonic and intronic segments, 5′ and 3′ flanking regions of IRS2 (∼14.5 kb), were bidirectionally sequenced for single nucleotide polymorphism (SNP) discovery in 934 Hispanic children using 3730XL DNA Sequencers. Additionally, 15 SNPs derived from Illumina HumanOmni1-Quad BeadChips were analyzed. Measured genotype analysis tested associations between SNPs and obesity and diabetes-related traits. Bayesian quantitative trait nucleotide analysis was used to statistically infer the most likely functional polymorphisms. A total of 140 SNPs were identified with minor allele frequencies (MAF) ranging from 0.001 to 0.47. Forty-two of the 70 coding SNPs result in nonsynonymous amino acid substitutions relative to the consensus sequence; 28 SNPs were detected in the promoter, 12 in introns, 28 in the 3′-UTR, and 2 in the 5′-UTR. Two insertion/deletions (indels) were detected. Ten independent rare SNPs (MAF = 0.001–0.009) were associated with obesity-related traits (P = 0.01–0.00002). SNP 10510452_139 in the promoter region was shown to have a high posterior probability (P = 0.77–0.86) of influencing BMI, fat mass, and waist circumference in Hispanic children. SNP 10510452_139 contributed between 2 and 4% of the population variance in body weight and composition. None of the SNPs or indels were associated with diabetes-related traits or accounted for a previously identified quantitative trait locus on chromosome 13 for fasting serum glucose. Rare but not common IRS2 variants may play a role in the regulation of body weight but not an essential role in fasting glucose homeostasis in Hispanic children. PMID:21771880

Analysis of exome sequence in 604 trios for recessive genotypes in schizophrenia

PubMed Central

Rees, E; Kirov, G; Walters, J T; Richards, A L; Howrigan, D; Kavanagh, D H; Pocklington, A J; Fromer, M; Ruderfer, D M; Georgieva, L; Carrera, N; Gormley, P; Palta, P; Williams, H; Dwyer, S; Johnson, J S; Roussos, P; Barker, D D; Banks, E; Milanova, V; Rose, S A; Chambert, K; Mahajan, M; Scolnick, E M; Moran, J L; Tsuang, M T; Glatt, S J; Chen, W J; Hwu, H-G; Faraone, Stephen V; Roe, Cheri A; Chandler, Sharon D; Liu, Chih-Min; Liu, Chen-Chung; Yeh, Ling-Ling; Ouyang, Wen-Chen; Chan, Hung-Yu; Chen, Chun-Ying; Neale, B M; Palotie, A; Sklar, P; Purcell, S M; McCarroll, S A; Holmans, P; Owen, M J; O'Donovan, M C

2015-01-01

Genetic associations involving both rare and common alleles have been reported for schizophrenia but there have been no systematic scans for rare recessive genotypes using fully phased trio data. Here, we use exome sequencing in 604 schizophrenia proband–parent trios to investigate the role of recessive (homozygous or compound heterozygous) nonsynonymous genotypes in the disorder. The burden of recessive genotypes was not significantly increased in probands at either a genome-wide level or in any individual gene after adjustment for multiple testing. At a system level, probands had an excess of nonsynonymous compound heterozygous genotypes (minor allele frequency, MAF ⩽1%) in voltage-gated sodium channels (VGSCs; eight in probands and none in parents, P=1.5 × 10−4). Previous findings of multiple de novo loss-of-function mutations in this gene family, particularly SCN2A, in autism and intellectual disability provide biological and genetic plausibility for this finding. Pointing further to the involvement of VGSCs in schizophrenia, we found that these genes were enriched for nonsynonymous mutations (MAF ⩽0.1%) in cases genotyped using an exome array, (5585 schizophrenia cases and 8103 controls), and that in the trios data, synaptic proteins interacting with VGSCs were also enriched for both compound heterozygosity (P=0.018) and de novo mutations (P=0.04). However, we were unable to replicate the specific association with compound heterozygosity at VGSCs in an independent sample of Taiwanese schizophrenia trios (N=614). We conclude that recessive genotypes do not appear to make a substantial contribution to schizophrenia at a genome-wide level. Although multiple lines of evidence, including several from this study, suggest that rare mutations in VGSCs contribute to the disorder, in the absence of replication of the original findings regarding compound heterozygosity, this conclusion requires evaluation in a larger sample of trios. PMID:26196440

Rare ADH Variant Constellations are Specific for Alcohol Dependence

PubMed Central

Zuo, Lingjun; Zhang, Heping; Malison, Robert T.; Li, Chiang-Shan R.; Zhang, Xiang-Yang; Wang, Fei; Lu, Lingeng; Lu, Lin; Wang, Xiaoping; Krystal, John H.; Zhang, Fengyu; Deng, Hong-Wen; Luo, Xingguang

2013-01-01

Aims: Some of the well-known functional alcohol dehydrogenase (ADH) gene variants (e.g. ADH1B*2, ADH1B*3 and ADH1C*2) that significantly affect the risk of alcohol dependence are rare variants in most populations. In the present study, we comprehensively examined the associations between rare ADH variants [minor allele frequency (MAF) <0.05] and alcohol dependence, with several other neuropsychiatric and neurological disorders as reference. Methods: A total of 49,358 subjects in 22 independent cohorts with 11 different neuropsychiatric and neurological disorders were analyzed, including 3 cohorts with alcohol dependence. The entire ADH gene cluster (ADH7–ADH1C–ADH1B–ADH1A–ADH6–ADH4–ADH5 at Chr4) was imputed in all samples using the same reference panels that included whole-genome sequencing data. We stringently cleaned the phenotype and genotype data to obtain a total of 870 single nucleotide polymorphisms with 0< MAF <0.05 for association analysis. Results: We found that a rare variant constellation across the entire ADH gene cluster was significantly associated with alcohol dependence in European-Americans (Fp1: simulated global P = 0.045), European-Australians (Fp5: global P = 0.027; collapsing: P = 0.038) and African-Americans (Fp5: global P = 0.050; collapsing: P = 0.038), but not with any other neuropsychiatric disease. Association signals in this region came principally from ADH6, ADH7, ADH1B and ADH1C. In particular, a rare ADH6 variant constellation showed a replicable association with alcohol dependence across these three independent cohorts. No individual rare variants were statistically significantly associated with any disease examined after group- and region-wide correction for multiple comparisons. Conclusion: We conclude that rare ADH variants are specific for alcohol dependence. The ADH gene cluster may harbor a causal variant(s) for alcohol dependence. PMID:23019235

A Comprehensive Analysis of Common and Rare Variants to Identify Adiposity Loci in Hispanic Americans: The IRAS Family Study (IRASFS)

PubMed Central

Gao, Chuan; Wang, Nan; Guo, Xiuqing; Ziegler, Julie T.; Taylor, Kent D.; Xiang, Anny H.; Hai, Yang; Kridel, Steven J.; Nadler, Jerry L.; Kandeel, Fouad; Raffel, Leslie J.; Chen, Yii-Der I.; Norris, Jill M.; Rotter, Jerome I.; Watanabe, Richard M.; Wagenknecht, Lynne E.; Bowden, Donald W.; Speliotes, Elizabeth K.; Goodarzi, Mark O.; Langefeld, Carl D.; Palmer, Nicholette D.

2015-01-01

Obesity is growing epidemic affecting 35% of adults in the United States. Previous genome-wide association studies (GWAS) have identified numerous loci associated with obesity. However, the majority of studies have been completed in Caucasians focusing on total body measures of adiposity. Here we report the results from genome-wide and exome chip association studies focusing on total body measures of adiposity including body mass index (BMI), percent body fat (PBF) and measures of fat deposition including waist circumference (WAIST), waist-hip ratio (WHR), subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) in Hispanic Americans (nmax = 1263) from the Insulin Resistance Atherosclerosis Family Study (IRASFS). Five SNPs from two novel loci attained genome-wide significance (P<5.00x10-8) in IRASFS. A missense SNP in the isocitrate dehydrogenase 1 gene (IDH1) was associated with WAIST (rs34218846, MAF = 6.8%, PDOM = 1.62x10-8). This protein is postulated to play an important role in fat and cholesterol biosynthesis as demonstrated in cell and knock-out animal models. Four correlated intronic SNPs in the Zinc finger, GRF-type containing 1 gene (ZGRF1; SNP rs1471880, MAF = 48.1%, PDOM = 1.00x10-8) were strongly associated with WHR. The exact biological function of ZGRF1 and the connection with adiposity remains unclear. SNPs with p-values less than 5.00x10-6 from IRASFS were selected for replication. Meta-analysis was computed across seven independent Hispanic-American cohorts (nmax = 4156) and the strongest signal was rs1471880 (PDOM = 8.38x10-6) in ZGRF1 with WAIST. In conclusion, a genome-wide and exome chip association study was conducted that identified two novel loci (IDH1 and ZGRF1) associated with adiposity. While replication efforts were inconclusive, when taken together with the known biology, IDH1 and ZGRF1 warrant further evaluation. PMID:26599207

A Comprehensive Analysis of Common and Rare Variants to Identify Adiposity Loci in Hispanic Americans: The IRAS Family Study (IRASFS).

PubMed

Gao, Chuan; Wang, Nan; Guo, Xiuqing; Ziegler, Julie T; Taylor, Kent D; Xiang, Anny H; Hai, Yang; Kridel, Steven J; Nadler, Jerry L; Kandeel, Fouad; Raffel, Leslie J; Chen, Yii-Der I; Norris, Jill M; Rotter, Jerome I; Watanabe, Richard M; Wagenknecht, Lynne E; Bowden, Donald W; Speliotes, Elizabeth K; Goodarzi, Mark O; Langefeld, Carl D; Palmer, Nicholette D

2015-01-01

Obesity is growing epidemic affecting 35% of adults in the United States. Previous genome-wide association studies (GWAS) have identified numerous loci associated with obesity. However, the majority of studies have been completed in Caucasians focusing on total body measures of adiposity. Here we report the results from genome-wide and exome chip association studies focusing on total body measures of adiposity including body mass index (BMI), percent body fat (PBF) and measures of fat deposition including waist circumference (WAIST), waist-hip ratio (WHR), subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) in Hispanic Americans (nmax = 1263) from the Insulin Resistance Atherosclerosis Family Study (IRASFS). Five SNPs from two novel loci attained genome-wide significance (P<5.00x10-8) in IRASFS. A missense SNP in the isocitrate dehydrogenase 1 gene (IDH1) was associated with WAIST (rs34218846, MAF = 6.8%, PDOM = 1.62x10-8). This protein is postulated to play an important role in fat and cholesterol biosynthesis as demonstrated in cell and knock-out animal models. Four correlated intronic SNPs in the Zinc finger, GRF-type containing 1 gene (ZGRF1; SNP rs1471880, MAF = 48.1%, PDOM = 1.00x10-8) were strongly associated with WHR. The exact biological function of ZGRF1 and the connection with adiposity remains unclear. SNPs with p-values less than 5.00x10-6 from IRASFS were selected for replication. Meta-analysis was computed across seven independent Hispanic-American cohorts (nmax = 4156) and the strongest signal was rs1471880 (PDOM = 8.38x10-6) in ZGRF1 with WAIST. In conclusion, a genome-wide and exome chip association study was conducted that identified two novel loci (IDH1 and ZGRF1) associated with adiposity. While replication efforts were inconclusive, when taken together with the known biology, IDH1 and ZGRF1 warrant further evaluation.

Using CSF biomarkers to replicate genetic associations in Alzheimer's disease.

PubMed

Schott, Jonathan M

2012-07-01

Defining cases and controls on the basis of biomarkers rather than clinical diagnosis may reduce sample sizes required for genetic studies. The aim of this study was to assess whether characterizing case/control status on the basis of cerebrospinal fluid (CSF) profile would increase power to replicate known genetic associations for Alzheimer's disease (AD). Independent of clinical diagnosis, Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects with 2 CSF biomarkers for AD (Aβ1-42 < 192 pg/mL and tau phosphorylated at threonine 181 (p-tau) > 23 pg/mL, "CSF-positive") were compared with those without CSF evidence for AD (Aβ1-42 > 192 pg/mL and 181-phosphorylated tau < 23 pg/mL, "CSF-negative"). Minor allele frequency (MAF) and odds ratios (ORs) between these 2 groups were calculated for 7 single-nucleotide polymorphisms (SNPs) of interest. Two hundred thirty-two individuals were CSF-positive and 94 CSF-negative. There were no differences in age (74.7 ± 7.2 vs. 75.0 ± 6.5 years, p = 0.7), but significant differences in Mini Mental State Examination (MMSE) (25.9 ± 2.6 vs. 28.2 ± 1.7, p < 0.001) between the CSF-positive and CSF-negative groups. Significant differences in MAF (p < 0.05, uncorrected) were seen for CR1 (rs1408077; OR, 1.59; 95% confidence interval [CI], 1.01-2.49), PICALM (rs541458; OR, 0.68, 95% CI, 0.47-0.98), TOMM40 (rs2075650; OR, 4.30; 95% CI, 2.61-7.06); and possession of 1 or more APOE ε4 alleles (OR, 9.84; 95% CI, 5.48-17.67). These results suggest that using biomarkers of AD pathology to define case and control status may increase power in genetic association studies. Copyright © 2012 Elsevier Inc. All rights reserved.

Whole genome sequence analyses of brain imaging measures in the Framingham Study.

PubMed

Sarnowski, Chloé; Satizabal, Claudia L; DeCarli, Charles; Pitsillides, Achilleas N; Cupples, L Adrienne; Vasan, Ramachandran S; Wilson, James G; Bis, Joshua C; Fornage, Myriam; Beiser, Alexa S; DeStefano, Anita L; Dupuis, Josée; Seshadri, Sudha

2018-01-16

We sought to identify rare variants influencing brain imaging phenotypes in the Framingham Heart Study by performing whole genome sequence association analyses within the Trans-Omics for Precision Medicine Program. We performed association analyses of cerebral and hippocampal volumes and white matter hyperintensity (WMH) in up to 2,180 individuals by testing the association of rank-normalized residuals from mixed-effect linear regression models adjusted for sex, age, and total intracranial volume with individual variants while accounting for familial relatedness. We conducted gene-based tests for rare variants using (1) a sliding-window approach, (2) a selection of functional exonic variants, or (3) all variants. We detected new loci in 1p21 for cerebral volume (minor allele frequency [MAF] 0.005, p = 10 -8 ) and in 16q23 for hippocampal volume (MAF 0.05, p = 2.7 × 10 -8 ). Previously identified associations in 12q24 for hippocampal volume (rs7294919, p = 4.4 × 10 -4 ) and in 17q25 for WMH (rs7214628, p = 2.0 × 10 -3 ) were confirmed. Gene-based tests detected associations ( p ≤ 2.3 × 10 -6 ) in new loci for cerebral (5q13, 8p12, 9q31, 13q12-q13, 15q24, 17q12, 19q13) and hippocampal volumes (2p12) and WMH (3q13, 4p15) including Alzheimer disease- ( UNC5D ) and Parkinson disease-associated genes ( GBA ). Pathway analyses evidenced enrichment of associated genes in immunity, inflammation, and Alzheimer disease and Parkinson disease pathways. Whole genome sequence-wide search reveals intriguing new loci associated with brain measures. Replication of novel loci is needed to confirm these findings. Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Genome-wide association study of 25(OH) Vitamin D concentrations in Punjabi Sikhs: Results of the Asian Indian diabetic heart study.

PubMed

Sapkota, Bishwa R; Hopkins, Ruth; Bjonnes, Andrew; Ralhan, Sarju; Wander, Gurpreet S; Mehra, Narinder K; Singh, Jai Rup; Blackett, Piers R; Saxena, Richa; Sanghera, Dharambir K

2016-04-01

Vitamin D deficiency is implicated in multiple disease conditions and accumulating evidence supports that the variation in serum vitamin D (25(OH)D) levels, including deficiency, is under strong genetic control. However, the underlying genetic mechanism associated with vitamin 25(OH)D concentrations is poorly understood. We earlier reported a very high prevalence of vitamin D deficiency associated with an increased risk for type 2 diabetes and obesity in a Punjabi Sikh diabetic cohort as part of the Asian Indian diabetic heart study (AIDHS). Here we have performed the first genome-wide association study (GWAS) of serum 25(OH)D on 3538 individuals from this Punjabi Sikh population. Our discovery GWAS comprised of 1387 subjects followed by validation of 24 putative SNPs (P<10(-4)) using an independent replication sample (n=2151) from the same population by direct genotyping. A novel locus at chromosome 20p11.21 represented by rs2207173 with minor allele frequency (MAF) 0.29, [β=-0.13, p=4.47×10(-9)] between FOXA2 and SSTR4 was identified to be associated with 25(OH)D levels. Another suggestive association signal at rs11586313 (MAF 0.54) [β=0.90; p=1.36×10(-6)] was found within the regulatory region of the IVL gene on chromosome 1q21.3. Additionally, our study replicated 3 of 5 known GWAS genes associated with 25(OH)D concentrations including GC (p=0.007) and CYP2R1 (p=0.019) reported in Europeans and the DAB1 (p=0.003), reported in Hispanics. Identification of novel association signals in biologically plausible regions with 25(OH)D metabolism will provide new molecular insights on genetic drivers of vitamin D status and its implications in health disparities. Copyright © 2015 Elsevier Ltd. All rights reserved.

Identification and functional characterization of G6PC2 coding variants influencing glycemic traits define an effector transcript at the G6PC2-ABCB11 locus.

PubMed

Mahajan, Anubha; Sim, Xueling; Ng, Hui Jin; Manning, Alisa; Rivas, Manuel A; Highland, Heather M; Locke, Adam E; Grarup, Niels; Im, Hae Kyung; Cingolani, Pablo; Flannick, Jason; Fontanillas, Pierre; Fuchsberger, Christian; Gaulton, Kyle J; Teslovich, Tanya M; Rayner, N William; Robertson, Neil R; Beer, Nicola L; Rundle, Jana K; Bork-Jensen, Jette; Ladenvall, Claes; Blancher, Christine; Buck, David; Buck, Gemma; Burtt, Noël P; Gabriel, Stacey; Gjesing, Anette P; Groves, Christopher J; Hollensted, Mette; Huyghe, Jeroen R; Jackson, Anne U; Jun, Goo; Justesen, Johanne Marie; Mangino, Massimo; Murphy, Jacquelyn; Neville, Matt; Onofrio, Robert; Small, Kerrin S; Stringham, Heather M; Syvänen, Ann-Christine; Trakalo, Joseph; Abecasis, Goncalo; Bell, Graeme I; Blangero, John; Cox, Nancy J; Duggirala, Ravindranath; Hanis, Craig L; Seielstad, Mark; Wilson, James G; Christensen, Cramer; Brandslund, Ivan; Rauramaa, Rainer; Surdulescu, Gabriela L; Doney, Alex S F; Lannfelt, Lars; Linneberg, Allan; Isomaa, Bo; Tuomi, Tiinamaija; Jørgensen, Marit E; Jørgensen, Torben; Kuusisto, Johanna; Uusitupa, Matti; Salomaa, Veikko; Spector, Timothy D; Morris, Andrew D; Palmer, Colin N A; Collins, Francis S; Mohlke, Karen L; Bergman, Richard N; Ingelsson, Erik; Lind, Lars; Tuomilehto, Jaakko; Hansen, Torben; Watanabe, Richard M; Prokopenko, Inga; Dupuis, Josee; Karpe, Fredrik; Groop, Leif; Laakso, Markku; Pedersen, Oluf; Florez, Jose C; Morris, Andrew P; Altshuler, David; Meigs, James B; Boehnke, Michael; McCarthy, Mark I; Lindgren, Cecilia M; Gloyn, Anna L

2015-01-01

Genome wide association studies (GWAS) for fasting glucose (FG) and insulin (FI) have identified common variant signals which explain 4.8% and 1.2% of trait variance, respectively. It is hypothesized that low-frequency and rare variants could contribute substantially to unexplained genetic variance. To test this, we analyzed exome-array data from up to 33,231 non-diabetic individuals of European ancestry. We found exome-wide significant (P<5×10-7) evidence for two loci not previously highlighted by common variant GWAS: GLP1R (p.Ala316Thr, minor allele frequency (MAF)=1.5%) influencing FG levels, and URB2 (p.Glu594Val, MAF = 0.1%) influencing FI levels. Coding variant associations can highlight potential effector genes at (non-coding) GWAS signals. At the G6PC2/ABCB11 locus, we identified multiple coding variants in G6PC2 (p.Val219Leu, p.His177Tyr, and p.Tyr207Ser) influencing FG levels, conditionally independent of each other and the non-coding GWAS signal. In vitro assays demonstrate that these associated coding alleles result in reduced protein abundance via proteasomal degradation, establishing G6PC2 as an effector gene at this locus. Reconciliation of single-variant associations and functional effects was only possible when haplotype phase was considered. In contrast to earlier reports suggesting that, paradoxically, glucose-raising alleles at this locus are protective against type 2 diabetes (T2D), the p.Val219Leu G6PC2 variant displayed a modest but directionally consistent association with T2D risk. Coding variant associations for glycemic traits in GWAS signals highlight PCSK1, RREB1, and ZHX3 as likely effector transcripts. These coding variant association signals do not have a major impact on the trait variance explained, but they do provide valuable biological insights.

Direct sequencing and comprehensive screening of genetic polymorphisms on CYP2 family genes (CYP2A6, CYP2B6, CYP2C8, and CYP2E1) in five ethnic populations.

PubMed

Kim, Jeong-Hyun; Cheong, Hyun Sub; Park, Byung Lae; Kim, Lyoung Hyo; Shin, Hee Jung; Na, Han Sung; Chung, Myeon Woo; Shin, Hyoung Doo

2015-01-01

Recently, CYP2A6, CYP2B6, CYP2C8, and CYP2E1 have been reported to play a role in the metabolic effect of pharmacological and carcinogenic compounds. Moreover, genetic variations of drug metabolism genes have been implicated in the interindividual variation in drug disposition and pharmacological response. To define the distribution of single nucleotide polymorphisms (SNPs) in these four CYP2 family genes and to discover novel SNPs across ethnic groups, 288 DNAs composed of 48 African-Americans, 48 European-Americans, 48 Japanese, 48 Han Chinese, and 96 Koreans were resequenced. A total of 143 SNPs, 26 in CYP2A6, 45 in CYP2B6, 29 in CYP2C8, and 43 in CYP2E1, were identified, including 13 novel variants. Notably, two SNPs in the regulatory regions, a promoter SNP rs2054675 and a nonsynonymous rs3745274 (p.172Q>H) in CYP2B6, showed significantly different minor allele frequencies (MAFs) among ethnic groups (minimum P = 4.30 × 10(-12)). In addition, rs2031920 in the promoter region of CYP2E1 showed a wide range of MAF between different ethnic groups, and even among other various ethnic groups based on public reports. Among 13 newly discovered SNPs in this study, 5 SNPs were estimated to have potential functions in further in silico analyses. Some differences in genetic variations and haplotypes of CYP2A6, CYP2B6, CYP2C8, and CYP2E1 were observed among populations. Our findings could be useful in further researches, such as genetic associations with drug responses.

Optimization of RAS/BRAF Mutational Analysis Confirms Improvement in Patient Selection for Clinical Benefit to Anti-EGFR Treatment in Metastatic Colorectal Cancer.

PubMed

Santos, Cristina; Azuara, Daniel; Garcia-Carbonero, Rocio; Alfonso, Pilar Garcia; Carrato, Alfredo; Elez, Mª Elena; Gomez, Auxiliadora; Losa, Ferran; Montagut, Clara; Massuti, Bartomeu; Navarro, Valenti; Varela, Mar; Lopez-Doriga, Adriana; Moreno, Victor; Valladares, Manuel; Manzano, Jose Luis; Vieitez, Jose Maria; Aranda, Enrique; Sanjuan, Xavier; Tabernero, Josep; Capella, Gabriel; Salazar, Ramon

2017-09-01

In metastatic colorectal cancer (mCRC), recent studies have shown the importance to accurately quantify low-abundance mutations of the RAS pathway because anti-EGFR therapy may depend on certain mutation thresholds. We aimed to evaluate the added predictive value of an extended RAS panel testing using two commercial assays and a highly sensitive and quantitative digital PCR (dPCR). Tumor samples from 583 mCRC patients treated with anti-EGFR- ( n = 255) or bevacizumab- ( n = 328) based therapies from several clinical trials and retrospective series from the TTD/RTICC Spanish network were analyzed by cobas, therascreen , and dPCR. We evaluated concordance between techniques using the Cohen kappa index. Response rate, progression-free survival (PFS), and overall survival (OS) were correlated to the mutational status and the mutant allele fraction (MAF). Concordance between techniques was high when analyzing RAS and BRAF (Cohen kappa index around 0.75). We observed an inverse correlation between MAF and response in the anti-EGFR cohort ( P < 0.001). Likelihood ratio analysis showed that a fraction of 1% or higher of any mutated alleles offered the best predictive value. PFS and OS were significantly longer in RAS / BRAF wild-type patients, independently of the technique. However, the predictability of both PFS and OS were higher when we considered a threshold of 1% in the RAS scenario (HR = 1.53; CI 95%, 1.12-2.09 for PFS, and HR = 1.9; CI 95%, 1.33-2.72 for OS). Although the rate of mutations observed among techniques is different, RAS and BRAF mutational analysis improved prediction of response to anti-EGFR therapy. Additionally, dPCR with a threshold of 1% outperformed the other platforms. Mol Cancer Ther; 16(9); 1999-2007. ©2017 AACR . ©2017 American Association for Cancer Research.

The Impact of Genetic and Non-Genetic Factors on Warfarin Dose Prediction in MENA Region: A Systematic Review

PubMed Central

2016-01-01

Background Warfarin is the most commonly used oral anticoagulant for the treatment and prevention of thromboembolic disorders. Pharmacogenomics studies have shown that variants in CYP2C9 and VKORC1 genes are strongly and consistently associated with warfarin dose variability. Although different populations from the Middle East and North Africa (MENA) region may share the same ancestry, it is still unclear how they compare in the genetic and non-genetic factors affecting their warfarin dosing. Objective To explore the prevalence of CYP2C9 and VKORC1 variants in MENA, and the effect of these variants along with other non-genetic factors in predicting warfarin dose. Methods In this systematic review, we included observational cross sectional and cohort studies that enrolled patients on stable warfarin dose and had the genetics and non-genetics factors associated with mean warfarin dose as the primary outcome. We searched PubMed, Medline, Scopus, PharmGKB, PHGKB, Google scholar and reference lists of relevant reviews. Results We identified 17 studies in eight different populations: Iranian, Israeli, Egyptian, Lebanese, Omani, Kuwaiti, Sudanese and Turkish. Most common genetic variant in all populations was the VKORC1 (-1639G>A), with a minor allele frequency ranging from 30% in Egyptians and up to 52% and 56% in Lebanese and Iranian, respectively. Variants in the CYP2C9 were less common, with the highest MAF for CYP2C9*2 among Iranians (27%). Variants in the VKORC1 and CYP2C9 were the most significant predictors of warfarin dose in all populations. Along with other genetic and non-genetic factors, they explained up to 63% of the dose variability in Omani and Israeli patients. Conclusion Variants of VKORC1 and CYP2C9 are the strongest predictors of warfarin dose variability among the different populations from MENA. Although many of those populations share the same ancestry and are similar in their warfarin dose predictors, a population specific dosing algorithm is needed for the prospective estimation of warfarin dose. PMID:27992547

The Impact of Genetic and Non-Genetic Factors on Warfarin Dose Prediction in MENA Region: A Systematic Review.

PubMed

Bader, Loulia Akram; Elewa, Hazem

2016-01-01

Warfarin is the most commonly used oral anticoagulant for the treatment and prevention of thromboembolic disorders. Pharmacogenomics studies have shown that variants in CYP2C9 and VKORC1 genes are strongly and consistently associated with warfarin dose variability. Although different populations from the Middle East and North Africa (MENA) region may share the same ancestry, it is still unclear how they compare in the genetic and non-genetic factors affecting their warfarin dosing. To explore the prevalence of CYP2C9 and VKORC1 variants in MENA, and the effect of these variants along with other non-genetic factors in predicting warfarin dose. In this systematic review, we included observational cross sectional and cohort studies that enrolled patients on stable warfarin dose and had the genetics and non-genetics factors associated with mean warfarin dose as the primary outcome. We searched PubMed, Medline, Scopus, PharmGKB, PHGKB, Google scholar and reference lists of relevant reviews. We identified 17 studies in eight different populations: Iranian, Israeli, Egyptian, Lebanese, Omani, Kuwaiti, Sudanese and Turkish. Most common genetic variant in all populations was the VKORC1 (-1639G>A), with a minor allele frequency ranging from 30% in Egyptians and up to 52% and 56% in Lebanese and Iranian, respectively. Variants in the CYP2C9 were less common, with the highest MAF for CYP2C9*2 among Iranians (27%). Variants in the VKORC1 and CYP2C9 were the most significant predictors of warfarin dose in all populations. Along with other genetic and non-genetic factors, they explained up to 63% of the dose variability in Omani and Israeli patients. Variants of VKORC1 and CYP2C9 are the strongest predictors of warfarin dose variability among the different populations from MENA. Although many of those populations share the same ancestry and are similar in their warfarin dose predictors, a population specific dosing algorithm is needed for the prospective estimation of warfarin dose.

Sequence data and association statistics from 12,940 type 2 diabetes cases and controls.

PubMed

Flannick, Jason; Fuchsberger, Christian; Mahajan, Anubha; Teslovich, Tanya M; Agarwala, Vineeta; Gaulton, Kyle J; Caulkins, Lizz; Koesterer, Ryan; Ma, Clement; Moutsianas, Loukas; McCarthy, Davis J; Rivas, Manuel A; Perry, John R B; Sim, Xueling; Blackwell, Thomas W; Robertson, Neil R; Rayner, N William; Cingolani, Pablo; Locke, Adam E; Tajes, Juan Fernandez; Highland, Heather M; Dupuis, Josee; Chines, Peter S; Lindgren, Cecilia M; Hartl, Christopher; Jackson, Anne U; Chen, Han; Huyghe, Jeroen R; van de Bunt, Martijn; Pearson, Richard D; Kumar, Ashish; Müller-Nurasyid, Martina; Grarup, Niels; Stringham, Heather M; Gamazon, Eric R; Lee, Jaehoon; Chen, Yuhui; Scott, Robert A; Below, Jennifer E; Chen, Peng; Huang, Jinyan; Go, Min Jin; Stitzel, Michael L; Pasko, Dorota; Parker, Stephen C J; Varga, Tibor V; Green, Todd; Beer, Nicola L; Day-Williams, Aaron G; Ferreira, Teresa; Fingerlin, Tasha; Horikoshi, Momoko; Hu, Cheng; Huh, Iksoo; Ikram, Mohammad Kamran; Kim, Bong-Jo; Kim, Yongkang; Kim, Young Jin; Kwon, Min-Seok; Lee, Juyoung; Lee, Selyeong; Lin, Keng-Han; Maxwell, Taylor J; Nagai, Yoshihiko; Wang, Xu; Welch, Ryan P; Yoon, Joon; Zhang, Weihua; Barzilai, Nir; Voight, Benjamin F; Han, Bok-Ghee; Jenkinson, Christopher P; Kuulasmaa, Teemu; Kuusisto, Johanna; Manning, Alisa; Ng, Maggie C Y; Palmer, Nicholette D; Balkau, Beverley; Stančáková, Alena; Abboud, Hanna E; Boeing, Heiner; Giedraitis, Vilmantas; Prabhakaran, Dorairaj; Gottesman, Omri; Scott, James; Carey, Jason; Kwan, Phoenix; Grant, George; Smith, Joshua D; Neale, Benjamin M; Purcell, Shaun; Butterworth, Adam S; Howson, Joanna M M; Lee, Heung Man; Lu, Yingchang; Kwak, Soo-Heon; Zhao, Wei; Danesh, John; Lam, Vincent K L; Park, Kyong Soo; Saleheen, Danish; So, Wing Yee; Tam, Claudia H T; Afzal, Uzma; Aguilar, David; Arya, Rector; Aung, Tin; Chan, Edmund; Navarro, Carmen; Cheng, Ching-Yu; Palli, Domenico; Correa, Adolfo; Curran, Joanne E; Rybin, Dennis; Farook, Vidya S; Fowler, Sharon P; Freedman, Barry I; Griswold, Michael; Hale, Daniel Esten; Hicks, Pamela J; Khor, Chiea-Chuen; Kumar, Satish; Lehne, Benjamin; Thuillier, Dorothée; Lim, Wei Yen; Liu, Jianjun; Loh, Marie; Musani, Solomon K; Puppala, Sobha; Scott, William R; Yengo, Loïc; Tan, Sian-Tsung; Taylor, Herman A; Thameem, Farook; Wilson, Gregory; Wong, Tien Yin; Njølstad, Pål Rasmus; Levy, Jonathan C; Mangino, Massimo; Bonnycastle, Lori L; Schwarzmayr, Thomas; Fadista, João; Surdulescu, Gabriela L; Herder, Christian; Groves, Christopher J; Wieland, Thomas; Bork-Jensen, Jette; Brandslund, Ivan; Christensen, Cramer; Koistinen, Heikki A; Doney, Alex S F; Kinnunen, Leena; Esko, Tõnu; Farmer, Andrew J; Hakaste, Liisa; Hodgkiss, Dylan; Kravic, Jasmina; Lyssenko, Valeri; Hollensted, Mette; Jørgensen, Marit E; Jørgensen, Torben; Ladenvall, Claes; Justesen, Johanne Marie; Käräjämäki, Annemari; Kriebel, Jennifer; Rathmann, Wolfgang; Lannfelt, Lars; Lauritzen, Torsten; Narisu, Narisu; Linneberg, Allan; Melander, Olle; Milani, Lili; Neville, Matt; Orho-Melander, Marju; Qi, Lu; Qi, Qibin; Roden, Michael; Rolandsson, Olov; Swift, Amy; Rosengren, Anders H; Stirrups, Kathleen; Wood, Andrew R; Mihailov, Evelin; Blancher, Christine; Carneiro, Mauricio O; Maguire, Jared; Poplin, Ryan; Shakir, Khalid; Fennell, Timothy; DePristo, Mark; de Angelis, Martin Hrabé; Deloukas, Panos; Gjesing, Anette P; Jun, Goo; Nilsson, Peter; Murphy, Jacquelyn; Onofrio, Robert; Thorand, Barbara; Hansen, Torben; Meisinger, Christa; Hu, Frank B; Isomaa, Bo; Karpe, Fredrik; Liang, Liming; Peters, Annette; Huth, Cornelia; O'Rahilly, Stephen P; Palmer, Colin N A; Pedersen, Oluf; Rauramaa, Rainer; Tuomilehto, Jaakko; Salomaa, Veikko; Watanabe, Richard M; Syvänen, Ann-Christine; Bergman, Richard N; Bharadwaj, Dwaipayan; Bottinger, Erwin P; Cho, Yoon Shin; Chandak, Giriraj R; Chan, Juliana Cn; Chia, Kee Seng; Daly, Mark J; Ebrahim, Shah B; Langenberg, Claudia; Elliott, Paul; Jablonski, Kathleen A; Lehman, Donna M; Jia, Weiping; Ma, Ronald C W; Pollin, Toni I; Sandhu, Manjinder; Tandon, Nikhil; Froguel, Philippe; Barroso, Inês; Teo, Yik Ying; Zeggini, Eleftheria; Loos, Ruth J F; Small, Kerrin S; Ried, Janina S; DeFronzo, Ralph A; Grallert, Harald; Glaser, Benjamin; Metspalu, Andres; Wareham, Nicholas J; Walker, Mark; Banks, Eric; Gieger, Christian; Ingelsson, Erik; Im, Hae Kyung; Illig, Thomas; Franks, Paul W; Buck, Gemma; Trakalo, Joseph; Buck, David; Prokopenko, Inga; Mägi, Reedik; Lind, Lars; Farjoun, Yossi; Owen, Katharine R; Gloyn, Anna L; Strauch, Konstantin; Tuomi, Tiinamaija; Kooner, Jaspal Singh; Lee, Jong-Young; Park, Taesung; Donnelly, Peter; Morris, Andrew D; Hattersley, Andrew T; Bowden, Donald W; Collins, Francis S; Atzmon, Gil; Chambers, John C; Spector, Timothy D; Laakso, Markku; Strom, Tim M; Bell, Graeme I; Blangero, John; Duggirala, Ravindranath; Tai, E Shyong; McVean, Gilean; Hanis, Craig L; Wilson, James G; Seielstad, Mark; Frayling, Timothy M; Meigs, James B; Cox, Nancy J; Sladek, Rob; Lander, Eric S; Gabriel, Stacey; Mohlke, Karen L; Meitinger, Thomas; Groop, Leif; Abecasis, Goncalo; Scott, Laura J; Morris, Andrew P; Kang, Hyun Min; Altshuler, David; Burtt, Noël P; Florez, Jose C; Boehnke, Michael; McCarthy, Mark I

2017-12-19

To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1-5%) non-coding variants in the whole-genome sequenced individuals and 99.7% of low-frequency coding variants in the whole-exome sequenced individuals. Each variant was tested for association with T2D in the sequenced individuals, and, to increase power, most were tested in larger numbers of individuals (>80% of low-frequency coding variants in ~82 K Europeans via the exome chip, and ~90% of low-frequency non-coding variants in ~44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D.

Sequence data and association statistics from 12,940 type 2 diabetes cases and controls

PubMed Central

Jason, Flannick; Fuchsberger, Christian; Mahajan, Anubha; Teslovich, Tanya M.; Agarwala, Vineeta; Gaulton, Kyle J.; Caulkins, Lizz; Koesterer, Ryan; Ma, Clement; Moutsianas, Loukas; McCarthy, Davis J.; Rivas, Manuel A.; Perry, John R. B.; Sim, Xueling; Blackwell, Thomas W.; Robertson, Neil R.; Rayner, N William; Cingolani, Pablo; Locke, Adam E.; Tajes, Juan Fernandez; Highland, Heather M.; Dupuis, Josee; Chines, Peter S.; Lindgren, Cecilia M.; Hartl, Christopher; Jackson, Anne U.; Chen, Han; Huyghe, Jeroen R.; van de Bunt, Martijn; Pearson, Richard D.; Kumar, Ashish; Müller-Nurasyid, Martina; Grarup, Niels; Stringham, Heather M.; Gamazon, Eric R.; Lee, Jaehoon; Chen, Yuhui; Scott, Robert A.; Below, Jennifer E.; Chen, Peng; Huang, Jinyan; Go, Min Jin; Stitzel, Michael L.; Pasko, Dorota; Parker, Stephen C. J.; Varga, Tibor V.; Green, Todd; Beer, Nicola L.; Day-Williams, Aaron G.; Ferreira, Teresa; Fingerlin, Tasha; Horikoshi, Momoko; Hu, Cheng; Huh, Iksoo; Ikram, Mohammad Kamran; Kim, Bong-Jo; Kim, Yongkang; Kim, Young Jin; Kwon, Min-Seok; Lee, Juyoung; Lee, Selyeong; Lin, Keng-Han; Maxwell, Taylor J.; Nagai, Yoshihiko; Wang, Xu; Welch, Ryan P.; Yoon, Joon; Zhang, Weihua; Barzilai, Nir; Voight, Benjamin F.; Han, Bok-Ghee; Jenkinson, Christopher P.; Kuulasmaa, Teemu; Kuusisto, Johanna; Manning, Alisa; Ng, Maggie C. Y.; Palmer, Nicholette D.; Balkau, Beverley; Stančáková, Alena; Abboud, Hanna E.; Boeing, Heiner; Giedraitis, Vilmantas; Prabhakaran, Dorairaj; Gottesman, Omri; Scott, James; Carey, Jason; Kwan, Phoenix; Grant, George; Smith, Joshua D.; Neale, Benjamin M.; Purcell, Shaun; Butterworth, Adam S.; Howson, Joanna M. M.; Lee, Heung Man; Lu, Yingchang; Kwak, Soo-Heon; Zhao, Wei; Danesh, John; Lam, Vincent K. L.; Park, Kyong Soo; Saleheen, Danish; So, Wing Yee; Tam, Claudia H. T.; Afzal, Uzma; Aguilar, David; Arya, Rector; Aung, Tin; Chan, Edmund; Navarro, Carmen; Cheng, Ching-Yu; Palli, Domenico; Correa, Adolfo; Curran, Joanne E.; Rybin, Dennis; Farook, Vidya S.; Fowler, Sharon P.; Freedman, Barry I.; Griswold, Michael; Hale, Daniel Esten; Hicks, Pamela J.; Khor, Chiea-Chuen; Kumar, Satish; Lehne, Benjamin; Thuillier, Dorothée; Lim, Wei Yen; Liu, Jianjun; Loh, Marie; Musani, Solomon K.; Puppala, Sobha; Scott, William R.; Yengo, Loïc; Tan, Sian-Tsung; Taylor, Herman A.; Thameem, Farook; Wilson, Gregory; Wong, Tien Yin; Njølstad, Pål Rasmus; Levy, Jonathan C.; Mangino, Massimo; Bonnycastle, Lori L.; Schwarzmayr, Thomas; Fadista, João; Surdulescu, Gabriela L.; Herder, Christian; Groves, Christopher J.; Wieland, Thomas; Bork-Jensen, Jette; Brandslund, Ivan; Christensen, Cramer; Koistinen, Heikki A.; Doney, Alex S. F.; Kinnunen, Leena; Esko, Tõnu; Farmer, Andrew J.; Hakaste, Liisa; Hodgkiss, Dylan; Kravic, Jasmina; Lyssenko, Valeri; Hollensted, Mette; Jørgensen, Marit E.; Jørgensen, Torben; Ladenvall, Claes; Justesen, Johanne Marie; Käräjämäki, Annemari; Kriebel, Jennifer; Rathmann, Wolfgang; Lannfelt, Lars; Lauritzen, Torsten; Narisu, Narisu; Linneberg, Allan; Melander, Olle; Milani, Lili; Neville, Matt; Orho-Melander, Marju; Qi, Lu; Qi, Qibin; Roden, Michael; Rolandsson, Olov; Swift, Amy; Rosengren, Anders H.; Stirrups, Kathleen; Wood, Andrew R.; Mihailov, Evelin; Blancher, Christine; Carneiro, Mauricio O.; Maguire, Jared; Poplin, Ryan; Shakir, Khalid; Fennell, Timothy; DePristo, Mark; de Angelis, Martin Hrabé; Deloukas, Panos; Gjesing, Anette P.; Jun, Goo; Nilsson, Peter; Murphy, Jacquelyn; Onofrio, Robert; Thorand, Barbara; Hansen, Torben; Meisinger, Christa; Hu, Frank B.; Isomaa, Bo; Karpe, Fredrik; Liang, Liming; Peters, Annette; Huth, Cornelia; O'Rahilly, Stephen P; Palmer, Colin N. A.; Pedersen, Oluf; Rauramaa, Rainer; Tuomilehto, Jaakko; Salomaa, Veikko; Watanabe, Richard M.; Syvänen, Ann-Christine; Bergman, Richard N.; Bharadwaj, Dwaipayan; Bottinger, Erwin P.; Cho, Yoon Shin; Chandak, Giriraj R.; Chan, Juliana CN; Chia, Kee Seng; Daly, Mark J.; Ebrahim, Shah B.; Langenberg, Claudia; Elliott, Paul; Jablonski, Kathleen A.; Lehman, Donna M.; Jia, Weiping; Ma, Ronald C. W.; Pollin, Toni I.; Sandhu, Manjinder; Tandon, Nikhil; Froguel, Philippe; Barroso, Inês; Teo, Yik Ying; Zeggini, Eleftheria; Loos, Ruth J. F.; Small, Kerrin S.; Ried, Janina S.; DeFronzo, Ralph A.; Grallert, Harald; Glaser, Benjamin; Metspalu, Andres; Wareham, Nicholas J.; Walker, Mark; Banks, Eric; Gieger, Christian; Ingelsson, Erik; Im, Hae Kyung; Illig, Thomas; Franks, Paul W.; Buck, Gemma; Trakalo, Joseph; Buck, David; Prokopenko, Inga; Mägi, Reedik; Lind, Lars; Farjoun, Yossi; Owen, Katharine R.; Gloyn, Anna L.; Strauch, Konstantin; Tuomi, Tiinamaija; Kooner, Jaspal Singh; Lee, Jong-Young; Park, Taesung; Donnelly, Peter; Morris, Andrew D.; Hattersley, Andrew T.; Bowden, Donald W.; Collins, Francis S.; Atzmon, Gil; Chambers, John C.; Spector, Timothy D.; Laakso, Markku; Strom, Tim M.; Bell, Graeme I.; Blangero, John; Duggirala, Ravindranath; Tai, E. Shyong; McVean, Gilean; Hanis, Craig L.; Wilson, James G.; Seielstad, Mark; Frayling, Timothy M.; Meigs, James B.; Cox, Nancy J.; Sladek, Rob; Lander, Eric S.; Gabriel, Stacey; Mohlke, Karen L.; Meitinger, Thomas; Groop, Leif; Abecasis, Goncalo; Scott, Laura J.; Morris, Andrew P.; Kang, Hyun Min; Altshuler, David; Burtt, Noël P.; Florez, Jose C.; Boehnke, Michael; McCarthy, Mark I.

2017-01-01

To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1–5%) non-coding variants in the whole-genome sequenced individuals and 99.7% of low-frequency coding variants in the whole-exome sequenced individuals. Each variant was tested for association with T2D in the sequenced individuals, and, to increase power, most were tested in larger numbers of individuals (>80% of low-frequency coding variants in ~82 K Europeans via the exome chip, and ~90% of low-frequency non-coding variants in ~44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D. PMID:29257133

Ares I Crew Launch Vehicle Upper Stage Element Overview

NASA Technical Reports Server (NTRS)

McArthur, J. Craig

2008-01-01

This viewgraph presentation gives an overview of NASA's Ares I Crew Launch Vehicle Upper Stage Element. The topics include: 1) What is NASA s Mission?; 2) NASA s Exploration Roadmap What is our time line?; 3) Building on a Foundation of Proven Technologies Launch Vehicle Comparisons; 4) Ares I Upper Stage; 5) Upper Stage Primary Products; 6) Ares I Upper Stage Development Approach; 7) What progress have we made?; 8) Upper Stage Subsystem Highlights; 9) Structural Testing; 10) Common Bulkhead Processing; 11) Stage Installation at Stennis Space Center; 12) Boeing Producibility Team; 13) Upper Stage Low Cost Strategy; 14) Ares I and V Production at Michoud Assembly Facility (MAF); 15) Merged Manufacturing Flow; and 16) Manufacturing and Assembly Weld Tools.

Analysis of the Material Removal Rate in Magnetic Abrasive Finishing of Thin Film Coated Pyrex Glass

NASA Astrophysics Data System (ADS)

Lee, Hee Hwan; Lee, Seoung Hwan

The material removal rate (MRR) during precision finishing/polishing is a key factor, which dictates the process performance. Moreover, the MRR or wear rate is closely related to the material/part reliability. For nanoscale patterning and/or planarization on nano-order thickness coatings, the prediction and in-process monitoring of the MRR is necessary, because the process is not characterizable due to size effects and material property/process condition variations as a result of the coating/substrate interactions. The purpose of this research was to develop a practical methodology for the prediction and in-process monitoring of MRR during nanoscale finishing of coated surfaces. Using a specially designed magnetic abrasive finishing (MAF) and acoustic emission (AE) monitoring setup, experiments were carried out on indium-zinc-oxide (IZO) coated Pyrex glasses. After a given polishing time interval, AFM indentation was conducted for each workpiece sample to measure the adhesion force variations of the coating layers (IZO), which are directly related to the MRR changes. The force variation and AE monitoring data were compared to the MRR calculated form the surface measurement (Nanoview) results. The experimental results demonstrate strong correlations between AFM indentation and MRR measurement data. In addition, the monitored AE signals show sensitivity of the material structure variations of the coating layer, as the polishing progresses.

Wear resistance of Ti/TiB composites produced by spark plasma sintering

NASA Astrophysics Data System (ADS)

Ozerov, M.; Stepanov, N.; Zherebtsov, S.

2017-12-01

The tribological characteristics of Ti/TiB composites were studied in as-sintered condition and after isothermal multiaxial forging. A mixture of commercially pure Ti and TiB2 powders was used to produce Ti/TiB composites with 8.5 and 17 vol % of TiB via in-situ Ti+TiB2→Ti+TiB reactions during spark plasma sintering at 1000°C. During isothermal multiaxial forging (MAF), the material was exposed to successive compressions along three orthogonal directions at a temperature of 700°C and strain rate of 10-3 s-1 to cumulative strains e = 5.2. The microstructure of the as-sintered composites consisted of TiB whiskers nonuniformly distributed within the Ti matrix. In the forged composites, intensive shortening of TiB whiskers occurred. The hardness of the composites increased greatly compared to that of commercially pure Ti; the hardness also increased with increasing the TiB fraction. The hardness in the forged composites decreased by ˜20% for both composite states. Tribological tests using a standard ball-on-disk geometry showed that the friction coefficient of the Ti/TiB composites increased in comparison with Ti. Increasing the TiB fraction in the composites increased the friction coefficient and decreased the wear factor. It was shown that the tribological characteristics after isothermal multiaxial forging were changed but slightly.

Conversion of immortal liver progenitor cells into pancreatic endocrine progenitor cells by persistent expression of Pdx-1.

PubMed

Jin, Cai-Xia; Li, Wen-Lin; Xu, Fang; Geng, Zhen H; He, Zhi-Ying; Su, Juan; Tao, Xin-Rong; Ding, Xiao-Yan; Wang, Xin; Hu, Yi-Ping

2008-05-01

The conversion of expandable liver progenitor cells into pancreatic beta cells would provide a renewable cell source for diabetes cell therapy. Previously, we reported the establishment of liver epithelial progenitor cells (LEPCs). In this work, LEPCs were modified into EGFP/Pdx-1 LEPCs, cells with stable expression of both Pdx-1 and EGFP. Unlike previous work, with persistent expression of Pdx-1, EGFP/Pdx-1 LEPCs acquired the phenotype of pancreatic endocrine progenitor cells rather than giving rise to insulin-producing cells directly. EGFP/Pdx-1 LEPCs proliferated vigorously and expressed the crucial transcription factors involved in beta cell development, including Ngn3, NeuroD, Nkx2.2, Nkx6.1, Pax4, Pax6, Isl1, MafA and endogenous Pdx-1, but did not secrete insulin. When cultured in high glucose/low serum medium supplemented with cytokines, EGFP/Pdx-1 LEPCs stopped proliferating and gave rise to functional beta cells without any evidence of exocrine or other islet cell lineage differentiation. When transplanted into diabetic SCID mice, EGFP/Pdx-1 LEPCs ameliorated hyperglycemia by secreting insulin in a glucose regulated manner. Considering the limited availability of beta cells, we propose that our experiments will provide a framework for utilizing the immortal liver progenitor cells as a renewable cell source for the generation of functional pancreatic beta cells.

Antioxidants Complement the Requirement for Protein Chaperone Function to Maintain β-Cell Function and Glucose Homeostasis

PubMed Central

Han, Jaeseok; Song, Benbo; Kim, Jiun; Kodali, Vamsi K.; Pottekat, Anita; Wang, Miao; Hassler, Justin; Wang, Shiyu; Pennathur, Subramaniam; Back, Sung Hoon; Katze, Michael G.

2015-01-01

Proinsulin misfolding in the endoplasmic reticulum (ER) initiates a cell death response, although the mechanism(s) remains unknown. To provide insight into how protein misfolding may cause β-cell failure, we analyzed mice with the deletion of P58IPK/DnajC3, an ER luminal co-chaperone. P58IPK−/− mice become diabetic as a result of decreased β-cell function and mass accompanied by induction of oxidative stress and cell death. Treatment with a chemical chaperone, as well as deletion of Chop, improved β-cell function and ameliorated the diabetic phenotype in P58IPK−/− mice, suggesting P58IPK deletion causes β-cell death through ER stress. Significantly, a diet of chow supplemented with antioxidant dramatically and rapidly restored β-cell function in P58IPK−/− mice and corrected abnormal localization of MafA, a critical transcription factor for β-cell function. Antioxidant feeding also preserved β-cell function in Akita mice that express mutant misfolded proinsulin. Therefore defective protein folding in the β-cell causes oxidative stress as an essential proximal signal required for apoptosis in response to ER stress. Remarkably, these findings demonstrate that antioxidant feeding restores cell function upon deletion of an ER molecular chaperone. Therefore antioxidant or chemical chaperone treatment may be a promising therapeutic approach for type 2 diabetes. PMID:25795214

Association of the FOXO3A locus with extreme longevity in a southern Italian centenarian study.

PubMed

Anselmi, Chiara Viviani; Malovini, Alberto; Roncarati, Roberta; Novelli, Valeria; Villa, Francesco; Condorelli, Gianluigi; Bellazzi, Riccardo; Puca, Annibale Alessandro

2009-04-01

A number of potential candidate genes in a variety of biological pathways have been associated with longevity in model organisms. Many of these genes have human homologs and thus have the potential to provide insights into human longevity. Recently, several studies suggested that FOXO3A functions as a key bridge for various signaling pathways that influence aging and longevity. Interestingly, Willcox and colleagues identified several variants that displayed significant genotype-gender interaction in male human longevity. In particular, a nested case-control study was performed in an ethnic Japanese population in Hawaii, and five candidate longevity genes were chosen based on links to the insulin-insulin-like growth factor-1 (IGF-1) signaling pathway. In the Willcox study, the investigated genetic variations (rs2802292, rs2764264, and rs13217795) within the FOXO3A gene were significantly associated with longevity in male centenarians. We validated the association of FOXO3A polymorphisms with extreme longevity in males from the Southern Italian Centenarian Study. Particularly, rs2802288, a proxy of rs2802292, showed the best allelic association--minor allele frequency (MAF) = 0.49; p = 0.003; odds ratio (OR) = 1.51; 95% confidence interval (CI), 1.15-1.98). Furthermore, we undertook a meta-analysis to explore the significance of rs2802292 association with longevity by combining the association results of the current study and the findings coming from the Willcox et al. investigation. Our data point to a key role of FOXO3A in human longevity and confirm the feasibility of the identification of such genes with centenarian-controls studies. Moreover, we hypothesize the susceptibility to the longevity phenotype may well be the result of complex interactions involving genes and environmental factors but also gender.

Altered MENIN expression disrupts the MAFA differentiation pathway in insulinoma.

PubMed

Hamze, Z; Vercherat, C; Bernigaud-Lacheretz, A; Bazzi, W; Bonnavion, R; Lu, J; Calender, A; Pouponnot, C; Bertolino, P; Roche, C; Stein, R; Scoazec, J Y; Zhang, C X; Cordier-Bussat, M

2013-12-01

The protein MENIN is the product of the multiple endocrine neoplasia type I (MEN1) gene. Altered MENIN expression is one of the few events that are clearly associated with foregut neuroendocrine tumours (NETs), classical oncogenes or tumour suppressors being not involved. One of the current challenges is to understand how alteration of MENIN expression contributes to the development of these tumours. We hypothesised that MENIN might regulate factors maintaining endocrine-differentiated functions. We chose the insulinoma model, a paradigmatic example of well-differentiated pancreatic NETs, to study whether MENIN interferes with the expression of v-MAF musculoaponeurotic fibrosarcoma oncogene homologue A (MAFA), a master glucose-dependent transcription factor in differentiated β-cells. Immunohistochemical analysis of a series of human insulinomas revealed a correlated decrease in both MENIN and MAFA. Decreased MAFA expression resulting from targeted Men1 ablation was also consistently observed in mouse insulinomas. In vitro analyses using insulinoma cell lines showed that MENIN regulated MAFA protein and mRNA levels, and bound to Mafa promoter sequences. MENIN knockdown concomitantly decreased mRNA expression of both Mafa and β-cell differentiation markers (Ins1/2, Gck, Slc2a2 and Pdx1) and, in parallel, increased the proliferation rate of tumours as measured by bromodeoxyuridine incorporation. Interestingly, MAFA knockdown alone also increased proliferation rate but did not affect the expression of candidate proliferation genes regulated by MENIN. Finally, MENIN variants with missense mutations detected in patients with MEN1 lost the WT MENIN properties to regulate MAFA. Together, our findings unveil a previously unsuspected MENIN/MAFA connection regarding control of the β-cell differentiation/proliferation balance, which could contribute to tumorigenesis.

Comparing strategies for selection of low-density SNPs for imputation-mediated genomic prediction in U. S. Holsteins.

PubMed

He, Jun; Xu, Jiaqi; Wu, Xiao-Lin; Bauck, Stewart; Lee, Jungjae; Morota, Gota; Kachman, Stephen D; Spangler, Matthew L

2018-04-01

SNP chips are commonly used for genotyping animals in genomic selection but strategies for selecting low-density (LD) SNPs for imputation-mediated genomic selection have not been addressed adequately. The main purpose of the present study was to compare the performance of eight LD (6K) SNP panels, each selected by a different strategy exploiting a combination of three major factors: evenly-spaced SNPs, increased minor allele frequencies, and SNP-trait associations either for single traits independently or for all the three traits jointly. The imputation accuracies from 6K to 80K SNP genotypes were between 96.2 and 98.2%. Genomic prediction accuracies obtained using imputed 80K genotypes were between 0.817 and 0.821 for daughter pregnancy rate, between 0.838 and 0.844 for fat yield, and between 0.850 and 0.863 for milk yield. The two SNP panels optimized on the three major factors had the highest genomic prediction accuracy (0.821-0.863), and these accuracies were very close to those obtained using observed 80K genotypes (0.825-0.868). Further exploration of the underlying relationships showed that genomic prediction accuracies did not respond linearly to imputation accuracies, but were significantly affected by genotype (imputation) errors of SNPs in association with the traits to be predicted. SNPs optimal for map coverage and MAF were favorable for obtaining accurate imputation of genotypes whereas trait-associated SNPs improved genomic prediction accuracies. Thus, optimal LD SNP panels were the ones that combined both strengths. The present results have practical implications on the design of LD SNP chips for imputation-enabled genomic prediction.