Combined deficiency of iron and (n-3) fatty acids in male rats disrupts brain monoamine metabolism and produces greater memory deficits than iron deficiency or (n-3) fatty acid deficiency alone.

PubMed

Baumgartner, Jeannine; Smuts, Cornelius M; Malan, Linda; Arnold, Myrtha; Yee, Benjamin K; Bianco, Laura E; Boekschoten, Mark V; Müller, Michael; Langhans, Wolfgang; Hurrell, Richard F; Zimmermann, Michael B

2012-08-01

Deficiencies of iron (Fe) (ID) and (n-3) fatty acids (FA) [(n-3)FAD] may impair brain development and function through shared mechanisms. However, little is known about the potential interactions between these 2 common deficiencies. We studied the effects of ID and (n-3)FAD, alone and in combination, on brain monoamine pathways (by measuring monoamines and related gene expression) and spatial working and reference memory (by Morris water maze testing). Using a 2 × 2 design, male rats were fed an ID, (n-3)FAD, ID+(n-3)FAD, or control diet for 5 wk postweaning (postnatal d 21-56) after (n-3)FAD had been induced over 2 generations. The (n-3)FAD and ID diets decreased brain (n-3) FA by 70-76% and Fe by 20-32%, respectively. ID and (n-3)FAD significantly increased dopamine (DA) concentrations in the olfactory bulb (OB) and striatum, with an additive 1- to 2-fold increase in ID+(n-3)FAD rats compared with controls (P < 0.05). ID decreased serotonin (5-HT) levels in OB, with a significant decrease in ID+(n-3)FAD rats. Furthermore, norepinephrine concentrations were increased 2-fold in the frontal cortex (FC) of (n-3)FAD rats (P < 0.05). Dopa decarboxylase was downregulated in the hippocampus of ID and ID+(n-3)FAD rats (fold-change = -1.33; P < 0.05). ID and (n-3)FAD significantly impaired working memory performance and the impairment positively correlated with DA concentrations in FC (r = 0.39; P = 0.026). Reference memory was impaired in the ID+(n-3)FAD rats (P < 0.05) and was negatively associated with 5-HT in FC (r = -0.42; P = 0.018). These results suggest that the combined deficiencies of Fe and (n-3) FA disrupt brain monoamine metabolism and produce greater deficits in reference memory than ID or (n-3)FAD alone.

[Expression of Id1 and Id3 in endometrial carcinoma and their roles in regulating biological behaviors of endometrial carcinoma cells in vitro].

PubMed

Sun, Lili; Li, Xuenong; Liu, Guobing

2013-06-01

To investigate the expression of inhibitor of DNA differentiation/DNA binding 1 (Id1) and Id3 in endometrial carcinoma and explore their roles in regulating the proliferation, invasion, migration and adhesion of endometrial carcinoma cells in vitro. Id1 and Id3 expression in 4 fresh endometrial cancer tissue specimens and matched adjacent tissues were detected using Western blotting. Two endometrial cancer cell lines, HEC-1-B and RL-952, were both divided into 4 groups, namely the untreated group, blank virus group, promoter group and Id1/Id3 double-knockdown group, and their expressions of MMP2, CXCR4 and P21 were detected by qRT-PCR and Western blotting. The proliferation, invasion, migration and adhesion of the cells were evaluated with MTT, Transwell, wound-healing, and adhesion assays. Endometrial carcinoma tissues showed significantly higher Id1 and Id3 expression than the adjacent tissues (P<0.05). In the two endometrial carcinoma cell lines, Id1/Id3 double-knockdown significantly decreased MMP2 and CXCR4 expression and increased P21 expression at both mRNA and protein levels (P<0.05), and resulted in suppressed cell proliferation, invasion, migration and adhesion. Id1 and Id3 expressions are up-regulated in endometrial carcinoma to promote the proliferation, invasion, migration and adhesion of the tumor cells by increasing MMP2 and CXCR4 expression and reducing P21 expression. Therapies targeting Id1/Id3 can be a novel strategy for treatment of endometrial carcinoma.

Id1, Id2 and Id3 are induced in rat melanotrophs of the pituitary gland by dopamine suppression under continuous stress.

PubMed

Konishi, H; Ogawa, T; Nakagomi, S; Inoue, K; Tohyama, M; Kiyama, H

2010-09-15

In rats under continuous stress (CS) there is decreased hypothalamic dopaminergic innervation to the intermediate lobe (IL) of the pituitary gland, which causes hyperactivation and subsequent degeneration of melanotrophs in the IL. In this study, we investigated the molecular basis for the changes that occur in melanotrophs during CS. Using microarray analysis, we identified several genes differentially expressed in the IL under CS conditions. Among the genes up-regulated under CS conditions, we focused on the inhibitor of DNA binding/differentiation (Id) family of dominant negative basic helix-loop-helix (bHLH) transcription factors. RT-PCR, Western blotting and in situ hybridization confirmed the significant inductions of Id1, Id2 and Id3 in the IL of CS rats. Administration of the dopamine D2 receptor agonist bromocriptine prevented the inductions of Id1-3 in the IL of CS rats, whereas application of the dopamine D2 antagonist sulpiride induced significant expressions of Id1-3 in the IL of normal rats. Moreover, an in vitro study using primary cultured melanotrophs demonstrated a direct effect on Id1-3 inductions by dopamine suppression. These results suggest that the decreased dopamine levels in the IL during CS induce Id1-3 expressions in melanotrophs. Because Id family members inhibit various bHLH transcription factors, it is conceivable that the induced Id1-3 would cooperatively modulate gene expressions in melanotrophs under CS conditions to induce hormone secretion. (c) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

High fat diet rescues disturbances to metabolic homeostasis and survival in the Id2 null mouse in a sex-specific manner

PubMed Central

Zhou, Peng; Hummel, Alyssa D.; Pywell, Cameron M.; Dong, X. Charlie; Duffield, Giles E.

2014-01-01

Inhibitor of DNA binding 2 (ID2) is a helix-loop-helix transcriptional repressor rhythmically expressed in many adult tissues. Our previous studies have demonstrated that Id2 null mice have altered expression of circadian genes involved in lipid metabolism, altered circadian feeding behavior, and sex-specific enhancement of insulin sensitivity and elevated glucose uptake in skeletal muscle and brown adipose tissue. Here we further characterized the Id2−/− mouse metabolic phenotype in a sex-specific context and under low and high fat diets, and examined metabolic and endocrine parameters associated with lipid and glucose metabolism. Under the low-fat diet Id2−/− mice showed decreased weight gain, reduced gonadal fat mass, and a lower survival rate. Under the high-fat diet, body weight and gonadal fat gain of Id2−/− male mice was comparable to control mice and survival rate improved markedly. Furthermore, the high-fat diet treated Id2−/− male mice lost the enhanced glucose tolerance feature observed in the other Id2−/− groups, and there was a sex-specific difference in white adipose tissue storage of Id2−/− mice. Additionally, a distinct pattern of hepatic lipid accumulation was observed in Id2−/− males: low lipids on the low-fat diet and steatosis on the high-fat diet. In summary, these data provides valuable insights into the impact of Id2 deficiency on metabolic homeostasis of mice in a sex-specific manner. PMID:25108156

Adenosine receptors as markers of brain iron deficiency: Implications for Restless Legs Syndrome.

PubMed

Quiroz, César; Gulyani, Seema; Ruiqian, Wan; Bonaventura, Jordi; Cutler, Roy; Pearson, Virginia; Allen, Richard P; Earley, Christopher J; Mattson, Mark P; Ferré, Sergi

2016-12-01

Deficits of sensorimotor integration with periodic limb movements during sleep (PLMS) and hyperarousal and sleep disturbances in Restless Legs Syndrome (RLS) constitute two pathophysiologically distinct but interrelated clinical phenomena, which seem to depend mostly on alterations in dopaminergic and glutamatergic neurotransmission, respectively. Brain iron deficiency is considered as a main pathogenetic mechanism in RLS. Rodents with brain iron deficiency represent a valuable pathophysiological model of RLS, although they do not display motor disturbances. Nevertheless, they develop the main neurochemical dopaminergic changes found in RLS, such as decrease in striatal dopamine D 2 receptor density. On the other hand, brain iron deficient mice exhibit the characteristic pattern of hyperarousal in RLS, providing a tool to find the link between brain iron deficiency and sleep disturbances in RLS. The present study provides evidence for a role of the endogenous sleep-promoting factor adenosine. Three different experimental preparations, long-term (22 weeks) severe or moderate iron-deficient (ID) diets (3- or 7-ppm iron diet) in mice and short-term (3 weeks) severe ID diet (3-ppm iron diet) in rats, demonstrated a significant downregulation (Western blotting in mouse and radioligand binding saturation experiments in rat brain tissue) of adenosine A 1 receptors (A1R) in the cortex and striatum, concomitant to striatal D2R downregulation. On the other hand, the previously reported upregulation of adenosine A 2A receptors (A2AR) was only observed with severe ID in both mice and rats. The results suggest a key role for A1R downregulation in the PLMS and hyperarousal in RLS. Published by Elsevier Ltd.

The introduction of the IDS-iSYS total IGF-1 assay may have far-reaching consequences for diagnosis and treatment of GH deficiency.

PubMed

Varewijck, A J; Lamberts, S W J; van der Lely, A J; Neggers, S J C M M; Hofland, L J; Janssen, J A M J L

2015-01-01

IGF-1 measurements are used for screening and monitoring GH deficiency (GHD) and acromegaly. Our objective was to study whether the introduction of the IDS-iSYS IGF-1 assay would lead to different clinical interpretations in GHD and acromegaly. In 106 GHD subjects and in 15 acromegalic subjects visiting our university hospital, total IGF-1 levels were measured before and during therapy by using the Immulite (IM) assay and IDS-iSYS (ID) assay. Z-scores were calculated by using assay-specific age-specific normative range values. All treatment decisions were based upon results obtained by the IM assay. In GHD subjects, absolute IGF-1 concentrations differed significantly between both IGF-1 assays before treatment (P < .001) but not during GH treatment (P = .32), and mean Z-scores for IGF-1 differed significantly before starting (IM, -2.23, vs ID, -1.43; P < .001) and during GH treatment (IM, -0.60, vs ID, +0.21; P < .001). In acromegalic subjects, absolute IGF-1 concentrations did not differ between both IGF-1 assays before treatment (P = .18) but were significantly different during treatment (P = 0.009), and mean Z-scores for IGF-1 were not different before starting (IM, 10.93, vs ID, 10.78; P = .41) or during treatment (IM, 3.60, vs ID, 3.18; P = .23). In GHD subjects, mean IGF-1 Z-scores significantly differed when measured by the IM assay compared with the ID assay irrespective of treatment. In contrast, in acromegaly, mean IGF-1 Z-scores did not differ significantly between both assays. Our study suggests that replacement of the IM assay by the ID assay may have far-reaching consequences for the clinical diagnosis and treatment of GHD.

Id-1 promotes TGF-{beta}1-induced cell motility through HSP27 activation and disassembly of adherens junction in prostate epithelial cells

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

Di Kaijun; Wong, Y.C.; Wang Xianghong

Id-1 (inhibitor of differentiation or DNA binding-1) has been positively associated with cell proliferation, cell cycle progression, and invasiveness during tumorigenesis. In addition, Id-1 has been shown to modulate cellular sensitivity to TGF-{beta}1 (transforming growth factor {beta}1). Here we demonstrate a novel role of Id-1 in promoting TGF-{beta}1-induced cell motility in a non-malignant prostate epithelial cell line, NPTX. We found that Id-1 promoted F-actin stress fiber formation in response to TGF-{beta}1, which was associated with increased cell-substrate adhesion and cell migration in NPTX cells. In addition, this positive effect of Id-1 on TGF-{beta}1-induced cell motility was mediated through activation ofmore » MEK-ERK signaling pathway and subsequent phosphorylation of HSP27 (heat shock protein 27). Furthermore, Id-1 disrupted the adherens junction complex in TGF-{beta}1-treated cells through down-regulation of E-cadherin, redistribution of {beta}-catenin, along with up-regulation of N-cadherin. These lines of evidence reveal a novel tumorigenic role of Id-1 through reorganization of actin cytoskeleton and disassembly of cell-cell adhesion in response to TGF-{beta}1 in human prostate epithelial cells, and suggest that intracellular Id-1 levels might be a determining factor for switching TGF-{beta}1 from a growth inhibitor to a tumor promoter during prostate carcinogenesis.« less

Iron deficiency and iron deficiency anaemia in women.

PubMed

Percy, Laura; Mansour, Diana; Fraser, Ian

2017-04-01

Iron deficiency (ID) is the most common micronutrient deficiency worldwide with >20% of women experiencing it during their reproductive lives. Hepcidin, a peptide hormone mostly produced by the liver, controls the absorption and regulation of iron. Understanding iron metabolism is pivotal in the successful management of ID and iron deficiency anaemia (IDA) using oral preparations, parenteral iron or blood transfusion. Oral preparations vary in their iron content and can result in gastrointestinal side effects. Parenteral iron is indicated when there are compliance/tolerance issues with oral iron, comorbidities which may affect absorption or ongoing iron losses that exceed absorptive capacity. It may also be the preferred option when rapid iron repletion is required to prevent physiological decompensation or given preoperatively for non-deferrable surgery. As gynaecologists, we focus on managing women's heavy menstrual bleeding (HMB) and assume that primary care clinicians are treating the associated ID/IDA. We now need to take the lead in diagnosing, managing and initiating treatment for ID/IDA and treating HMB simultaneously. This dual management will significantly improve their quality of life. In this chapter we will summarise the importance of iron in cellular functioning, describe how to diagnose ID/IDA and help clinicians choose between the available treatment options. Copyright © 2016. Published by Elsevier Ltd.

The Role of Id2 Protein in Neuroblatoma in Children.

PubMed

Wieczorek, Aleksandra; Balwierz, Walentyna

2015-09-01

Id (DNA binding and/or differentiation) proteins occur physiologically during ontogenesis and negatively regulate the activity of other helix-loop-helix (HLH) proteins. Id2 protein causes block of cells differentiation in the S phase of the cell cycle and regulates the activity of Rb protein. The role of Id2 protein in physiological cell cycle progression and in neuroblastoma (NBL) pathogenesis was proposed by Lasorella. The aim of the study was evaluation of Id2 expression and its prognostic significance in NBL cells coming from primary tumors and evaluation of its prognostic significance, and correlation of Id2 expression with known prognostic factors. Sixty patients with primary NBL treated from 1991 to 2005 were included in the analysis. We found 50 patients with high and 10 patients with low intensity of Id2 expression. The median percentage of NBL cells with Id2 expression was 88 %. We found no correlation between the number of NBL cells or the intensity of Id2 expression and OS and DFS. In patients with stage 4 NBL, almost all patients had high expression of Id2 and it was significantly more common than in other disease stages (p = 0,03). We found no correlation between Id2 expression and other known prognostic factor in NBL patients. We assume that Id2 is not prognostic factor. However, due to its abundant expression in most of NBL cells and its role in cell cycle, it may be potential therapeutic target. Exact knowledge of expression time may be helpful in explaining mechanisms of oncogenesis.

Id-1 and Id-2 genes and products as therapeutic targets for treatment of breast cancer and other types of carcinoma

DOEpatents

Desprez, Pierre-Yves; Campisi, Judith

2014-09-30

A method for treatment and amelioration of breast, cervical, ovarian, endometrial, squamous cells, prostate cancer and melanoma in a patient comprising targeting Id-1 or Id-2 gene expression with a delivery vehicle comprising a product which modulates Id-1 or Id-2 expression.

Iron Deficiency and Iron-deficiency Anemia in Toddlers Ages 18 to 36 Months: A Prospective Study.

PubMed

Levin, Carina; Harpaz, Shira; Muklashi, Isam; Lumelsky, Nadia; Komisarchik, Ina; Katzap, Ilia; Abu Hanna, Manhal; Koren, Ariel

2016-04-01

In young children, iron deficiency (ID)-the most common cause of anemia-may adversely affect long-term neurodevelopment and behavior. We prospectively evaluated the prevalence of ID and iron deficiency anemia (IDA) in 256 healthy 18- to 36-month-old children in Northern Israel. Complete blood count and ferritin evaluation were performed, and risk factors were assessed. Hemoglobin (Hgb) was compared with first-year routine screening. Complete data were obtained from 208 children: 56.2% were boys; the mean age was 26.1±5.27 months. A prevalence of 5.8% IDA, 16.3% ID without anemia, 9.6% anemia with normal ferritin, and 68.3% normal Hgb and ferritin was found. In nonanemic infants at 1 year of age (n=156), ID/IDA was found in 19.9%, and 12.8% became anemic at study evaluation. Despite iron supplementation in the first year, and normal Hgb at first-year screening, ID and IDA were still prevalent, and might develop during the second year of life. Recognition of this child subset and consideration of iron supplementation are mandatory.

Iron deficiency, anemia, and mortality in renal transplant recipients.

PubMed

Eisenga, Michele F; Minović, Isidor; Berger, Stefan P; Kootstra-Ros, Jenny E; van den Berg, Else; Riphagen, Ineke J; Navis, Gerjan; van der Meer, Peter; Bakker, Stephan J L; Gaillard, Carlo A J M

2016-11-01

Anemia, iron deficiency anemia (IDA), and iron deficiency (ID) are highly prevalent in renal transplant recipients (RTR). Anemia is associated with poor outcome, but the role of ID is unknown. Therefore, we aimed to investigate the association of ID, irrespective of anemia, with all-cause mortality in RTR. Cox regression analyses were used to investigate prospective associations. In 700 RTR, prevalences of anemia, IDA, and ID were 34%, 13%, and 30%, respectively. During follow-up for 3.1 (2.7-3.9) years, 81 (12%) RTR died. In univariable analysis, anemia [HR, 1.72 (95%CI: 1.11-2.66), P = 0.02], IDA [2.44 (1.48-4.01), P < 0.001], and ID [2.04 (1.31-3.16), P = 0.001] were all associated with all-cause mortality. In multivariable analysis, the association of anemia with mortality became weaker after adjustment for ID [1.52 (0.97-2.39), P = 0.07] and disappeared after adjustment for proteinuria and eGFR [1.09 (0.67-1.78), P = 0.73]. The association of IDA with mortality attenuated after adjustment for potential confounders. In contrast, the association of ID with mortality remained independent of potential confounders, including anemia [1.77 (1.13-2.78), P = 0.01]. In conclusion, ID is highly prevalent among RTR and is associated with an increased risk of mortality, independent of anemia. As ID is a modifiable factor, correction of ID could be a target to improve survival. © 2016 The Authors. Transplant International published by John Wiley & Sons Ltd on behalf of Steunstichting ESOT.

The Wnt/β-catenin signaling/Id2 cascade mediates the effects of hypoxia on the hierarchy of colorectal-cancer stem cells.

PubMed

Dong, Hye-Jin; Jang, Gyu-Beom; Lee, Hwa-Yong; Park, Se-Ra; Kim, Ji-Young; Nam, Jeong-Seok; Hong, In-Sun

2016-03-11

Hypoxia, a feature common to most solid tumors, is known to regulate many aspects of tumorigenesis. Recently, it was suggested that hypoxia increased the size of the cancer stem-cell (CSC) subpopulations and promoted the acquisition of a CSC-like phenotype. However, candidate hypoxia-regulated mediators specifically relevant to the stemness-related functions of colorectal CSCs have not been examined in detail. In the present study, we showed that hypoxia specifically promoted the self-renewal potential of CSCs. Through various in vitro studies, we found that hypoxia-induced Wnt/β-catenin signaling increased the occurrence of CSC-like phenotypes and the level of Id2 expression in colorectal-cancer cells. Importantly, the levels of hypoxia-induced CSC-sphere formation and Id2 expression were successfully attenuated by treatment with a Wnt/β-catenin-signaling inhibitor. We further demonstrated, for the first time, that the degree of hypoxia-induced CSC-sphere formation (CD44(+) subpopulation) in vitro and of tumor metastasis/dissemination in vivo were markedly suppressed by knocking down Id2 expression. Taken together, these data suggested that Wnt/β-catenin signaling mediated the hypoxia-induced self-renewal potential of colorectal-cancer CSCs through reactivating Id2 expression.

Switchgrass ubiquitin promoter (PVUBI2) and uses thereof

DOEpatents

Stewart, C. Neal; Mann, David George James

2013-12-10

The subject application provides polynucleotides, compositions thereof and methods for regulating gene expression in a plant. Polynucleotides disclosed herein comprise novel sequences for a promoter isolated from Panicum virgatum (switchgrass) that initiates transcription of an operably linked nucleotide sequence. Thus, various embodiments of the invention comprise the nucleotide sequence of SEQ ID NO: 2 or fragments thereof comprising nucleotides 1 to 692 of SEQ ID NO: 2 that are capable of driving the expression of an operably linked nucleic acid sequence.

Id2 Complexes with the SNAG Domain of Snai1 Inhibiting Snai1-Mediated Repression of Integrin β4

PubMed Central

Chang, Cheng; Yang, Xiaofang; Pursell, Bryan

2013-01-01

The epithelial-mesenchymal transition (EMT) is a fundamental process that underlies development and cancer. Although the EMT involves alterations in the expression of specific integrins that mediate stable adhesion to the basement membrane, such as α6β4, the mechanisms involved are poorly understood. Here, we report that Snai1 inhibits β4 transcription by increasing repressive histone modification (trimethylation of histone H3 at K27 [H3K27Me3]). Surprisingly, Snai1 is expressed and localized in the nucleus in epithelial cells, but it does not repress β4. We resolved this paradox by discovering that Id2 complexes with the SNAG domain of Snai1 on the β4 promoter and constrains the repressive function of Snai1. Disruption of the complex by depleting Id2 resulted in Snai1-mediated β4 repression with a concomitant increase in H3K27Me3 modification on the β4 promoter. These findings establish a novel function for Id2 in regulating Snai1 that has significant implications for the regulation of epithelial gene expression. PMID:23878399

Physical activity prevents augmented body fat accretion in moderately iron-deficient rats.

PubMed

McClung, James P; Andersen, Nancy E; Tarr, Tyson N; Stahl, Chad H; Young, Andrew J

2008-07-01

Recent studies describe an association between poor iron status and obesity in humans, although the mechanism explaining this relationship is unclear. The present study aimed to determine the effect of moderate iron deficiency and physical activity (PA) on body composition in an animal model. Male Sprague-Dawley rats consumed iron-adequate (IA; 40 mg/kg) or moderately iron-deficient (ID; 9 mg/kg) diets ad libitum for 12 wk. Rats were assigned to 4 treatment groups (n = 10 per group): IA, sedentary (IAS); IA, PA (IAPA); ID, sedentary (IDS); or ID, PA (IDPA). Activity involved running on motorized running wheels at 4 m/min for 1 h/d for 5 d/wk. After 12 wk, ID rats were not anemic, but body iron stores were reduced as indicated by diminished (P < 0.05) femur iron compared with IA rats. Treatment group did not affect body weight or feed consumption. However, fat mass was greater (P < 0.05) in IDS rats (38.6 +/- 6.7%) than IAS (31.8 +/- 2.9%), IAPA (31.8 +/- 2.0%), and IDPA (32.8 +/- 4.5%) rats. Furthermore, lean body mass was diminished in IDS rats (58.7 +/- 6.8%) compared with IAS (65.6 +/- 3.0%), IAPA (65.6 +/- 2.1%), and IDPA (64.7 +/- 4.5%) rats. Thus, moderate iron deficiency may cause increased body fat accretion in rats and PA attenuates that effect.

The Implementation of C-ID, R2D2 Model on Learning Reading Comprehension

ERIC Educational Resources Information Center

Rayanto, Yudi Hari; Rusmawan, Putu Ngurah

2016-01-01

The purposes of this research are to find out, (1) whether C-ID, R2D2 model is effective to be implemented on learning Reading comprehension, (2) college students' activity during the implementation of C-ID, R2D2 model on learning Reading comprehension, and 3) college students' learning achievement during the implementation of C-ID, R2D2 model on…

The ID23-2 structural biology microfocus beamline at the ESRF

PubMed Central

Flot, David; Mairs, Trevor; Giraud, Thierry; Guijarro, Matias; Lesourd, Marc; Rey, Vicente; van Brussel, Denis; Morawe, Christian; Borel, Christine; Hignette, Olivier; Chavanne, Joel; Nurizzo, Didier; McSweeney, Sean; Mitchell, Edward

2010-01-01

The first phase of the ESRF beamline ID23 to be constructed was ID23-1, a tunable MAD-capable beamline which opened to users in early 2004. The second phase of the beamline to be constructed is ID23-2, a monochromatic microfocus beamline dedicated to macromolecular crystallography experiments. Beamline ID23-2 makes use of well characterized optical elements: a single-bounce silicon (111) monochromator and two mirrors in Kirkpatrick–Baez geometry to focus the X-ray beam. A major design goal of the ID23-2 beamline is to provide a reliable, easy-to-use and routine microfocus beam. ID23-2 started operation in November 2005, as the first beamline dedicated to microfocus macromolecular crystallography. The beamline has taken the standard automated ESRF macromolecular crystallography environment (both hardware and software), allowing users of ID23-2 to be rapidly familiar with the microfocus environment. This paper describes the beamline design, the special considerations taken into account given the microfocus beam, and summarizes the results of the first years of the beamline operation. PMID:20029119

HMGB1 promotes ductular reaction and tumorigenesis in autophagy-deficient livers.

PubMed

Khambu, Bilon; Huda, Nazmul; Chen, Xiaoyun; Antoine, Daniel J; Li, Yong; Dai, Guoli; Köhler, Ulrike A; Zong, Wei-Xing; Waguri, Satoshi; Werner, Sabine; Oury, Tim D; Dong, Zheng; Yin, Xiao-Ming

2018-06-01

Autophagy is important for liver homeostasis, and the deficiency leads to injury, inflammation, ductular reaction (DR), fibrosis, and tumorigenesis. It is not clear how these events are mechanistically linked to autophagy deficiency. Here, we reveal the role of high-mobility group box 1 (HMGB1) in two of these processes. First, HMGB1 was required for DR, which represents the expansion of hepatic progenitor cells (HPCs) implicated in liver repair and regeneration. DR caused by hepatotoxic diets (3,5-diethoxycarbonyl-1,4-dihydrocollidine [DDC] or choline-deficient, ethionine-supplemented [CDE]) also depended on HMGB1, indicating that HMGB1 may be generally required for DR in various injury scenarios. Second, HMGB1 promoted tumor progression in autophagy-deficient livers. Receptor for advanced glycation end product (RAGE), a receptor for HMGB1, was required in the same two processes and could mediate the proliferative effects of HMBG1 in isolated HPCs. HMGB1 was released from autophagy-deficient hepatocytes independently of cellular injury but depended on NRF2 and the inflammasome, which was activated by NRF2. Pharmacological or genetic activation of NRF2 alone, without disabling autophagy or causing injury, was sufficient to cause inflammasome-dependent HMGB1 release. In conclusion, HMGB1 release is a critical mechanism in hepatic pathogenesis under autophagy-deficient conditions and leads to HPC expansion as well as tumor progression.

A new module in neural differentiation control: two microRNAs upregulated by retinoic acid, miR-9 and -103, target the differentiation inhibitor ID2.

PubMed

Annibali, Daniela; Gioia, Ubaldo; Savino, Mauro; Laneve, Pietro; Caffarelli, Elisa; Nasi, Sergio

2012-01-01

The transcription factor ID2 is an important repressor of neural differentiation strongly implicated in nervous system cancers. MicroRNAs (miRNAs) are increasingly involved in differentiation control and cancer development. Here we show that two miRNAs upregulated on differentiation of neuroblastoma cells--miR-9 and miR-103--restrain ID2 expression by directly targeting the coding sequence and 3' untranslated region of the ID2 encoding messenger RNA, respectively. Notably, the two miRNAs show an inverse correlation with ID2 during neuroblastoma cell differentiation induced by retinoic acid. Overexpression of miR-9 and miR-103 in neuroblastoma cells reduces proliferation and promotes differentiation, as it was shown to occur upon ID2 inhibition. Conversely, an ID2 mutant that cannot be targeted by either miRNA prevents retinoic acid-induced differentiation more efficient than wild-type ID2. These findings reveal a new regulatory module involving two microRNAs upregulated during neural differentiation that directly target expression of the key differentiation inhibitor ID2, suggesting that its alteration may be involved in neural cancer development.

IRON DEFICIENCY AND INFANT MOTOR DEVELOPMENT

PubMed Central

Shafir, Tal; Angulo-Barroso, Rosa; Jing, Yuezhou; Lu Angelilli, Mary; Jacobson, Sandra W.; Lozoff, Betsy

2011-01-01

Background Iron deficiency (ID) during early development impairs myelination and basal ganglia function in animal models. Aims To examine the effects of iron deficiency anemia (IDA) and iron deficiency (ID) without anemia on infant motor skills that are likely related to myelination and basal ganglia function. Study design Observational study. Subjects Full-term inner-city African-American 9- to 10-month-old infants who were free of acute or chronic health problems with iron status indicators ranging from IDA to iron sufficiency (n = 106). Criteria for final iron status classification were met by 77 of these infants: 28 IDA, 28 non-anemic iron-deficient (NA ID), and 21 iron-sufficient (IS). Outcome measures Gross motor developmental milestones, Peabody Developmental Motor Scale, Infant Neurological International Battery (INFANIB), motor quality factor of the Bayley Behavioral Rating Scale, and a sequential/bi-manual coordination toy retrieval task. General linear model analyses tested for linear effects of iron status group and thresholds for effects. Results There were linear effects of iron status on developmental milestones, Peabody gross motor (suggestive trend), INFANIB standing item, motor quality, and toy retrieval. The threshold for effects was ID with or without anemia for developmental milestones, INFANIB standing item, and motor quality and IDA for toy retrieval. Conclusions Using a comprehensive and sensitive assessment of motor development, this study found poorer motor function in ID infants with and without anemia. Poorer motor function among non-anemic ID infants is particularly concerning, since ID without anemia is not detected by common screening procedures and is more widespread than IDA. PMID:18272298

Increased Ca2+ signaling through CaV1.2 promotes bone formation and prevents estrogen deficiency-induced bone loss.

PubMed

Cao, Chike; Ren, Yinshi; Barnett, Adam S; Mirando, Anthony J; Rouse, Douglas; Mun, Se Hwan; Park-Min, Kyung-Hyun; McNulty, Amy L; Guilak, Farshid; Karner, Courtney M; Hilton, Matthew J; Pitt, Geoffrey S

2017-11-16

While the prevalence of osteoporosis is growing rapidly with population aging, therapeutic options remain limited. Here, we identify potentially novel roles for CaV1.2 L-type voltage-gated Ca2+ channels in osteogenesis and exploit a transgenic gain-of-function mutant CaV1.2 to stem bone loss in ovariectomized female mice. We show that endogenous CaV1.2 is expressed in developing bone within proliferating chondrocytes and osteoblasts. Using primary BM stromal cell (BMSC) cultures, we found that Ca2+ influx through CaV1.2 activates osteogenic transcriptional programs and promotes mineralization. We used Prx1-, Col2a1-, or Col1a1-Cre drivers to express an inactivation-deficient CaV1.2 mutant in chondrogenic and/or osteogenic precursors in vivo and found that the resulting increased Ca2+ influx markedly thickened bone not only by promoting osteogenesis, but also by inhibiting osteoclast activity through increased osteoprotegerin secretion from osteoblasts. Activating the CaV1.2 mutant in osteoblasts at the time of ovariectomy stemmed bone loss. Together, these data highlight roles for CaV1.2 in bone and demonstrate the potential dual anabolic and anticatabolic therapeutic actions of tissue-specific CaV1.2 activation in osteoblasts.

Usefulness of Iron Deficiency Correction in Management of Patients With Heart Failure [from the Registry Analysis of Iron Deficiency-Heart Failure (RAID-HF) Registry].

PubMed

Wienbergen, Harm; Pfister, Otmar; Hochadel, Matthias; Michel, Stephan; Bruder, Oliver; Remppis, Björn Andrew; Maeder, Micha Tobias; Strasser, Ruth; von Scheidt, Wolfgang; Pauschinger, Matthias; Senges, Jochen; Hambrecht, Rainer

2016-12-15

Iron deficiency (ID) has been identified as an important co-morbidity in patients with heart failure (HF). Intravenous iron therapy reduced symptoms and rehospitalizations of iron-deficient patients with HF in randomized trials. The present multicenter study investigated the "real-world" management of iron status in patients with HF. Consecutive patients with HF and ejection fraction ≤40% were recruited and analyzed from December 2010 to October 2015 by 11 centers in Germany and Switzerland. Of 1,484 patients with HF, iron status was determined in only 923 patients (62.2%), despite participation of the centers in a registry focusing on ID and despite guideline recommendation to determine iron status. In patients with determined iron status, a prevalence of 54.7% (505 patients) for ID was observed. Iron therapy was performed in only 8.5% of the iron-deficient patients with HF; 2.6% were treated with intravenous iron therapy. The patients with iron therapy were characterized by a high rate of symptomatic HF and anemia. In conclusion, despite strong evidence of beneficial effects of iron therapy on symptoms and rehospitalizations, diagnostic and therapeutic efforts on ID in HF are low in the actual clinical practice, and the awareness to diagnose and treat ID in HF should be strongly enforced. Copyright © 2016 Elsevier Inc. All rights reserved.

A New Module in Neural Differentiation Control: Two MicroRNAs Upregulated by Retinoic Acid, miR-9 and -103, Target the Differentiation Inhibitor ID2

PubMed Central

Savino, Mauro; Laneve, Pietro; Caffarelli, Elisa; Nasi, Sergio

2012-01-01

The transcription factor ID2 is an important repressor of neural differentiation strongly implicated in nervous system cancers. MicroRNAs (miRNAs) are increasingly involved in differentiation control and cancer development. Here we show that two miRNAs upregulated on differentiation of neuroblastoma cells – miR-9 and miR-103 – restrain ID2 expression by directly targeting the coding sequence and 3′ untranslated region of the ID2 encoding messenger RNA, respectively. Notably, the two miRNAs show an inverse correlation with ID2 during neuroblastoma cell differentiation induced by retinoic acid. Overexpression of miR-9 and miR-103 in neuroblastoma cells reduces proliferation and promotes differentiation, as it was shown to occur upon ID2 inhibition. Conversely, an ID2 mutant that cannot be targeted by either miRNA prevents retinoic acid-induced differentiation more efficient than wild-type ID2. These findings reveal a new regulatory module involving two microRNAs upregulated during neural differentiation that directly target expression of the key differentiation inhibitor ID2, suggesting that its alteration may be involved in neural cancer development. PMID:22848373

Iron Deficiency and Iron Deficiency Anemia in 3-5 months-old, Breastfed Healthy Infants.

PubMed

Krishnaswamy, Sudarsan; Bhattarai, Dharmagat; Bharti, Bhavneet; Bhatia, Prateek; Das, Reena; Bansal, Deepak

2017-07-01

To assess the prevalence of iron deficiency (ID) and iron deficiency anemia (IDA) in predominantly breastfed, 3-5-mo-old infants, born at term, with a birth weight ≥ 2.5 kg. The cross-sectional study was conducted in the outpatient department of a tertiary care center from January 2013 through December 2014. Age: 90-180 d, exclusively/predominantly breastfed, birth weight ≥ 2.5 kg and term gestation. systemic illness, leucocytosis, leucopenia, thrombocytopenia, peripheral smear abnormality or iron supplementation. Blood sample was collected for complete blood count and ferritin assay. ID was defined as serum ferritin <12 μg/L. IDA was defined as ID plus Hb ≤ 10.5 g/dl. Two hundred ninety six infants were initially recruited; 29 declined consent; 22 had leukocytosis, leucopenia or eosinophilia; 15 had thrombocytopenia; 15 samples were hemolyzed or insufficient. Finally, 215 infants were evaluated. The male-female ratio was 1.8:1. The mean birth weight was 2.9 (0.4) kg. The mean Hb was 10.8 (1.2) g/dl. The median serum ferritin was 44 μg/L (18, 120). The prevalence of ID at 3, 4 and 5 mo of age was 5.4%, 21.4% and 36.4%, while that of IDA was 4.6%, 16.7% and 11.4%, respectively. The prevalence of ID at 4 and 5 mo of age in predominantly breastfed, term infants was 21.4% and 36.4%, respectively. The study generates evidence for considering iron supplementation for well-babies from 4 mo of age, instead of the currently recommended 6 mo by National Iron plus Initiative in India.

Institutional care and iron deficiency increase ADHD symptomology and lower IQ 2.5-5 years post-adoption.

PubMed

Doom, Jenalee R; Georgieff, Michael K; Gunnar, Megan R

2015-05-01

Increased ADHD symptomology and lower IQ have been reported in internationally adopted (IA) children compared to non-adopted peers (Hostinar, Stellern, Schaefer, Carlson & Gunnar, 2012; Kreppner, O'Connor & Rutter, 2001). However, it is unclear whether these outcomes are due to institutional deprivation specifically or to co-occurring micronutrient deficiencies that disrupt brain development (Fuglestad, Rao & Georgieff, 2008b). In this study, IA children were compared to children raised in their biological families to examine differences in ADHD symptomology and IQ 2.5-5 years post-adoption and to assess the contributions of iron deficiency (ID) and duration of deprivation to these cognitive outcomes. ADHD symptoms (parent- and experimenter-reported) and IQ were evaluated in 88 IA (M = 62.1 months, SD = 2.4) and 35 non-adopted children (M = 61.4 months, SD = 1.6). IA children were assessed 29-64 months post-adoption (M = 41.9 months, SD = 10.2). ID was assessed during the initial post-adoption medical visit in 69 children, and children were classified into four groups by iron status, ranging from normal to ID anemia (most severe). IA children had greater ADHD symptomology, p < .01, and lower IQ, p = .001, than non-adopted children. Within the IA group, children with more severe ID at adoption had greater ADHD symptomology, r(69) = 0.40, p = .001, and lower IQ, r(68) = -0.28, p < .05. Duration of institutional care was positively correlated with ADHD symptoms, r(86) = .28, p < .01, but not IQ, r(85) = -.08, p = .52. Longitudinal results indicate improvement in IQ from 12 months post-adoption to age 5 for children with greater ID severity at adoption and longer duration of institutional care but no improvement in ADHD symptoms. These results signify continuing effects of early deprivation and ID on ADHD symptoms and IQ years after adoption. A video abstract of this article can be viewed at http://www.youtube.com/watch?v=vUFDAS3DD1c. © 2014 John Wiley & Sons Ltd.

Cox-2-derived PGE2 induces Id1-dependent radiation resistance and self-renewal in experimental glioblastoma.

PubMed

Cook, Peter J; Thomas, Rozario; Kingsley, Philip J; Shimizu, Fumiko; Montrose, David C; Marnett, Lawrence J; Tabar, Viviane S; Dannenberg, Andrew J; Benezra, Robert

2016-10-01

In glioblastoma (GBM), Id1 serves as a functional marker for self-renewing cancer stem-like cells. We investigated the mechanism by which cyclooxygenase-2 (Cox-2)-derived prostaglandin E2 (PGE2) induces Id1 and increases GBM self-renewal and radiation resistance. Mouse and human GBM cells were stimulated with dimethyl-PGE2 (dmPGE2), a stabilized form of PGE2, to test for Id1 induction. To elucidate the signal transduction pathway governing the increase in Id1, a combination of short interfering RNA knockdown and small molecule inhibitors and activators of PGE2 signaling were used. Western blotting, quantitative real-time (qRT)-PCR, and chromatin immunoprecipitation assays were employed. Sphere formation and radiation resistance were measured in cultured primary cells. Immunohistochemical analyses were carried out to evaluate the Cox-2-Id1 axis in experimental GBM. In GBM cells, dmPGE2 stimulates the EP4 receptor leading to activation of ERK1/2 MAPK. This leads, in turn, to upregulation of the early growth response1 (Egr1) transcription factor and enhanced Id1 expression. Activation of this pathway increases self-renewal capacity and resistance to radiation-induced DNA damage, which are dependent on Id1. In GBM, Cox-2-derived PGE2 induces Id1 via EP4-dependent activation of MAPK signaling and the Egr1 transcription factor. PGE2-mediated induction of Id1 is required for optimal tumor cell self-renewal and radiation resistance. Collectively, these findings identify Id1 as a key mediator of PGE2-dependent modulation of radiation response and lend insight into the mechanisms underlying radiation resistance in GBM patients. © The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Mitochondrial oxidative stress caused by Sod2 deficiency promotes cellular senescence and aging phenotypes in the skin

PubMed Central

Velarde, Michael C.; Flynn, James M.; Day, Nicholas U.; Melov, Simon; Campisi, Judith

2012-01-01

Cellular senescence arrests the proliferation of mammalian cells at risk for neoplastic transformation, and is also associated with aging. However, the factors that cause cellular senescence during aging are unclear. Excessive reactive oxygen species (ROS) have been shown to cause cellular senescence in culture, and accumulated molecular damage due to mitochondrial ROS has long been thought to drive aging phenotypes in vivo. Here, we test the hypothesis that mitochondrial oxidative stress can promote cellular senescence in vivo and contribute to aging phenotypes in vivo, specifically in the skin. We show that the number of senescent cells, as well as impaired mitochondrial (complex II) activity increase in naturally aged mouse skin. Using a mouse model of genetic Sod2 deficiency, we show that failure to express this important mitochondrial anti-oxidant enzyme also impairs mitochondrial complex II activity, causes nuclear DNA damage, and induces cellular senescence but not apoptosis in the epidermis. Sod2 deficiency also reduced the number of cells and thickness of the epidermis, while increasing terminal differentiation. Our results support the idea that mitochondrial oxidative stress and cellular senescence contribute to aging skin phenotypes in vivo. PMID:22278880

An essential role for the Id1/PI3K/Akt/NFkB/survivin signalling pathway in promoting the proliferation of endothelial progenitor cells in vitro.

PubMed

Li, Wei; Wang, Hang; Kuang, Chun-Yan; Zhu, Jin-Kun; Yu, Yang; Qin, Zhe-Xue; Liu, Jie; Huang, Lan

2012-04-01

The enhancement of re-endothelialisation is a critical therapeutic option for repairing injured blood vessels. Endothelial progenitor cells (EPCs) are the major source of cells that participate in endothelium repair and contribute to re-endothelialisation by reducing neointima formation after vascular injury. The over-expression of the inhibitor of differentiation or DNA binding 1 (Id1) significantly improved EPC proliferation. This study aimed to investigate the effects of Id1 on the phosphatidylinositol-3-kinase (PI3K)/Akt/nuclear factor kappa B (NFκB)/survivin signalling pathway and its significance in promoting EPC proliferation in vitro. Spleen-derived EPCs were cultured as previously described. Id1 was presented at low levels in EPCs, and was rapidly up-regulated by stimulation with vascular endothelial growth factor. We demonstrated that transient transfection of Id1 into EPCs activated the PI3K/Akt/NFκB/survivin signalling pathway and promoted EPC proliferation. The proliferation of EPCs was extensively inhibited by silencing of endogenous Id1, and knockdown of Id1 expression led to suppression of PI3K/Akt/NFκB/survivin signalling pathway in EPCs. In addition, blockade by the PI3K-specific inhibitor LY294002, Akt inhibitor, the NFκB inhibitor BAY 11-7082, the survivin inhibitor Curcumin, or the survivin inhibitor YM155 reduced the effects of Id1 transfection. These results suggest that the Id1/PI3K/Akt/NFκB/survivin signalling pathway plays a critical role in EPC proliferation. The Id1/PI3K/Akt/NFκB/survivin signalling pathway may represent a novel therapeutic target in the prevention of restenosis after vascular injury.

Iron deficiency is unacceptably high in refugee children from Burma.

PubMed

Kemmer, Teresa M; Bovill, Maria E; Kongsomboon, Wantanee; Hansch, Steven J; Geisler, Karen L; Cheney, Carrie; Shell-Duncan, Bettina K; Drewnowski, Adam

2003-12-01

Iron-deficiency anemia (IDA) in refugees is reported to be among the major medical problems worldwide. Because food rations are typically inadequate in iron, long-term reliance is a key predictor of anemia among displaced people. Comprehensive nutritional assessments of refugee children from Burma have not previously been completed. Refugee children aged 6-59 mo were studied to determine 1) the prevalences of anemia, iron deficiency (ID) and IDA and 2) the factors associated with anemia and ID. Cluster sampling in three camps and convenience sampling in two additional camps were used. Hemoglobin (Hb) levels were measured and micro mol zinc protoporphyrin/mol heme were determined in 975 children. Logistic regression analyses (95% CI) determined predictors of anemia and ID. The prevalences of IDA, anemia and ID in these refugee children were 64.9, 72.0 and 85.4%, respectively. Predictors of anemia included young age (P < 0.001), food ration lasting <1 mo (P = 0.001), daily consumption of dietary iron inhibitors (P < 0.05), weight-for-height Z-score of <-2 (P < 0.05), male gender (P < 0.05) and uneducated father (P < 0.001). Predictors of ID were young age (P < 0.001) and recently reported illness (P < 0.05). Laboratory tests confirmed that anemia and ID are major health problems among these refugee children and that ID is the leading cause of anemia. A comprehensive nutrition and public health-focused approach to combating anemia and ID is essential. Following the presentation of results to policy makers, the improvement of the micronutrient content of rations has been initiated.

Progesterone and estradiol synergistically promote the lung metastasis of tuberin-deficient cells in a preclinical model of lymphangioleiomyomatosis

PubMed Central

Sun, Yang; Zhang, Erik; Lao, Taotao; Pereira, Ana M.; Li, Chenggang; Xiong, Li; Morrison, Tasha; Haley, Kathleen J.; Zhou, Xiaobo; Yu, Jane J.

2014-01-01

Lymphangioleiomyomatosis (LAM) is a female-predominant lung disease that can lead to respiratory failure. LAM cells typically have inactivating TSC2 mutations, leading to mTORC1 hyperactivation. The gender specificity of LAM suggests that female hormones contribute to disease progression. Clinical findings indicate that estradiol exacerbates LAM behaviors and symptoms. Although hormonal therapy with progesterone has been employed, the benefit in LAM improvement has not been achieved. We have previously found that estradiol promotes the survival and lung metastasis of cells lacking tuberin in a preclinical model of LAM. In this study, we hypothesize that progesterone alone or in combination with estradiol promote metastatic behaviors of TSC2-deficient cells. In cell culture models of TSC2-deficient LAM patient-derived and rat uterine leiomyoma-derived cells, we found that progesterone treatment or progesterone plus estradiol resulted in increased phosphorylation of Akt and ERK1/2, induced the proliferation, and enhanced the migration and invasiveness. In addition, treatment of progesterone plus estradiol synergistically decreased the levels of reactive oxygen species, and enhanced cell survival under oxidative stress. In a murine model of LAM, treatment of progesterone plus estradiol promoted the growth of xenograft tumors; however, progesterone treatment did not affect the development of xenograft tumors of Tsc2-deficient cells. Importantly, treatment of progesterone plus estradiol resulted in alteration of lung morphology, and significantly increased the number of lung micrometastases of Tsc2-deficient cells compared with estradiol treatment alone. Collectively, these data indicate that progesterone increases the metastatic potential of TSC2-deficient LAM patient-derived cells in vitro and lung metastasis in vivo. Thus, targeting progesterone-mediated signaling events may have therapeutic benefit for LAM and possibly other hormonally dependent cancers. PMID

Higher Rate of Iron Deficiency in Obese Pregnant Sudanese Women.

PubMed

Abbas, Wisal; Adam, Ishag; Rayis, Duria A; Hassan, Nada G; Lutfi, Mohamed F

2017-06-15

To assess the association between obesity and iron deficiency (ID). Pregnant women were recruited from Saad Abualila Hospital, Khartoum, Sudan, during January-April 2015. Medical history (age, parity, gestational age) was gathered using questionnaire. Weight and height were measured, and body mass index (BMI) was calculated. Women were sub-grouped based on BMI into underweight (< 18.5 kg/m^2), normal weight (18.5-24.9 kg/m^2), overweight (25-29.9 kg/m^2) and obese (≥ 30 kg/m^2). Serum ferritin and red blood indices were measured in all studied women. Two (0.5%), 126 (29.8%), 224 (53.0%) and 71 (16.8%) out of the 423 women were underweight, normal weight, overweight and obese, respectively. Anemia (Hb <11 g/dl), ID (ferritin <15µg/l) and iron deficiency anemia (IDA) were prevalent in 57.7%, 21.3% and 12.1%, respectively. Compared with the women with normal BMI, significantly fewer obese women were anemic [25 (35.2%) vs. 108 (85.7%), P < 0.001] and significantly higher number of obese women [25 (35.2) vs. 22 (17.5, P = 0.015] had iron deficiency. Linear regression analysis demonstrated a significant negative association between serum ferritin and BMI (- 0.010 µg/, P= 0.006). It is evident from the current findings that prevalence of anaemia and ID showed different trends about BMI of pregnant women.

Zinc deficiency enhanced inflammatory response by increasing immune cell activation and inducing IL6 promoter demethylation

PubMed Central

Wong, Carmen P.; Rinaldi, Nicole A.; Ho, Emily

2015-01-01

Scope Zinc deficiency results in immune dysfunction and promotes systemic inflammation. The objective of this study was to examine the effects of zinc deficiency on cellular immune activation and epigenetic mechanisms that promote inflammation. This work is potentially relevant to the aging population given that age-related immune defects, including chronic inflammation, coincide with declining zinc status. Methods and results An in vitro cell culture system and the aged mouse model were used to characterize immune activation and DNA methylation profiles that may contribute to the enhanced proinflammatory response mediated by zinc deficiency. Zinc deficiency up-regulated cell activation markers ICAM1, MHC class II, and CD86 in THP1 cells, that coincided with increased IL1β and IL6 responses following LPS stimulation. A decreased zinc status in aged mice was similarly associated with increased ICAM1 and IL6 gene expression. Reduced IL6 promoter methylation was observed in zinc deficient THP1 cells, as well as in aged mice and human lymphoblastoid cell lines derived from aged individuals. Conclusion Zinc deficiency induced inflammatory response in part by eliciting aberrant immune cell activation and altered promoter methylation. Our results suggested potential interactions between zinc status, epigenetics, and immune function, and how their dysregulation could contribute to chronic inflammation. PMID:25656040

Breastfeeding, mixed or formula feeding at 9 months and the prevalence of iron deficiency and iron deficiency anemia in two cohorts of infants in China

PubMed Central

Clark, Katy M.; Li, Ming; Zhu, Bingquan; Liang, Furong; Shao, Jie; Zhang, Yueyang; Ji, Chai; Zhao, Zhengyan; Kaciroti, Niko; Lozoff, Betsy

2016-01-01

Objective To assess associations between breastfeeding and iron status at 9 months in two samples of Chinese infants. Study design Associations between feeding at 9 months (breastfed [BF] as sole milk source, mixed-fed [MF], or formula-fed [FF]) and iron deficiency anemia (IDA), iron deficiency (ID), and iron sufficiency were determined in infants from Zhejiang and Hebei provinces (ns = 142 and 813). ID was defined as body iron < 0 mg/kg, IDA as ID + hemoglobin < 110 g/L. Multiple logistic regression assessed associations between feeding pattern and iron status. Results Breastfeeding was associated with iron status (P-values < .001). In Zhejiang, 27.5% of BF infants had IDA compared with 0% of FF infants. The odds of ID/IDA were increased in BF and MF infants compared with FF: BF vs. FF odds ratio (OR): 28.8, 95% CI: 3.7–226.4; MF vs. FF OR: 11.0, 95% CI: 1.2–103.2. In Hebei, 44.0% of BF infants had IDA compared with 2.8% of FF infants. With covariable adjustment, odds of IDA were increased in BF and MF groups: BF vs. FF OR: 78.8, 95% CI: 27.2–228.1; MF vs. FF OR: 21.0, 95% CI: 7.3–60.9. Conclusions In both cohorts, the odds of ID/IDA at 9 months were increased in BF and MF infants, and ID/IDA was common. Although the benefits of breastfeeding are indisputable, these findings add to the evidence that breastfeeding in later infancy identifies infants at risk for ID/IDA in many settings. Protocols for detecting and preventing ID/IDA in BF infants are needed. Trial registration ClinicalTrials.gov: NCT00642863 and NCT00613717 PMID:27836288

Enhancing dopaminergic signaling and histone acetylation promotes long-term rescue of deficient fear extinction.

PubMed

Whittle, N; Maurer, V; Murphy, C; Rainer, J; Bindreither, D; Hauschild, M; Scharinger, A; Oberhauser, M; Keil, T; Brehm, C; Valovka, T; Striessnig, J; Singewald, N

2016-12-06

Extinction-based exposure therapy is used to treat anxiety- and trauma-related disorders; however, there is the need to improve its limited efficacy in individuals with impaired fear extinction learning and to promote greater protection against return-of-fear phenomena. Here, using 129S1/SvImJ mice, which display impaired fear extinction acquisition and extinction consolidation, we revealed that persistent and context-independent rescue of deficient fear extinction in these mice was associated with enhanced expression of dopamine-related genes, such as dopamine D1 (Drd1a) and -D2 (Drd2) receptor genes in the medial prefrontal cortex (mPFC) and amygdala, but not hippocampus. Moreover, enhanced histone acetylation was observed in the promoter of the extinction-regulated Drd2 gene in the mPFC, revealing a potential gene-regulatory mechanism. Although enhancing histone acetylation, via administering the histone deacetylase (HDAC) inhibitor MS-275, does not induce fear reduction during extinction training, it promoted enduring and context-independent rescue of deficient fear extinction consolidation/retrieval once extinction learning was initiated as shown following a mild conditioning protocol. This was associated with enhanced histone acetylation in neurons of the mPFC and amygdala. Finally, as a proof-of-principle, mimicking enhanced dopaminergic signaling by L-dopa treatment rescued deficient fear extinction and co-administration of MS-275 rendered this effect enduring and context-independent. In summary, current data reveal that combining dopaminergic and epigenetic mechanisms is a promising strategy to improve exposure-based behavior therapy in extinction-impaired individuals by initiating the formation of an enduring and context-independent fear-inhibitory memory.

Enhancing dopaminergic signaling and histone acetylation promotes long-term rescue of deficient fear extinction

PubMed Central

Whittle, N; Maurer, V; Murphy, C; Rainer, J; Bindreither, D; Hauschild, M; Scharinger, A; Oberhauser, M; Keil, T; Brehm, C; Valovka, T; Striessnig, J; Singewald, N

2016-01-01

Extinction-based exposure therapy is used to treat anxiety- and trauma-related disorders; however, there is the need to improve its limited efficacy in individuals with impaired fear extinction learning and to promote greater protection against return-of-fear phenomena. Here, using 129S1/SvImJ mice, which display impaired fear extinction acquisition and extinction consolidation, we revealed that persistent and context-independent rescue of deficient fear extinction in these mice was associated with enhanced expression of dopamine-related genes, such as dopamine D1 (Drd1a) and -D2 (Drd2) receptor genes in the medial prefrontal cortex (mPFC) and amygdala, but not hippocampus. Moreover, enhanced histone acetylation was observed in the promoter of the extinction-regulated Drd2 gene in the mPFC, revealing a potential gene-regulatory mechanism. Although enhancing histone acetylation, via administering the histone deacetylase (HDAC) inhibitor MS-275, does not induce fear reduction during extinction training, it promoted enduring and context-independent rescue of deficient fear extinction consolidation/retrieval once extinction learning was initiated as shown following a mild conditioning protocol. This was associated with enhanced histone acetylation in neurons of the mPFC and amygdala. Finally, as a proof-of-principle, mimicking enhanced dopaminergic signaling by L-dopa treatment rescued deficient fear extinction and co-administration of MS-275 rendered this effect enduring and context-independent. In summary, current data reveal that combining dopaminergic and epigenetic mechanisms is a promising strategy to improve exposure-based behavior therapy in extinction-impaired individuals by initiating the formation of an enduring and context-independent fear-inhibitory memory. PMID:27922638

[Strategies to promote testosterone deficiency syndrome: a paradigm of disease mongering].

PubMed

Gavilán, Enrique; Jiménez de Gracia, Laura; Gérvas, Juan

2014-01-01

The so-called «testosterone deficiency syndrome» is a blend of nonspecific symptoms typical of the physiological process of aging. This syndrome has been the subject of intense promotional activity that has presented the phenomenon as highly prevalent and with a major public health impact. This strategy has been accompanied by the emergence of new and easy to administer testosterone devices into the pharmaceutical market and has generated significant sales for drug companies. The commercial promotion of testosterone deficiency syndrome and its remedies has exploited cultural stereotypes of aging and sexuality through awareness campaigns promoted by the laboratories involved and has been disseminated by media with the participation of numerous experts and with the support of scientific associations, representing a paradigmatic case of disease mongering. This example might be of use in the response to disease mongering activities from the clinical and public health fields. Copyright © 2013 SESPAS. Published by Elsevier Espana. All rights reserved.

Tumor-derived CXCL8 signaling augments stroma-derived CCL2-promoted proliferation and CXCL12-mediated invasion of PTEN-deficient prostate cancer cells

PubMed Central

Maxwell, Pamela J.; Neisen, Jessica; Messenger, Johanna; Waugh, David J.J.

2014-01-01

Impaired PTEN function is a genetic hallmark of aggressive prostate cancers (CaP) and is associated with increased CXCL8 expression and signaling. The current aim was to further characterize biological responses and mechanisms underpinning CXCL8-promoted progression of PTEN-depleted prostate cancer, focusing on characterizing the potential interplay between CXCL8 and other disease-promoting chemokines resident within the prostate tumor microenvironment. Autocrine CXCL8-stimulation (i) increased expression of CXCR1 and CXCR2 in PTEN-deficient CaP cells suggesting a self-potentiating signaling axis and (ii) induced expression of CXCR4 and CCR2 in PTEN-wild-type and PTEN-depleted CaP cells. In contrast, paracrine CXCL8 signaling induced expression and secretion of the chemokines CCL2 and CXCL12 from prostate stromal WPMY-1 fibroblasts and monocytic macrophage-like THP-1 cells. In vitro studies demonstrated functional co-operation of tumor-derived CXCL8 with stromal-derived chemokines. CXCL12-induced migration of PC3 cells and CCL2-induced proliferation of prostate cancer cells were dependent upon intrinsic CXCL8 signaling within the prostate cancer cells. For example, in co-culture experiments, CXCL12/CXCR4 signaling but not CCL2/CCR2 signaling supported fibroblast-mediated migration of PC3 cells while CXCL12/CXCR4 and CCL2/CCR2 signaling underpinned monocyte-enhanced migration of PC3 cells. Combined inhibition of both CXCL8 and CXCL12 signaling was more effective in inhibiting fibroblast-promoted cell motility while repression of CXCL8 attenuated CCL2-promoted proliferation of prostate cancer cells. We conclude that tumor-derived CXCL8 signaling from PTEN-deficient tumor cells increases the sensitivity and responsiveness of CaP cells to stromal chemokines by concurrently upregulating receptor expression in cancer cells and inducing stromal chemokine synthesis. Combined chemokine targeting may be required to inhibit their multi-faceted actions in promoting the

Tumor promotion and inhibition by phenobarbital in livers of conditional Apc-deficient mice.

PubMed

Braeuning, Albert; Gavrilov, Alina; Geissler, Miriam; Wenz, Christine; Colnot, Sabine; Templin, Markus F; Metzger, Ute; Römer, Michael; Zell, Andreas; Schwarz, Michael

2016-06-01

Activation of Wnt/β-catenin signaling is important for human and rodent hepatocarcinogenesis. In mice, the tumor promoter phenobarbital (PB) selects for hepatocellular tumors with activating β-catenin mutations via constitutive androstane receptor activation. PB-dependent tumor promotion was studied in mice with genetic inactivation of Apc, a negative regulator of β-catenin, to circumvent the problem of randomly induced mutations by chemical initiators and to allow monitoring of PB- and Wnt/β-catenin-dependent tumorigenesis in the absence of unknown genomic alterations. Moreover, the study was designed to investigate PB-induced proliferation of liver cells with activated β-catenin. PB treatment provided Apc-deficient hepatocytes with only a minor proliferative advantage, and additional connexin 32 deficiency did not affect the proliferative response. PB significantly promoted the outgrowth of Apc-deficient hepatocellular adenoma (HCA), but simultaneously inhibited the formation of Apc-deficient hepatocellular carcinoma (HCC). The probability of tumor promotion by PB was calculated to be much lower for hepatocytes with loss of Apc, as compared to mutational β-catenin activation. Comprehensive transcriptomic and phosphoproteomic characterization of HCA and HCC revealed molecular details of the two tumor types. HCC were characterized by a loss of differentiated hepatocellular gene expression, enhanced proliferative signaling, and massive over-activation of Wnt/β-catenin signaling. In conclusion, PB exerts a dual role in liver tumor formation by promoting the growth of HCA but inhibiting the growth of HCC. Data demonstrate that one and the same compound can produce opposite effects on hepatocarcinogenesis, depending on context, highlighting the necessity to develop a more differentiated view on the tumorigenicity of this model compound.

Congenital Limb Deficiency Associated with Intellectual Disability: Unusual Presentation in Two Subjects.

PubMed

Raza, Muhammad Ummear; Ullah, Waheed; Malik, Sajid

2016-09-01

Congenital constriction ring (CCR) and symbrachydactyly are two distinct, rare, and heterogeneous limb deficiency conditions which affect the digits. Here, we report on two different individuals with an unusual presentation of limb deficiency accompanying intellectual disability (ID) and certain other malformations. In the first index female, CCR occurred with mild ID, squint eyes, obesity, and metatarsus adductus. The second index male was presented with symbrachydactyly, profound ID, and speech/hearing impairments. The association of limb deficiency conditions with these anomalies is very rare. Differential diagnosis and literature survey have been offered to establish the rarity of these entities.

Iron deficiency in a tertiary gastroenterology center in Romania: prevalence and significancy.

PubMed

Preda, Carmen Monica; Proca, Doina; Sandra, Irina; Horeanga, Boroka Claudia; Fulger, Larisa Elena; Manuc, Teodora; Bancila, Ion; Balas, Oana Elena; Manuc, Mircea; Diculescu, Mircea; Baicus, Cristian; Tieranu, Cristian; Constantinescu, Ileana

2018-01-01

Introduction: Iron deficiency has been known to cause significant functional impairment, lower quality of life and higher morbidity and mortality. The aim of this study was to estimate the prevalence and significance of iron deficiency in our patients and medical staff. Material and methods: We performed a prospective cross-sectional study: In July 2016, 383 persons were screened for the presence of iron deficiency (ID): 325 patients and 58 people from the medical staff. Transferrin saturation (TSAT), serum ferritin (SF) and complete blood count were performed. Absolute ID was diagnosed if SF <100 ng/ml and TSAT <20%. Relative ID was defined by SF >100 ng/ml and TSAT <20%. Results: The group of medical staff was younger and had a greater proportion of women. The prevalence of absolute ID was 22.5% in patients and 43.1% in medical staff; relative ID was present in 15% of patients and 1.7% of medical staff. Among patients, the absolute ID was significantly correlated with the female sex (p=0.002) and pre-menopausal status (p=0.01) but did not correlate with diagnosis, age, BMI, nonsteroidal anti-inflammatory drug (NSAID), aspirin or acenocoumarol consumption. The relative ID is associated with advanced age (p=0.03) and diagnosis of cancer and liver cirrhosis (p=0.01). Conclusions: Absolute ID had a high prevalence among patients (22.5%), but there was even a bigger issue among the medical staff (43.1%). Absolute ID was correlated with female sex and pre-menopausal status. Relative ID was related to advanced age, cancer and liver cirrhosis. Abbreviations: serum ferritine- SF, transferrin saturation coefficient- TSAT, iron deficiency- ID, inflammatory bowel diseases- IBD, quality of life- QoL, GI- gastrointestinal.

Iron deficiency in a tertiary gastroenterology center in Romania: prevalence and significancy

PubMed Central

Preda, Carmen Monica; Proca, Doina; Sandra, Irina; Horeanga, Boroka Claudia; Fulger, Larisa Elena; Manuc, Teodora; Bancila, Ion; Balas, Oana Elena; Manuc, Mircea; Diculescu, Mircea; Baicus, Cristian; Tieranu, Cristian; Constantinescu, Ileana

2018-01-01

Introduction:Iron deficiency has been known to cause significant functional impairment, lower quality of life and higher morbidity and mortality. The aim of this study was to estimate the prevalence and significance of iron deficiency in our patients and medical staff. Material and methods:We performed a prospective cross-sectional study: In July 2016, 383 persons were screened for the presence of iron deficiency (ID): 325 patients and 58 people from the medical staff. Transferrin saturation (TSAT), serum ferritin (SF) and complete blood count were performed. Absolute ID was diagnosed if SF <100 ng/ml and TSAT <20%. Relative ID was defined by SF >100 ng/ml and TSAT <20%. Results:The group of medical staff was younger and had a greater proportion of women. The prevalence of absolute ID was 22.5% in patients and 43.1% in medical staff; relative ID was present in 15% of patients and 1.7% of medical staff. Among patients, the absolute ID was significantly correlated with the female sex (p=0.002) and pre-menopausal status (p=0.01) but did not correlate with diagnosis, age, BMI, nonsteroidal anti-inflammatory drug (NSAID), aspirin or acenocoumarol consumption. The relative ID is associated with advanced age (p=0.03) and diagnosis of cancer and liver cirrhosis (p=0.01). Conclusions:Absolute ID had a high prevalence among patients (22.5%), but there was even a bigger issue among the medical staff (43.1%). Absolute ID was correlated with female sex and pre-menopausal status. Relative ID was related to advanced age, cancer and liver cirrhosis. Abbreviations: serum ferritine- SF, transferrin saturation coefficient- TSAT, iron deficiency- ID, inflammatory bowel diseases- IBD, quality of life- QoL, GI- gastrointestinal PMID:29696062

Progranulin deficiency promotes neuroinflammation and neuron loss following toxin-induced injury.

PubMed

Martens, Lauren Herl; Zhang, Jiasheng; Barmada, Sami J; Zhou, Ping; Kamiya, Sherry; Sun, Binggui; Min, Sang-Won; Gan, Li; Finkbeiner, Steven; Huang, Eric J; Farese, Robert V

2012-11-01

Progranulin (PGRN) is a widely expressed secreted protein that is linked to inflammation. In humans, PGRN haploinsufficiency is a major inherited cause of frontotemporal dementia (FTD), but how PGRN deficiency causes neurodegeneration is unknown. Here we show that loss of PGRN results in increased neuron loss in response to injury in the CNS. When exposed acutely to 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydrophine (MPTP), mice lacking PGRN (Grn⁻/⁻) showed more neuron loss and increased microgliosis compared with wild-type mice. The exacerbated neuron loss was due not to selective vulnerability of Grn⁻/⁻ neurons to MPTP, but rather to an increased microglial inflammatory response. Consistent with this, conditional mutants lacking PGRN in microglia exhibited MPTP-induced phenotypes similar to Grn⁻/⁻ mice. Selective depletion of PGRN from microglia in mixed cortical cultures resulted in increased death of wild-type neurons in the absence of injury. Furthermore, Grn⁻/⁻ microglia treated with LPS/IFN-γ exhibited an amplified inflammatory response, and conditioned media from these microglia promoted death of cultured neurons. Our results indicate that PGRN deficiency leads to dysregulated microglial activation and thereby contributes to increased neuron loss with injury. These findings suggest that PGRN deficiency may cause increased neuron loss in other forms of CNS injury accompanied by neuroinflammation.

Acupuncture Improves Intestinal Absorption of Iron in Iron-deficient Obese Patients: A Randomized Controlled Preliminary Trial

PubMed Central

Xie, Xin-Cai; Cao, Yan-Qiang; Gao, Qian; Wang, Chen; Li, Man; Wei, Shou-Gang

2017-01-01

Background: Obesity has an adverse effect on iron status. Hepcidin-mediated inhibition of iron absorption in the duodenum is a potential mechanism. Iron-deficient obese patients have diminished response to oral iron therapy. This study was designed to assess whether acupuncture could promote the efficacy of oral iron supplementation for the treatment of obesity-related iron deficiency (ID). Methods: Sixty ID or ID anemia (IDA) patients with obesity were screened at Beijing Hospital of Traditional Chinese Medicine and were randomly allocated to receive either oral iron replacement allied with acupuncture weight loss treatment (acupuncture group, n = 30) or oral iron combined with sham-acupuncture treatment (control group, n = 30). Anthropometric parameters were measured and blood samples were tested pre- and post-treatment. Differences in the treatment outcomes of ID/IDA were compared between the two groups. Results: After 8 weeks of acupuncture treatment, there was a significant decrease in body weight, body mass index, waist circumference, and waist/hip circumference ratio of patients in the acupuncture group, while no significant changes were observed in the control group. Oral iron supplementation brought more obvious improvements of iron status indicators including absolute increases in serum iron (11.08 ± 2.19 μmol/L vs. 4.43 ± 0.47 μmol/L), transferrin saturation (11.26 ± 1.65% vs. 1.01 ± 0.23%), and hemoglobin (31.47 ± 1.19 g/L vs. 21.00 ± 2.69 g/L) in the acupuncture group than control group (all P < 0.05). Meanwhile, serum leptin (2.26 ± 0.45 ng/ml vs. 8.13 ± 0.55 ng/ml, P < 0.05) and hepcidin (3.52 ± 1.23 ng/ml vs. 6.77 ± 0.84 ng/ml, P < 0.05) concentrations declined significantly in the acupuncture group than those in the control group. Conclusion: Acupuncture-based weight loss can enhance the therapeutic effects of iron replacement therapy for obesity-related ID/IDA through improving intestinal iron absorption, probably by downregulating the

Higher Rate of Iron Deficiency in Obese Pregnant Sudanese Women

PubMed Central

Abbas, Wisal; Adam, Ishag; Rayis, Duria A.; Hassan, Nada G.; Lutfi, Mohamed F.

2017-01-01

AIM: To assess the association between obesity and iron deficiency (ID). MATERIAL AND METHODS: Pregnant women were recruited from Saad Abualila Hospital, Khartoum, Sudan, during January–April 2015. Medical history (age, parity, gestational age) was gathered using questionnaire. Weight and height were measured, and body mass index (BMI) was calculated. Women were sub-grouped based on BMI into underweight (< 18.5 kg/m^2), normal weight (18.5–24.9 kg/m^2), overweight (25–29.9 kg/m^2) and obese (≥ 30 kg/m^2). Serum ferritin and red blood indices were measured in all studied women. RESULTS: Two (0.5%), 126 (29.8%), 224 (53.0%) and 71 (16.8%) out of the 423 women were underweight, normal weight, overweight and obese, respectively. Anemia (Hb <11 g/dl), ID (ferritin <15µg/l) and iron deficiency anemia (IDA) were prevalent in 57.7%, 21.3% and 12.1%, respectively. Compared with the women with normal BMI, significantly fewer obese women were anemic [25 (35.2%) vs. 108 (85.7%), P < 0.001] and significantly higher number of obese women [25 (35.2) vs. 22 (17.5, P = 0.015] had iron deficiency. Linear regression analysis demonstrated a significant negative association between serum ferritin and BMI (– 0.010 µg/, P= 0.006). CONCLUSION: It is evident from the current findings that prevalence of anaemia and ID showed different trends about BMI of pregnant women PMID:28698743

TLR4 deficiency promotes autophagy during cigarette smoke-induced pulmonary emphysema.

PubMed

An, Chang Hyeok; Wang, Xiao Mei; Lam, Hilaire C; Ifedigbo, Emeka; Washko, George R; Ryter, Stefan W; Choi, Augustine M K

2012-11-01

Toll-like receptors (TLRs) exert important nonimmune functions in lung homeostasis. TLR4 deficiency promotes pulmonary emphysema. We examined the role of TLR4 in regulating cigarette smoke (CS)-induced autophagy, apoptosis, and emphysema. Lung tissue was obtained from chronic obstructive lung disease (COPD) patients. C3H/HeJ (Tlr4-mutated) mice and C57BL/10ScNJ (Tlr4-deficient) mice and their respective control strains were exposed to chronic CS or air. Human or mouse epithelial cells (wild-type, Tlr4-knockdown, and Tlr4-deficient) were exposed to CS-extract (CSE). Samples were analyzed for TLR4 expression, and for autophagic or apoptotic proteins by Western blot analysis or confocal imaging. Chronic obstructive lung disease lung tissues and human pulmonary epithelial cells exposed to CSE displayed increased TLR4 expression, and increased autophagic [microtubule-associated protein-1 light-chain-3B (LC3B)] and apoptotic (cleaved caspase-3) markers. Beas-2B cells transfected with TLR4 siRNA displayed increased expression of LC3B relative to control cells, basally and after exposure to CSE. The basal and CSE-inducible expression of LC3B and cleaved caspase-3 were elevated in pulmonary alveolar type II cells from Tlr4-deficient mice. Wild-type mice subjected to chronic CS-exposure displayed airspace enlargement;, however, the Tlr4-mutated or Tlr4-deficient mice exhibited a marked increase in airspace relative to wild-type mice after CS-exposure. The Tlr4-mutated or Tlr4-deficient mice showed higher levels of LC3B under basal conditions and after CS exposure. The expression of cleaved caspase-3 was markedly increased in Tlr4-deficient mice exposed to CS. We describe a protective regulatory function of TLR4 against emphysematous changes of the lung in response to CS.

TLR4 deficiency promotes autophagy during cigarette smoke-induced pulmonary emphysema

PubMed Central

An, Chang Hyeok; Wang, Xiao Mei; Lam, Hilaire C.; Ifedigbo, Emeka; Washko, George R.; Ryter, Stefan W.

2012-01-01

Toll-like receptors (TLRs) exert important nonimmune functions in lung homeostasis. TLR4 deficiency promotes pulmonary emphysema. We examined the role of TLR4 in regulating cigarette smoke (CS)-induced autophagy, apoptosis, and emphysema. Lung tissue was obtained from chronic obstructive lung disease (COPD) patients. C3H/HeJ (Tlr4-mutated) mice and C57BL/10ScNJ (Tlr4-deficient) mice and their respective control strains were exposed to chronic CS or air. Human or mouse epithelial cells (wild-type, Tlr4-knockdown, and Tlr4-deficient) were exposed to CS-extract (CSE). Samples were analyzed for TLR4 expression, and for autophagic or apoptotic proteins by Western blot analysis or confocal imaging. Chronic obstructive lung disease lung tissues and human pulmonary epithelial cells exposed to CSE displayed increased TLR4 expression, and increased autophagic [microtubule-associated protein-1 light-chain-3B (LC3B)] and apoptotic (cleaved caspase-3) markers. Beas-2B cells transfected with TLR4 siRNA displayed increased expression of LC3B relative to control cells, basally and after exposure to CSE. The basal and CSE-inducible expression of LC3B and cleaved caspase-3 were elevated in pulmonary alveolar type II cells from Tlr4-deficient mice. Wild-type mice subjected to chronic CS-exposure displayed airspace enlargement;, however, the Tlr4-mutated or Tlr4-deficient mice exhibited a marked increase in airspace relative to wild-type mice after CS-exposure. The Tlr4-mutated or Tlr4-deficient mice showed higher levels of LC3B under basal conditions and after CS exposure. The expression of cleaved caspase-3 was markedly increased in Tlr4-deficient mice exposed to CS. We describe a protective regulatory function of TLR4 against emphysematous changes of the lung in response to CS. PMID:22983353

Do patients with iron deficiency without anemia benefit from an endoscopic examination?

PubMed

García García de Paredes, Ana; Teruel Sánchez-Vegazo, Carlos; Hernanz Ruiz, Nerea; Ferre Aracil, Carlos; Rodríguez de Santiago, Enrique; Aguilera Castro, Lara; Sierra Morales, María; Albillos, Agustín

2017-07-01

The need for endoscopic investigation in patients with iron deficiency without anemia (ID) is not established. Data from patients with ID (serum ferritin ≤20 ng/mL, normal hemoglobin) studied with upper and lower endoscopies were retrospectively analyzed. Patients evaluated for iron deficiency anemia (IDA) served as controls, matched by sex and age in the proportion of 2:1. The groups were compared for the presence, type, location and age distribution of endoscopic findings. Altogether 109 patients (55% women; mean age 59.6 ± 13.5 years; aged <50 years [27.5%]; 50-69 years [43.1%]; ≥70 years [29.4%]) were included in the ID group and 218 matched controls in the IDA group. Lesions were found in a similar proportion of patients (53.2% in the ID group vs 49.1% in the IDA group, P = 0.48) irrespective of age (P = 0.92). The colonoscopy diagnostic yield was low in both the ID and IDA subgroups of aged <50 years (6.3% vs 4.2%, P = 0.76). Multivariate analysis revealed a significant relationship between age (odds ratio [OR] 1.04, 95% confidence interval [CI] 1.02-1.06) and male sex (OR 2.28, 95% CI 1.18-4.39) with a positive colonoscopy. Malignancy was significantly less frequent in the ID group (1.8% vs 14.2%, P < 0.05). The prevalence of gastrointestinal lesions in patients with and without anemia was similar but malignancy was eight times less frequent in the ID group. Systematic endoscopic evaluation in patients with ID is therefore questionable. © 2017 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.

Low prevalence of iron-deficiency anaemia among Inuit preschool children: Nunavut Inuit Child Health Survey, 2007-2008.

PubMed

Pacey, Angela; Weiler, Hope; Egeland, Grace M

2011-08-01

To report the prevalence rates and correlates for anaemia, iron deficiency (ID) and iron-deficiency anaemia (IDA) among Inuit preschool-aged children. A cross-sectional study assessed iron intake, demographic information, medical history, anthropometrics, Hb, ferritin, C-reactive protein and antibodies to Helicobacter pylori. Sixteen selected Inuit communities in Nunavut Territory, Canada. Inuit (n 388) aged 3-5 years randomly recruited from communities. Anaemia (3-4 years: Hb < 110 g/l; 5 years: Hb < 115 g/l) was prevalent in 16·8 % of children. The prevalence of ID (ferritin < 12 μg/l) was 18·0 % and that of IDA was 5·4 %. When ID was defined as ferritin <10 μg/l, 10·8 % of children were iron deficient and 3·3 % had IDA. In multiple logistic regression, boys were more likely to be iron deficient (OR = 2·28, 95 % CI 1·17, 8·25), but no other risk factor emerged for ID. Three- to 4-year-olds were less likely than 5-year-olds to have anaemia from causes other than ID (OR = 0·11, 95 % CI 0·08, 0·58). Anaemia from other causes was more common among children residing in crowded homes (OR = 2·30, 95 % CI 1·37, 12·31) and those treated for past-year ear infection (OR = 1·35, 95 % CI 1·05, 7·21). The low prevalence of ID and IDA is encouraging, but efforts are still needed to reduce rates as they continue to be higher than general population rates. Household crowding and infections may contribute to anaemia and warrant further research.

Control of regulatory T cell and Th17 cell differentiation by inhibitory helix-loop-helix protein Id3

PubMed Central

Maruyama, Takashi; Li, Jun; Vaque, Jose P.; Konkel, Joanne E.; Wang, Weifeng; Zhang, Baojun; Zhang, Pin; Zamarron, Brian; Yu, Dongyang; Wu, Yuntao; Zhuang, Yuan; Gutkind, J. Silvio; Chen, WanJun

2010-01-01

The molecular mechanisms directing Foxp3 gene transcription in CD4+ T cells remain ill defined. We show that deletion of the inhibitory helix-loop-helix (HLH) protein Id3 results in defective Foxp3+ Treg cell generation. We identified two transforming grothw factor-β1 (TGF-β1)-dependent mechanisms that are vital for activation of Foxp3 gene transcription, and are defective in Id3−/− CD4+ T cells. Enhanced binding of the HLH protein E2A to the Foxp3 promoter promoted Foxp3 gene transcription. Id3 was required to relieve inhibition by GATA-3 at the Foxp3 promoter. Further, Id3−/− T cells increased differentiation of Th17 cells in vitro and in a mouse asthma model. A network of factors therefore act in a TGF-β-dependent manner to control Foxp3 expression and inhibit Th17 cell development. PMID:21131965

[Iron deficiency in infants and toddlers: impact on health and preventive strategies].

PubMed

Moráis López, A; Dalmau Serra, J

2011-06-01

Infants and toddlers represent a risk population for iron deficiency (ID), due to their relatively high requirements, which are frequently associated with a poor intake of iron-rich foods. A possible association between ID and impaired cognitive and psychomotor development has been described, and it has been suggested that some of these effects can be irreversible. For this reason, prevention of ID has become a subject of much concern. To promote an adequate dietetic iron intake is the most important approach for the prevention of ID. Exclusive breast-feeding provides adequate amounts of iron during the first 4-6 months of life, and iron-fortified formula should be used when an alternative is necessary. Fortified cereals and foods containing haem iron, such as meat, should be introduced early in complementary feeding. In toddlers, iron requirements can be satisfied with a daily consumption of at least one serving of iron-containing foods, along with enhancers of iron absorption. When daily requirements are not properly met by food intake, and in some high-risk populations, screening for ID and iron supplementation should be considered. Copyright © 2010 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.

In male rats with concurrent iron and (n-3) fatty acid deficiency, provision of either iron or (n-3) fatty acids alone alters monoamine metabolism and exacerbates the cognitive deficits associated with combined deficiency.

PubMed

Baumgartner, Jeannine; Smuts, Cornelius M; Malan, Linda; Arnold, Myrtha; Yee, Benjamin K; Bianco, Laura E; Boekschoten, Mark V; Müller, Michael; Langhans, Wolfgang; Hurrell, Richard F; Zimmermann, Michael B

2012-08-01

Concurrent deficiencies of iron (Fe) (ID) and (n-3) fatty acids [(n-3)FAD)] in rats can alter brain monoamine pathways and impair learning and memory. We examined whether repletion with Fe and DHA/EPA, alone and in combination, corrects the deficits in brain monoamine activity (by measuring monoamines and related gene expression) and spatial working and reference memory [by Morris water maze (MWM) testing] associated with deficiency. Using a 2 × 2 design, male rats with concurrent ID and (n-3)FAD [ID+(n-3)FAD] were fed an Fe+DHA/EPA, Fe+(n-3)FAD, ID+DHA/EPA, or ID+(n-3)FAD diet for 5 wk [postnatal d 56-91]. Biochemical measures and MWM performance after repletion were compared to age-matched control rats. The provision of Fe in combination with DHA/EPA synergistically increased Fe concentrations in the olfactory bulb (OB) (Fe x DHA/EPA interaction). Similarly, provision of DHA/EPA in combination with Fe resulted in higher brain DHA concentrations than provision of DHA alone in the frontal cortex (FC) and OB (P < 0.05). Dopamine (DA) receptor D1 was upregulated in the hippocampus of Fe+DHA/EPA rats (fold-change = 1.25; P < 0.05) and there were significant Fe x DHA/EPA interactions on serotonin (5-HT) in the OB and on the DA metabolite dihydroxyphenylacetic acid in the FC and striatum. Working memory performance was impaired in ID+DHA/EPA rats compared with controls (P < 0.05). In the reference memory task, Fe+DHA/EPA improved learning behavior, but Fe or DHA/EPA alone did not. These findings suggest that feeding either Fe or DHA/EPA alone to adult rats with both ID and (n-3)FAD affects the DA and 5-HT pathways differently than combined repletion and exacerbates the cognitive deficits associated with combined deficiency.

Working memory impairment and recovery in iron deficient children.

PubMed

Otero, Gloria A; Pliego-Rivero, F Bernardo; Porcayo-Mercado, Rosario; Mendieta-Alcántara, Gustavo

2008-08-01

Iron is an important oligoelement participating in multiple metabolic processes, including the synthesis of catecholamines, and its deficiency (ID) throughout development is particularly insidious on brain maturation and the emergence of cognitive functions during school age. A working memory (WM) study in 8-10-year-old ID children is presented. It is hypothesized that an impairment in WM exists in ID school-age children and a substantial restoration of this mental ability should occur after iron supplementation. Event-related potentials (ERPs) were recorded during the completion of a Sternberg-type task in control, ID and ID-iron supplemented children. ID children showed less correct answers and diminished ERP amplitude in frontal, central, parietal and temporal regions compared to control children. After iron supplementation and normalizing bodily iron stores, behavioral and ERP differences disappeared between ID and control children. Considering that WM is fundamentally related to attention ability, the results presented here confirm and reinforce previous observations: ID severely diminishes attention [Otero GA, Pliego-Rivero FB, Contreras G, Ricardo J, Fernandez T. Iron supplementation brings up a lacking P300 in iron deficient children. Clin Neurophysiol 2004;115:2259-66] and WM while iron supplementation substantially restores the cognitive capabilities tested. This is one of very few reports using ERP showing a diminished WM capability in ID school-age children.

Ablation of the transcriptional regulator Id1 enhances energy expenditure, increases insulin sensitivity, and protects against age and diet induced insulin resistance, and hepatosteatosis

PubMed Central

Satyanarayana, Ande; Klarmann, Kimberly D.; Gavrilova, Oksana; Keller, Jonathan R.

2012-01-01

Obesity is a major health concern that contributes to the development of diabetes, hyperlipidemia, coronary artery disease, and cancer. Id proteins are helix-loop-helix transcription factors that regulate the proliferation and differentiation of cells from multiple tissues, including adipocytes. We screened mouse tissues for the expression of Id1 and found that Id1 protein is highly expressed in brown adipose tissue (BAT) and white adipose tissue (WAT), suggesting a role for Id1 in adipogenesis and cell metabolism. Id1−/− mice are viable but show a significant reduction in fat mass (P<0.005) over the life of the animal that was not due to decreased number of adipocytes. Analysis of Id1−/− mice revealed higher energy expenditure, increased lipolysis, and fatty acid oxidation, resulting in reduced triglyceride accumulation in WAT compared to Id1+/+ mice. Serum levels of triglycerides (193.9±32.2 vs. 86.5±33.8, P<0.0005), cholesterol (189.4±33.8 vs. 110.6±8.23, P<0.0005) and leptin (1263±835 vs. 222±260, P<0.005) were significantly lower in aged Id1−/− mice compared to Id1+/+ mice. Id1-deficient mice have higher resting (P<0.005) and total (P<0.05) O2 consumption and lower respiratory exchange ratio (P<0.005), confirming that Id1−/− mice use a higher proportion of lipid as an energy source for the increased energy expenditure. The expression of PGC1α and UCP1 were 2- to 3-fold up-regulated in Id1−/− BAT, suggesting that loss of Id1 increases thermogenesis. As a consequence of higher energy expenditure and reduced fat mass, Id1−/− mice displayed enhanced insulin sensitivity. Id1 deficiency protected mice against age- and high-fat-diet-induced adiposity, insulin resistance, and hepatosteatosis. Our findings suggest that Id1 plays a critical role in the regulation of energy homeostasis and could be a potential target in the treatment of insulin resistance and fatty liver disease.—Satyanarayana, A., Klarmann, K. D., Gavrilova, l O., Keller

Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice.

PubMed

Fuster, José J; MacLauchlan, Susan; Zuriaga, María A; Polackal, Maya N; Ostriker, Allison C; Chakraborty, Raja; Wu, Chia-Ling; Sano, Soichi; Muralidharan, Sujatha; Rius, Cristina; Vuong, Jacqueline; Jacob, Sophia; Muralidhar, Varsha; Robertson, Avril A B; Cooper, Matthew A; Andrés, Vicente; Hirschi, Karen K; Martin, Kathleen A; Walsh, Kenneth

2017-02-24

Human aging is associated with an increased frequency of somatic mutations in hematopoietic cells. Several of these recurrent mutations, including those in the gene encoding the epigenetic modifier enzyme TET2, promote expansion of the mutant blood cells. This clonal hematopoiesis correlates with an increased risk of atherosclerotic cardiovascular disease. We studied the effects of the expansion of Tet2 -mutant cells in atherosclerosis-prone, low-density lipoprotein receptor-deficient ( Ldlr -/- ) mice. We found that partial bone marrow reconstitution with TET2-deficient cells was sufficient for their clonal expansion and led to a marked increase in atherosclerotic plaque size. TET2-deficient macrophages exhibited an increase in NLRP3 inflammasome-mediated interleukin-1β secretion. An NLRP3 inhibitor showed greater atheroprotective activity in chimeric mice reconstituted with TET2-deficient cells than in nonchimeric mice. These results support the hypothesis that somatic TET2 mutations in blood cells play a causal role in atherosclerosis. Copyright © 2017, American Association for the Advancement of Science.

Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice

PubMed Central

Fuster, José J.; MacLauchlan, Susan; Zuriaga, María A.; Polackal, Maya N.; Ostriker, Allison C.; Chakraborty, Raja; Wu, Chia-Ling; Sano, Soichi; Muralidharan, Sujatha; Rius, Cristina; Vuong, Jacqueline; Jacob, Sophia; Muralidhar, Varsha; Robertson, Avril A. B.; Cooper, Matthew A.; Andrés, Vicente; Hirschi, Karen K.; Martin, Kathleen A.; Walsh, Kenneth

2017-01-01

Human aging is associated with an increased frequency of somatic mutations in hematopoietic cells. Several of these recurrent mutations, including those in the gene encoding the epigenetic modifier enzyme TET2, promote expansion of the mutant blood cells. This clonal hematopoiesis correlates with an increased risk of atherosclerotic cardiovascular disease. We studied the effects of the expansion of Tet2-mutant cells in atherosclerosis-prone, low-density lipoprotein receptor–deficient (Ldlr−/−) mice. We found that partial bone marrow reconstitution with TET2-deficient cells was sufficient for their clonal expansion and led to a marked increase in atherosclerotic plaque size. TET2-deficient macrophages exhibited an increase in NLRP3 inflammasome–mediated interleukin-1β secretion. An NLRP3 inhibitor showed greater atheroprotective activity in chimeric mice reconstituted with TET2-deficient cells than in nonchimeric mice. These results support the hypothesis that somatic TET2 mutations in blood cells play a causal role in atherosclerosis. PMID:28104796

DNA Mismatch Repair Deficiency Promotes Genomic Instability in a Subset of Papillary Thyroid Cancers.

PubMed

Javid, Mahsa; Sasanakietkul, Thanyawat; Nicolson, Norman G; Gibson, Courtney E; Callender, Glenda G; Korah, Reju; Carling, Tobias

2018-02-01

Efficient DNA damage repair by MutL-homolog DNA mismatch repair (MMR) enzymes, MLH1, MLH3, PMS1 and PMS2, are required to maintain thyrocyte genomic integrity. We hypothesized that persistent oxidative stress and consequent transcriptional dysregulation observed in thyroid follicles will lead to MMR deficiency and potentiate papillary thyroid tumorigenesis. MMR gene expression was analyzed by targeted microarray in 18 papillary thyroid cancer (PTC), 9 paracarcinoma normal thyroid (PCNT) and 10 normal thyroid (NT) samples. The findings were validated by qRT-PCR, and in follicular thyroid cancers (FTC) and follicular thyroid adenomas (FTA) for comparison. FOXO transcription factor expression was also analyzed. Protein expression was assessed by immunohistochemistry. Genomic integrity was evaluated by whole-exome sequencing-derived read-depth analysis and Mann-Whitney U test. Clinical correlations were assessed using Fisher's exact and t tests. Microarray and qRT-PCR revealed reduced expression of all four MMR genes in PTC compared with PCNT and of PMS2 compared with NT. FTC and FTA showed upregulation in MLH1, MLH3 and PMS2. PMS2 protein expression correlated with the mRNA expression pattern. FOXO1 showed lower expression in PMS2-deficient PTCs (log2-fold change -1.72 vs. -0.55, U = 11, p < 0.05 two-tailed). Rate of LOH, a measure of genomic instability, was higher in PMS2-deficient PTCs (median 3 and 1, respectively; U = 26, p < 0.05 two-tailed). No correlation was noted between MMR deficiency and clinical characteristics. MMR deficiency, potentially promoted by FOXO1 suppression, may explain the etiology for PTC development in some patients. FTC and FTA retain MMR activity and are likely caused by a different tumorigenic pathway.

Reticulocyte hemoglobin equivalent as a potential marker for diagnosis of iron deficiency.

PubMed

Toki, Yasumichi; Ikuta, Katsuya; Kawahara, Yoshie; Niizeki, Noriyasu; Kon, Masayuki; Enomoto, Motoki; Tada, Yuko; Hatayama, Mayumi; Yamamoto, Masayo; Ito, Satoshi; Shindo, Motohiro; Kikuchi, Yoko; Inoue, Mitsutaka; Sato, Kazuya; Fujiya, Mikihiro; Okumura, Toshikatsu

2017-07-01

Evaluation of parameters relating to serum ferritin and iron is critically important in the diagnosis of iron deficiency anemia (IDA). The recent development of automated systems for hematology analysis has made it possible to measure reticulocyte hemoglobin equivalent (RET-He), which is thought to reflect iron content in reticulocytes, in the same sample used for complete blood count tests. If RET-He is, indeed, capable of evaluating iron deficiency (ID), it would be useful for immediate diagnosis of IDA. In the present study, we examined the usefulness of RET-He for diagnosis of ID. Blood samples were obtained from 211 patients. Anemia was defined as hemoglobin (Hb) level of <12 g/dL. Iron deficiency was defined as serum ferritin level of <12 ng/mL. Patients were classified into four groups: IDA, ID, control, and non-ID with anemia. Patients in the IDA group had significantly lower RET-He levels than those in the control group. RET-He correlated with serum ferritin in the IDA and ID groups. The area under the curve for RET-He was 0.902, indicating that RET-He facilitates the diagnosis of ID with high accuracy. RET-He changed in parallel with changes in Hb during iron administration for 21 IDA patients. Our results indicate that RET-He may be a clinically useful marker for determining ID in the general population.

FAN1 acts with FANCI-FANCD2 to promote DNA interstrand cross-link repair.

PubMed

Liu, Ting; Ghosal, Gargi; Yuan, Jingsong; Chen, Junjie; Huang, Jun

2010-08-06

Fanconi anemia (FA) is caused by mutations in 13 Fanc genes and renders cells hypersensitive to DNA interstrand cross-linking (ICL) agents. A central event in the FA pathway is mono-ubiquitylation of the FANCI-FANCD2 (ID) protein complex. Here, we characterize a previously unrecognized nuclease, Fanconi anemia-associated nuclease 1 (FAN1), that promotes ICL repair in a manner strictly dependent on its ability to accumulate at or near sites of DNA damage and that relies on mono-ubiquitylation of the ID complex. Thus, the mono-ubiquitylated ID complex recruits the downstream repair protein FAN1 and facilitates the repair of DNA interstrand cross-links.

Role of ID Proteins in BMP4 Inhibition of Profibrotic Effects of TGF-β2 in Human TM Cells.

PubMed

Mody, Avani A; Wordinger, Robert J; Clark, Abbot F

2017-02-01

Increased expression of TGF-β2 in primary open-angle glaucoma (POAG) aqueous humor (AH) and trabecular meshwork (TM) causes deposition of extracellular matrix (ECM) in the TM and elevated IOP. Bone morphogenetic proteins (BMPs) regulate TGF-β2-induced ECM production. The underlying mechanism for BMP4 inhibition of TGF-β2-induced fibrosis remains undetermined. Bone morphogenic protein 4 induces inhibitor of DNA binding proteins (ID1, ID3), which suppress transcription factor activities to regulate gene expression. Our study will determine whether ID1and ID3 proteins are downstream targets of BMP4, which attenuates TGF-β2 induction of ECM proteins in TM cells. Primary human TM cells were treated with BMP4, and ID1 and ID3 mRNA, and protein expression was determined by quantitative PCR (Q-PCR) and Western immunoblotting. Intracellular ID1 and ID3 protein localization was studied by immunocytochemistry. Transformed human TM cells (GTM3 cells) were transfected with ID1 or ID3 expression vectors to determine their potential inhibitory effects on TGF-β2-induced fibronectin and plasminogen activator inhibitor-I (PAI-1) protein expression. Basal expression of ID1-3 was detected in primary human TM cells. Bone morphogenic protein 4 significantly induced early expression of ID1 and ID3 mRNA (P < 0.05) and protein in primary TM cells, and a BMP receptor inhibitor blocked this induction. Overexpression of ID1 and ID3 significantly inhibited TGF-β2-induced expression of fibronectin and PAI-1 in TM cells (P < 0.01). Bone morphogenic protein 4 induced ID1 and ID3 expression suppresses TGF-β2 profibrotic activity in human TM cells. In the future, targeting specific regulators may control the TGF-β2 profibrotic effects on the TM, leading to disease modifying IOP lowering therapies.

New insights into iron deficiency and iron deficiency anemia.

PubMed

Camaschella, Clara

2017-07-01

Recent advances in iron metabolism have stimulated new interest in iron deficiency (ID) and its anemia (IDA), common conditions worldwide. Absolute ID/IDA, i.e. the decrease of total body iron, is easily diagnosed based on decreased levels of serum ferritin and transferrin saturation. Relative lack of iron in specific organs/tissues, and IDA in the context of inflammatory disorders, are diagnosed based on arbitrary cut offs of ferritin and transferrin saturation and/or marker combination (as the soluble transferrin receptor/ferritin index) in an appropriate clinical context. Most ID patients are candidate to traditional treatment with oral iron salts, while high hepcidin levels block their absorption in inflammatory disorders. New iron preparations and new treatment modalities are available: high-dose intravenous iron compounds are becoming popular and indications to their use are increasing, although long-term side effects remain to be evaluated. Copyright © 2017 Elsevier Ltd. All rights reserved.

Prenatal iron deficiency and monoamine oxidase A (MAOA) polymorphisms: combined risk for later cognitive performance in rhesus monkeys.

PubMed

Golub, Mari; Hogrefe, Casey

2014-03-01

Monoamine oxidase A (MAOA) gene polymorphisms resulting in high and low transcription rates are associated with individual differences in reward efficacy and response inhibition. Iron deficiency (ID) is the most frequent single-nutrient deficiency worldwide, and prenatal ID has recently been shown to carry a risk for lower mental development scores in infants. In this study, a potential interaction of MAOA genotype and prenatal ID was studied in young male rhesus monkeys. Cognitive tasks, including problem solving, responsiveness to reward and attention, were used to characterize the potential interaction of these two fetal risks. ID was induced by feeding rhesus monkey dams an iron-deficient (10 ppm, ID) or an iron-sufficient (100 ppm, IS) diet during gestation (n = 10/group). Subgroups of the ID and IS diet offspring had low-MAOA or high-MAOA transcription rate polymorphisms. ID combined with low-MAOA genotype showed distinctive effects on reward preference and problem solving while ID in hi-MAOA juveniles modified response inhibition. Given the incidence of ID and MAOA polymorphisms in humans, this interaction could be a significant determinant of cognitive performance.

ANGPTL4 deficiency in haematopoietic cells promotes monocyte expansion and atherosclerosis progression

NASA Astrophysics Data System (ADS)

Aryal, Binod; Rotllan, Noemi; Araldi, Elisa; Ramírez, Cristina M.; He, Shun; Chousterman, Benjamin G.; Fenn, Ashley M.; Wanschel, Amarylis; Madrigal-Matute, Julio; Warrier, Nikhil; Martín-Ventura, Jose L.; Swirski, Filip K.; Suárez, Yajaira; Fernández-Hernando, Carlos

2016-07-01

Lipid accumulation in macrophages has profound effects on macrophage gene expression and contributes to the development of atherosclerosis. Here, we report that angiopoietin-like protein 4 (ANGPTL4) is the most highly upregulated gene in foamy macrophages and it's absence in haematopoietic cells results in larger atherosclerotic plaques, characterized by bigger necrotic core areas and increased macrophage apoptosis. Furthermore, hyperlipidemic mice deficient in haematopoietic ANGPTL4 have higher blood leukocyte counts, which is associated with an increase in the common myeloid progenitor (CMP) population. ANGPTL4-deficient CMPs have higher lipid raft content, are more proliferative and less apoptotic compared with the wild-type (WT) CMPs. Finally, we observe that ANGPTL4 deficiency in macrophages promotes foam cell formation by enhancing CD36 expression and reducing ABCA1 localization in the cell surface. Altogether, these findings demonstrate that haematopoietic ANGPTL4 deficiency increases atherogenesis through regulating myeloid progenitor cell expansion and differentiation, foam cell formation and vascular inflammation.

Anemia and iron deficiency in Mexican elderly population: Results from the Ensanut 2012.

PubMed

Contreras-Manzano, Alejandra; Cruz, Vanessa de la; Villalpando, Salvador; Rebollar, Rosario; Shamah-Levy, Teresa

2015-01-01

To describe de prevalence of iron deficiency (ID) and anemia in a sample of Mexican elderly population from the National Health and Nutrition Survey (Ensanut) 2012. 1 920 subjects ≥60 years of age were included. Hemoglobin, serum concentrations of ferritin and CRP were measured. The risk for ID and anemia adjusted for potential confounders was assessed in logistic regression models. The overall prevalence of anemia was 13.9%, 15.2% in males and 12.8% females. For ID, overall it was 4.2%, males 4.0% and females 4.3%. The greatest prevalence of ID was found in males and females over 80 years old (6.9 and 7.0%, respectively). ID was present in 1.5 of 10 Mexican elders with anemia. The prevalence of anemia was high in the elderly, however the prevalence of ID was low; there is a need to further investigate the causes of anemia in this age group.

ACE Gene I/D Polymorphism and Obesity in 1,574 Patients with Type 2 Diabetes Mellitus.

PubMed

Pan, Yan-Hong; Wang, Min; Huang, Yan-Mei; Wang, Ying-Hui; Chen, Yin-Ling; Geng, Li-Jun; Zhang, Xiao-Xi; Zhao, Hai-Lu

2016-01-01

Association between ACE gene I/D polymorphism and the risk of overweight/obesity remains controversial. We investigated the possible relationship between ACE gene I/D polymorphism and obesity in Chinese type 2 diabetes mellitus (T2DM) patients. In this study, obesity was defined as a body mass index (BMI) value ≥ 25 kg/m 2 and subjects were classified into 4 groups (lean, normal, overweight, and obese). PCR (polymerase chain reaction) was used to detect the ACE gene I/D polymorphism in T2DM patients. Metabolic measurements including blood glucose, lipid profile, and blood pressure were obtained. Frequencies of the ACE genotypes (DD, ID, and II) were not significant among the 4 groups of BMI-defined patients ( P = 0.679) while ACE II carriers showed higher systolic blood pressure (SBP) and pulse pressure (PP) (all P < 0.050). Hyperglycemia, hypertension, and dyslipidemia in these T2DM patients were found to be significantly associated with BMI. In conclusion, the relationship of ACE gene I/D polymorphism with obesity is insignificant in Chinese patients with T2DM. SBP and PP might be higher in the ACE II carriers than in the DD and ID carriers.

Expansion and maintenance of human embryonic stem cell–derived endothelial cells by TGFβ inhibition is Id1 dependent

PubMed Central

James, Daylon; Nam, Hyung-song; Seandel, Marco; Nolan, Daniel; Janovitz, Tyler; Tomishima, Mark; Studer, Lorenz; Lee, Gabsang; Lyden, David; Benezra, Robert; Zaninovic, Nikica; Rosenwaks, Zev; Rabbany, Sina Y; Rafii, Shahin

2010-01-01

Previous efforts to differentiate human embryonic stem cells (hESCs) into endothelial cells have not achieved sustained expansion and stability of vascular cells. To define vasculogenic developmental pathways and enhance differentiation, we used an endothelial cell–specific VE-cadherin promoter driving green fluorescent protein (GFP) (hVPr-GFP) to screen for factors that promote vascular commitment. In phase 1 of our method, inhibition of transforming growth factor (TGF)β at day 7 of differentiation increases hVPr-GFP+ cells by tenfold. In phase 2, TGFβ inhibition maintains the proliferation and vascular identity of purified endothelial cells, resulting in a net 36-fold expansion of endothelial cells in homogenous monolayers, which exhibited a transcriptional profile of Id1highVEGFR2highVE-cadherin+ ephrinB2+. Using an Id1-YFP hESC reporter line, we showed that TGFβ inhibition sustains Id1 expression in hESC-derived endothelial cells and that Id1 is required for increased proliferation and preservation of endothelial cell commitment. Our approach provides a serum-free method for differentiation and long-term maintenance of hESC-derived endothelial cells at a scale relevant to clinical application. PMID:20081865

Clinical iron deficiency disturbs normal human responses to hypoxia

PubMed Central

Frise, Matthew C.; Cheng, Hung-Yuan; Nickol, Annabel H.; Curtis, M. Kate; Pollard, Karen A.; Roberts, David J.; Ratcliffe, Peter J.; Dorrington, Keith L.; Robbins, Peter A.

2016-01-01

BACKGROUND. Iron bioavailability has been identified as a factor that influences cellular hypoxia sensing, putatively via an action on the hypoxia-inducible factor (HIF) pathway. We therefore hypothesized that clinical iron deficiency would disturb integrated human responses to hypoxia. METHODS. We performed a prospective, controlled, observational study of the effects of iron status on hypoxic pulmonary hypertension. Individuals with absolute iron deficiency (ID) and an iron-replete (IR) control group were exposed to two 6-hour periods of isocapnic hypoxia. The second hypoxic exposure was preceded by i.v. infusion of iron. Pulmonary artery systolic pressure (PASP) was serially assessed with Doppler echocardiography. RESULTS. Thirteen ID individuals completed the study and were age- and sex-matched with controls. PASP did not differ by group or study day before each hypoxic exposure. During the first 6-hour hypoxic exposure, the rise in PASP was 6.2 mmHg greater in the ID group (absolute rises 16.1 and 10.7 mmHg, respectively; 95% CI for difference, 2.7–9.7 mmHg, P = 0.001). Intravenous iron attenuated the PASP rise in both groups; however, the effect was greater in ID participants than in controls (absolute reductions 11.1 and 6.8 mmHg, respectively; 95% CI for difference in change, –8.3 to –0.3 mmHg, P = 0.035). Serum erythropoietin responses to hypoxia also differed between groups. CONCLUSION. Clinical iron deficiency disturbs normal responses to hypoxia, as evidenced by exaggerated hypoxic pulmonary hypertension that is reversed by subsequent iron administration. Disturbed hypoxia sensing and signaling provides a mechanism through which iron deficiency may be detrimental to human health. TRIAL REGISTRATION. ClinicalTrials.gov (NCT01847352). FUNDING. M.C. Frise is the recipient of a British Heart Foundation Clinical Research Training Fellowship (FS/14/48/30828). K.L. Dorrington is supported by the Dunhill Medical Trust (R178/1110). D.J. Roberts was

TGFβ-Id1 Signaling Opposes Twist1 and Promotes Metastatic Colonization Via a Mesenchymal-to-Epithelial Transition

PubMed Central

Stankic, Marko; Pavlovic, Svetlana; Chin, Yvette; Brogi, Edi; Padua, David; Norton, Larry; Massague, Joan; Benezra, Robert

2014-01-01

SUMMARY ID genes are required for breast cancer colonization of the lungs, but the mechanism remains poorly understood. Here, we show that Id1 expression induces a stem-like phenotype in breast cancer cells, while retaining epithelial properties, contrary to the notion that cancer stem-like properties are inextricably linked to the mesenchymal state. During metastatic colonization, Id1 induces a mesenchymal-to-epithelial transition (MET), specifically in cells whose mesenchymal state is dependent on the Id1 target protein Twist1 but not at the primary site, where this state is controlled by the zinc-finger protein Snail1. Knockdown of Id expression in metastasizing cells prevents MET and dramatically reduces lung colonization. Furthermore, Id1 is induced by TGFβ only in cells that have first undergone EMT, demonstrating that EMT is a pre-requisite for subsequent Id1-induced MET during lung colonization. Collectively, these studies underscore the importance of Id-mediated phenotypic switching during distinct stages of breast cancer metastasis. PMID:24332369

[Iron Deficiency in Chronic Heart Failure: Diagnostic Algorithm and Present-Day Therapeutic Options].

PubMed

Doehner, Wolfram; Blankenberg, Stefan; Erdmann, Erland; Ertl, Georg; Hasenfuß, Gerd; Landmesser, Ulf; Pieske, Burkert; Schieffer, Bernhard; Schunkert, Heribert; von Haehling, Stephan; Zeiher, Andreas; Anker, Stefan D

2017-05-01

Iron deficiency (ID) occurs in up to 50% of patients with heart failure (HF). Even without presence of anaemia ID contributes to more severe symptoms, increased hospitalization and mortality. A number of randomized controlled trials demonstrated the clinical benefit of replenishment of iron stores with improvement of symptoms and fewer hospitalizations. Assessment of iron status should therefore become routine assessment in newly diagnosed and in symptomatic patients with HF. ID can be identified with simple and straightforward diagnostic steps. Assessment of Ferritin (indicating iron stores) and transferrin saturation (TSAT, indication capability to mobilise internal iron stores) are sufficient to detect ID. In this review a plain diagnostic algorithm for ID is suggested. Confounding factors for diagnosis and adequate treatment of ID in HF are discussed. A regular workup for iron deficiency parameters may benefit patients with heart failure by providing symptomatic improvements and fewer hospitalizations. © Georg Thieme Verlag KG Stuttgart · New York.

Iron Deficiency in Preschool Children with Autistic Spectrum Disorders

ERIC Educational Resources Information Center

Bilgic, Ayhan; Gurkan, Kagan; Turkoglu, Serhat; Akca, Omer Faruk; Kilic, Birim Gunay; Uslu, Runa

2010-01-01

Iron deficiency (ID) causes negative outcomes on psychomotor and behavioral development of infants and young children. Children with autistic spectrum disorders (ASD) are under risk for ID and this condition may increase the severity of psychomotor and behavioral problems, some of which already inherently exist in these children. In the present…

SNP ID-info: SNP ID searching and visualization platform.

PubMed

Yang, Cheng-Hong; Chuang, Li-Yeh; Cheng, Yu-Huei; Wen, Cheng-Hao; Chang, Phei-Lang; Chang, Hsueh-Wei

2008-09-01

Many association studies provide the relationship between single nucleotide polymorphisms (SNPs), diseases and cancers, without giving a SNP ID, however. Here, we developed the SNP ID-info freeware to provide the SNP IDs within inputting genetic and physical information of genomes. The program provides an "SNP-ePCR" function to generate the full-sequence using primers and template inputs. In "SNPosition," sequence from SNP-ePCR or direct input is fed to match the SNP IDs from SNP fasta-sequence. In "SNP search" and "SNP fasta" function, information of SNPs within the cytogenetic band, contig position, and keyword input are acceptable. Finally, the SNP ID neighboring environment for inputs is completely visualized in the order of contig position and marked with SNP and flanking hits. The SNP identification problems inherent in NCBI SNP BLAST are also avoided. In conclusion, the SNP ID-info provides a visualized SNP ID environment for multiple inputs and assists systematic SNP association studies. The server and user manual are available at http://bio.kuas.edu.tw/snpid-info.

GATA2 Deficiency and Epstein-Barr Virus Disease.

PubMed

Cohen, Jeffrey I

2017-01-01

GATA2 is a transcription factor that binds to the promoter of hematopoietic genes. Mutations in one copy of the gene are associated with haploinsufficiency and reduced levels of protein. This results in reduced numbers of several cell types important for immune surveillance including dendritic cells, monocytes, CD4, and NK cells, as well as impaired NK cell function. Recently, GATA2 has been associated with several different presentations of severe Epstein-Barr virus (EBV) disease including primary infection requiring repeated hospitalizations, chronic active EBV disease, EBV-associated hydroa vacciniforme with hemophagocytosis, and EBV-positive smooth muscle tumors. EBV was found predominantly in B cells in each of the cases in which it was studied, unlike most cases of chronic active EBV disease in which the virus is usually present in T or NK cells. The variety of EBV-associated diseases seen in patients with GATA2 deficiency suggest that additional forms of severe EBV disease may be found in patients with GATA2 deficiency in the future.

Akt1-Inhibitor of DNA binding2 is essential for growth cone formation and axon growth and promotes central nervous system axon regeneration

PubMed Central

Ko, Hyo Rim; Kwon, Il-Sun; Hwang, Inwoo; Jin, Eun-Ju; Shin, Joo-Ho; Brennan-Minnella, Angela M; Swanson, Raymond; Cho, Sung-Woo; Lee, Kyung-Hoon; Ahn, Jee-Yin

2016-01-01

Mechanistic studies of axon growth during development are beneficial to the search for neuron-intrinsic regulators of axon regeneration. Here, we discovered that, in the developing neuron from rat, Akt signaling regulates axon growth and growth cone formation through phosphorylation of serine 14 (S14) on Inhibitor of DNA binding 2 (Id2). This enhances Id2 protein stability by means of escape from proteasomal degradation, and steers its localization to the growth cone, where Id2 interacts with radixin that is critical for growth cone formation. Knockdown of Id2, or abrogation of Id2 phosphorylation at S14, greatly impairs axon growth and the architecture of growth cone. Intriguingly, reinstatement of Akt/Id2 signaling after injury in mouse hippocampal slices redeemed growth promoting ability, leading to obvious axon regeneration. Our results suggest that Akt/Id2 signaling is a key module for growth cone formation and axon growth, and its augmentation plays a potential role in CNS axonal regeneration. DOI: http://dx.doi.org/10.7554/eLife.20799.001 PMID:27938661

Endogenous Siderophore 2,5-Dihydroxybenzoic Acid Deficiency Promotes Anemia and Splenic Iron Overload in Mice

PubMed Central

Liu, Zhuoming; Ciocea, Alieta

2014-01-01

Eukaryotes produce a siderophore-like molecule via a remarkably conserved biosynthetic pathway. 3-OH butyrate dehydrogenase (BDH2), a member of the short-chain dehydrogenase (SDR) family of reductases, catalyzes a rate-limiting step in the biogenesis of the mammalian siderophore 2,5-dihydroxybenzoic acid (2,5-DHBA). Depletion of the mammalian siderophore by inhibiting expression of bdh2 results in abnormal accumulation of intracellular iron and mitochondrial iron deficiency in cultured mammalian cells, as well as in yeast cells and zebrafish embryos We disrupted murine bdh2 by homologous recombination to analyze the effect of bdh2 deletion on erythropoiesis and iron metabolism. bdh2 null mice developed microcytic anemia and tissue iron overload, especially in the spleen. Exogenous supplementation with 2,5-DHBA alleviates splenic iron overload in bdh2 null mice. Additionally, bdh2 null mice exhibit reduced serum iron. Although BDH2 has been proposed to oxidize ketone bodies, we found that BDH2 deficiency did not alter ketone body metabolism in vivo. In sum, our findings demonstrate a key role for BDH2 in erythropoiesis. PMID:24777603

Hypothyroxinemia induced by mild iodine deficiency deregulats thyroid proteins during gestation and lactation in dams.

PubMed

Wei, Wei; Wang, Yi; Dong, Jing; Wang, Yuan; Min, Hui; Song, Binbin; Shan, Zhongyan; Teng, Weiping; Xi, Qi; Chen, Jie

2013-08-02

The main object of the present study was to explore the effect on thyroidal proteins following mild iodine deficiency (ID)-induced maternal hypothyroxinemia during pregnancy and lactation. In the present study, we established a maternal hypothyroxinemia model in female Wistar rats by using a mild ID diet. Maternal thyroid iodine content and thyroid weight were measured. Expressions of thyroid-associated proteins were analyzed. The results showed that the mild ID diet increased thyroid weight, decreased thyroid iodine content and increased expressions of thyroid transcription factor 1, paired box gene 8 and Na+/I- symporter on gestational day (GD) 19 and postpartum days (PN) 21 in the maternal thyroid. Moreover, the up-regulated expressions of type 1 iodothyronine deiodinase (DIO1) and type 2 iodothyronine deiodinase (DIO2) were detected in the mild ID group on GD19 and PN21. Taken together, our data indicates that during pregnancy and lactation, a maternal mild ID could induce hypothyroxinemia and increase the thyroidal DIO1 and DIO2 levels.

Aberrant expression of IFN-γ in Th2 cells from Th2 LCR-deficient mice.

PubMed

Hwang, Soo Seok; Kim, Kiwan; Lee, Wonyong; Lee, Gap Ryol

2012-08-03

The Th2 locus control region (LCR) has been shown to be a crucial cis-acting element for Th2 cytokine expression and Th2 cell differentiation. To study the role of Th2 LCR in ifng locus regulation, we examined the expression of IFN-γ in Th2 cells from Th2 LCR-deficient mice. We found IFN-γ to be aberrantly up-regulated. In addition, histone 3(H3)-acetylation and histone 3 lysine 4 (H3-K4)-methylation greatly increased at the ifng locus of the Th2 cells. GATA-3 and STAT6 bound to the ifng promoter in Th2 cells from the wild type but not from the Th2 LCR-deficient mice, and they directly repressed ifng expression in transient reporter assay. Moreover, ectopic expression of GATA-3 and STAT6-VT repressed the aberrant expression of the ifng gene and restored repressive chromatin state at the ifng locus in Th2 cells from Th2 LCR-deficient mice. These results suggest that expression of the ifng gene and chromatin remodeling of the ifng locus are under the control of a Th2 LCR-mediated Th2 differentiation program. Copyright © 2012 Elsevier Inc. All rights reserved.

What Is the Real Public Health Significance of Iron Deficiency and Iron Deficiency Anaemia in Croatia? A Population-Based Observational Study on Pregnant Women at Early Pregnancy from Eastern Croatia.

PubMed

Banjari, Ines; Kenjerić, Daniela; Mandić, Milena L

2015-06-01

Studies imply that significance of iron deficiency (ID) and iron deficiency anaemia (IDA) for pregnancy outcomes is especially highlighted in the early pregnancy. Prevalence around the world varies widely, however, no data is available up to date for Croatia or neighbouring countries. Therefore, the objective was to determine the prevalence of ID and IDA among pregnant women from Croatia at the first trimester. Also, the aim was to compare two criterions; the World Health Organization (WHO) one and the clinical one. Randomised observational population based study was set up and 265 pregnant women at the first trimester were enrolled. Based on the WHO criteria, 17.7% on haemoglobin basis and 18.5% on haematocrit basis had either ID or IDA. Clinical criteria showed that even 32.8% had either ID or IDA (transferrin saturation <20.0%). The WHO criterion shows less sensitivity, especially in detecting less severe stages of IDA. Regardless of the criteria used, ID and IDA present a mild to moderate public health problem in pregnant women population. This high share of pregnant women who are starting their pregnancy as iron deficient, presents a potentially high risk for the pregnancy outcomes, especially in terms of a newborn, and it is fully justified to treat them as diseases of public health significance. Copyright© by the National Institute of Public Health, Prague 2015.

Activation of the Yeast UBI4 Polyubiquitin Gene by Zap1 Transcription Factor via an Intragenic Promoter Is Critical for Zinc-deficient Growth*

PubMed Central

MacDiarmid, Colin W.; Taggart, Janet; Jeong, Jeeyon; Kerdsomboon, Kittikhun; Eide, David J.

2016-01-01

Stability of many proteins requires zinc. Zinc deficiency disrupts their folding, and the ubiquitin-proteasome system may help manage this stress. In Saccharomyces cerevisiae, UBI4 encodes five tandem ubiquitin monomers and is essential for growth in zinc-deficient conditions. Although UBI4 is only one of four ubiquitin-encoding genes in the genome, a dramatic decrease in ubiquitin was observed in zinc-deficient ubi4Δ cells. The three other ubiquitin genes were strongly repressed under these conditions, contributing to the decline in ubiquitin. In a screen for ubi4Δ suppressors, a hypomorphic allele of the RPT2 proteasome regulatory subunit gene (rpt2E301K) suppressed the ubi4Δ growth defect. The rpt2E301K mutation also increased ubiquitin accumulation in zinc-deficient cells, and by using a ubiquitin-independent proteasome substrate we found that proteasome activity was reduced. These results suggested that increased ubiquitin supply in suppressed ubi4Δ cells was a consequence of more efficient ubiquitin release and recycling during proteasome degradation. Degradation of a ubiquitin-dependent substrate was restored by the rpt2E301K mutation, indicating that ubiquitination is rate-limiting in this process. The UBI4 gene was induced ∼5-fold in low zinc and is regulated by the zinc-responsive Zap1 transcription factor. Surprisingly, Zap1 controls UBI4 by inducing transcription from an intragenic promoter, and the resulting truncated mRNA encodes only two of the five ubiquitin repeats. Expression of a short transcript alone complemented the ubi4Δ mutation, indicating that it is efficiently translated. Loss of Zap1-dependent UBI4 expression caused a growth defect in zinc-deficient conditions. Thus, the intragenic UBI4 promoter is critical to preventing ubiquitin deficiency in zinc-deficient cells. PMID:27432887

A proangiogenic signaling axis in myeloid cells promotes malignant progression of glioma.

PubMed

Huang, Yujie; Rajappa, Prajwal; Hu, Wenhuo; Hoffman, Caitlin; Cisse, Babacar; Kim, Joon-Hyung; Gorge, Emilie; Yanowitch, Rachel; Cope, William; Vartanian, Emma; Xu, Raymond; Zhang, Tuo; Pisapia, David; Xiang, Jenny; Huse, Jason; Matei, Irina; Peinado, Hector; Bromberg, Jacqueline; Holland, Eric; Ding, Bi-Sen; Rafii, Shahin; Lyden, David; Greenfield, Jeffrey

2017-05-01

Tumors are capable of coopting hematopoietic cells to create a suitable microenvironment to support malignant growth. Here, we have demonstrated that upregulation of kinase insert domain receptor (KDR), also known as VEGFR2, in a myeloid cell sublineage is necessary for malignant progression of gliomas in transgenic murine models and is associated with high-grade tumors in patients. KDR expression increased in myeloid cells as myeloid-derived suppressor cells (MDSCs) accumulated, which was associated with the transformation and progression of low-grade fibrillary astrocytoma to high-grade anaplastic gliomas. KDR deficiency in murine BM-derived cells (BMDCs) suppressed the differentiation of myeloid lineages and reduced granulocytic/monocytic populations. The depletion of myeloid-derived KDR compromised its proangiogenic function, which inhibited the angiogenic switch necessary for malignant progression of low-grade to high-grade tumors. We also identified inhibitor of DNA binding protein 2 (ID2) as a key upstream regulator of KDR activation during myeloid differentiation. Deficiency of ID2 in BMDCs led to downregulation of KDR, suppression of proangiogenic myeloid cells, and prevention of low-grade to high-grade transition. Tumor-secreted TGF-β and granulocyte-macrophage CSF (GM-CSF) enhanced the KDR/ID2 signaling axis in BMDCs. Our results suggest that modulation of KDR/ID2 signaling may restrict tumor-associated myeloid cells and could potentially be a therapeutic strategy for preventing transformation of premalignant gliomas.

A proangiogenic signaling axis in myeloid cells promotes malignant progression of glioma

PubMed Central

Huang, Yujie; Rajappa, Prajwal; Hu, Wenhuo; Hoffman, Caitlin; Cisse, Babacar; Kim, Joon-Hyung; Gorge, Emilie; Yanowitch, Rachel; Cope, William; Vartanian, Emma; Xu, Raymond; Pisapia, David; Xiang, Jenny; Huse, Jason; Matei, Irina; Peinado, Hector; Bromberg, Jacqueline; Holland, Eric; Ding, Bi-sen; Rafii, Shahin; Lyden, David; Greenfield, Jeffrey

2017-01-01

Tumors are capable of coopting hematopoietic cells to create a suitable microenvironment to support malignant growth. Here, we have demonstrated that upregulation of kinase insert domain receptor (KDR), also known as VEGFR2, in a myeloid cell sublineage is necessary for malignant progression of gliomas in transgenic murine models and is associated with high-grade tumors in patients. KDR expression increased in myeloid cells as myeloid-derived suppressor cells (MDSCs) accumulated, which was associated with the transformation and progression of low-grade fibrillary astrocytoma to high-grade anaplastic gliomas. KDR deficiency in murine BM-derived cells (BMDCs) suppressed the differentiation of myeloid lineages and reduced granulocytic/monocytic populations. The depletion of myeloid-derived KDR compromised its proangiogenic function, which inhibited the angiogenic switch necessary for malignant progression of low-grade to high-grade tumors. We also identified inhibitor of DNA binding protein 2 (ID2) as a key upstream regulator of KDR activation during myeloid differentiation. Deficiency of ID2 in BMDCs led to downregulation of KDR, suppression of proangiogenic myeloid cells, and prevention of low-grade to high-grade transition. Tumor-secreted TGF-β and granulocyte-macrophage CSF (GM-CSF) enhanced the KDR/ID2 signaling axis in BMDCs. Our results suggest that modulation of KDR/ID2 signaling may restrict tumor-associated myeloid cells and could potentially be a therapeutic strategy for preventing transformation of premalignant gliomas. PMID:28394259

Repeated whiskey binges promote liver injury in rats fed a choline-deficient diet.

PubMed

Nieto, Natalia; Rojkind, Marcos

2007-02-01

Alcoholic liver disease is associated with nutritional deficiency and it may aggravate within the context of fatty liver. We investigated the relationship between alcohol intake (whiskey binge drinking) and a choline-deficient diet (CD) and assessed whether stellate cells could contribute to liver injury in this model. Rats fed the CD diet plus whiskey showed increased liver damage compared to rats fed the CD diet, as demonstrated by H&E staining, elevated transaminases, steatosis, TNF-alpha levels, enhanced CYP2E1 activity, impaired antioxidant defense, elevated lipid peroxidation, and protein carbonyls. The combined treatment triggered an apoptotic response as determined by elevated Bax, caspase-3 activity, cytochrome-c release, and decreased Bcl-2 and Bcl-XL. Stellate cells were activated as increased expression of alpha-Sma was observed over that by the CD diet alone. The combined treatment shifted extracellular matrix remodeling towards a pro-fibrogenic response due to up-regulation of collagen I, TIMP1, and Hsp47 proteins, along with down-regulation of MMP13, MMP2, and MMP9 expression, proteases which degrade collagen I. These events were accompanied by increased phosphorylation of p38, a kinase that elevates collagen I. Repeated alcohol binges in the context of mild steatosis may promote activation of stellate cells and contribute to liver injury.

Anaemia in infancy in rural Bangladesh: contribution of iron deficiency, infections and poor feeding practices.

PubMed

Rawat, Rahul; Saha, Kuntal Kumar; Kennedy, Andrew; Rohner, Fabian; Ruel, Marie; Menon, Purnima

2014-01-14

Few data exist on the aetiology of anaemia and Fe deficiency (ID) during early infancy in South Asia. The present study aimed to determine the contribution of ID, infections and feeding practices to anaemia in Bangladeshi infants aged 6-11 months. Baseline data from 1600 infants recruited into a cluster-randomised trial testing the effectiveness of micronutrient powder sales by frontline health workers on the prevalence of anaemia were used. Multivariate logistic regression was used to identify risk factors for anaemia and ID, and population attributable fractions (PAF) were computed to estimate the proportion of anaemia that might be prevented by the elimination of individual risk factors. It was found that 68 % of the infants were anaemic, 56 % were Fe deficient, and one-third had evidence of subclinical infections. The prevalence of anaemia and ID increased rapidly, until 8-9 months of age, while that of subclinical infections was constant. ID (adjusted OR (AOR) 2·6-5·0; P< 0·001) and subclinical infections (AOR 1·4-1·5; P< 0·01) were major risk factors for anaemia, in addition to age and male sex. Similarly, subclinical infections, age and male sex were significant risk factors for ID. Previous-day consumption of Fe-rich foods was very low and not associated with anaemia or ID. The PAF of anaemia attributable to ID was 67 % (95 % CI 62, 71) and that of subclinical infections was 16 % (95 % CI 11, 20). These results suggest that a multipronged strategy that combines improvements in dietary Fe intake alongside infection control strategies is needed to prevent anaemia during infancy in Bangladesh.

Arrhythmogenic right ventricular cardiomyopathy in Boxer dogs is associated with calstabin2 deficiency

PubMed Central

Oyama, Mark A.; Reiken, Steve; Lehnart, Stephan E.; Chittur, Sridar V.; Meurs, Kathryn M.; Stern, Joshua; Marks, Andrew R.

2010-01-01

Objective To examine the presence and effect of calstabin2-deficiency in Boxer dogs with arrhythmogenic right ventricular cardiomyopathy (ARVC). Animals Thirteen Boxer dogs with ARVC. Materials and methods Tissue samples were collected for histopathology, oligonucleotide microarray, PCR, immunoelectrophoresis, ryanodine channel immunoprecipitation and single-channel recordings, and calstabin2 DNA sequencing. Results In cardiomyopathic Boxer dogs, myocardial calstabin2 mRNA and protein were significantly decreased as compared to healthy control dogs (calstabin2 protein normalized to tetrameric cardiac ryanodine receptor (RyR2) complex: affected, 0.51 ± 0.04; control, 3.81 ± 0.22; P < 0.0001). Calstabin2 deficiency in diseased dog hearts was associated with a significantly increased open probability of single RyR2 channels indicating intracellular Ca2+ leak. PCR-based sequencing of the promoter, exonic and splice site regions of the canine calstabin2 gene did not identify any causative mutations. Conclusions Calstabin2 deficiency is a potential mechanism of Ca2+ leak-induced ventricular arrhythmias and heart disease in Boxer dogs with ARVC. PMID:18515204

UBR2 Enriched in p53 Deficient Mouse Bone Marrow Mesenchymal Stem Cell-Exosome Promoted Gastric Cancer Progression via Wnt/β-Catenin Pathway.

PubMed

Mao, Jiahui; Liang, Zhaofeng; Zhang, Bin; Yang, Huan; Li, Xia; Fu, Hailong; Zhang, Xu; Yan, Yongmin; Xu, Wenrong; Qian, Hui

2017-11-01

The deficiency or mutation of p53 has been linked to several types of cancers. The mesenchymal stem cell (MSC) is an important component in the tumor microenvironment, and exosomes secreted by MSCs can transfer bioactive molecules, including proteins and nucleic acid, to other cells in the tumor microenvironment to influence the progress of a tumor. However, whether the state of p53 in MSCs can impact the bioactive molecule secretion of exosomes to promote cancer progression and the regulatory mechanism remains elusive. Our study aimed to investigate the regulation of ubiquitin protein ligase E3 component n-recognin 2 (UBR2) enriched in exosomes secreted by p53 deficient mouse bone marrow MSC (p53 -/- mBMMSC) in gastric cancer progression in vivo and in vitro. We found that the concentration of exosome was significantly higher in p53 -/- mBMMSC than that in p53 wild-type mBMMSC (p53 +/+ mBMMSC). In particular, UBR2 was highly expressed in p53 -/- mBMMSC cells and exosomes. P53 -/- mBMMSC exosomes enriched UBR2 could be internalized into p53 +/+ mBMMSC and murine foregastric carcinoma (MFC) cells and induce the overexpression of UBR2 in these cells which elevated cell proliferation, migration, and the expression of stemness-related genes. Mechanistically, the downregulation of UBR2 in p53 -/- mBMMSC exosomes could reverse these actions. Moreover, a majority of Wnt family members, β-catenin, and its downstream genes (CD44, CyclinD1, CyclinD3, and C-myc) were significantly decreased in MFC knockdown UBR2 and β-catenin depletion, an additional depletion of UBR2 had no significant difference in the expression of Nanog, OCT4, Vimentin, and E-cadherin. Taken together, our findings indicated that p53 -/- mBMMSC exosomes could deliver UBR2 to target cells and promote gastric cancer growth and metastasis by regulating Wnt/β-catenin pathway. Stem Cells 2017;35:2267-2279. © 2017 AlphaMed Press.

Pitx2 promotes heart repair by activating the antioxidant response after cardiac injury

PubMed Central

Tao, Ge; Kahr, Peter C.; Morikawa, Yuka; Zhang, Min; Rahmani, Mahdis; Heallen, Todd R.; Li, Lele; Sun, Zhao; Olson, Eric N.; Amendt, Brad A.; Martin, James F.

2016-01-01

Summary Myocardial infarction results in compromised myocardial function with heart failure due to insufficient cardiomyocyte self-renewal1. Unlike lower vertebrates, mammalian hearts only have a transient neonatal renewal capacity2. Reactivating primitive reparative ability in the mature heart requires knowledge of the mechanisms promoting early heart repair. By testing an established Hippo-deficient heart regeneration model for renewal promoting factors, we found that Pitx2 expression was induced in injured, Hippo-deficient ventricles. Pitx2-deficient neonatal hearts failed to repair after apex resection while Pitx2-gain-of-function in adult cardiomyocytes conferred reparative ability after myocardial infarction. Genomic analyses indicated that Pitx2 activated genes encoding electron transport chain components and reactive oxygen species scavengers. A subset of Pitx2 target genes was cooperatively regulated with the Hippo effector, Yap. Furthermore, Nrf2, a regulator of antioxidant response3, directly regulated Pitx2 expression and subcellular localization. Pitx2 mutant myocardium had elevated reactive oxygen species levels while antioxidant supplementation suppressed the Pitx2-loss-of-function phenotype. These findings reveal a genetic pathway, activated by tissue damage that is essential for cardiac repair. PMID:27251288

Pitx2 promotes heart repair by activating the antioxidant response after cardiac injury.

PubMed

Tao, Ge; Kahr, Peter C; Morikawa, Yuka; Zhang, Min; Rahmani, Mahdis; Heallen, Todd R; Li, Lele; Sun, Zhao; Olson, Eric N; Amendt, Brad A; Martin, James F

2016-06-02

Myocardial infarction results in compromised myocardial function and heart failure owing to insufficient cardiomyocyte self-renewal. Unlike many vertebrates, mammalian hearts have only a transient neonatal renewal capacity. Reactivating primitive reparative ability in the mature mammalian heart requires knowledge of the mechanisms that promote early heart repair. By testing an established Hippo-deficient heart regeneration mouse model for factors that promote renewal, here we show that the expression of Pitx2 is induced in injured, Hippo-deficient ventricles. Pitx2-deficient neonatal mouse hearts failed to repair after apex resection, whereas adult mouse cardiomyocytes with Pitx2 gain-of-function efficiently regenerated after myocardial infarction. Genomic analyses indicated that Pitx2 activated genes encoding electron transport chain components and reactive oxygen species scavengers. A subset of Pitx2 target genes was cooperatively regulated with the Hippo pathway effector Yap. Furthermore, Nrf2, a regulator of the antioxidant response, directly regulated the expression and subcellular localization of Pitx2. Pitx2 mutant myocardium had increased levels of reactive oxygen species, while antioxidant supplementation suppressed the Pitx2 loss-of-function phenotype. These findings reveal a genetic pathway activated by tissue damage that is essential for cardiac repair.

Hypothyroxinemia Induced by Mild Iodine Deficiency Deregulats Thyroid Proteins during Gestation and Lactation in Dams

PubMed Central

Wei, Wei; Wang, Yi; Dong, Jing; Wang, Yuan; Min, Hui; Song, Binbin; Shan, Zhongyan; Teng, Weiping; Xi, Qi; Chen, Jie

2013-01-01

The main object of the present study was to explore the effect on thyroidal proteins following mild iodine deficiency (ID)-induced maternal hypothyroxinemia during pregnancy and lactation. In the present study, we established a maternal hypothyroxinemia model in female Wistar rats by using a mild ID diet. Maternal thyroid iodine content and thyroid weight were measured. Expressions of thyroid-associated proteins were analyzed. The results showed that the mild ID diet increased thyroid weight, decreased thyroid iodine content and increased expressions of thyroid transcription factor 1, paired box gene 8 and Na+/I− symporter on gestational day (GD) 19 and postpartum days (PN) 21 in the maternal thyroid. Moreover, the up-regulated expressions of type 1 iodothyronine deiodinase (DIO1) and type 2 iodothyronine deiodinase (DIO2) were detected in the mild ID group on GD19 and PN21. Taken together, our data indicates that during pregnancy and lactation, a maternal mild ID could induce hypothyroxinemia and increase the thyroidal DIO1 and DIO2 levels. PMID:23917811

The helix-loop-helix protein id1 controls stem cell proliferation during regenerative neurogenesis in the adult zebrafish telencephalon.

PubMed

Rodriguez Viales, Rebecca; Diotel, Nicolas; Ferg, Marco; Armant, Olivier; Eich, Julia; Alunni, Alessandro; März, Martin; Bally-Cuif, Laure; Rastegar, Sepand; Strähle, Uwe

2015-03-01

The teleost brain has the remarkable ability to generate new neurons and to repair injuries during adult life stages. Maintaining life-long neurogenesis requires careful management of neural stem cell pools. In a genome-wide expression screen for transcription regulators, the id1 gene, encoding a negative regulator of E-proteins, was found to be upregulated in response to injury. id1 expression was mapped to quiescent type I neural stem cells in the adult telencephalic stem cell niche. Gain and loss of id1 function in vivo demonstrated that Id1 promotes stem cell quiescence. The increased id1 expression observed in neural stem cells in response to injury appeared independent of inflammatory signals, suggesting multiple antagonistic pathways in the regulation of reactive neurogenesis. Together, we propose that Id1 acts to maintain the neural stem cell pool by counteracting neurogenesis-promoting signals. © 2014 AlphaMed Press.

Changes in Physiological Parameters after Combined Exercise according to the I/D Polymorphism of hUCP2 Gene in Middle-Aged Obese Females

PubMed Central

DUK OH, Sang

2014-01-01

Abstract Background The purpose of this study was to determine whether a 45 bp insertion/deletion (I/D) polymorphism in human uncoupling protein 2 (hUCP2) gene was associated with changes in several cardiovascular risk and physical fitness factors in response to combined exercise during 12 weeks in Korean middle-aged women. The changes in physiological parameters after combined exercise during 12 weeks were compared between each genotype subgroups of hUCP2 gene to clarify the inter-individual differences in exercised-induced changes according to genetic predisposition. Methods A total of 185 women aged over 40 years living in Seoul, Korea were participated in this study, and analyzed before and after 12 weeks on combined exercise including aerobic exercise and strength training for body composition, hemodynamic parameters, physical fitness and metabolic variables. A 45 bp I/D polymorphism in hUCP2 gene was genotyped by polymerase chain reaction (PCR) amplification and agarose gel electrophoresis method. Results Combined exercise program during 12 weeks indicated the significant health-promoting effects for our participants on multiple body composition, hemodynamic parameters, physical fitness factors and metabolic parameters, respectively. With respect to a 45 bp I/D polymorphism in hUCP2 gene, this polymorphism was significantly associated with baseline %body fat of our participants (P <.05). Moreover, this polymorphism was significantly associated with the changes in %body fat and serum triglyceride(TG) level after combined exercise program during 12 weeks(P <.05). Conclusion Our data suggest that a 45 bp I/D polymorphism in hUCP2 gene may at least in part contribute to the inter-individual differences on the changes in some clinical and metabolic parameters following combined exercise in middle-aged women. PMID:25909061

Selenium deficiency aggravates T-2 toxin-induced injury of primary neonatal rat cardiomyocytes through ER stress.

PubMed

Xu, Jing; Pan, Shengchi; Gan, Fang; Hao, Shu; Liu, Dandan; Xu, Haibin; Huang, Kehe

2018-04-01

Keshan disease is a potentially fatal cardiomyopathy in humans. Selenium deficiency, T-2 toxin, and myocarditis virus are thought to be the major factors contributing to Keshan disease. But the relationship among these three factors is poorly described. This study aims to explore whether selenium deficiency aggravates T-2 toxin-induced cardiomyocyte injury and its underlying mechanism. Cardiomyocytes were isolated from neonatal rat and cultured at the physiological (2.0 μM) or lower concentrations of selenium with different concentrations of T-2 toxin. Our results showed that selenium deficiencies aggravated T-2 toxin-induced cardiomyocyte injury in a concentration-dependent manner as demonstrated by MTT bioassay, LDH activity, reactive oxygen species levels and caspase 3 protein expressions. T-2 toxin treatment significantly increased mRNA expressions for stress proteins GRP78 and CHOP in cardiomyocytes compared with the control. Selenium deficiencies further promoted GRP78, CHOP and p-eIF2α expressions. Knockdown of CHOP by the specific small interfering RNA eliminated the effect of selenium deficiencies on T-2 toxin-induced injury. It could be concluded that selenium deficiency aggravates T-2 toxin-induced cardiomyocyte injury through initiating more aggressive endoplasmic reticulum stress. Copyright © 2018 Elsevier B.V. All rights reserved.

Beyond Stimulus Deprivation: Iron Deficiency and Cognitive Deficits in Postinstitutionalized Children

ERIC Educational Resources Information Center

Doom, Jenalee R.; Gunnar, Megan R.; Georgieff, Michael K.; Kroupina, Maria G.; Frenn, Kristin; Fuglestad, Anita J.; Carlson, Stephanie M.

2014-01-01

Children adopted from institutions have been studied as models of the impact of stimulus deprivation on cognitive development (Nelson, Bos, Gunnar, & Sonuga-Barke, 2011), but these children may also suffer from micronutrient deficiencies (Fuglestad et al., 2008). The contributions of iron deficiency (ID) and duration of deprivation on…

Inflammation and airway hyperresponsiveness after chlorine exposure are prolonged by Nrf2 deficiency in mice.

PubMed

Ano, Satoshi; Panariti, Alice; Allard, Benoit; O'Sullivan, Michael; McGovern, Toby K; Hamamoto, Yoichiro; Ishii, Yukio; Yamamoto, Masayuki; Powell, William S; Martin, James G

2017-01-01

Chlorine gas (Cl 2 ) is a potent oxidant and trigger of irritant induced asthma. We explored NF-E2-related factor 2 (Nrf2)-dependent mechanisms in the asthmatic response to Cl 2 , using Nrf2-deficient mice, buthionine sulfoximine (BSO), an inhibitor of glutathione (GSH) synthesis and sulforaphane (SFN), a phytochemical regulator of Nrf2. Airway inflammation and airway hyperresponsiveness (AHR) were assessed 24 and 48h after a 5-min nose-only exposure to 100ppm Cl 2 of Nrf2-deficient and wild type Balb/C mice treated with BSO or SFN. Animals were anesthetized, paralyzed and mechanically ventilated (FlexiVent™) and challenged with aerosolized methacholine. Bronchoalveolar lavage (BAL) was performed and lung tissues were harvested for assessment of gene expression. Cl 2 exposure induced a robust AHR and an intense neutrophilic inflammation that, although similar in Nrf2-deficient mice and wild-type mice at 24h after Cl 2 exposure, were significantly greater at 48h post exposure in Nrf2-deficient mice. Lung GSH and mRNA for Nrf2-dependent phase II enzymes (NQO-1 and GPX2) were significantly lower in Nrf2-deficient than wild-type mice after Cl 2 exposure. BSO reduced GSH levels and promoted Cl 2 -induced airway inflammation in wild-type mice, but not in Nrf2-deficient mice, whereas SFN suppressed Cl 2 -induced airway inflammation in wild-type but not in Nrf2-deficient mice. AHR was not affected by either BSO or SFN at 48h post Cl 2 exposure. Nrf2-dependent phase II enzymes play a role in the resolution of airway inflammation and AHR after Cl 2 exposure. Moderate deficiency of GSH affects the magnitude of acute inflammation but not AHR. Copyright © 2016 Elsevier Inc. All rights reserved.

Badging, Real ID

Science.gov Websites

. REAL ID LANL Impacts and Solutions The federal government has determined New Mexico is non-compliant Identification Cards whom will also become Non-Compliant. Access through LANL Vehicle Access Portals unaffected alternate ID if they are coming from "non-compliant" REAL-ID states LANS and the Field Office have

PINK1 deficiency impairs mitochondrial homeostasis and promotes lung fibrosis

PubMed Central

Bueno, Marta; Lai, Yen-Chun; Romero, Yair; Brands, Judith; St. Croix, Claudette M.; Kamga, Christelle; Corey, Catherine; Herazo-Maya, Jose D.; Sembrat, John; Lee, Janet S.; Duncan, Steve R.; Rojas, Mauricio; Shiva, Sruti; Chu, Charleen T.; Mora, Ana L.

2014-01-01

Although aging is a known risk factor for idiopathic pulmonary fibrosis (IPF), the pathogenic mechanisms that underlie the effects of advancing age remain largely unexplained. Some age-related neurodegenerative diseases have an etiology that is related to mitochondrial dysfunction. Here, we found that alveolar type II cells (AECIIs) in the lungs of IPF patients exhibit marked accumulation of dysmorphic and dysfunctional mitochondria. These mitochondrial abnormalities in AECIIs of IPF lungs were associated with upregulation of ER stress markers and were recapitulated in normal mice with advancing age in response to stimulation of ER stress. We found that impaired mitochondria in IPF and aging lungs were associated with low expression of PTEN-induced putative kinase 1 (PINK1). Knockdown of PINK1 expression in lung epithelial cells resulted in mitochondria depolarization and expression of profibrotic factors. Moreover, young PINK1-deficient mice developed similarly dysmorphic, dysfunctional mitochondria in the AECIIs and were vulnerable to apoptosis and development of lung fibrosis. Our data indicate that PINK1 deficiency results in swollen, dysfunctional mitochondria and defective mitophagy, and promotes fibrosis in the aging lung. PMID:25562319

Melanocortin 1 Receptor Deficiency Promotes Atherosclerosis in Apolipoprotein E-/- Mice.

PubMed

Rinne, Petteri; Kadiri, James J; Velasco-Delgado, Mauricio; Nuutinen, Salla; Viitala, Miro; Hollmén, Maija; Rami, Martina; Savontaus, Eriika; Steffens, Sabine

2018-02-01

The MC1-R (melanocortin 1 receptor) is expressed by monocytes and macrophages where it mediates anti-inflammatory actions. MC1-R also protects against macrophage foam cell formation primarily by promoting cholesterol efflux through the ABCA1 (ATP-binding cassette transporter subfamily A member 1) and ABCG1 (ATP-binding cassette transporter subfamily G member 1). In this study, we aimed to investigate whether global deficiency in MC1-R signaling affects the development of atherosclerosis. Apoe -/- (apolipoprotein E deficient) mice were crossed with recessive yellow (Mc1r e/e ) mice carrying dysfunctional MC1-R and fed a high-fat diet to induce atherosclerosis. Apoe -/- Mc1r e/e mice developed significantly larger atherosclerotic lesions in the aortic sinus and in the whole aorta compared with Apoe -/- controls. In terms of plaque composition, MC1-R deficiency was associated with less collagen and smooth muscle cells and increased necrotic core, indicative of more vulnerable lesions. These changes were accompanied by reduced Abca1 and Abcg1 expression in the aorta. Furthermore, Apoe -/- Mc1r e/e mice showed a defect in bile acid metabolism that aggravated high-fat diet-induced hypercholesterolemia and hepatic lipid accumulation. Flow cytometric analysis of leukocyte profile revealed that dysfunctional MC1-R enhanced arterial accumulation of classical Ly6C high monocytes and macrophages, effects that were evident in mice fed a normal chow diet but not under high-fat diet conditions. In support of enhanced arterial recruitment of Ly6C high monocytes, these cells had increased expression of L-selectin and P-selectin glycoprotein ligand 1. The present study highlights the importance of MC1-R in the development of atherosclerosis. Deficiency in MC1-R signaling exacerbates atherosclerosis by disturbing cholesterol handling and by increasing arterial monocyte accumulation. © 2017 The Authors.

Prenatal Iron Supplementation Reduces Maternal Anemia, Iron Deficiency, and Iron Deficiency Anemia in a Randomized Clinical Trial in Rural China, but Iron Deficiency Remains Widespread in Mothers and Neonates.

PubMed

Zhao, Gengli; Xu, Guobin; Zhou, Min; Jiang, Yaping; Richards, Blair; Clark, Katy M; Kaciroti, Niko; Georgieff, Michael K; Zhang, Zhixiang; Tardif, Twila; Li, Ming; Lozoff, Betsy

2015-08-01

Previous trials of prenatal iron supplementation had limited measures of maternal or neonatal iron status. The purpose was to assess effects of prenatal iron-folate supplementation on maternal and neonatal iron status. Enrollment occurred June 2009 through December 2011 in Hebei, China. Women with uncomplicated singleton pregnancies at ≤20 wk gestation, aged ≥18 y, and with hemoglobin ≥100 g/L were randomly assigned 1:1 to receive daily iron (300 mg ferrous sulfate) or placebo + 0.40 mg folate from enrollment to birth. Iron status was assessed in maternal venous blood (at enrollment and at or near term) and cord blood. Primary outcomes were as follows: 1) maternal iron deficiency (ID) defined in 2 ways as serum ferritin (SF) <15 μg/L and body iron (BI) <0 mg/kg; 2) maternal ID anemia [ID + anemia (IDA); hemoglobin <110 g/L]; and 3) neonatal ID (cord blood ferritin <75 μg/L or zinc protoporphyrin/heme >118 μmol/mol). A total of 2371 women were randomly assigned, with outcomes for 1632 women or neonates (809 placebo/folate, 823 iron/folate; 1579 mother-newborn pairs, 37 mothers, 16 neonates). Most infants (97%) were born at term. At or near term, maternal hemoglobin was significantly higher (+5.56 g/L) for iron vs. placebo groups. Anemia risk was reduced (RR: 0.53; 95% CI: 0.43, 0.66), as were risks of ID (RR: 0.74; 95% CI: 0.69, 0.79 by SF; RR: 0.65; 95% CI: 0.59, 0.71 by BI) and IDA (RR: 0.49; 95% CI: 0.38, 0.62 by SF; RR: 0.51; 95% CI: 0.40, 0.65 by BI). Most women still had ID (66.8% by SF, 54.7% by BI). Adverse effects, all minor, were similar by group. There were no differences in cord blood iron measures; >45% of neonates in each group had ID. However, dose-response analyses showed higher cord SF with more maternal iron capsules reported being consumed (β per 10 capsules = 2.60, P < 0.05). Prenatal iron supplementation reduced anemia, ID, and IDA in pregnant women in rural China, but most women and >45% of neonates had ID, regardless of

Dietary folate deficiency in pseudopregnant mice has no effect on homeobox A10 promoter methylation or expression.

PubMed

Long, Chunlan; He, Junlin; Liu, Xueqing; Chen, Xuemei; Gao, Rufei; Wang, Yingxiong; Ding, Yubin

2012-12-01

During the reproductive cycle, a number of genes controlling endometrial changes are regulated by DNA methylation, a common epigenetic modification. Because dietary folate affects DNA methylation, we determined whether a folate-deficient diet (FDD) alters DNA methylation in endometria of pseudopregnant mice, focusing on the homeobox A10 (Hoxa10) promoter. Mice were given an FDD or control diet for 40 to 45 days and examined on day 5 of pseudopregnancy. Compared to control mice, FDD mice had lower folate levels in liver and serum (P = .004). However, the FDD did not significantly affect DNA methylation within the cytosine-guanine dinucleotide (CpG)-rich Hoxa10 promoter, even when specific CpG sites were examined (P > .05). In endometrial tissue sections, the localization of anti-Hoxa10 staining was unchanged in FDD mice. Therefore, folate deficiency did not significantly affect promoter methylation or expression of Hoxa10.

High prevalence of anaemia among African migrants in Germany persists after exclusion of iron deficiency and erythrocyte polymorphisms.

PubMed

Müller, Sophie A; Amoah, Stephen K B; Meese, Stefanie; Spranger, Joachim; Mockenhaupt, Frank P

2015-09-01

Haematological parameters differ between individuals of African and European ancestry. However, respective data of first-generation African migrants are virtually absent. We assessed these in Ghanaian migrants living in Berlin, compared them with reference data from Germany and Ghana, and estimated the role of iron deficiency (ID) and erythrocyte polymorphisms in anaemia. A total of 576 Ghanaians (median age, 45 years) were analysed. Blood counts were performed, haemoglobinopathies and glucose-6-phosphate dehydrogenase (G6PD) deficiency were genotyped, and concentrations of ferritin and C-reactive protein were measured to define ID. Most individuals had resided in Germany for more than a decade (median, 18 years). By WHO definition, anaemia was present in 30.9% of females and 9.4% of males. Median haemoglobin (Hb) levels were lower than among Germans (women, -0.8 g/dl, men, -0.7 g/dl). However, applying reference values from Ghana, only 1.9% of the migrants were considered anaemic. Alpha-thalassaemia, Hb variants and G6PD deficiency were observed in 33.9%, 28.3% and 23.6%, respectively. ID was highly prevalent in women (32.0%; men, 3.9%). The population fraction of anaemia cases attributable to ID was 29.0% (alpha-thalassaemia, 13.6%; G6PD deficiency, 13.5%). Nevertheless, excluding ID, alpha-thalassaemia, G6PD deficiency and sickle cell disease, anaemia prevalence remained high (women, 18.4%; men, 6.5%), and was also high when applying uncensored thresholds proposed for African Americans (females, 19.3%; males, 7.8%). Iron deficiency and erythrocyte polymorphisms are common among first-generation Ghanaian migrants but explain only part of the increased prevalence of anaemia. Common Hb thresholds for the definition of anaemia may not be appropriate for this group. © 2015 John Wiley & Sons Ltd.

Preweaning iron deficiency increases non-contingent responding during cocaine self-administration in rats.

PubMed

Jenney, Christopher B; Alexander, Danielle N; Jones, Byron C; Unger, Erica L; Grigson, Patricia S

2016-12-01

Iron deficiency (ID) is the most prevalent single-nutrient deficiency worldwide. There is evidence that ID early in development (preweaning in rat) causes irreversible neurologic, behavioral, and motor development deficits. Many of these effects have been attributed to damage to dopamine systems, including ID-induced changes in transporter and receptor numbers in the striatum and nucleus accumbens. These mesolimbic dopaminergic neurons are, in part, responsible for mediating reward and thus play a key role in addiction. However, there has been relatively little investigation into the behavioral effects of ID on drug addiction. In 2002, we found that rats made ID from weaning (postnatal day 21) and throughout the experiment acquired cocaine self-administration significantly more slowly than controls and failed to increase responding when the dose of the drug was decreased. In the present study, we assessed addiction for self-administered cocaine in rats with a history of preweaning ID only during postnatal days 4 through 21, and iron replete thereafter. The results showed that while ID did not affect the number of cocaine infusions or the overall addiction-like behavior score, ID rats scored higher on a measure of continued responding for drug than did iron replete controls. This increase in responding, however, was less goal-directed as ID rats also responded more quickly to the non-rewarded manipulandum than did control rats. Thus, while ID early in infancy did not significantly increase addiction-like behaviors for cocaine in this small study, the pattern of data suggests a possible underlying learning or performance impairment. Future studies will be needed to elucidate the exact neuro-behavioral deficits that lead to the increase in indiscriminate responding for drug in rats with a history of perinatal ID. Copyright © 2016. Published by Elsevier Inc.

Prenatal Iron Supplementation Reduces Maternal Anemia, Iron Deficiency, and Iron Deficiency Anemia in a Randomized Clinical Trial in Rural China, but Iron Deficiency Remains Widespread in Mothers and Neonates123

PubMed Central

Zhao, Gengli; Xu, Guobin; Zhou, Min; Jiang, Yaping; Richards, Blair; Clark, Katy M; Kaciroti, Niko; Georgieff, Michael K; Zhang, Zhixiang; Tardif, Twila; Li, Ming; Lozoff, Betsy

2015-01-01

Background: Previous trials of prenatal iron supplementation had limited measures of maternal or neonatal iron status. Objective: The purpose was to assess effects of prenatal iron-folate supplementation on maternal and neonatal iron status. Methods: Enrollment occurred June 2009 through December 2011 in Hebei, China. Women with uncomplicated singleton pregnancies at ≤20 wk gestation, aged ≥18 y, and with hemoglobin ≥100 g/L were randomly assigned 1:1 to receive daily iron (300 mg ferrous sulfate) or placebo + 0.40 mg folate from enrollment to birth. Iron status was assessed in maternal venous blood (at enrollment and at or near term) and cord blood. Primary outcomes were as follows: 1) maternal iron deficiency (ID) defined in 2 ways as serum ferritin (SF) <15 μg/L and body iron (BI) <0 mg/kg; 2) maternal ID anemia [ID + anemia (IDA); hemoglobin <110 g/L]; and 3) neonatal ID (cord blood ferritin <75 μg/L or zinc protoporphyrin/heme >118 μmol/mol). Results: A total of 2371 women were randomly assigned, with outcomes for 1632 women or neonates (809 placebo/folate, 823 iron/folate; 1579 mother-newborn pairs, 37 mothers, 16 neonates). Most infants (97%) were born at term. At or near term, maternal hemoglobin was significantly higher (+5.56 g/L) for iron vs. placebo groups. Anemia risk was reduced (RR: 0.53; 95% CI: 0.43, 0.66), as were risks of ID (RR: 0.74; 95% CI: 0.69, 0.79 by SF; RR: 0.65; 95% CI: 0.59, 0.71 by BI) and IDA (RR: 0.49; 95% CI: 0.38, 0.62 by SF; RR: 0.51; 95% CI: 0.40, 0.65 by BI). Most women still had ID (66.8% by SF, 54.7% by BI). Adverse effects, all minor, were similar by group. There were no differences in cord blood iron measures; >45% of neonates in each group had ID. However, dose-response analyses showed higher cord SF with more maternal iron capsules reported being consumed (β per 10 capsules = 2.60, P < 0.05). Conclusions: Prenatal iron supplementation reduced anemia, ID, and IDA in pregnant women in rural China, but most women

Five years of health promoting work with bottle shops on the Central Coast of NSW Australia. How can we best ensure outlets check ID?

PubMed

Bauer, Lyndon; Smith, Jeff; Kajons, Nicole; Tutt, Doug

2018-04-24

Australian surveys indicate that a large proportion of packaged liquor outlets do not check identification for young people before selling alcohol to them. There are a substantial number of presentations to Emergency Departments from young people aged 15 to 17 years. This subgroup is second only to those aged 18 to 24 years. In the 15- to 17-year-old age group, supply from direct purchase or underage friends, who have purchased alcohol, represents substantial sources of alcohol that is more likely to be consumed without parental supervision. Teenagers 18-19 years of age approached a randomly selected sample of bottle shops, on the NSW Central Coast Region, to attempt to purchase alcohol without producing identification (ID). Legally we are unable to test with teens under the age of 18. If outlets do not check ID for customers 18 or 19 years of age, we propose they might not check identification for 15- to 17-year-olds. A raft of local interventions was employed over four-survey periods to attempt to reduce selling rates. The lowest alcohol sales without ID occurred in 2015 when NSW Liquor and Gaming successfully prosecuted a Central Coast outlet for an underage sale. The rate of alcohol sales without checking ID each year was as follows: 2012-43.8%, 2014-37.55%, 2015-21.5% and 2016-45%. Alcohol sales to young customers without checking ID are common, widespread and seemingly resistant to non-punitive interventions. The NSW Liquor Act could be modified to allow compliance testing and much more practical enforcement. While Central Coast bottle shops have a better record than other Australian areas showing some improvements with our non-punitive industry education interventions, the results need to improve substantially to stifle primary supply. © 2018 Australian Health Promotion Association.

Addiction to the IGF2-ID1-IGF2 circuit for maintenance of the breast cancer stem-like cells

PubMed Central

Tominaga, K; Shimamura, T; Kimura, N; Murayama, T; Matsubara, D; Kanauchi, H; Niida, A; Shimizu, S; Nishioka, K; Tsuji, E-i; Yano, M; Sugano, S; Shimono, Y; Ishii, H; Saya, H; Mori, M; Akashi, K; Tada, K-i; Ogawa, T; Tojo, A; Miyano, S; Gotoh, N

2017-01-01

The transcription factor nuclear factor-κB (NF-κB) has important roles for tumorigenesis, but how it regulates cancer stem cells (CSCs) remains largely unclear. We identified insulin-like growth factor 2 (IGF2) is a key target of NF-κB activated by HER2/HER3 signaling to form tumor spheres in breast cancer cells. The IGF2 receptor, IGF1 R, was expressed at high levels in CSC-enriched populations in primary breast cancer cells. Moreover, IGF2-PI3K (IGF2-phosphatidyl inositol 3 kinase) signaling induced expression of a stemness transcription factor, inhibitor of DNA-binding 1 (ID1), and IGF2 itself. ID1 knockdown greatly reduced IGF2 expression, and tumor sphere formation. Finally, treatment with anti-IGF1/2 antibodies blocked tumorigenesis derived from the IGF1Rhigh CSC-enriched population in a patient-derived xenograft model. Thus, NF-κB may trigger IGF2-ID1-IGF2-positive feedback circuits that allow cancer stem-like cells to appear. Then, they may become addicted to the circuits. As the circuits are the Achilles' heels of CSCs, it will be critical to break them for eradication of CSCs. PMID:27546618

PAR2 (Protease-Activated Receptor 2) Deficiency Attenuates Atherosclerosis in Mice.

PubMed

Jones, Shannon M; Mann, Adrien; Conrad, Kelsey; Saum, Keith; Hall, David E; McKinney, Lisa M; Robbins, Nathan; Thompson, Joel; Peairs, Abigail D; Camerer, Eric; Rayner, Katey J; Tranter, Michael; Mackman, Nigel; Owens, A Phillip

2018-06-01

PAR2 (protease-activated receptor 2)-dependent signaling results in augmented inflammation and has been implicated in the pathogenesis of several autoimmune conditions. The objective of this study was to determine the effect of PAR2 deficiency on the development of atherosclerosis. PAR2 mRNA and protein expression is increased in human carotid artery and mouse aortic arch atheroma versus control carotid and aortic arch arteries, respectively. To determine the effect of PAR2 deficiency on atherosclerosis, male and female low-density lipoprotein receptor-deficient ( Ldlr -/- ) mice (8-12 weeks old) that were Par2 +/+ or Par2 -/- were fed a fat- and cholesterol-enriched diet for 12 or 24 weeks. PAR2 deficiency attenuated atherosclerosis in the aortic sinus and aortic root after 12 and 24 weeks. PAR2 deficiency did not alter total plasma cholesterol concentrations or lipoprotein distributions. Bone marrow transplantation showed that PAR2 on nonhematopoietic cells contributed to atherosclerosis. PAR2 deficiency significantly attenuated levels of the chemokines Ccl2 and Cxcl1 in the circulation and macrophage content in atherosclerotic lesions. Mechanistic studies using isolated primary vascular smooth muscle cells showed that PAR2 deficiency is associated with reduced Ccl2 and Cxcl1 mRNA expression and protein release into the supernatant resulting in less monocyte migration. Our results indicate that PAR2 deficiency is associated with attenuation of atherosclerosis and may reduce lesion progression by blunting Ccl2 - and Cxcl1 -induced monocyte infiltration. © 2018 American Heart Association, Inc.

Stress Induces AMP-Dependent Loss of Potency Factors Id2 and Cdx2 in Early Embryos and Stem Cells

PubMed Central

Xie, Yufen; Awonuga, Awoniyi; Liu, Jian; Rings, Edmond; Puscheck, Elizabeth Ella

2013-01-01

The AMP-activated protein kinase (AMPK) mediates rapid, stress-induced loss of the inhibitor of differentiation (Id)2 in blastocysts and trophoblast stem cells (TSC), and a lasting differentiation in TSC. However, it is not known if AMPK regulates other potency factors or regulates them before the blastocyst stage. The caudal-related homeodomain protein (Cdx)2 is a regulatory gene for determining TSC, the earliest placental lineage in the preimplantation mouse embryo, but is expressed in the oocyte and in early cleavage stage embryos before TSC arise. We assayed the expression of putative potency-maintaining phosphorylated Cdx2 ser60 in the oocyte, two-cell stage embryo, blastocyst, and in TSC. We studied the loss of Cdx2 phospho ser60 expression induced by hyperosmolar stress and its underlying mechanisms. Hyperosmolar stress caused rapid loss of nuclear Cdx2 phospho ser60 and Id2 in the two-cell stage embryo by 0.5 h. Stress-induced Cdx2 phospho ser60 and Id2 loss is reversed by the AMPK inhibitor compound C and is induced by the AMPK agonist 5-amino-1-β-d-ribofuranosyl-imidazole-4-carboxamide in the absence of stress. In the two-cell stage embryo and TSC hyperosmolar, stress caused AMPK-mediated loss of Cdx2 phospho ser60 as detected by immunofluorescence and immunoblot. We propose that AMPK may be the master regulatory enzyme for mediating stress-induced loss of potency as AMPK is also required for stress-induced loss of Id2 in blastocysts and TSC. Since AMPK mediates potency loss in embryos and stem cells it will be important to measure, test mechanisms for, and manage the AMPK function to optimize the stem cell and embryo quality in vitro and in vivo. PMID:23316940

Timing, duration, and severity of iron deficiency in early development and motor outcomes at 9 months

PubMed Central

Santos, Denise CC; Angulo-Barroso, Rosa M; Li, Ming; Bian, Yang; Sturza, Julie; Richards, Blair; Lozoff, Betsy

2017-01-01

BACKGROUND/OBJECTIVES Poorer motor development is reported in infants with iron deficiency (ID). The role of timing, duration and severity is unclear. We assessed relations between ID timing, duration, and severity and gross motor scores, neurological integrity, and motor behavior quality at 9 months. METHODS Iron status was determined at birth and 9 months in otherwise healthy term Chinese infants. The 9-month motor evaluation included the Peabody Developmental Motor Scale (PDMS-2), Infant Neurological International Battery (INFANIB), and motor quality factor. Motor outcomes were analyzed by ID timing (fetal-neonatal, infancy), duration, and severity. For severity, we also considered maternal iron status. RESULTS Data were available for 1194 infants. Iron status was classified as fetal-neonatal and infancy ID (n=253), fetal-neonatal ID (n=256), infancy ID (n=288), and not ID (n=397). Compared with not ID, infants with fetal-neonatal or infancy ID had lower locomotion scores (effect size ds=0.19, 0.18) and those with ID in both periods (longer duration) had lower locomotion and overall PDMS-2 gross motor scores (ds=0.20, 0.18); ID groups did not differ. More severe ID in late pregnancy was associated with lower INFANIB Vestibular function (p=0.01), and total score (p=0.03). More severe ID in infancy was associated with lower scores for locomotion (p=0.03), overall gross motor (p=0.05). CONCLUSIONS Fetal-neonatal and/or infancy ID was associated with lower overall gross motor development and locomotion test scores at 9 months. Associations with ID severity varied by ID timing: more severe ID in late pregnancy, poorer neurological integrity; more severe ID in infancy, poorer gross motor development. PMID:29235557

Chronic Vitamin C Deficiency Promotes Redox Imbalance in the Brain but Does Not Alter Sodium-Dependent Vitamin C Transporter 2 Expression

PubMed Central

Paidi, Maya D.; Schjoldager, Janne G.; Lykkesfeldt, Jens; Tveden-Nyborg, Pernille

2014-01-01

Vitamin C (VitC) has several roles in the brain acting both as a specific and non-specific antioxidant. The brain upholds a very high VitC concentration and is able to preferentially retain VitC even during deficiency. The accumulation of brain VitC levels much higher than in blood is primarily achieved by the sodium dependent VitC transporter (SVCT2). This study investigated the effects of chronic pre-and postnatal VitC deficiency as well as the effects of postnatal VitC repletion, on brain SVCT2 expression and markers of oxidative stress in young guinea pigs. Biochemical analyses demonstrated significantly decreased total VitC and an increased percentage of dehydroascorbic acid, as well as increased lipid oxidation (malondialdehyde), in the brains of VitC deficient animals (p < 0.0001) compared to controls. VitC repleted animals were not significantly different from controls. No significant changes were detected in either gene or protein expression of SVCT2 between groups or brain regions. In conclusion, chronic pre-and postnatal VitC deficiency increased brain redox imbalance but did not increase SVCT2 expression. Our findings show potential implications for VitC deficiency induced negative effects of redox imbalance in the brain and provide novel insight to the regulation of VitC in the brain during deficiency. PMID:24787032

A high prevalence of zinc- but not iron-deficiency among women in rural Malawi: a cross-sectional study.

PubMed

Siyame, Edwin W P; Hurst, Rachel; Wawer, Anna A; Young, Scott D; Broadley, Martin R; Chilimba, Allan D C; Ander, Louise E; Watts, Michael J; Chilima, Benson; Gondwe, Jellita; Kang'ombe, Dalitso; Kalimbira, Alexander; Fairweather-Tait, Susan J; Bailey, Karl B; Gibson, Rosalind S

2013-01-01

Zinc deficiency is often associated with nutritional iron deficiency (ID), and may be exacerbated by low selenium status. To investigate risk of iron and zinc deficiency in women with contrasting selenium status. In a cross-sectional study, 1-day diet composites and blood samples were collected from self-selected Malawian women aged 18-50 years from low- (Zombwe) (n=60) and high-plant-available soil selenium (Mikalango) (n=60) districts. Diets were analyzed for trace elements and blood for biomarkers. Zinc deficiency (>90 %) was greater than ID anemia (6 %), or ID (5 %), attributed to diets low in zinc (median 5.7 mg/day) with high phytate:zinc molar ratios (20.0), but high in iron (21.0 mg/day) from soil contaminant iron. Zombwe compared to Mikalango women had lower (p<0.05) intakes of selenium (6.5 vs. 55.3 µg/day), zinc (4.8 vs. 6.4 mg/day), iron (16.6 vs. 29.6 mg/day), lower plasma selenium (0.72 vs. 1.60 µmol/L), and higher body iron (5.3 vs. 3.8 mg/kg), although plasma zinc was similar (8.60 vs. 8.87 µmol/L). Body iron and plasma zinc were positive determinants of hemoglobin. Risk of zinc deficiency was higher than ID and was shown not to be associated with selenium status. Plasma zinc was almost as important as body iron as a hemoglobin determinant.

Intra-tumoral delivery of functional ID4 protein via PCL/maltodextrin nano-particle inhibits prostate cancer growth

PubMed Central

Morton, Derrick; Sharma, Pankaj; Gorantla, Yamini; Joshi, Jugal; Nagappan, Perri; Pallaniappan, Ravi; Chaudhary, Jaideep

2016-01-01

ID4, a helix loop helix transcriptional regulator has emerged as a tumor suppressor in prostate cancer. Epigenetic silencing of ID4 promotes prostate cancer whereas ectopic expression in prostate cancer cell lines blocks cancer phenotype. To directly investigate the anti-tumor property, full length human recombinant ID4 encapsulated in biodegradable Polycaprolactone/Maltodextrin (PCL-MD) nano-carrier was delivered to LNCaP cells in which the native ID4 was stably silenced (LNCaP(-)ID4). The cellular uptake of ID4 resulted in increased apoptosis, decreased proliferation and colony formation. Intratumoral delivery of PCL-MD ID4 into growing LNCaP(-)ID4 tumors in SCID mice significantly reduced the tumor volume compared to the tumors treated with chemotherapeutic Docetaxel. The study supports the feasibility of using nano-carrier encapsulated ID4 protein as a therapeutic. Mechanistically, ID4 may assimilate multiple regulatory pathways for example epigenetic re-programming, integration of multiple AR co-regulators or signaling pathways resulting in tumor suppressor activity of ID4. PMID:27487149

Estrogen Deficiency Promotes Cerebral Aneurysm Rupture by Upregulation of Th17 Cells and Interleukin-17A Which Downregulates E-Cadherin.

PubMed

Hoh, Brian L; Rojas, Kelley; Lin, Li; Fazal, Hanain Z; Hourani, Siham; Nowicki, Kamil W; Schneider, Matheus B; Hosaka, Koji

2018-04-13

Estrogen deficiency is associated with the development of cerebral aneurysms; however, the mechanism remains unknown. We explored the pathway of cerebral aneurysm development by investigating the potential link between estrogen deficiency and inflammatory factors. First, we established the role of interleukin-17 (IL-17)A. We performed a cytokine screen demonstrating that IL-17A is significantly expressed in mouse and human aneurysms ( P =0.03). Likewise, IL-17A inhibition was shown to prevent aneurysm formation by 42% ( P =0.02) and rupture by 34% ( P <0.05). Second, we found that estrogen deficiency upregulates T helper 17 cells and IL-17A and promotes aneurysm rupture. Estrogen-deficient mice had more ruptures than control mice (47% versus 7%; P =0.04). Estradiol supplementation or IL-17A inhibition decreased the number of ruptures in estrogen-deficient mice (estradiol 6% versus 37%; P =0.04; IL-17A inhibition 18% versus 47%; P =0.018). Third, we found that IL-17A-blockade protects against aneurysm formation and rupture by increased E-cadherin expression. IL-17-inhibited mice had increased E-cadherin expression ( P =0.003). E-cadherin inhibition reversed the protective effect of IL-17A inhibition and increased the rate of aneurysm formation (65% versus 28%; P =0.04) and rupture (12% versus 0%; P =0.22). However, E-cadherin inhibition alone does not significantly increase aneurysm formation in normal mice or in estrogen-deficient mice. In cell migration assays, E-cadherin inhibition promoted macrophage infiltration across endothelial cells ( P <0.05), which may be the mechanism for the estrogen deficiency/IL-17/E-cadherin aneurysm pathway. Our data suggest that estrogen deficiency promotes cerebral aneurysm rupture by upregulating IL-17A, which downregulates E-cadherin, encouraging macrophage infiltration in the aneurysm vessel wall. © 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Iodine deficiency a persisting problem: assessment of iodine nutrition and evaluation of thyroid nodular pathology in Portugal.

PubMed

Santos, J E C; Freitas, M; Fonseca, C P; Castilho, P; Carreira, I M; Rombeau, J L; Branco, M C

2017-02-01

The goal of eliminating iodine deficiency (ID) by the year 2000 has still not been achieved in several countries. More than 2 billion people worldwide (over 260 million school age children) remain ID. In Europe, there are still countries, such as Portugal, without national general population data on iodine nutrition (IN). This study aims at evaluating combined complementary data of the IN of the general population through urinary iodine concentration (UIC) and the thyroid histology profile from the inland region of Beira Interior (BI), in Portugal. UIC from a population sample of 214 volunteers (131 females and 83 males), with ages ranging from 8 to 97 years (mean 51.5 years ± SD 20.74 years), from BI was determined; the thyroid histology pattern in BI (6-year period) was evaluated; and the iodine content of the largest surface water reservoir of BI, never previously reported, was measured. Median UIC of 62.6 μg/L was measured. Over 92 % of the population had UIC less than 100 μg/L. From 279 histology reports evaluated, the incidence of the different types of thyroid nodular pathology in BI was established. There were 60 histologic diagnoses of malignancy. The observed ratio of papillary to follicular carcinoma relatively close to 1 and the fairly high percentage of anaplastic carcinomas are characteristic of ID areas. The findings of this first general population study on IN from the inland region of BI, Portugal, document significant ID. This problem, with its serious public health implications, could be corrected by having affordable iodised salt widely and generally available and by promoting a proactive population attitude generated by ample public information and educational programs as to the negative consequences of ID.

BMP9 induces EphrinB2 expression in endothelial cells through an Alk1-BMPRII/ActRII-ID1/ID3-dependent pathway: Implications for Hereditary Hemorrhagic Telangiectasia Type II

PubMed Central

Kim, Jai-Hyun; Peacock, Matthew R.; George, Steven C.; Hughes, Christopher C.W.

2012-01-01

ALK1 (ACVRL1) is a member of the TGFβ receptor family and is expressed predominantly by arterial endothelial cells (EC). Mutations in ACVRL1 are responsible for Hereditary Hemorrhagic Telangiectasia Type 2 (HHT2), a disease manifesting as fragile vessels, capillary overgrowth, and numerous arterio-venous malformations (AVMs). Arterial EC also express EphrinB2, which has multiple roles in vascular development and angiogenesis and is known to be reduced in ACVRL1 knockout mice. Using an in vitro angiogenesis model we find that the Alk1 ligand BMP9 induces EphrinB2 in EC, and this is entirely dependent on expression of Alk1 and at least one of the co-receptors BMPRII or ActRII. BMP9 induces both ID1 and ID3, and both are necessary for full induction of EphrinB2. Loss of Alk1 or EphrinB2 results in increased arterial-venous anastomosis, while loss of Alk1 but not EphrinB2 results in increased VEGFR2 expression and enhanced capillary sprouting. Conversely, BMP9 blocks EC sprouting and this is dependent on Alk1, BMPRII/ActRII and ID1/ID3. Finally, notch signaling overcomes the loss of Alk1 – restoring EphrinB2 expression in EC, and curbing excess sprouting. Thus, in an in vitro model of HHT2, loss of Alk1 blocks BMP9 signaling, resulting in reduced EphrinB2 expression, enhanced VEGFR2 expression, and misregulated EC sprouting and anastomosis. PMID:22622516

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

PubMed

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

2015-03-01

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

The biopsychology of salt hunger and sodium deficiency

PubMed Central

Hurley, Seth W.; Johnson, Alan Kim

2015-01-01

Sodium is a necessary dietary macromineral that tended to be sparsely distributed in mankind’s environment in the past. Evolutionary selection pressure shaped physiological mechanisms including hormonal systems and neural circuits that serve to promote sodium ingestion. Sodium deficiency triggers the activation of these hormonal systems and neural circuits to engage motivational processes that elicit a craving for salty substances and a state of reward when salty foods are consumed. Sodium deficiency also appears to be associated with aversive psychological states including anhedonia, impaired cognition, and fatigue. Under certain circumstances the psychological processes that promote salt intake can become powerful enough to cause “salt gluttony,” or salt intake far in excess of physiological need. The present review discusses three aspects of the biopsychology of salt hunger and sodium deficiency: 1) the psychological processes that promote salt intake during sodium deficiency, 2) the effects of sodium deficiency on mood and cognition, and 3) the sensitization of sodium appetite as a possible cause of salt gluttony. PMID:25572931

Calpain-2 Compensation Promotes Angiotensin II-Induced Ascending and Abdominal Aortic Aneurysms in Calpain-1 Deficient Mice

PubMed Central

Subramanian, Venkateswaran; Moorleghen, Jessica J.; Balakrishnan, Anju; Howatt, Deborah A.; Chishti, Athar H.; Uchida, Haruhito A.

2013-01-01

Background and Objective Recently, we demonstrated that angiotensin II (AngII)-infusion profoundly increased both aortic protein and activity of calpains, calcium-activated cysteine proteases, in mice. In addition, pharmacological inhibition of calpain attenuated AngII-induced abdominal aortic aneurysm (AA) in mice. Recent studies have shown that AngII infusion into mice leads to aneurysmal formation localized to the ascending aorta. However, the precise functional contribution of calpain isoforms (-1 or -2) in AngII-induced abdominal AA formation is not known. Similarly, a functional role of calpain in AngII-induced ascending AA remains to be defined. Using BDA-410, an inhibitor of calpains, and calpain-1 genetic deficient mice, we examined the relative contribution of calpain isoforms in AngII-induced ascending and abdominal AA development. Methodology/Results To investigate the relative contribution of calpain-1 and -2 in development of AngII-induced AAs, male LDLr −/− mice that were either calpain-1 +/+ or −/− were fed a saturated fat-enriched diet and infused with AngII (1,000 ng/kg/min) for 4 weeks. Calpain-1 deficiency had no significant effect on body weight or blood pressure during AngII infusion. Moreover, calpain-1 deficiency showed no discernible effects on AngII-induced ascending and abdominal AAs. Interestingly, AngII infusion induced increased expression of calpain-2 protein, thus compensating for total calpain activity in aortas of calpain-1 deficient mice. Oral administration of BDA-410, a calpain inhibitor, along with AngII-infusion significantly attenuated AngII-induced ascending and abdominal AA formation in both calpain-1 +/+ and −/− mice as compared to vehicle administered mice. Furthermore, BDA-410 administration attenuated AngII-induced aortic medial hypertrophy and macrophage accumulation. Western blot and immunostaining analyses revealed BDA-410 administration attenuated AngII-induced C-terminal fragmentation of filamin A, an

Antiaging Gene Klotho Deficiency Promoted High-Fat Diet-Induced Arterial Stiffening via Inactivation of AMP-Activated Protein Kinase.

PubMed

Lin, Yi; Chen, Jianglei; Sun, Zhongjie

2016-03-01

Klotho was originally discovered as an aging-suppressor gene. The objective of this study is to investigate whether klotho gene deficiency affects high-fat diet (HFD)-induced arterial stiffening. Heterozygous Klotho-deficient (KL(+/-)) mice and WT littermates were fed on HFD or normal diet. HFD increased pulse wave velocity within 5 weeks in KL(+/-) mice but not in wild-type mice, indicating that klotho deficiency accelerates and exacerbates HFD-induced arterial stiffening. A greater increase in blood pressure was found in KL(+/-) mice fed on HFD. Protein expressions of phosphorylated AMP-activated protein kinase-α (AMPKα), phosphorylated endothelial nitric oxide synthase (eNOS), and manganese-dependent superoxide dismutase (Mn-SOD) were decreased, whereas protein expressions of collagen I, transforming growth factor-β1, and Runx2 were increased in aortas of KL(+/-) mice fed on HFD. Interestingly, daily injections of an AMPKα activator, 5-aminoimidazole-4-carboxamide-3-ribonucleoside, abolished the increases in pulse wave velocity, blood pressure, and blood glucose in KL(+/-) mice fed on HFD. Treatment with 5-aminoimidazole-4-carboxamide-3-ribonucleoside for 2 weeks not only abolished the downregulation of phosphorylated AMPKα, phosphorylated eNOS, and Mn-SOD levels but also attenuated the increased levels of collagen I, transforming growth factor-β1, Runx2, superoxide, elastic lamellae breaks, and calcification in aortas of KL(+/-) mice fed on HFD. In cultured mouse aortic smooth muscle cells, cholesterol plus KL-deficient serum decreased phosphorylation levels of AMPKα and LKB1 (an important upstream regulator of AMPKα activity) but increased collagen I synthesis, which can be eliminated by activation of AMPKα by 5-aminoimidazole-4-carboxamide-3-ribonucleoside. In conclusions, Klotho deficiency promoted HFD-induced arterial stiffening and hypertension via downregulation of AMPKα activity. © 2016 American Heart Association, Inc.

Prenatal Iron Deficiency, Neonatal Ferritin, and Infant Cognitive Function

PubMed Central

Davidson, Leslie L.; Boivin, Michael J.; Zoumenou, Romeo; Massougbodji, Achille; Cot, Michel; Bodeau-Livinec, Florence

2016-01-01

OBJECTIVE: To investigate the impact of prenatal maternal iron deficiency (ID) on cord blood serum ferritin (CBSF) concentration and infant cognitive and motor development. METHODS: Our prospective cohort study included 636 mother-singleton child pairs from 828 eligible pregnant women who were enrolled during their first antenatal care (ANC) visit in Allada, Benin, into a clinical trial comparing the efficacy of mefloquine and sulfadoxine-pyrimethamine. Venous blood samples of women were assessed for ferritin and hemoglobin concentrations at the first and second ANC visits (occurring at least 1-month apart) and at delivery. Women were prescribed daily iron and folic acid supplements throughout pregnancy. Hematologic examinations were repeated for cord blood at birth. At age 1 year, cognitive and motor functions of children were assessed by using the Mullen Scales of Early Learning. RESULTS: The prevalence of prenatal ID at first and second ANC visits, and at delivery was 30.5%, 34.0%, and 28.4%, respectively. CBSF concentrations were similar between ID and non-ID pregnant women. Neither prenatal ID nor CBSF concentration was associated with poor cognitive or gross motor function of children at age 1 year. CBSF concentrations were lower among mothers who had ID anemia (IDA) at delivery compared with non-IDA pregnant women (adjusted mean difference: –0.2 [95% confidence interval: –0.4 to –0.0]). CONCLUSIONS: In a malaria-endemic region, ID in pregnancy in the context of iron supplementation is neither associated with CBSF concentration nor with infant cognitive and motor development. Prenatal IDA around the time of delivery is associated with lower CBSF concentrations. PMID:27940685

Protease-Activated Receptor-2 Deficiency Attenuates Atherosclerotic Lesion Progression and Instability in Apolipoprotein E-Deficient Mice

PubMed Central

Zuo, Pengfei; Zuo, Zhi; Zheng, Yueyue; Wang, Xin; Zhou, Qianxing; Chen, Long; Ma, Genshan

2017-01-01

Inflammatory mechanisms are involved in the process of atherosclerotic plaque formation and rupture. Accumulating evidence suggests that protease-activated receptor (PAR)-2 contributes to the pathophysiology of chronic inflammation on the vasculature. To directly examine the role of PAR-2 in atherosclerosis, we generated apolipoprotein E/PAR-2 double-deficient mice. Mice were fed with high-fat diet for 12 weeks starting at ages of 6 weeks. PAR-2 deficiency attenuated atherosclerotic lesion progression with reduced total lesion area, reduced percentage of stenosis and reduced total necrotic core area. PAR-2 deficiency increased fibrous cap thickness and collagen content of plaque. Moreover, PAR-2 deficiency decreased smooth muscle cell content, macrophage accumulation, matrix metallopeptidase-9 expression and neovascularization in plaque. Relative quantitative PCR assay using thoracic aorta revealed that PAR-2 deficiency reduced mRNA expression of inflammatory molecules, such as vascular cell adhesion molecule-1, intercellular adhesion molecule-1, tumor necrosis factor (TNF)-α and monocyte chemoattractant protein (MCP)-1. In vitro experiment, we found that PAR-2 deficiency reduced mRNA expression of interferon-γ, interleukin-6, TNF-α and MCP-1 in macrophage under unstimulated and lipopolysaccharide-stimulated conditions. These results suggest that PAR-2 deficiency attenuates the progression and instability of atherosclerotic plaque. PMID:28959204

BCM-95 and (2-hydroxypropyl)-β-cyclodextrin reverse autophagy dysfunction and deplete stored lipids in Sap C-deficient fibroblasts.

PubMed

Tatti, Massimo; Motta, Marialetizia; Scarpa, Susanna; Di Bartolomeo, Sabrina; Cianfanelli, Valentina; Tartaglia, Marco; Salvioli, Rosa

2015-08-01

Saposin (Sap) C deficiency is a rare variant form of Gaucher disease caused by impaired Sap C expression or accelerated degradation, and associated with accumulation of glucosylceramide and other lipids in the endo/lysosomal compartment. No effective therapies are currently available for the treatment of Sap C deficiency. We previously reported that a reduced amount and enzymatic activity of cathepsin (Cath) B and Cath D, and defective autophagy occur in Sap C-deficient fibroblasts. Here, we explored the use of two compounds, BCM-95, a curcumin derivative, and (2-hydroxypropyl)-β-cyclodextrin (HP-β-CD), to improve lysosomal function of Sap C-deficient fibroblasts. Immunofluorescence and biochemical studies documented that each compound promotes an increase of the expression levels and activities of Cath B and Cath D, and efficient clearance of cholesterol (Chol) and ceramide (Cer) in lysosomes. We provide evidence that BCM-95 and HP-β-CD enhance lysosomal function promoting autophagic clearance capacity and lysosome reformation. Our findings suggest a novel pharmacological approach to Sap C deficiency directed to treat major secondary pathological aspects in this disorder. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Prevalence and Determinants of Anemia and Iron Deficiency in Kuwait

PubMed Central

Al Zenki, Sameer; Alomirah, Husam; Al Hooti, Suad; Al Hamad, Nawal; Jackson, Robert T.; Rao, Aravinda; Al Jahmah, Nasser; Al Obaid, Ina’am; Al Ghanim, Jameela; Al Somaie, Mona; Zaghloul, Sahar; Al Othman, Amani

2015-01-01

The objective of this study was to assess the prevalence of anemia and iron deficiency (ID) of a nationally representative sample of the Kuwait population. We also determined if anemia differed by socioeconomic status or by RBC folate and vitamins A and B12 levels. The subjects who were made up of 1830 males and females between the ages of 2 months to 86 years, were divided into the following age groups (0–5, 5–11, 12–14, 15–19, 20–49, ≥50 years). Results showed that the prevalence of anemia was 3% in adult males and 17% in females. The prevalence of ID varied according to age between 4% (≥50 years) and 21% (5–11 years) and 9% (12–14 years) and 23% (15–19 years), respectively, in males and females. The prevalence of anemia and ID was higher in females compared to males. Adults with normal ferritin level, but with low RBC folate and vitamins A and B12 levels had higher prevalence of anemia than those with normal RBC folate and vitamins A and B12 levels. This first nationally representative nutrition and health survey in Kuwait indicated that anemia and ID are prevalent and ID contributes significantly to anemia prevalence. PMID:26264015

PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORα (PPARα) AGONISTS DIFFERENTIALLY REGULATE INHIBITOR OF DNA BINDING (ID2) EXPRESSION IN RODENTS AND HUMAN CELLS

EPA Science Inventory

Abstract Inhibitor of DNA binding (Id2) is a member of the helix-loop-helix (HLH) transcription factor family whose members play important roles in cell differentiation and proliferation. Id2 has been linked to the development of cardiovascular diseases since thiazolidinediones,...

Insulated hsp70B' promoter: stringent heat-inducible activity in replication-deficient, but not replication-competent adenoviruses.

PubMed

Rohmer, Stanimira; Mainka, Astrid; Knippertz, Ilka; Hesse, Andrea; Nettelbeck, Dirk M

2008-04-01

Key to the realization of gene therapy is the development of efficient and targeted gene transfer vectors. Therapeutic gene transfer by replication-deficient or more recently by conditionally replication-competent/oncolytic adenoviruses has shown much promise. For specific applications, however, it will be advantageous to provide vectors that allow for external control of gene expression. The efficient cellular heat shock system in combination with available technology for focused and controlled hyperthermia suggests heat-regulated transcription control as a promising tool for this purpose. We investigated the feasibility of a short fragment of the human hsp70B' promoter, with and without upstream insulator elements, for the regulation of transgene expression by replication-deficient or oncolytic adenoviruses. Two novel adenoviral vectors with an insulated hsp70B' promoter were developed and showed stringent heat-inducible gene expression with induction ratios up to 8000-fold. In contrast, regulation of gene expression from the hsp70B' promoter without insulation was suboptimal. In replication-competent/oncolytic adenoviruses regulation of the hsp70B' promoter was lost specifically during late replication in permissive cells and could not be restored by the insulators. We developed novel adenovirus gene transfer vectors that feature improved and stringent regulation of transgene expression from the hsp70B' promoter using promoter insulation. These vectors have potential for gene therapy applications that benefit from external modulation of therapeutic gene expression or for combination therapy with hyperthermia. Furthermore, our study reveals that vector replication can deregulate inserted cellular promoters, an observation which is of relevance for the development of replication-competent/oncolytic gene transfer vectors. (c) 2008 John Wiley & Sons, Ltd.

IDS contribution to ITRF2008

NASA Astrophysics Data System (ADS)

Valette, Jean-Jacques; Lemoine, Frank G.; Ferrage, Pascale; Yaya, Philippe; Altamimi, Zuheir; Willis, Pascal; Soudarin, Laurent

2010-12-01

For the first time, the International DORIS Service (IDS) has produced a technique level combination based on the contributions of seven analysis centers (ACs), including the European Space Operations Center (ESOC), Geodetic Observatory Pecny (GOP), Geoscience Australia (GAU), the NASA Goddard Space Flight Center (GSFC), the Institut Géographique National (IGN), the Institute of Astronomy, Russian Academy of Sciences (INASAN, named as INA), and CNES/CLS (named as LCA). The ACs used five different software packages to process the DORIS data from 1992 to 2008, including NAPEOS (ESA), Bernese (GOP), GEODYN (GAU, GSC), GIPSY/OASIS (INA), and GINS (LCA). The data from seven DORIS satellites, TOPEX/Poseidon, SPOT-2, SPOT-3, SPOT-4, SPOT-5, Envisat and Jason-1 were processed and all the analysis centers produced weekly SINEX files in either variance-covariance or normal equation format. The processing by the analysis centers used the latest GRACE-derived gravity models, forward modelling of atmospheric gravity, updates to the radiation pressure modelling to improve the DORIS geocenter solutions, denser parameterization of empirically determined drag coefficients to improve station and EOP solutions, especially near the solar maximum in 2001-2002, updated troposphere mapping functions, and an ITRF2005-derived station set for orbit determination, DPOD2005. The CATREF software was used to process the weekly AC solutions, and produce three iterations of an IDS global weekly combination. Between the development of the initial solution IDS-1, and the final solution, IDS-3, the ACs improved their analysis strategies and submitted updated solutions to eliminate troposphere-derived biases in the solution scale, to reduce drag-related degradations in station positioning, and to refine the estimation strategy to improve the combination geocenter solution. An analysis of the frequency content of the individual AC geocenter and scale solutions was used as the basis to define the

Level-2 Milestone 3504: Scalable Applications Preparations and Outreach for the Sequoia ID (Dawn)

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

Futral, W. Scott; Gyllenhaal, John C.; Hedges, Richard M.

2010-07-02

This report documents LLNL SAP project activities in anticipation of the ASC Sequoia system, ASC L2 milestone 3504: Scalable Applications Preparations and Outreach for the Sequoia ID (Dawn), due June 30, 2010.

IDS plot tools for time series of DORIS station positions and orbit residuals

NASA Astrophysics Data System (ADS)

Soudarin, L.; Ferrage, P.; Moreaux, G.; Mezerette, A.

2012-12-01

DORIS (Doppler Orbitography and Radiopositioning Integrated by Satellite) is a Doppler satellite tracking system developed for precise orbit determination and precise ground location. It is onboard the Cryosat-2, Jason-1, Jason-2 and HY-2A altimetric satellites and the remote sensing satellites SPOT-4 and SPOT-5. It also flew with SPOT-2, SPOT-3, TOPEX/POSEIDON and ENVISAT. Since 1994 and thanks to its worldwide distributed network of more than fifty permanent stations, DORIS contributes to the realization and maintenance of the ITRS (International Terrestrial Reference System). 3D positions and velocities of the reference sites at a cm and mm/yr accuracy lead to scientific studies in geodesy and geophysics. The primary objective of the International DORIS Service (IDS) is to provide a support, through DORIS data and products, to research and operational activities. In order to promote the use of the DORIS products, the IDS has made available on its web site (ids-doris.org) a new set of tools, called Plot tools, to interactively build and display graphs of DORIS station coordinates time series and orbit residuals. These web tools are STCDtool providing station coordinates time series (North, East, Up position evolution) from the IDS Analysis Centers, and POEtool providing statistics time series (orbit residuals and number of measurements for the DORIS stations) from CNES (the French Space Agency) Precise Orbit Determination processing. Complementary data about station and satellites events can also be displayed (e.g. antenna changes, system failures, degraded data...). Information about earthquakes obtained from USGS survey service can also be superimposed on the position time series. All these events can help in interpreting the discontinuities in the time series. The purpose of this presentation is to show the functionalities of these tools and their interest for the monitoring of the crustal deformation at DORIS sites.

Iron deficiency and anemia are prevalent in women with multiple gestations.

PubMed

Ru, Yuan; Pressman, Eva K; Cooper, Elizabeth M; Guillet, Ronnie; Katzman, Philip J; Kent, Tera R; Bacak, Stephen J; O'Brien, Kimberly O

2016-10-01

Little attention has been placed on the unique iron demands that may exist in women with multiple gestations. This merits attention because iron deficiency (ID) during pregnancy is associated with adverse pregnancy outcomes that are known to be more prevalent in multiple births. We characterized longitudinal changes in iron status across pregnancy in a cohort of healthy women with multiple gestations and identified determinants of maternal ID and anemia. A group of 83 women carrying twins, triplets, or quadruplets (aged 20-46 y) was recruited from 2011 to 2014. Blood samples obtained during pregnancy (∼24 wk; n = 73) and at delivery (∼35 wk; n = 61) were used to assess hemoglobin, serum ferritin (SF), soluble transferrin receptor (sTfR), hepcidin, serum iron, erythropoietin, serum folate, vitamin B-12, C-reactive protein, and interleukin-6. The prevalence of tissue ID (sTfR >8.5 mg/L) increased significantly from pregnancy to delivery (9.6% compared with 23%, P = 0.03). Women with depleted iron stores (SF <12 μg/L, n = 20) during pregnancy had a 2-fold greater risk of anemia at delivery, and 25% (n = 5) developed iron deficiency anemia (IDA). Overall, 44.6% of women studied (n = 37/83) were anemic at delivery, and 18% of women (n = 11/61) had IDA. Erythropoietin during pregnancy was significantly negatively associated with hemoglobin at delivery. Women with erythropoietin >75th percentile during pregnancy exhibited a 3-fold greater risk of anemia, suggesting that erythropoietin is a sensitive predictor of anemia at delivery. Inflammation was present at delivery, which limited the utility of ferritin or hepcidin as iron-status indicators at delivery. ID and anemia are highly prevalent in women with multiple gestations. Additional screening and iron supplementation may be warranted in this high-risk population given the known associations between ID anemia and adverse maternal and neonatal outcomes. This trial was registered at clinicaltrials.gov as NCT01582802

Prenatal Choline Supplementation Diminishes Early-Life Iron Deficiency-Induced Reprogramming of Molecular Networks Associated with Behavioral Abnormalities in the Adult Rat Hippocampus.

PubMed

Tran, Phu V; Kennedy, Bruce C; Pisansky, Marc T; Won, Kyoung-Jae; Gewirtz, Jonathan C; Simmons, Rebecca A; Georgieff, Michael K

2016-03-01

Early-life iron deficiency is a common nutrient deficiency worldwide. Maternal iron deficiency increases the risk of schizophrenia and autism in the offspring. Postnatal iron deficiency in young children results in cognitive and socioemotional abnormalities in adulthood despite iron treatment. The rat model of diet-induced fetal-neonatal iron deficiency recapitulates the observed neurobehavioral deficits. We sought to establish molecular underpinnings for the persistent psychopathologic effects of early-life iron deficiency by determining whether it permanently reprograms the hippocampal transcriptome. We also assessed the effects of maternal dietary choline supplementation on the offspring's hippocampal transcriptome to identify pathways through which choline mitigates the emergence of long-term cognitive deficits. Male rat pups were made iron deficient (ID) by providing pregnant and nursing dams an ID diet (4 g Fe/kg) from gestational day (G) 2 through postnatal day (PND) 7 and an iron-sufficient (IS) diet (200 g Fe/kg) thereafter. Control pups were provided IS diet throughout. Choline (5 g/kg) was given to half the pregnant dams in each group from G11 to G18. PND65 hippocampal transcriptomes were assayed by next generation sequencing (NGS) and analyzed with the use of knowledge-based Ingenuity Pathway Analysis. Real-time polymerase chain reaction was performed to validate a subset of altered genes. Formerly ID rats had altered hippocampal expression of 619 from >10,000 gene loci sequenced by NGS, many of which map onto molecular networks implicated in psychological disorders, including anxiety, autism, and schizophrenia. There were significant interactions between iron status and prenatal choline treatment in influencing gene expression. Choline supplementation reduced the effects of iron deficiency, including those on gene networks associated with autism and schizophrenia. Fetal-neonatal iron deficiency reprograms molecular networks associated with the

DE-Cadherin regulates unconventional Myosin ID and Myosin IC in Drosophila left-right asymmetry establishment.

PubMed

Petzoldt, Astrid G; Coutelis, Jean-Baptiste; Géminard, Charles; Spéder, Pauline; Suzanne, Magali; Cerezo, Delphine; Noselli, Stéphane

2012-05-01

In bilateria, positioning and looping of visceral organs requires proper left-right (L/R) asymmetry establishment. Recent work in Drosophila has identified a novel situs inversus gene encoding the unconventional type ID myosin (MyoID). In myoID mutant flies, the L/R axis is inverted, causing reversed looping of organs, such as the gut, spermiduct and genitalia. We have previously shown that MyoID interacts physically with β-Catenin, suggesting a role of the adherens junction in Drosophila L/R asymmetry. Here, we show that DE-Cadherin co-immunoprecipitates with MyoID and is required for MyoID L/R activity. We further demonstrate that MyoIC, a closely related unconventional type I myosin, can antagonize MyoID L/R activity by preventing its binding to adherens junction components, both in vitro and in vivo. Interestingly, DE-Cadherin inhibits MyoIC, providing a protective mechanism to MyoID function. Conditional genetic experiments indicate that DE-Cadherin, MyoIC and MyoID show temporal synchronicity for their function in L/R asymmetry. These data suggest that following MyoID recruitment by β-Catenin at the adherens junction, DE-Cadherin has a twofold effect on Drosophila L/R asymmetry by promoting MyoID activity and repressing that of MyoIC. Interestingly, the product of the vertebrate situs inversus gene inversin also physically interacts with β-Catenin, suggesting that the adherens junction might serve as a conserved platform for determinants to establish L/R asymmetry both in vertebrates and invertebrates.

Iron Deficiency Anemia and Cognitive Function in Infancy

PubMed Central

Carter, R. Colin; Jacobson, Joseph L.; Burden, Matthew J.; Armony-Sivan, Rinat; Dodge, Neil C.; Angelilli, Mary Lu; Lozoff, Betsy; Jacobson, Sandra W.

2011-01-01

OBJECTIVES This study examined effects of iron deficiency anemia (IDA) on specific domains of infant cognitive function and the role of IDA-related socioemotional deficits in mediating and/or moderating these effects. METHODS Infants were recruited during routine 9-month visits to an inner-city clinic. IDA was defined as hemoglobin level <110 g/L with ≥2 abnormal iron deficiency indicators (mean corpuscular volume, red cell distribution width, zinc protoporphyrin, transferrin saturation, and ferritin). At 9 and 12 months, the Fagan Test of Infant Intelligence (FTII); A-not-B task; Emotionality, Activity, and Sociability Temperament Survey; and Behavior Rating Scale were administered. Analyses were adjusted for potential confounders, including age and sociodemographic variables. RESULTS Twenty-eight infants met criteria for IDA, 28 had nonanemic iron deficiency (NA ID) and 21 had iron sufficiency (IS). There was a linear effect for object permanence at 9 months: infants with IDA were least likely to exhibit object permanence, IS most likely, and NA ID intermediate. Infants with IDA and those with hemoglobin level ≤105 g/L showed poorer recognition memory on the FTII than infants without IDA. The Behavior Rating Scale orientation/engagement measure partially mediated these effects. Stronger effects of IDA on these outcomes were seen in infants who scored more poorly on the socioemotional measures. CONCLUSIONS These data indicate poorer object permanence and short-term memory encoding and/or retrieval in infants with IDA at 9 months. These cognitive effects were attributable, in part, to IDA-related deficits in socioemotional function. Children with poor socioemotional performance seem to be more vulnerable to the effects of IDA on cognitive function. PMID:20660551

Iron deficiency anemia and cognitive function in infancy.

PubMed

Carter, R Colin; Jacobson, Joseph L; Burden, Matthew J; Armony-Sivan, Rinat; Dodge, Neil C; Angelilli, Mary Lu; Lozoff, Betsy; Jacobson, Sandra W

2010-08-01

This study examined effects of iron deficiency anemia (IDA) on specific domains of infant cognitive function and the role of IDA-related socioemotional deficits in mediating and/or moderating these effects. Infants were recruited during routine 9-month visits to an inner-city clinic. IDA was defined as hemoglobin level <110 g/L with > or =2 abnormal iron deficiency indicators (mean corpuscular volume, red cell distribution width, zinc protoporphyrin, transferrin saturation, and ferritin). At 9 and 12 months, the Fagan Test of Infant Intelligence (FTII); A-not-B task; Emotionality, Activity, and Sociability Temperament Survey; and Behavior Rating Scale were administered. Analyses were adjusted for potential confounders, including age and sociodemographic variables. Twenty-eight infants met criteria for IDA, 28 had nonanemic iron deficiency (NA ID) and 21 had iron sufficiency (IS). There was a linear effect for object permanence at 9 months: infants with IDA were least likely to exhibit object permanence, IS most likely, and NA ID intermediate. Infants with IDA and those with hemoglobin level < or =105 g/L showed poorer recognition memory on the FTII than infants without IDA. The Behavior Rating Scale orientation/engagement measure partially mediated these effects. Stronger effects of IDA on these outcomes were seen in infants who scored more poorly on the socioemotional measures. These data indicate poorer object permanence and short-term memory encoding and/or retrieval in infants with IDA at 9 months. These cognitive effects were attributable, in part, to IDA-related deficits in socioemotional function. Children with poor socioemotional performance seem to be more vulnerable to the effects of IDA on cognitive function.

TNFRp55 deficiency promotes the development of ectopic endometriotic-like lesions in mice.

PubMed

Vallcaneras, Sandra; Ghersa, Federica; Bastón, Juan; Delsouc, María Belén; Meresman, Gabriela; Casais, Marilina

2017-09-01

Endometriosis is an inflammatory disease depending on estradiol, with TNF-α being one of the most representative cytokines involved in its pathogenesis. TNF-α acts through its bond to the TNFRp55 and TNFRp75 membrane receptors. The aim of this study was to analyze the effect of the TNFRp55 deficiency on the development of ectopic endometriotic-like lesions. Endometriosis was induced surgically in mice of the C57BL/6 strain, wild type (WT) and TNFRp55-/- (KO). After four weeks, the peritoneal fluid was collected and the lesions were counted, measured with a caliper, removed, weighed, fixed or kept at -80°C. We evaluated the cell proliferation by proliferating cell nuclear antigen (PCNA) immunohistochemistry and apoptosis by TUNEL technique in the ectopic lesions. MMP-2 and MMP-9 activities (factors involved in invasiveness) were measured by zymography in the peritoneal fluid; estradiol and progesterone levels were measured by radioimmunoassay in the lesions and in the peritoneal fluid. We found that in KO animals the mean number of lesions established per mouse, the lesion volume, weight and cell proliferation increased and apoptosis decreased. In addition, the activity of MMP-2 and the estradiol level increased, whereas the progesterone level was not significantly modified. In conclusion, the deficiency of TNFRp55 promoted the establishment and development of endometriosis through an increase in the lesion size and high levels of estradiol which correlate with an increase in the MMP-2 activity. This is evidence of the possible association of the deregulation of the TNFRp55 expression and the survival of the endometriotic tissue in ectopic sites. © 2017 Society for Endocrinology.

MicroRNAs and intellectual disability (ID) in Down syndrome, X-linked ID, and Fragile X syndrome

PubMed Central

Siew, Wei-Hong; Tan, Kai-Leng; Babaei, Maryam Abbaspour; Cheah, Pike-See; Ling, King-Hwa

2013-01-01

Intellectual disability (ID) is one of the many features manifested in various genetic syndromes leading to deficits in cognitive function among affected individuals. ID is a feature affected by polygenes and multiple environmental factors. It leads to a broad spectrum of affected clinical and behavioral characteristics among patients. Until now, the causative mechanism of ID is unknown and the progression of the condition is poorly understood. Advancement in technology and research had identified various genetic abnormalities and defects as the potential cause of ID. However, the link between these abnormalities with ID is remained inconclusive and the roles of many newly discovered genetic components such as non-coding RNAs have not been thoroughly investigated. In this review, we aim to consolidate and assimilate the latest development and findings on a class of small non-coding RNAs known as microRNAs (miRNAs) involvement in ID development and progression with special focus on Down syndrome (DS) and X-linked ID (XLID) [including Fragile X syndrome (FXS)]. PMID:23596395

In HepG2 cells, coexisting carnitine deficiency masks important indicators of marginal biotin deficiency.

PubMed

Bogusiewicz, Anna; Boysen, Gunnar; Mock, Donald M

2015-01-01

A large number of birth defects are related to nutrient deficiencies; concern that biotin deficiency is teratogenic in humans is reasonable. Surprisingly, studies indicate that increased urinary 3-hydroxyisovalerylcarnitine (3HIAc), a previously validated marker of biotin deficiency, is not a valid biomarker in pregnancy. In this study we hypothesized that coexisting carnitine deficiency can prevent the increase in 3HIAc due to biotin deficiency. We used a 2-factor nutrient depletion design to induce isolated and combined biotin and carnitine deficiency in HepG2 cells and then repleted cells with carnitine. To elucidate the metabolic pathogenesis, we quantitated intracellular and extracellular free carnitine, acylcarnitines, and acylcarnitine ratios using liquid chromatography-tandem mass spectrometry. Relative to biotin-sufficient, carnitine-sufficient cells, intracellular acetylcarnitine increased by 90%, propionylcarnitine more than doubled, and 3HIAc increased by >10-fold in biotin-deficient, carnitine-sufficient (BDCS) cells, consistent with a defensive mechanism in which biotin-deficient cells transesterify the acyl-coenzyme A (acyl-CoA) substrates of the biotin-dependent carboxylases to the related acylcarnitines. Likewise, in BDCS cells, the ratio of acetylcarnitine to malonylcarnitine and the ratio of propionylcarnitine to methylmalonylcarnitine both more than tripled, and the ratio of 3HIAc to 3-methylglutarylcarnitine (MGc) increased by >10-fold. In biotin-deficient, carnitine-deficient (BDCD) cells, the 3 substrate-derived acylcarnitines changed little, but the substrate:product ratios were masked to a lesser extent. Moreover, carnitine repletion unmasked biotin deficiency in BDCD cells as shown by increases in acetylcarnitine, propionylcarnitine, and 3HIAc (each increased by >50-fold). Likewise, ratios of acetylcarnitine:malonylcarnitine, propionylcarnitine:methylmalonylcarnitine, and 3HIAc:MGc all increased by >8-fold. Our findings provide strong

Modulation of the Phosphate-Deficient Responses by MicroRNA156 and its Targeted SQUAMOSA PROMOTER BINDING PROTEIN-LIKE 3 in Arabidopsis.

PubMed

Lei, Kai-Jian; Lin, Ya-Ming; Ren, Jing; Bai, Ling; Miao, Yu-Chen; An, Guo-Yong; Song, Chun-Peng

2016-01-01

The microRNA156 (miR156)-modulated SQUAMOSA PROMOTER BINDING PROTEIN-LIKE (SPL) is involved in diverse biological processes that include growth, development and metabolism. Here, we report that the Arabidopsis miR156 and SPL3 as regulators play important roles in phosphate (Pi) deficiency response. MiR156 was induced during Pi starvation whereas SPL3 expression was repressed. Phenotypes of reduced rhizosphere acidification and decreased anthocyanin accumulation were observed in 35S:MIM156 (via target mimicry) transgenic plants under Pi deficiency. The content and uptake of Pi in 35S:MIM156 Arabidopsis plants were increased compared with wild-type (Col-0 ecotype) plants. 35S:rSPL3 seedlings showed similar anthocyanin accumulation and Pi content phenotypes to those of 35S:MIM156 plants. Chromatin immunoprecipitation and an electrophoretic mobility shift assay indicated that the SPL3 protein directly bound to GTAC motifs in the PLDZ2, Pht1;5 and miR399f promoters. The expression of several Pi starvation-induced genes was increased in 35S:MIM156 and 35S:rSPL3 plants, including high-affinity Pi transporters, Mt4/TPS1-like genes and phosphatases. Collectively, our results suggest that the miR156-SPL3-Pht1;5 (-PLDZ2 and -miR399f) pathways constitute a component of the Pi deficiency-induced regulatory mechanism of Arabidopsis. © The Author 2015. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Infant Iron Deficiency, Child Affect, and Maternal Unresponsiveness: Testing the Long-Term Effects of Functional Isolation

ERIC Educational Resources Information Center

East, Patricia; Lozoff, Betsy; Blanco, Estela; Delker, Erin; Delva, Jorge; Encina, Pamela; Gahagan, Sheila

2017-01-01

Children who are iron deficient (ID) or iron-deficient anemic (IDA) have been shown to seek and receive less stimulation from their caregivers, contributing to "functional isolation". Over time, the reduced interactions between child and caregiver are thought to interfere with the acquisition of normative social competencies and…

Abscisic acid alleviates iron deficiency by promoting root iron reutilization and transport from root to shoot in Arabidopsis.

PubMed

Lei, Gui Jie; Zhu, Xiao Fang; Wang, Zhi Wei; Dong, Fang; Dong, Ning Yu; Zheng, Shao Jian

2014-04-01

Abscisic acid (ABA) has been demonstrated to be involved in iron (Fe) homeostasis, but the underlying mechanism is largely unknown. Here, we found that Fe deficiency induced ABA accumulation rapidly (within 6 h) in the roots of Arabidopsis. Exogenous ABA at 0.5 μM decreased the amount of root apoplastic Fe bound to pectin and hemicellulose, and increased the shoot Fe content significantly, thus alleviating Fe deficiency-induced chlorosis. Exogenous ABA promoted the secretion of phenolics to release apoplastic Fe and up-regulated the expression of AtNRAMP3 to enhance reutilization of Fe stored in the vacuoles, leading to a higher level of soluble Fe and lower ferric-chelate reductase (FCR) activity in roots. Treatment with ABA also led to increased Fe concentrations in the xylem sap, partially because of the up-regulation of AtFRD3, AtYSL2 and AtNAS1, genes related to long-distance transport of Fe. Exogenous ABA could not alleviate the chlorosis of abi5 mutant resulting from the significantly low expression of AtYSL2 and low transport of Fe from root to shoot. Taken together, our data support the conclusion that ABA is involved in the reutilization and transport of Fe from root to shoot under Fe deficiency conditions in Arabidopsis. © 2013 John Wiley & Sons Ltd.

Prolyl hydroxylase domain 2 deficiency promotes skeletal muscle fiber-type transition via a calcineurin/NFATc1-dependent pathway.

PubMed

Shin, Junchul; Nunomiya, Aki; Kitajima, Yasuo; Dan, Takashi; Miyata, Toshio; Nagatomi, Ryoichi

2016-01-01

Hypoxia exposure is known to induce an alteration in skeletal muscle fiber-type distribution mediated by hypoxia-inducible factor (HIF)-α. The downstream pathway of HIF-α leading to fiber-type shift, however, has not been elucidated. The calcineurin pathway is one of the pathways responsible for slow muscle fiber transition. Because calcineurin pathway is activated by vascular endothelial growth factor (VEGF), one of the factors induced by HIF-1α, we hypothesized that the stabilization of HIF-1α may lead to slow muscle fiber transition via the activation of calcineurin pathway in skeletal muscles. To induce HIF-1α stabilization, we used a loss of function strategy to abrogate Prolyl hydroxylase domain protein (PHD) 2 responsible for HIF-1α hydroxylation making HIF-1α susceptible to ubiquitin dependent degradation by proteasome. The purpose of this study was therefore to examine the effect of HIF-1α stabilization in PHD2 conditional knockout mouse on skeletal muscle fiber-type transition and to elucidate the involvement of calcineurin pathway on muscle fiber-type transition. PHD2 deficiency resulted in an increased capillary density in skeletal muscles due to the induction of vascular endothelial growth factor. It also elicited an alteration of skeletal muscle phenotype toward the type I fibers in both of the soleus (35.8 % in the control mice vs. 46.7 % in the PHD2-deficient mice, p < 0.01) and the gastrocnemius muscle (0.94 vs. 1.89 %, p < 0.01), and the increased proportion of type I fibers appeared to correspond to the area of increased capillary density. In addition, calcineurin and nuclear factor of activated T cell (NFATc1) protein levels were increased in both the gastrocnemius and soleus muscles, suggesting that the calcineurin/NFATc1 pathway was responsible for the type I fiber transition regardless of PGC-1α, which responded minimally to PHD2 deficiency. Indeed, we found that tacrolimus (FK-506), a calcineurin inhibitor, successfully

Midkine-A functions upstream of Id2a to regulate cell cycle kinetics in the developing vertebrate retina

PubMed Central

2012-01-01

Background Midkine is a small heparin binding growth factor expressed in numerous tissues during development. The unique midkine gene in mammals has two paralogs in zebrafish: midkine-a (mdka) and midkine-b (mdkb). In the zebrafish retina, during both larval development and adult photoreceptor regeneration, mdka is expressed in retinal stem and progenitor cells and functions as a molecular component of the retina’s stem cell niche. In this study, loss-of-function and conditional overexpression were used to investigate the function of Mdka in the retina of the embryonic zebrafish. Results The results show that during early retinal development Mdka functions to regulate cell cycle kinetics. Following targeted knockdown of Mdka synthesis, retinal progenitors cycle more slowly, and this results in microphthalmia, a diminished rate of cell cycle exit and a temporal delay of cell cycle exit and neuronal differentiation. In contrast, Mdka overexpression results in acceleration of the cell cycle and retinal overgrowth. Mdka gain-of-function, however, does not temporally advance cell cycle exit. Experiments to identify a potential Mdka signaling pathway show that Mdka functions upstream of the HLH regulatory protein, Id2a. Gene expression analysis shows Mdka regulates id2a expression, and co-injection of Mdka morpholinos and id2a mRNA rescues the Mdka loss-of-function phenotype. Conclusions These data show that in zebrafish, Mdka resides in a shared Id2a pathway to regulate cell cycle kinetics in retinal progenitors. This is the first study to demonstrate the function of Midkine during retinal development and adds Midkine to the list of growth factors that transcriptionally regulate Id proteins. PMID:23111152

Midkine-A functions upstream of Id2a to regulate cell cycle kinetics in the developing vertebrate retina.

PubMed

Luo, Jing; Uribe, Rosa A; Hayton, Sarah; Calinescu, Anda-Alexandra; Gross, Jeffrey M; Hitchcock, Peter F

2012-10-30

Midkine is a small heparin binding growth factor expressed in numerous tissues during development. The unique midkine gene in mammals has two paralogs in zebrafish: midkine-a (mdka) and midkine-b (mdkb). In the zebrafish retina, during both larval development and adult photoreceptor regeneration, mdka is expressed in retinal stem and progenitor cells and functions as a molecular component of the retina's stem cell niche. In this study, loss-of-function and conditional overexpression were used to investigate the function of Mdka in the retina of the embryonic zebrafish. The results show that during early retinal development Mdka functions to regulate cell cycle kinetics. Following targeted knockdown of Mdka synthesis, retinal progenitors cycle more slowly, and this results in microphthalmia, a diminished rate of cell cycle exit and a temporal delay of cell cycle exit and neuronal differentiation. In contrast, Mdka overexpression results in acceleration of the cell cycle and retinal overgrowth. Mdka gain-of-function, however, does not temporally advance cell cycle exit. Experiments to identify a potential Mdka signaling pathway show that Mdka functions upstream of the HLH regulatory protein, Id2a. Gene expression analysis shows Mdka regulates id2a expression, and co-injection of Mdka morpholinos and id2a mRNA rescues the Mdka loss-of-function phenotype. These data show that in zebrafish, Mdka resides in a shared Id2a pathway to regulate cell cycle kinetics in retinal progenitors. This is the first study to demonstrate the function of Midkine during retinal development and adds Midkine to the list of growth factors that transcriptionally regulate Id proteins.

Prevalence of anaemia, deficiencies of iron and vitamin A and their determinants in rural women and young children: a cross-sectional study in Kalalé district of northern Benin.

PubMed

Alaofè, Halimatou; Burney, Jennifer; Naylor, Rosamond; Taren, Douglas

2017-05-01

To identify the magnitude of anaemia and deficiencies of Fe (ID) and vitamin A (VAD) and their associated factors among rural women and children. Cross-sectional, comprising a household, health and nutrition survey and determination of Hb, biochemical (serum concentrations of ferritin, retinol, C-reactive protein and α1-acid glycoprotein) and anthropometric parameters. Multivariate logistic regression examined associations of various factors with anaemia and micronutrient deficiencies. Kalalé district, northern Benin. Mother-child pairs (n 767): non-pregnant women of reproductive age (15-49 years) and children 6-59 months old. In women, the overall prevalence of anaemia, ID, Fe-deficiency anaemia (IDA) and VAD was 47·7, 18·3, 11·3 and 17·7 %, respectively. A similar pattern for anaemia (82·4 %), ID (23·6 %) and IDA (21·2 %) was observed among children, while VAD was greater at 33·6 %. Greater risk of anaemia, ID and VAD was found for low maternal education, maternal farming activity, maternal health status, low food diversity, lack of fruits and vegetables consumption, low protein foods consumption, high infection, anthropometric deficits, large family size, poor sanitary conditions and low socio-economic status. Strong differences were also observed by ethnicity, women's group participation and source of information. Finally, age had a significant effect in children, with those aged 6-23 months having the highest risk for anaemia and those aged 12-23 months at risk for ID and IDA. Anaemia, ID and VAD were high among rural women and their children in northern Benin, although ID accounted for a small proportion of anaemia. Multicentre studies in various parts of the country are needed to substantiate the present results, so that appropriate and beneficial strategies for micronutrient supplementation and interventions to improve food diversity and quality can be planned.

Promotion of Wound Healing by an Agonist of Adenosine A2A Receptor Is Dependent on Tissue Plasminogen Activator.

PubMed

Montesinos, M Carmen; Desai-Merchant, Avani; Cronstein, Bruce N

2015-12-01

Impaired wound healing, as it occurs in diabetes mellitus or long-term corticoid treatment, is commonly associated with disability, diminished quality of life, and high economic costs. Selective agonists of the A2A receptor subtype of adenosine, an endogenous regulator of inflammation, promote tissue repair in animal models, both healthy and with impaired healing. Plasmin-mediated proteolysis of fibrin and other matrix proteins is essential for cell migration at sites of injury. Since adenosine A2A receptor activation increases plasminogen activator release from macrophages and mast cells, we studied the effect of a selective agonist, CGS-21680, on full-thickness excisional wound closure in wild-type, urokinase plasminogen activator (uPA)-deficient, and tissue plasminogen activator (tPA)-deficient mice. Wound closure was impaired in tPA- and uPA-deficient mice as compared with wild-type mice, and topical application of CGS-21680 significantly increased the rate at which wounds closed in wild-type mice and uPA-deficient mice, but not in tPA-deficient mice. Immunostaining of tissue sections showed that tPA was present in endothelial cells and histiocytes by day 3 post-wound and also by day 6. In contrast, uPA was more prominent in these cell types only by day 6 post-wound. Our results confirm that plasminogen activation contributes to wound repair and are consistent with the hypothesis that adenosine A2A receptor activation promotes wound closure by a mechanism that depends upon tPA, but not uPA. Moreover, our results suggest that topical adenosine A2A receptor agonists may be useful in promotion of wound closure in patients with impaired wound healing.

A novel UBE2A mutation causes X-linked intellectual disability type Nascimento.

PubMed

Tsurusaki, Yoshinori; Ohashi, Ikuko; Enomoto, Yumi; Naruto, Takuya; Mitsui, Jun; Aida, Noriko; Kurosawa, Kenji

2017-01-01

X-linked intellectual disability (ID) type Nascimento (MIM #300860), also known as ubiquitin-conjugating enzyme E2 A (UBE2A) deficiency syndrome, is a congenital malformation syndrome characterized by moderate to severe ID, speech impairment, dysmorphic facial features, genital anomalies and skin abnormalities. Here, we report a Japanese patient with severe ID and congenital cataract. We identified a novel hemizygous mutation (c.76G>A, p.Gly26Arg) in UBE2A by whole-exome sequencing.

INTERFERON α ACTIVATES NF-κ B IN JAK1-DEFICIENT CELLS THROUGH A TYK2-DEPENDENT PATHWAY

PubMed Central

Yang, Chuan He; Murti, Aruna; Valentine, William J.; Du, Ziyun; Pfeffer, Lawrence M.

2005-01-01

In addition to activating members of the STAT transcription factor family, IFN α/β activates the NF-κ B transcription factor. To determine the role of the JAK-STAT pathway in NF-κ B activation by IFN, we examined NF-κ B activation in JAK1-deficient mutant human fibrosarcoma cells. In wild-type fibrosarcoma cells (2fTGH) IFN activates STAT1, STAT2 and STAT3, as well as NF-κB complexes comprised of p50 and p65. In contrast, in JAK1-deficient cells IFN induces NF-κB activation and NF-κB dependent gene transcription, but does not activate these STAT proteins and has no effect on STAT-dependent gene transcription. Expression of a catalytically-inactive TYK2 tyrosine kinase in JAK1-deficient cells, as well as in the highly IFN-sensitive Daudi lymphoblastoid cell line, abrogates NF-κB activation by IFN. Moreover, IFN does not promote NF-κB activation in TYK2-deficient mutant fibrosarcoma cells. Our results demonstrate a dichotomy between the classical JAK-STAT pathway and the NF-κB signaling pathway. In the IFN signaling pathway leading to STAT activation both JAK1 and TYK2 are essential, while NF-κB activation requires only TYK2. PMID:15883164

Genetics Home Reference: complement component 2 deficiency

MedlinePlus

... deficiency Sources for This Page Jönsson G, Sjöholm AG, Truedsson L, Bengtsson AA, Braconier JH, Sturfelt G. ... L, Sturfelt G, Oxelius VA, Braconier JH, Sjöholm AG. Hereditary C2 deficiency in Sweden: frequent occurrence of ...

Aberrant RSPO3-LGR4 signaling in Keap1-deficient lung adenocarcinomas promotes tumor aggressiveness.

PubMed

Gong, X; Yi, J; Carmon, K S; Crumbley, C A; Xiong, W; Thomas, A; Fan, X; Guo, S; An, Z; Chang, J T; Liu, Q J

2015-09-03

The four R-spondins (RSPO1-4) and their three related receptors LGR4, 5 and 6 (LGR4-6) have emerged as a major ligand-receptor system with critical roles in development and stem cell survival through modulation of Wnt signaling. Recurrent, gain-of-expression gene fusions of RSPO2 (to EIF3E) and RSPO3 (to PTPRK) occur in a subset of human colorectal cancer. However, the exact roles and mechanisms of the RSPO-LGR system in oncogenesis remain largely unknown. We found that RSPO3 is aberrantly expressed at high levels in approximately half of Keap1-mutated lung adenocarcinomas (ADs). This high RSPO3 expression is driven by a combination of demethylation of its own promoter region and deficiency in Keap1 instead of gene fusion as in colon cancer. Patients with RSPO3-high tumors (~9%, 36/412) displayed much poorer survival than the rest of the cohort (median survival of 28 vs 163 months, log-rank test P<0.0001). Knockdown (KD) of RSPO3, LGR4 or their signaling mediator IQGAP1 in lung cancer cell lines with Keap1 deficiency and high RSPO3-LGR4 expression led to reduction in cell proliferation and migration in vitro, and KD of LGR4 or IQGAP1 resulted in decrease in tumor growth and metastasis in vivo. These findings suggest that aberrant RSPO3-LGR4 signaling potentially acts as a driving mechanism in the aggressiveness of Keap1-deficient lung ADs.

Aberrant RSPO3-LGR4 signaling in Keap1-deficient lung adenocarcinomas promotes tumor aggressiveness

PubMed Central

Gong, Xing; Yi, Jing; Carmon, Kendra S.; Crumbley, Christine A.; Xiong, Wei; Thomas, Anthony; Fan, Xuejun; Guo, Shan; An, Zhiqiang; Chang, Jeffrey T.; Liu, Qingyun J.

2015-01-01

The four R-spondins (RSPO1-4) and their three related receptors LGR4, 5 and 6 (LGR4-6) have emerged as a major ligand-receptor system with critical roles in development and stem cell survival through modulation of Wnt signaling. Recurrent, gain-of-expression gene fusions of RSPO2 (to EIF3E) and RSPO3 (to PTPRK) occur in a subset of human colorectal cancer. However, the exact roles and mechanisms of the RSPO-LGR system in oncogenesis remain largely unknown. We found that RSPO3 is aberrantly expressed at high levels in approximately half of the Keap1-mutated lung adenocarcinomas. This high RSPO3 expression is driven by a combination of demethylation of its own promoter region and deficiency in Keap1 instead of gene fusion as in colon cancer. Patients with RSPO3-high tumors (~9%, 36/412) displayed much poorer survival than the rest of the cohorts (median survival of 28 vs. 163 months, logrank test p < 0.0001). Knockdown of RSPO3, LGR4, or their signaling mediator IQGAP1 in lung cancer cell lines with Keap1 deficiency and high RSPO3-LGR4 expression led to reduction in cell proliferation and migration in vitro, and knockdown of LGR4 or IQGAP1 resulted in decrease in tumor growth and metastasis in vivo. These findings suggest that aberrant RSPO3-LGR4 signaling potentially acts as a driving mechanism in the aggressiveness of Keap1-deficient lung adenocarcinomas. PMID:25531322

Multimodal biometrics for identity documents (MBioID).

PubMed

Dessimoz, Damien; Richiardi, Jonas; Champod, Christophe; Drygajlo, Andrzej

2007-04-11

The MBioID initiative has been set up to address the following germane question: What and how biometric technologies could be deployed in identity documents in the foreseeable future? This research effort proposes to look at current and future practices and systems of establishing and using biometric identity documents (IDs) and evaluate their effectiveness in large-scale developments. The first objective of the MBioID project is to present a review document establishing the current state-of-the-art related to the use of multimodal biometrics in an IDs application. This research report gives the main definitions, properties and the framework of use related to biometrics, an overview of the main standards developed in the biometric industry and standardisation organisations to ensure interoperability, as well as some of the legal framework and the issues associated to biometrics such as privacy and personal data protection. The state-of-the-art in terms of technological development is also summarised for a range of single biometric modalities (2D and 3D face, fingerprint, iris, on-line signature and speech), chosen according to ICAO recommendations and availabilities, and for various multimodal approaches. This paper gives a summary of the main elements of that report. The second objective of the MBioID project is to propose relevant acquisition and evaluation protocols for a large-scale deployment of biometric IDs. Combined with the protocols, a multimodal database will be acquired in a realistic way, in order to be as close as possible to a real biometric IDs deployment. In this paper, the issues and solutions related to the acquisition setup are briefly presented.

A double burden of overall or central adiposity and anemia or iron deficiency is prevalent but with little socioeconomic patterning among Moroccan and Tunisian urban women.

PubMed

Gartner, Agnès; El Ati, Jalila; Traissac, Pierre; Bour, Abdellatif; Berger, Jacques; Landais, Edwige; El Hsaïni, Houda; Ben Rayana, Chiheb; Delpeuch, Francis

2014-01-01

In North Africa, overnutrition has dramatically increased with the nutrition transition while micronutrient deficiencies persist, resulting in clustering of opposite types of malnutrition that can present a unique difficulty for public health interventions. We assessed the magnitude of the double burden of malnutrition among urban Moroccan and Tunisian women, as defined by the coexistence of overall or central adiposity and anemia or iron deficiency (ID), and explored the sociodemographic patterning of individual double burden. In cross-sectional surveys representative of the region around the capital city, we randomly selected 811 and 1689 nonpregnant women aged 20-49 y in Morocco and Tunisia, respectively. Four double burdens were analyzed: overweight (body mass index ≥25 kg/m(2)) or increased risk abdominal obesity (waist circumference ≥80 cm) and anemia (blood hemoglobin <120 g/L) or ID (C-reactive protein-corrected serum ferritin <15 μg/L). Adjusted associations with 9 sociodemographic factors were estimated by logistic regression. The prevalence of overweight and ID was 67.0% and 45.2% in Morocco, respectively, and 69.5% and 27.0% in Tunisia, respectively, illustrating the population-level double burden. The coexistence of overall or central adiposity with ID was found in 29.8% and 30.1% of women in Morocco, respectively, and in 18.2% and 18.3% of women in Tunisia, respectively, quite evenly distributed across age, economic, or education groups. Generally, the rare, associated sociodemographic factors varied across the 4 subject-level double burdens and the 2 countries and differed from those usually associated with adiposity, anemia, or ID. Any double burden combining adiposity and anemia or ID should therefore be taken into consideration in all women. This trial was registered at clinicaltrials.gov as NCT01844349.

RNA-ID, a Powerful Tool for Identifying and Characterizing Regulatory Sequences.

PubMed

Brule, C E; Dean, K M; Grayhack, E J

2016-01-01

The identification and analysis of sequences that regulate gene expression is critical because regulated gene expression underlies biology. RNA-ID is an efficient and sensitive method to discover and investigate regulatory sequences in the yeast Saccharomyces cerevisiae, using fluorescence-based assays to detect green fluorescent protein (GFP) relative to a red fluorescent protein (RFP) control in individual cells. Putative regulatory sequences can be inserted either in-frame or upstream of a superfolder GFP fusion protein whose expression, like that of RFP, is driven by the bidirectional GAL1,10 promoter. In this chapter, we describe the methodology to identify and study cis-regulatory sequences in the RNA-ID system, explaining features and variations of the RNA-ID reporter, as well as some applications of this system. We describe in detail the methods to analyze a single regulatory sequence, from construction of a single GFP variant to assay of variants by flow cytometry, as well as modifications required to screen libraries of different strains simultaneously. We also describe subsequent analyses of regulatory sequences. © 2016 Elsevier Inc. All rights reserved.

In HepG2 Cells, Coexisting Carnitine Deficiency Masks Important Indicators of Marginal Biotin Deficiency123

PubMed Central

Bogusiewicz, Anna; Boysen, Gunnar; Mock, Donald M

2015-01-01

Background: A large number of birth defects are related to nutrient deficiencies; concern that biotin deficiency is teratogenic in humans is reasonable. Surprisingly, studies indicate that increased urinary 3-hydroxyisovalerylcarnitine (3HIAc), a previously validated marker of biotin deficiency, is not a valid biomarker in pregnancy. Objective: In this study we hypothesized that coexisting carnitine deficiency can prevent the increase in 3HIAc due to biotin deficiency. Methods: We used a 2-factor nutrient depletion design to induce isolated and combined biotin and carnitine deficiency in HepG2 cells and then repleted cells with carnitine. To elucidate the metabolic pathogenesis, we quantitated intracellular and extracellular free carnitine, acylcarnitines, and acylcarnitine ratios using liquid chromatography–tandem mass spectrometry. Results: Relative to biotin-sufficient, carnitine-sufficient cells, intracellular acetylcarnitine increased by 90%, propionylcarnitine more than doubled, and 3HIAc increased by >10-fold in biotin-deficient, carnitine-sufficient (BDCS) cells, consistent with a defensive mechanism in which biotin-deficient cells transesterify the acyl-coenzyme A (acyl-CoA) substrates of the biotin-dependent carboxylases to the related acylcarnitines. Likewise, in BDCS cells, the ratio of acetylcarnitine to malonylcarnitine and the ratio of propionylcarnitine to methylmalonylcarnitine both more than tripled, and the ratio of 3HIAc to 3-methylglutarylcarnitine (MGc) increased by >10-fold. In biotin-deficient, carnitine-deficient (BDCD) cells, the 3 substrate-derived acylcarnitines changed little, but the substrate:product ratios were masked to a lesser extent. Moreover, carnitine repletion unmasked biotin deficiency in BDCD cells as shown by increases in acetylcarnitine, propionylcarnitine, and 3HIAc (each increased by >50-fold). Likewise, ratios of acetylcarnitine:malonylcarnitine, propionylcarnitine:methylmalonylcarnitine, and 3HIAc:MGc all increased

Relationship Between being Overweight and Iron Deficiency in Adolescents.

PubMed

Huang, Ya-Fang; Tok, Teck-Siang; Lu, Chin-Li; Ko, Hsing-Ching; Chen, Min-Yu; Chen, Solomon Chih-Cheng

2015-12-01

Being overweight has been considered to be a risk factor of iron deficiency (ID). The objective of this study was to examine the relationship between being overweight and body iron status among Taiwanese adolescents. A total of 2099 adolescents (1327 female) aged 12-19 years from four middle schools and one college in southern Taiwan participated in this study. Data on sex, age, body weight, height, hemoglobin concentration, plasma ferritin (PF), and serum iron (SI) levels were collected. According to the age- and sex-specific body mass index (BMI) percentiles, the participants were divided into four weight groups: underweight (<5(th) percentile), normal weight (5-84(th) percentile), overweight (85-94(th) percentile), and obese (≥95(th) percentile). A multivariate logistic regression model was used to estimate the odds ratio (OR) and the 95% confidence interval (CI) for each factor. The correlation coefficients of linear regression were positive for BMI-hemoglobin and BMI-PF, but negative for BMI-SI. Compared with the normal-weight group, the obese group had a lower risk of PF level <15 μg/L with an OR (95% CI) of 0.51 (0.30-0.87) but a higher risk of SI <60 μg/dL with an OR (95% CI) of 1.78 (1.34-2.37). The percentages of low PF declined as BMI increased, but the percentages of low SI rose, from underweight to obesity groups. The relationship between being overweight and depleted iron store depends on which indicator is used to define the iron deficiency. Being overweight or obese would not be a risk factor of ID in adolescents, if ID were defined by PF rather than SI level. Copyright © 2015. Published by Elsevier B.V.

Genetic advantageous predisposition of angiotensin converting enzyme id polymorphism in Tunisian athletes.

PubMed

Znazen, Hela; Mejri, Aouatef; Touhami, Imed; Chtara, Moktar; Siala, Hajer; LE Gallais, Daniel; Ahmetov, Ildus I; Messaoud, Taeib; Chamari, Karim; Soussi, Nizar

2016-06-01

ID polymorphism of the gene coding for the angiotensin I-converting enzyme (ACE) represents a determining factor in physical and athletic performance in the context of genetic conditioning of sports predisposition. The aim of this study was to show the potential importance of genetic factors in relation to the athletic status in Tunisian athletes. The ACE genotypes were established using polymerase chain reaction (PCR) amplification for 282 Tunisian athletes (endurance: N.=149 - power: N.=133), and 211 sedentary volunteers. No significant difference was found in the ACE genotype distribution between athletes (36% DD, 49% ID, 15% II) and controls (CTR) (39% DD, 46% ID, 15% II; P=0.72). In contrast, a high significant difference between endurance and power groups were noted in genotype and alleles (χ2=10.32, P=0.0057; χ2=4,752, P=0.029, respectively). The elite endurance-athletes (N.=72) possess some inherent genetic advantage predisposing them to superior athletic performances compared to CTR for ACE alleles (χ2=3.51, P=0.06). In addition endurance trained athletes were also significantly different from CTR for ACE genotype (χ2=6.05, P=0.04). Furthermore, a significant difference have been found between elite power-athletes (N.=59) and CTR for ACE alleles (χ2=3.79, P=0.05). Tunisian athletes exhibit insertion (I) and deletion (D) alleles of the ACE polymorphism associated with a high level of human endurance and power performance, respectively. This genetic background plays an important role in sporting potential and causes some individuals to be better adapted to specific physical training. This should be considered in athlete development to identify which sporting specialties should be trained for Tunisian talent promotion.

POWERS forID: Personalized Online Weight and Exercise Response System for Individuals with Intellectual Disability: study protocol for a randomized controlled trial.

PubMed

Neumeier, William H; Guerra, Nichole; Thirumalai, Mohanraj; Geer, Betty; Ervin, David; Rimmer, James H

2017-10-23

Intellectual disability (ID) is characterized by limitations in intellectual functioning and adaptive behavior. Adults with ID exhibit higher rates of obesity and poorer health status compared to the general population. Continuity of care and barriers to health-related activities may contribute to the poorer health status observed in this population. To address this problem, a tailored weight management online health information and communication technology platform, known as POWERS forID , was developed and is being tested to determine if this delivery mechanism can improve weight maintenance/weight loss in adults with ID. Obese adults with mild-to-moderate ID (n = 70) are randomized to the POWERS forID intervention or control group for a 24-week trial. Each group undergoes an assessment that includes body weight, waist circumference, and percent body fat at baseline and at weeks 6, 12, and 24. Physical activity barriers, healthy eating barriers, food frequency, and psychosocial wellbeing are measured at baseline and at weeks 12 and 24. Blood lipids are assessed at baseline and 24 weeks. Participants randomized to POWERS forID receive access to the POWERS forID website and calls from a health coach (weekly during weeks 1-12, biweekly during weeks 13-24). The health coach employs motivational interviewing techniques adapted for individuals with ID to promote behavior change. Participants randomized to the control group receive standard clinical weight-loss care. Differences in weight, waist circumference, blood lipids, percent body fat, and psychosocial self-report will be assessed. Barriers and facilitators of implementation as well as perception of study outcomes will be conducted via qualitative analysis. POWERS forID is a novel information and communication technology platform designed to address health needs for adults with ID. This article describes the development and components of POWERS forID . The overall aim is to assess usability and feasibility of

A novel UBE2A mutation causes X-linked intellectual disability type Nascimento

PubMed Central

Tsurusaki, Yoshinori; Ohashi, Ikuko; Enomoto, Yumi; Naruto, Takuya; Mitsui, Jun; Aida, Noriko; Kurosawa, Kenji

2017-01-01

X-linked intellectual disability (ID) type Nascimento (MIM #300860), also known as ubiquitin-conjugating enzyme E2 A (UBE2A) deficiency syndrome, is a congenital malformation syndrome characterized by moderate to severe ID, speech impairment, dysmorphic facial features, genital anomalies and skin abnormalities. Here, we report a Japanese patient with severe ID and congenital cataract. We identified a novel hemizygous mutation (c.76G>A, p.Gly26Arg) in UBE2A by whole-exome sequencing. PMID:28611923

Iron deficiency impairs developing hippocampal neuron gene expression, energy metabolism and dendrite complexity

PubMed Central

Bastian, Thomas W.; von Hohenberg, William C.; Mickelson, Daniel J.; Lanier, Lorene M.; Georgieff, Michael K.

2016-01-01

Iron deficiency (ID), with and without anemia, affects an estimated 2 billion people worldwide. ID is particularly deleterious during early-life brain development, leading to long-term neurological impairments, including deficits in hippocampus-mediated learning and memory. Neonatal rats with fetal/neonatal ID anemia (IDA) have shorter hippocampal CA1 apical dendrites with disorganized branching. ID-induced dendritic structural abnormalities persist into adulthood despite normalization of iron status. However, the specific developmental effects of neuronal iron loss on hippocampal neuron dendrite growth and branching are unknown. Embryonic hippocampal neuron cultures were chronically treated with deferoxamine (DFO, an iron chelator) beginning at 3 days in vitro (DIV). Levels of mRNA for Tfr1 and Slc11a2, iron-responsive genes involved in iron uptake, were significantly elevated in DFO-treated cultures at 11DIV and 18DIV, indicating a similar degree of neuronal ID as seen in rodent ID models. DFO treatment decreased mRNA levels for genes indexing dendritic and synaptic development (i.e., BdnfVI, Camk2a, Vamp1, Psd95, Cfl1, Pfn1, Pfn2, and Gda) and mitochondrial function (i.e., Ucp2, Pink1, and Cox6a1). At 18DIV, DFO reduced key aspects of energy metabolism including basal respiration, maximal respiration, spare respiratory capacity, ATP production, and glycolytic rate, capacity, and reserve. Sholl analysis revealed a significant decrease in distal dendritic complexity in DFO-treated neurons at both 11DIV and 18DIV. At 11DIV, the length of primary dendrites and the number and length of branches in DFO-treated neurons was reduced. By 18DIV, a partial recovery of dendritic branch number in DFO-treated neurons was counteracted by a significant reduction in the number and length of primary dendrites and length of branches. Our findings suggest that early neuronal iron loss, at least partially driven through altered mitochondrial function and neuronal energy metabolism

Marginal iodide deficiency and thyroid function: dose-response analysis for quantitative pharmacokinetic modeling.

PubMed

Gilbert, M E; McLanahan, E D; Hedge, J; Crofton, K M; Fisher, J W; Valentín-Blasini, L; Blount, B C

2011-04-28

Severe iodine deficiency (ID) results in adverse health outcomes and remains a benchmark for understanding the effects of developmental hypothyroidism. The implications of marginal ID, however, remain less well known. The current study examined the relationship between graded levels of ID in rats and serum thyroid hormones, thyroid iodine content, and urinary iodide excretion. The goals of this study were to provide parametric and dose-response information for development of a quantitative model of the thyroid axis. Female Long Evans rats were fed casein-based diets containing varying iodine (I) concentrations for 8 weeks. Diets were created by adding 975, 200, 125, 25, or 0 μg/kg I to the base diet (~25 μg I/kg chow) to produce 5 nominal I levels, ranging from excess (basal+added I, Treatment 1: 1000 μg I/kg chow) to deficient (Treatment 5: 25 μg I/kg chow). Food intake and body weight were monitored throughout and on 2 consecutive days each week over the 8-week exposure period, animals were placed in metabolism cages to capture urine. Food, water intake, and body weight gain did not differ among treatment groups. Serum T4 was dose-dependently reduced relative to Treatment 1 with significant declines (19 and 48%) at the two lowest I groups, and no significant changes in serum T3 or TSH were detected. Increases in thyroid weight and decreases in thyroidal and urinary iodide content were observed as a function of decreasing I in the diet. Data were compared with predictions from a recently published biologically based dose-response (BBDR) model for ID. Relative to model predictions, female Long Evans rats under the conditions of this study appeared more resilient to low I intake. These results challenge existing models and provide essential information for development of quantitative BBDR models for ID during pregnancy and lactation. Published by Elsevier Ireland Ltd.

Iron Deficiency Treatment in Patients with Heart Failure.

PubMed

Jankowska, Ewa A; Drozd, Marcin; Ponikowski, Piotr

2017-01-01

Iron deficiency (ID) is one of the major risk factors for disability and mortality worldwide, and it was identified as a common and ominous comorbidity in patients with heart failure (HF), both with and without anaemia. Based on two clinical trials (FAIR-HF and CONFIRM-HF) and other epidemiological evidence, ID has been recognized as an important therapeutic target in symptomatic patients with HF and LVEF ≤45%.Intravenous iron supplementation has been demonstrated to be safe and effective for iron repletion and related with an improvement in clinical status, exercise capacity, and quality of life. Ongoing trials are testing the hypothesis that such a therapy may also reduce the risk of HF hospitalizations and cardiovascular death.

Providing male rats deficient in iron and n-3 fatty acids with iron and alpha-linolenic acid alone affects brain serotonin and cognition differently from combined provision.

PubMed

Baumgartner, Jeannine; Smuts, Cornelius M; Zimmermann, Michael B

2014-06-13

We recently showed that a combined deficiency of iron (ID) and n-3 fatty acids (n-3 FAD) in rats disrupts brain monoamine metabolism and produces greater memory deficits than ID or n-3 FAD alone. Providing these double-deficient rats with either iron (Fe) or preformed docosahexaenoic acid (DHA)/eicosapentaenoic acid (EPA) alone affected brain monoamine pathways differently from combined repletion and even exacerbated cognitive deficits associated with double-deficiency. Iron is a co-factor of the enzymes responsible for the conversion of alpha-linolenic acid (ALA) to EPA and DHA, thus, the provision of ALA with Fe might be more effective in restoring brain EPA and DHA and improving cognition in double-deficient rats than ALA alone. In this study we examined whether providing double-deficient rats with ALA and Fe, alone or in combination, can correct deficits in monoamine metabolism and cognition associated with double-deficiency. Using a 2 × 2 design, male rats with concurrent ID and n-3 FAD were fed an Fe + ALA, Fe + n-3 FAD, ID + ALA, or ID + n-3 FAD diet for 5 weeks (postnatal day 56-91). Biochemical measures, and spatial working and reference memory (using the Morris water maze) were compared to age-matched controls. In the hippocampus, we found a significant Fe × ALA interaction on DHA: Compared to the group receiving ALA alone, DHA was significantly higher in the Fe + ALA group. In the brain, we found significant antagonistic Fe × ALA interactions on serotonin concentrations. Provision of ALA alone impaired working memory compared with age-matched controls, while in the reference memory task ALA provided with Fe significantly improved performance. These results indicate that providing either iron or ALA alone to double-deficient rats affects serotonin pathways and cognitive performance differently from combined provision. This may be partly explained by the enhancing effect of Fe on the conversion of ALA to EPA and DHA.

Providing male rats deficient in iron and n-3 fatty acids with iron and alpha-linolenic acid alone affects brain serotonin and cognition differently from combined provision

PubMed Central

2014-01-01

Background We recently showed that a combined deficiency of iron (ID) and n-3 fatty acids (n-3 FAD) in rats disrupts brain monoamine metabolism and produces greater memory deficits than ID or n-3 FAD alone. Providing these double-deficient rats with either iron (Fe) or preformed docosahexaenoic acid (DHA)/eicosapentaenoic acid (EPA) alone affected brain monoamine pathways differently from combined repletion and even exacerbated cognitive deficits associated with double-deficiency. Iron is a co-factor of the enzymes responsible for the conversion of alpha-linolenic acid (ALA) to EPA and DHA, thus, the provision of ALA with Fe might be more effective in restoring brain EPA and DHA and improving cognition in double-deficient rats than ALA alone. Methods In this study we examined whether providing double-deficient rats with ALA and Fe, alone or in combination, can correct deficits in monoamine metabolism and cognition associated with double-deficiency. Using a 2 × 2 design, male rats with concurrent ID and n-3 FAD were fed an Fe + ALA, Fe + n-3 FAD, ID + ALA, or ID + n-3 FAD diet for 5 weeks (postnatal day 56–91). Biochemical measures, and spatial working and reference memory (using the Morris water maze) were compared to age-matched controls. Results In the hippocampus, we found a significant Fe × ALA interaction on DHA: Compared to the group receiving ALA alone, DHA was significantly higher in the Fe + ALA group. In the brain, we found significant antagonistic Fe × ALA interactions on serotonin concentrations. Provision of ALA alone impaired working memory compared with age-matched controls, while in the reference memory task ALA provided with Fe significantly improved performance. Conclusion These results indicate that providing either iron or ALA alone to double-deficient rats affects serotonin pathways and cognitive performance differently from combined provision. This may be partly explained by the enhancing effect of Fe on

Single mimivirus particles intercepted and imaged with an X-ray laser (CXIDB ID 2)

DOE Data Explorer

Seibert, M. Marvin; Ekeberg, Tomas

2011-02-02

These are the files used to reconstruct the images in the paper "Single Mimivirus particles intercepted and imaged with an X-ray laser". Besides the diffracted intensities, the Hawk configuration files used for the reconstructions are also provided. The files from CXIDB ID 2 are the pattern and configuration files for the pattern showed in Figure 2b in the paper.

Id-1 activation of PI3K/Akt/NFkappaB signaling pathway and its significance in promoting survival of esophageal cancer cells.

PubMed

Li, Bin; Cheung, Pak Yan; Wang, Xianghong; Tsao, Sai Wah; Ling, Ming Tat; Wong, Yong Chuan; Cheung, Annie L M

2007-11-01

Inhibitor of differentiation or DNA binding (Id-1) is a helix-loop-helix protein that is over-expressed in many types of cancer including esophageal cancer. This study aims to investigate its effects on the phosphatidylinositol-3-kinase (PI3K)/Akt/ nuclear factor kappa B (NFkappaB) signaling pathway and the significance in protecting esophageal cancer cells against apoptosis. We found elevated expression of phosphorylated forms of Akt, glycogen synthase kinase 3beta and inhibitor of kappa B, as well as increased nuclear translocation of NFkappaB subunit p65 and NFkappaB DNA-binding activity, in esophageal cancer cells with stable ectopic Id-1 expression. Transient transfection of Id-1 into HEK293 cells confirmed activation of PI3K/Akt/NFkappaB signaling and the effects were counteracted by the PI3K inhibitor LY294002. Treatment with tumor necrosis factor-alpha (TNF-alpha) elicited a significantly weaker apoptotic response, following a marked and sustained activation of Akt and NFkappaB in the Id-1-over-expressing cells, compared with the vector control. The effects of Id-1 on the PI3K/Akt/NFkappaB signaling pathway and apoptosis were reversed in esophageal cancer cells transfected with siRNA against Id-1. In addition, inhibition of PI3K or NFkappaB signaling using the PI3K inhibitor LY294002 or the NFkappaB inhibitor Bay11-7082 increased the sensitivity of Id-1-over-expressing esophageal cancer cells to TNF-alpha-induced apoptosis. Our results provide the first evidence that Id-1 induces the activation of PI3K/Akt/NFkappaB signaling pathway, and protects esophageal cancer cells from TNF-alpha-induced apoptosis in vitro. Inactivation of Id-1 may provide us with a novel strategy to improve the treatment and survival of patients with esophageal cancer.

MLH1-deficient Colorectal Carcinoma With Wild-type BRAF and MLH1 Promoter Hypermethylation Harbor KRAS Mutations and Arise From Conventional Adenomas.

PubMed

Farchoukh, Lama; Kuan, Shih-Fan; Dudley, Beth; Brand, Randall; Nikiforova, Marina; Pai, Reetesh K

2016-10-01

Between 10% and 15% of colorectal carcinomas demonstrate sporadic DNA mismatch-repair protein deficiency as a result of MLH1 promoter methylation and are thought to arise from sessile serrated adenomas, termed the serrated neoplasia pathway. Although the presence of the BRAF V600E mutation is indicative of a sporadic cancer, up to 30% to 50% of colorectal carcinomas with MLH1 promoter hypermethylation will lack a BRAF mutation. We report the clinicopathologic and molecular features of MLH1-deficient colorectal carcinoma with wild-type BRAF and MLH1 promoter hypermethylation (referred to as MLH1-hypermethylated BRAF wild-type colorectal carcinoma, n=36) in comparison with MLH1-deficient BRAF-mutated colorectal carcinoma (n=113) and Lynch syndrome-associated colorectal carcinoma (n=36). KRAS mutations were identified in 31% of MLH1-hypermethylated BRAF wild-type colorectal carcinomas compared with 0% of MLH1-deficient BRAF-mutated colorectal carcinomas and 37% of Lynch syndrome-associated colorectal carcinomas. When a precursor polyp was identified, MLH1-hypermethylated BRAF wild-type colorectal carcinomas arose from precursor polyps resembling conventional tubular/tubulovillous adenomas in contrast to MLH1-deficient BRAF-mutated colorectal carcinomas, which arose from precursor sessile serrated adenomas (P<0.001). Both MLH1-hypermethylated BRAF wild-type colorectal carcinoma and MLH1-deficient BRAF-mutated colorectal carcinoma had a predilection for the right colon compared with Lynch syndrome-associated colorectal carcinoma (86% vs. 92% vs. 49%, P<0.001). There was no significant difference in mucinous differentiation, tumor-infiltrating lymphocytes, Crohn-like reaction, and medullary differentiation between the 3 tumor groups. Using Kaplan-Meier survival functions, there was no significant difference in disease-specific survival between the 3 patient groups (P>0.05). In conclusion, our results indicate that MLH1-hypermethylated BRAF wild-type colorectal carcinomas

Combined vitamin C and vitamin E deficiency worsens early atherosclerosis in apolipoprotein E-deficient mice.

PubMed

Babaev, Vladimir R; Li, Liying; Shah, Sanket; Fazio, Sergio; Linton, MacRae F; May, James M

2010-09-01

To assess the role of combined deficiencies of vitamins C and E on the earliest stages of atherosclerosis (an inflammatory condition associated with oxidative stress), 4 combinations of vitamin supplementation (low C/low E, low C/high E, high C/low E, and high C/high E) were studied in atherosclerosis-prone apolipoprotein E-deficient mice also unable to synthesize their own vitamin C (gulonolactone oxidase(-/-)); and to evaluate the effect of a more severe depletion of vitamin C alone in a second experiment using gulonolactone oxidase(-/-) mice carrying the hemizygous deletion of SVCT2 (the vitamin C transporter). After 8 weeks of a high-fat diet (16% lard and 0.2% cholesterol), atherosclerosis developed in the aortic sinus areas of mice in all diet groups. Each vitamin-deficient diet significantly decreased liver and brain contents of the corresponding vitamin. Combined deficiency of both vitamins increased lipid peroxidation, doubled plaque size, and increased plaque macrophage content by 2- to 3-fold in male mice, although only plaque macrophage content was increased in female mice. A more severe deficiency of vitamin C in gulonolactone oxidase(-/-) mice with defective cellular uptake of vitamin C increased both oxidative stress and atherosclerosis in apolipoprotein E(-/-) mice compared with littermates receiving a diet replete in vitamin C, again most clearly in males. Combined deficiencies of vitamins E and C are required to worsen early atherosclerosis in an apolipoprotein E-deficient mouse model. However, a more severe cellular deficiency of vitamin C alone promotes atherosclerosis when vitamin E is replete.

Gut bacteria selectively promoted by dietary fibers alleviate type 2 diabetes.

PubMed

Zhao, Liping; Zhang, Feng; Ding, Xiaoying; Wu, Guojun; Lam, Yan Y; Wang, Xuejiao; Fu, Huaqing; Xue, Xinhe; Lu, Chunhua; Ma, Jilin; Yu, Lihua; Xu, Chengmei; Ren, Zhongying; Xu, Ying; Xu, Songmei; Shen, Hongli; Zhu, Xiuli; Shi, Yu; Shen, Qingyun; Dong, Weiping; Liu, Rui; Ling, Yunxia; Zeng, Yue; Wang, Xingpeng; Zhang, Qianpeng; Wang, Jing; Wang, Linghua; Wu, Yanqiu; Zeng, Benhua; Wei, Hong; Zhang, Menghui; Peng, Yongde; Zhang, Chenhong

2018-03-09

The gut microbiota benefits humans via short-chain fatty acid (SCFA) production from carbohydrate fermentation, and deficiency in SCFA production is associated with type 2 diabetes mellitus (T2DM). We conducted a randomized clinical study of specifically designed isoenergetic diets, together with fecal shotgun metagenomics, to show that a select group of SCFA-producing strains was promoted by dietary fibers and that most other potential producers were either diminished or unchanged in patients with T2DM. When the fiber-promoted SCFA producers were present in greater diversity and abundance, participants had better improvement in hemoglobin A1c levels, partly via increased glucagon-like peptide-1 production. Promotion of these positive responders diminished producers of metabolically detrimental compounds such as indole and hydrogen sulfide. Targeted restoration of these SCFA producers may present a novel ecological approach for managing T2DM. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

SIRT6 deficiency culminates in low-turnover osteopenia.

PubMed

Sugatani, Toshifumi; Agapova, Olga; Malluche, Hartmut H; Hruska, Keith A

2015-12-01

Deficiency of Sirtuin 6 (SIRT6), a chromatin-related deacetylase, in mice reveals severe premature aging phenotypes including osteopenia. However, the underlying molecular mechanisms of SIRT6 in bone metabolism are unknown. Here we show that SIRT6 deficiency in mice produces low-turnover osteopenia caused by impaired bone formation and bone resorption, which are mechanisms similar to those of age-related bone loss. Mechanistically, SIRT6 interacts with runt-related transcription factor 2 (Runx2) and osterix (Osx), which are the two key transcriptional regulators of osteoblastogenesis, and deacetylates histone H3 at Lysine 9 (H3K9) at their promoters. Hence, excessively elevated Runx2 and Osx in SIRT6(-/-) osteoblasts lead to impaired osteoblastogenesis. In addition, SIRT6 deficiency produces hyperacetylation of H3K9 in the promoter of dickkopf-related protein 1 (Dkk1), a potent negative regulator of osteoblastogenesis, and osteoprotegerin, an inhibitor of osteoclastogenesis. Therefore, the resulting up-regulation of Dkk1 and osteoprotegerin levels contribute to impaired bone remodeling, leading to osteopenia with a low bone turnover in SIRT6-deficient mice. These results establish a new link between SIRT6 and bone remodeling that positively regulates osteoblastogenesis and osteoclastogenesis. Copyright © 2015 Elsevier Inc. All rights reserved.

Replication and Comparison of the Newly Proposed ADOS-2, Module 4 Algorithm in ASD without ID: A Multi-Site Study

ERIC Educational Resources Information Center

Pugliese, Cara E.; Kenworthy, Lauren; Bal, Vanessa Hus; Wallace, Gregory L.; Yerys, Benjamin E.; Maddox, Brenna B.; White, Susan W.; Popal, Haroon; Armour, Anna Chelsea; Miller, Judith; Herrington, John D.; Schultz, Robert T.; Martin, Alex; Anthony, Laura Gutermuth

2015-01-01

Recent updates have been proposed to the Autism Diagnostic Observation Schedule-2 Module 4 diagnostic algorithm. This new algorithm, however, has not yet been validated in an independent sample without intellectual disability (ID). This multi-site study compared the original and revised algorithms in individuals with ASD without ID. The revised…

A Contextual Model for Identity Management (IdM) Interfaces

ERIC Educational Resources Information Center

Fuller, Nathaniel J.

2014-01-01

The usability of Identity Management (IdM) systems is highly dependent upon design that simplifies the processes of identification, authentication, and authorization. Recent findings reveal two critical problems that degrade IdM usability: (1) unfeasible techniques for managing various digital identifiers, and (2) ambiguous security interfaces.…

Misregulation effect of a novel allelic variant in the Z promoter region found in cis with the CYP21A2 p.P482S mutation: implications for 21-hydroxylase deficiency.

PubMed

Fernández, Cecilia S; Bruque, Carlos D; Taboas, Melisa; Buzzalino, Noemí D; Espeche, Lucia D; Pasqualini, Titania; Charreau, Eduardo H; Alba, Liliana G; Ghiringhelli, Pablo D; Dain, Liliana

2015-09-01

The aim of the current study was to search for the presence of genetic variants in the CYP21A2 Z promoter regulatory region in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Screening of the 10 most frequent pseudogene-derived mutations was followed by direct sequencing of the entire coding sequence, the proximal promoter, and a distal regulatory region in DNA samples from patients with at least one non-determined allele. We report three non-classical patients that presented a novel genetic variant-g.15626A>G-within the Z promoter regulatory region. In all the patients, the novel variant was found in cis with the mild, less frequent, p.P482S mutation located in the exon 10 of the CYP21A2 gene. The putative pathogenic implication of the novel variant was assessed by in silico analyses and in vitro assays. Topological analyses showed differences in the curvature and bendability of the DNA region bearing the novel variant. By performing functional studies, a significantly decreased activity of a reporter gene placed downstream from the regulatory region was found by the G transition. Our results may suggest that the activity of an allele bearing the p.P482S mutation may be influenced by the misregulated CYP21A2 transcriptional activity exerted by the Z promoter A>G variation.

Inhibitor of DNA binding 1 regulates cell cycle progression of endothelial progenitor cells through induction of Wnt2 expression

PubMed Central

Xia, Xi; Yu, Yang; Zhang, Li; Ma, Yang; Wang, Hong

2016-01-01

Endothelial injury is a risk factor for atherosclerosis. Endothelial progenitor cell (EPC) proliferation contributes to vascular injury repair. Overexpression of inhibitor of DNA binding 1 (Id1) significantly promotes EPC proliferation; however, the underlying molecular mechanism remains to be fully elucidated. The present study investigated the role of Id1 in cell cycle regulation of EPCs, which is closely associated with proliferation. Overexpression of Id1 increased the proportion of EPCs in the S/G2M phase and significantly increased cyclin D1 expression levels, while knockdown of Id1 arrested the cell cycle progression of EPCs in the G1 phase and inhibited cyclin D1 expression levels. In addition, it was demonstrated that Id1 upregulated wingless-type mouse mammary tumor virus integration site family member 2 (Wnt2) expression levels and promoted β-catenin accumulation and nuclear translocation. Furthermore, Wnt2 knockdown counteracted the effects of Id1 on cell cycle progression of EPCs. In conclusion, the results of the present study indicate that Id1 promoted Wnt2 expression, which accelerated cell cycle progression from G1 to S phase. This suggests that Id1 may promote cell cycle progression of EPCs, and that Wnt2 may be important in Id1 regulation of the cell cycle of EPCs. PMID:27432753

Evaluation of red blood cell and platelet antigen genotyping platforms (ID CORE XT/ID HPA XT) in routine clinical practice.

PubMed

Finning, Kirstin; Bhandari, Radhika; Sellers, Fiona; Revelli, Nicoletta; Villa, Maria Antonietta; Muñiz-Díaz, Eduardo; Nogués, Núria

2016-03-01

High-throughput genotyping platforms enable simultaneous analysis of multiple polymorphisms for blood group typing. BLOODchip® ID is a genotyping platform based on Luminex® xMAP technology for simultaneous determination of 37 red blood cell (RBC) antigens (ID CORE XT) and 18 human platelet antigens (HPA) (ID HPA XT) using the BIDS XT software. In this international multicentre study, the performance of ID CORE XT and ID HPA XT, using the centres' current genotyping methods as the reference for comparison, and the usability and practicality of these systems, were evaluated under working laboratory conditions. DNA was extracted from whole blood in EDTA with Qiagen methodologies. Ninety-six previously phenotyped/genotyped samples were processed per assay: 87 testing samples plus five positive controls and four negative controls. Results were available for 519 samples: 258 with ID CORE XT and 261 with ID HPA XT. There were three "no calls" that were either caused by human error or resolved after repeating the test. Agreement between the tests and reference methods was 99.94% for ID CORE XT (9,540/9,546 antigens determined) and 100% for ID HPA XT (all 4,698 alleles determined). There were six discrepancies in antigen results in five RBC samples, four of which (in VS, N, S and Do(a)) could not be investigated due to lack of sufficient sample to perform additional tests and two of which (in S and C) were resolved in favour of ID CORE XT (100% accuracy). The total hands-on time was 28-41 minutes for a batch of 16 samples. Compared with the reference platforms, ID CORE XT and ID HPA XT were considered simpler to use and had shorter processing times. ID CORE XT and ID HPA XT genotyping platforms for RBC and platelet systems were accurate and user-friendly in working laboratory settings.

Deletion of Snai2 and Snai3 Results in Impaired Physical Development Compounded by Lymphocyte Deficiency

PubMed Central

Pioli, Peter D.; Dahlem, Timothy J.; Weis, Janis J.; Weis, John H.

2013-01-01

The Snail family of transcriptional regulators consists of three highly conserved members. These proteins regulate (repress) transcription via the recruitment of histone deacetylases to target gene promoters that possess the appropriate E-box binding sequences. Murine Snai1 is required for mouse development while Snai2 deficient animals survive with some anomalies. Less is known about the third member of the family, Snai3. To investigate the function of Snai3, we generated a conditional knockin mouse. Utilizing Cre-mediated deletion to facilitate the ablation of Snai3 in T cells or the entire animal, we found little to no effect of the loss of Snai3 in the entire animal or in T cell lineages. This finding provided the hypothesis that absence of Snai3 was mitigated, in part, by the presence of Snai2. To test this hypothesis we created Snai2/Snai3 double deficient mice. The developmental consequences of lacking both of these proteins was manifested in stunted growth, a paucity of offspring including a dramatic deficiency of female mice, and impaired immune cell development within the lymphoid lineages. PMID:23874916

Effect of folate deficiency on promoter methylation and gene expression of Esr1, Cav1, and Elavl1, and its influence on spermatogenesis.

PubMed

Yuan, Hong-Fang; Zhao, Kai; Zang, Yu; Liu, Chun-Yan; Hu, Zhi-Yong; Wei, Jia-Jing; Zhou, Ting; Li, Ying; Zhang, Hui-Ping

2017-04-11

This study aims to investigate the effect of folate deficiency on the male reproductive function and the underlying mechanism. A total of 269 screened participants from 421 recruitments were enrolled in this study. An animal model of folate deficiency was constructed. Folate concentration was measured in the ejaculate, and its association with semen parameters was then determined. The expression and promoter methylation status of ESR1, CAV1, and ELAVL1 were also evaluated. Results showed that seminal plasma folate level was significantly lower among subjects with azoospermia than those with normozoospermia. Low folate level was significantly correlated with low sperm concentration in men with normozoospermia. Folate deficiency significantly reduced the expression of ESR1, CAV1, and ELAVL1, which are critical to spermatogenesis. However, low folate levels did not increase the methylation levels of the promoter regions of ESR1, CAV1, and ELAVL1 in human sperm DNA. Thus, folate deficiency impairs spermatogenesis may partly due to inhibiting the expression of these genes. Thus future research should determine the significance of sufficient folate status in male fertilization and subsequent pregnancy outcomes.

Combined Vitamin C and Vitamin E Deficiency Worsens Early Atherosclerosis in ApoE-Deficient Mice

PubMed Central

Babaev, Vladimir R.; Li, Liying; Shah, Sanket; Fazio, Sergio; Linton, MacRae F.; May, James M.

2010-01-01

Objective Atherosclerosis is an inflammatory condition associated with oxidative stress, but controversy persists regarding whether antioxidants such as vitamins C and E are preventative. To assess the role of combined deficiencies of vitamins C and E on the earliest stages of atherosclerosis, four combinations of vitamin supplementation (Low C/Low E, Low C/High E, High C/Low E, High C/High E) were studied in atherosclerosis-prone apolipoprotein E (apoE)-deficient mice also unable to synthesize their own vitamin C (gulo−/−). The effect of a more severe depletion of vitamin C alone was evaluated in a second experiment using gulo−/− mice carrying the hemizygous deletion of SVCT2, the vitamin C transporter. Methods and Results After 8 weeks on a high-fat diet (16% lard, 0.2% cholesterol), atherosclerosis developed in the aortic sinus areas of mice in all diet groups. Each vitamin-deficient diet significantly decreased liver and brain contents of the corresponding vitamin. Combined deficiency of both vitamins increased lipid peroxidation, doubled plaque size, and increased plaque macrophage content by 2-3-fold in males, although only plaque macrophage content was increased in females. A more severe deficiency of vitamin C in gulo−/− mice with defective cellular uptake of vitamin C increased both oxidative stress and atherosclerosis in apoE−/− mice compared to littermates on a diet replete in vitamin C, again most clearly in males. Conclusion Combined vitamin E and C deficiencies are required to worsen early atherosclerosis in an apoE-deficient mouse model. However, a more severe cellular deficiency of vitamin C alone promotes atherosclerosis when vitamin E is replete. PMID:20558818

Earth observing system. Output data products and input requirements, version 2.0. Volume 2: Analysis of IDS input requirements

NASA Technical Reports Server (NTRS)

Lu, Yun-Chi; Chang, Hyo Duck; Krupp, Brian; Kumar, Ravindra; Swaroop, Anand

1992-01-01

On 18 Jan. 1991, NASA confirmed 29 Inter-Disciplinary Science (IDS) teams, each involving a group of investigators, to conduct interdisciplinary research using data products from Earth Observing System (EOS) instruments. These studies are multi-disciplinary and require output data products from multiple EOS instruments, including both FI and PI instruments. The purpose of this volume is to provide information on output products expected from IDS investigators, required input data, and retrieval algorithms. Also included in this volume is the revised analysis of the 'best' and 'alternative' match data products for IDS input requirements. The original analysis presented in the August 1991 release of the SPSO Report was revised to incorporate the restructuring of the EOS platform. As a result of the reduced EOS payload, some of EOS instruments were deselected and their data products would not be available for IDS research. Information on these data products is also presented.

[Generation and comparison of two genetically engineered mouse models of ErbB2/Neu positive-PTEN deficient breast cancer].

PubMed

Wang, Qing-fei; Ding, Hui; Liu, Bao-rui; Zhang, Kui

2014-07-01

To generate two genetically engineered mouse models of ErbB2/Neu positive-PTEN deficient breast cancer and to compare their biological properties. The genetically engineered mice previously developed with mouse mammary tumor virus (MMTV) promoter driven expression of activated ErbB2/Neu and recombinant Cre (FVB/N-MMTV-NIC) were interbred with Flox-PTEN mice; and FVB/N-ErbB2KI mice, harboring endogenous promoter driven activated ErbB2/Neu expression, FVB/N-MMTV-Cre mice and the flox-PTEN mice were interbred. Neu, Cre and PTEN genes were amplified by PCR for genotyping of the offsprings. ErbB2/Neu and PTEN expression in mammary tumors were detected by immunohistochemistry. Tumor formation time, tumor number, histopathology and lung metastasis were compared between two models, Ki-67 expression was detected by immunohistochemistry, and TUNEL staining of tumor tissues was performed. Two genetically engineered mouse models of ErbB2/Neu positive-PTEN homozygous deficient breast cancer were generated. The models were confirmed by genotyping and immunohistochemistry. One model with exogenous MMTV promoter driven expression of activated ErbB2/Neu and Cre coupling PTEN disruption was designated as NIC/PTEN(-/-) mice, and the other with MMTV-Cre induced endogenous promoter driven expression of activated ErbB2/Neu with PTEN disruption was designated as ErbB2KI/PTEN(-/-) mice. The tumor formation time in NIC/PTEN(-/-) mice was significantly shorter than that of ErbB2KI/PTEN(-/-) mice (30 vs 368 d, P<0.01); the number of tumor and incidence of lung metastasis was also significantly higher in NIC/PTEN(-/-) mice (10 vs 1-2 and 75.0% vs 37.5%, respectively, Ps<0.01). The Two models displayed distinct histopathological morphology. NIC/PTEN(-/-) tumor showed more Ki-67 positive cells than ErbB2KI/PTEN(-/-) tumor did (86.9%±2.8% vs 37.4%±7.2%, P<0.01), while the amount of cell apoptosis in tumors was not significantly different between two models. Two genetically engineered mouse

Forty to fifty-five-year-old women and iron deficiency: clinical considerations and quality of life.

PubMed

Firquet, Anne; Kirschner, Wolf; Bitzer, Johannes

2017-07-01

Between the age of 40 and 55 years, women experience important changes in their lives. This period, which corresponds to the perimenopause for most women, is associated with the risk of iron deficiency anemia (IDA). The clinical presentation of anemia can be misleading, and the underlying cause, particularly bleeding, is frequently treated without concomitant iron prescription. Iron deficiency (ID) remains a social and economic burden in European countries. Underdiagnosed and undertreated, this problem has a strong negative impact on women's quality of life. The risk factors for ID are well known. The physician's role is essential in recognizing the symptoms, identifying the risk factors, detecting IDA by testing hemoglobin, and evaluating the degree of ID by measuring serum ferritin (SF). Iron therapy treats the anemia and restores iron stores, thus decreasing symptoms such as fatigue and restoring quality of life. Among the available forms of iron, evidence is in favor of ferrous sulfate in a slow release formulation, which is well-tolerated and results in good adherence, a key factor for efficacious supplementation.

Inhibitor of Differentiation/DNA Binding 1 (ID1) Inhibits Etoposide-induced Apoptosis in a c-Jun/c-Fos-dependent Manner.

PubMed

Zhao, Yahui; Luo, Aiping; Li, Sheng; Zhang, Wei; Chen, Hongyan; Li, Yi; Ding, Fang; Huang, Furong; Liu, Zhihua

2016-03-25

ID1 (inhibitor of differentiation/DNA binding 1) acts an important role in metastasis, tumorigenesis, and maintenance of cell viability. It has been shown that the up-regulation of ID1 is correlated with poor prognosis and the resistance to chemotherapy of human cancers. However, the underlying molecular mechanism remains elusive. Here, we determined for the first time that up-regulating ID1 upon etoposide activation was mediated through AP-1 binding sites within theID1promoter and confirmed that ID1 enhanced cell resistance to DNA damage-induced apoptosis in esophageal squamous cell carcinoma cells. Ablation of c-Jun/c-Fos or ID1 expression enhanced etoposide-mediated apoptosis through increasing activity of caspase 3 and PARP cleavage. Moreover, c-Jun/c-Fos and ID1 were positively correlated in human cancers. More importantly, simultaneous high expression of ID1 and c-Jun or c-Fos was correlated with poor survival in cancer patients. Collectively, we demonstrate the importance of c-Jun/c-Fos-ID1 signaling pathway in chemoresistance of esophageal cancer cells and provide considerable insight into understanding the underlying molecular mechanisms in esophageal squamous cell carcinoma cell biology. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Non-canonical microRNAs miR-320 and miR-702 promote proliferation in Dgcr8-deficient embryonic stem cells

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

Kim, Byeong-Moo; Department of Medicine, Harvard Medical School, Boston, MA 02115; Choi, Michael Y., E-mail: mchoi@partners.org

2012-09-21

Highlights: Black-Right-Pointing-Pointer Embryonic stem cells (ESCs) lacking non-canonical miRNAs proliferate slower. Black-Right-Pointing-Pointer miR-320 and miR-702 are two non-canonical miRNAs expressed in ESCs. Black-Right-Pointing-Pointer miR-320 and miR-702 promote proliferation of Dgcr8-deficient ESCs. Black-Right-Pointing-Pointer miR-320 targets p57 and helps to release Dgcr8-deficient ESCs from G1 arrest. Black-Right-Pointing-Pointer miR-702 targets p21 and helps to release Dgcr8-deficient ESCs from G1 arrest. -- Abstract: MicroRNAs are known to contribute significantly to stem cell phenotype by post-transcriptionally regulating gene expression. Most of our knowledge of microRNAs comes from the study of canonical microRNAs that require two sequential cleavages by the Drosha/Dgcr8 heterodimer and Dicer to generatemore » mature products. In contrast, non-canonical microRNAs bypass the cleavage by the Drosha/Dgcr8 heterodimer within the nucleus but still require cytoplasmic cleavage by Dicer. The function of non-canonical microRNAs in embryonic stem cells (ESCs) remains obscure. It has been hypothesized that non-canonical microRNAs have important roles in ESCs based upon the phenotypes of ESC lines that lack these specific classes of microRNAs; Dicer-deficient ESCs lacking both canonical and non-canonical microRNAs have much more severe proliferation defect than Dgcr8-deficient ESCs lacking only canonical microRNAs. Using these cell lines, we identified two non-canonical microRNAs, miR-320 and miR-702, that promote proliferation of Dgcr8-deficient ESCs by releasing them from G1 arrest. This is accomplished by targeting the 3 Prime -untranslated regions of the cell cycle inhibitors p57 and p21 and thereby inhibiting their expression. This is the first report of the crucial role of non-canonical microRNAs in ESCs.« less

Adenosine A2B Receptor Deficiency Promotes Host Defenses against Gram-Negative Bacterial Pneumonia

PubMed Central

Barletta, Kathryn E.; Cagnina, R. Elaine; Burdick, Marie D.; Linden, Joel

2012-01-01

Rationale: Activation of the adenosine A2B receptor (A2BR) promotes antiinflammatory effects in diverse biological settings, but the role of this receptor in antimicrobial host defense in the lung has not been established. Gram-negative bacillary pneumonia is a common and serious illness associated with high morbidity and mortality, the treatment of which is complicated by increasing rates of antibiotic resistance. Objectives: To test the hypothesis that absence of adenosine A2B receptor signaling promotes host defense against bacterial pneumonia. Methods: We used a model of Klebsiella pneumoniae pneumonia in wild-type mice and mice with targeted deletion of the A2BR. Host responses were compared in vivo and leukocyte responses to the bacteria were examined in vitro. Measurements and Main Results: A2BR–/– mice demonstrated enhanced bacterial clearance from the lung and improved survival after infection with K. pneumoniae compared with wild-type controls, an effect that was mediated by bone marrow–derived cells. Leukocyte recruitment to the lungs and expression of inflammatory cytokines did not differ between A2BR–/– and wild-type mice, but A2BR–/– neutrophils exhibited sixfold greater bactericidal activity and enhanced production of neutrophil extracellular traps compared with wild-type neutrophils when incubated with K. pneumoniae. Consistent with this finding, bronchoalveolar lavage fluid from A2BR–/– mice with Klebsiella pneumonia contained more extracellular DNA compared with wild-type mice with pneumonia. Conclusions: These data suggest that the absence of A2BR signaling enhances antimicrobial activity in gram-negative bacterial pneumonia. PMID:22997203

The impacts of maternal iron deficiency and being overweight during pregnancy on neurodevelopment of the offspring.

PubMed

Berglund, Staffan K; Torres-Espínola, Francisco J; García-Valdés, Luz; Segura, Mª Teresa; Martínez-Zaldívar, Cristina; Padilla, Carmen; Rueda, Ricardo; Pérez García, Miguel; McArdle, Harry J; Campoy, Cristina

2017-10-01

Both maternal Fe deficiency (ID) and being overweight or obese (Ow/Ob, BMI≥25 kg/m2) may negatively affect offspring brain development. However, the two risk factors correlate and their independent effects on infant neurodevelopment are unclear. PREOBE is a prospective observational study that included 331 pregnant Spanish women, of whom 166 had pre-gestational Ow/Ob. Fe status was analysed at 34 weeks and at delivery, and babies were assessed using Bayley III scales of neurodevelopment at 18 months. In confounder-adjusted analyses, maternal ID at 34 weeks was associated with lower composite motor scores at 18 months (mean 113·3 (sd 9·9) v. 117·1 (sd 9·2), P=0·039). Further, the offspring of mothers with ID at delivery had lower cognitive scores (114·0 (sd 9·7) v. 121·5 (sd 10·9), P=0·039) and lower receptive, expressive and composite (99·5 (sd 8·6) v. 107·6 (sd 8·3), P=0·004) language scores. The negative associations between maternal ID at delivery and Bayley scores remained even when adjusting for maternal Ow/Ob and gestational diabetes. Similarly, maternal Ow/Ob correlated with lower gross motor scores in the offspring (12·3 (sd 2·0) v. 13·0 (sd 2·1), P=0·037), a correlation that remained when adjusting for maternal ID. In conclusion, maternal ID and pre-gestational Ow/Ob are both negatively associated with Bayley scores at 18 months, but independently and on different subscales. These results should be taken into account when considering Fe supplementation for pregnant women.

Iron supplementation until 6 months protects marginally low-birth-weight infants from iron deficiency during their first year of life.

PubMed

Berglund, Staffan K; Westrup, Björn; Domellöf, Magnus

2015-03-01

Low-birth-weight (LBW) infants (<2500 g) have an increased risk of iron deficiency (ID) during their first 6 months of life. The optimal dose and duration of iron supplementation to LBW infants are, however, unknown. The objective of the present study was to investigate the long-term effect on iron status and growth in marginally LBW (2000-2500 g) infants, of iron supplements given until 6 months of life. In a randomized controlled trial, 285 healthy marginally LBW infants received 0, 1, or 2 mg · kg(-1) · day(-1) of iron supplements from 6 weeks to 6 months of age. At 12 months and 3.5 years of life we measured length, weight, head circumference, and indicators of iron status (hemoglobin, ferritin, mean corpuscular volume, and transferrin saturation) and assessed the prevalence of iron depletion, functional ID, and ID anemia. At 12 months of age, there was a significant difference in ferritin between the groups (P = 0.006). Furthermore, there was a significant difference in the prevalence of iron depletion (23.7%, 10.6%, and 6.8%, respectively, in the placebo, 1-mg, and 2-mg groups, P = 0.009) and similar nonsignificant trends for functional ID and ID anemia. At 3.5 years of life there were no significant differences in iron status and the mean prevalence of iron depletion was 3.2%. Anthropometric data were not affected by the intervention. Iron supplements with 2 mg · kg(-1) · day(-1) until 6 months of life effectively reduces the risk of ID during the first 12 months of life and is an effective intervention for preventing early ID in marginally LBW infants.

41 CFR 101-26.803-2 - Reporting quality deficiencies.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 41 Public Contracts and Property Management 2 2010-07-01 2010-07-01 true Reporting quality... § 101-26.803-2 Reporting quality deficiencies. (a) Quality deficiencies are defined as defects or nonconforming conditions which limit or prohibit the item received from fulfilling its intended purpose. Quality...

Multidrug Resistance Protein 1 Deficiency Promotes Doxorubicin-Induced Ovarian Toxicity in Female Mice.

PubMed

Wang, Yingzheng; Liu, Mingjun; Zhang, Jiyang; Liu, Yuwen; Kopp, Megan; Zheng, Weiwei; Xiao, Shuo

2018-05-01

Multidrug resistance protein 1 (MDR1), a phase III drug transporter that exports substrates out of cells, has been discovered in both cancerous and normal tissues. The over expression of MDR1 in cancer cells contributes to multiple drug resistance, whereas the MDR1 in normal tissues protects them from chemical-induced toxicity. Currently, the role of MDR1 in the ovary has not been entirely understood. Our objective is to determine the function of MDR1 in protecting against chemotherapy-induced ovarian toxicity. Using both the in vivo transgenic mouse model and in vitro follicle culture model, we investigated the expression of MDR1 in the ovary, the effect of MDR1 deficiency on doxorubicin (DOX)-induced ovarian toxicity, and the ovarian steroid hormonal regulation of MDR1. Results showed that the MDR1 was expressed in the ovarian epithelial cells, stroma cells, theca cell layers, endothelial cells, and luteal cells. The lack of MDR1 did not affect female ovarian function and fertility; however, its deficiency significantly exacerbated the DOX-induced ovarian toxicity in both in vivo and in vitro models. The MDR1 showed significantly higher expression levels in the ovaries at estrus and metestrus stages than those at proestrus and diestrus stages. However, this dynamic expression pattern was not regulated by the ovarian steroid hormones of estrogen (E2) and progesterone (P4) but correlated to the number and status of corpus luteum. In conclusion, our study demonstrates that the lack of MDR1 promotes DOX-induced ovarian toxicity, suggesting the critical role of MDR1 in protecting female ovarian functions during chemotherapy.

A calcium-deficient diet in pregnant, nursing rats induces hypomethylation of specific cytosines in the 11β-hydroxysteroid dehydrogenase-1 promoter in pup liver.

PubMed

Takaya, Junji; Iharada, Anna; Okihana, Hiroyuki; Kaneko, Kazunari

2013-11-01

Prenatal undernutrition affects offspring phenotype via changes in the epigenetic regulation of specific genes. We hypothesized that pregnant females that were fed a calcium (Ca)-deficient diet would have offspring with altered hepatic glucocorticoid-related gene expression and altered epigenetic gene regulation. Female Wistar rats ate either a Ca-deficient or control diet from 3 weeks before conception to 21 days after parturition. Pups were allowed to nurse from their original mothers and then euthanized on day 21. Methylation of individual cytosine-guanine dinucleotides in the phosphoenolpyruvate carboxykinase (Pck1), peroxisome proliferator-activated receptor α (Ppara), glucocorticoid receptor (Nr3c1), 11β-hydroxysteroid dehydrogenase-1 (Hsd11b1), and 11β-hydroxysteroid dehydrogenase-2 (Hsd11b2) promoters was measured in liver tissue using pyrosequencing. For each gene, quantitative real-time polymerase chain reaction was used to assess mRNA levels in liver tissue. Overall Hsd11b1 methylation was lower in the Ca-deficient group than in the control group; however, overall methylation of each other gene did not differ between groups. Serum corticosterone levels in male pups from Ca-deficient dams were higher than those in control pups. Expression of Pck1 and Nr3c1 was lower in the Ca-deficient group than in the control group. A Ca-deficient diet for a dam during gestation and early nursing may alter glucocorticoid metabolism and lead to higher intracellular glucocorticoid concentrations in the hepatic cells of her offspring; moreover, this abnormal glucocorticoid metabolism may induce the metabolic complications that are associated with Ca deficiency. These findings indicated that prenatal nutrition affected glucocorticoid metabolism in offspring in part by affecting the epigenome of offspring. © 2013.

Reframing Health Promotion for People With Intellectual Disabilities

PubMed Central

2015-01-01

The World Health Organization calls for health promotion to expand beyond the health care system by considering social determinants of health, engaging multiple levels, targeting policy change, and including social action. This qualitative study embraces this holistic stance as a means to address the health disparities and inequities experienced by people with intellectual disabilities (ID) by supporting the development of interventions that consider components of social justice along with embracing this population’s potential and acknowledging influences of the context. A content analysis of the data is presented to illustrate how an occupational viewpoint can promote positive health and well-being of people with ID. The four gerunds of Wilcock’s Occupational Perspective on Health—doing, being, belonging, and becoming—are utilized and supported by the literature to offer actions that can be taken by health promotion professionals to address the health needs of people with ID. PMID:28462304

Prevalence and clinical impact of iron deficiency and anaemia among outpatients with chronic heart failure: The PrEP Registry.

PubMed

von Haehling, Stephan; Gremmler, Uwe; Krumm, Michael; Mibach, Frank; Schön, Norbert; Taggeselle, Jens; Dahm, Johannes B; Angermann, Christiane E

2017-06-01

Iron deficiency (ID) and anaemia are common in heart failure (HF). The prospective, observational PReP registry (Prävalenz des Eisenmangels bei Patienten mit Herzinsuffizienz) studied prevalence and clinical impact of ID and anaemia in HF outpatients attending cardiology practices in Germany. A total of 42 practices enrolled consecutive patients with chronic HF [left ventricular ejection fraction (LVEF) ≤45%]. ID was defined as serum ferritin <100 µg/l, or serum ferritin ≥100 µg/l/<300 µg/l plus transferrin saturation <20%, and anaemia as haemoglobin <13 g/dl (12 g/dl) in men (women). Exercise capacity was assessed using spiroergometry (69.4%) or 6-min walk test (30.4%). Amongst 1198 PReP-participants [69.0  ± 10.6 years, 25.3% female, New York Heart Association (NYHA) class 2.4  ± 0.5, LVEF 35.3 ± 7.2%], ID was found in 42.5% (previously unknown in all), and anaemia in 18.9% (previously known in 4.8%). ID was associated with female gender, lower body weight and haemoglobin, higher NYHA class and natriuretic peptide (NP) levels (all p < 0.05). ID was also more common in anaemic than non-anaemic patients (p < 0.0001), and 9.8% of PrEP-participants had both, ID and anaemia. On spiroergometry, ID independently predicted maximum exercise capacity even after multivariable adjustment, including anaemia (p = 0.0004). In all PrEP-participants, ID predicted reduced physical performance (adjusted for age, gender, anaemia, serum creatinine, C-reactive protein, LVEF, and NP level). Despite high prevalence, ID was previously unknown in all PrEP-participants, and anaemia was often unappreciated. Given the clinical relevance, treatability, and independent association with reduced physical performance, ID should be considered more in real-world ambulatory healthcare settings and ID-screening be advocated to cardiologists in such populations.

Fake ID ownership and heavy drinking in underage college students: prospective findings.

PubMed

Martinez, Julia A; Rutledge, Patricia C; Sher, Kenneth J

2007-06-01

The authors examined the ownership of false identification (fake ID) for the purpose of obtaining alcohol and the relation of fake ID ownership to heavy drinking in a longitudinal sample of college students under 21 years of age. A sample of 3,720 undergraduates was assessed the summer prior to college entrance and during the 4 semesters comprising freshman and sophomore years. Regression analyses were used to estimate bidirectional relations between consumption and fake ID ownership. Sex, Greek membership, and prior drinking were controlled. Results showed that fake ID ownership increased over time (12.5% pre-college to 32.2% fourth semester) and that Greek members were more likely than others to own fake IDs. Fake ID ownership predicted concurrent and next-semester heavy drinking with increasing strength over time. Also, the acquisition (onset) of fake ID ownership at each time point was predicted by previous-semester consumption. When traditional, robust risk factors of consumption are controlled, fake ID ownership meaningfully relates to heavy drinking in college. It thus presents a significant public health problem, addressable through training for alcohol servers and retailers, punitive measures toward fake ID owners, and other possible interventions.

MicroRNA-155 deficiency promotes nephrin acetylation and attenuates renal damage in hyperglycemia-induced nephropathy.

PubMed

Lin, Xu; You, Yanwu; Wang, Jie; Qin, Youling; Huang, Peng; Yang, Fafen

2015-04-01

MiR-155 has been reported to be involved in both innate and adaptive immune responses. But the role of miR-155 in hyperglycemia-induced nephropathy is still unknown. In our current study, 3-month-old male wild-type C57 mice and Mir-155(-/-) mice were used to establish hyperglycemia-induced nephropathy. In our hyperglycemia-induced nephropathy model, the expression of podocyte injury marker desmin was markedly increased in the diabetes group when compared with control. Diabetes also significantly decreased the levels of nephrin and acetylated nephrin, whereas the expression of miR-155 was markedly increased in diabetes group when compared with control. MiR-155(-/-) mice showed significantly increased expression of nephrin, acetylated nephrin, and Wilm's tumor-1 protein (WT-1) when compared with wild-type control. MiR-155 deficiency results in significantly decrease in IL-17A expression both in vivo and in vitro. And the increased expression of WT-1, nephrin, and ac-nephrin was reversed with additional treatment of rmIL-17. Furthermore, we found that the inhibited Th17 differentiation induced by miR-155 deficiency was dependent on increased expression of SOCS1. In conclusion, miR-155 deficiency promotes nephrin acetylation and attenuates renal damage in hyperglycemia-induced nephropathy. This was associated with inhibited IL-17 production through enhancement of SOCS1 expression.

Deficiency in Nrf2 transcription factor decreases adipose tissue mass and hepatic lipid accumulation in leptin-deficient mice.

PubMed

Xu, Jialin; Donepudi, Ajay C; More, Vijay R; Kulkarni, Supriya R; Li, Liya; Guo, Liangran; Yan, Bingfang; Chatterjee, Tapan; Weintraub, Neal; Slitt, Angela L

2015-02-01

To evaluate whether Nrf2 deficiency impacts insulin resistance and lipid accumulation in liver and white adipose tissue. Lep(ob/ob) mice (OB) with targeted Nrf2 deletion (OB-Nrf2KO) were generated. Pathogenesis of obesity and type 2 diabetes was measured in C57BL/6J, Nrf2KO, OB, and OB-Nrf2KO mice. Hepatic lipid content, lipid clearance, and very low-density lipoprotein (VLDL) secretion were determined between OB and OB-Nrf2KO mice. OB-Nrf2KO mice exhibited decreased white adipose tissue mass and decreased adipogenic and lipogenic gene expression compared with OB mice. Nrf2 deficiency prolonged hyperglycemia in response to glucose challenge, which was paralleled by reduced insulin-stimulated Akt phosphorylation. In OB mice, Nrf2 deficiency decreased hepatic lipid accumulation, decreased peroxisome proliferator-activated receptor γ expression and nicotinamide adenine dinucleotide phosphate (NADPH) content, and enhanced VLDL secretion. However, this observation was opposite in lean mice. Additionally, OB-Nrf2KO mice exhibited increased plasma triglyceride content, decreased HDL-cholesterol content, and enhanced apolipoprotein B expression, suggesting Nrf2 deficiency caused dyslipidemia in these mice. Nrf2 deficiency in Lep(ob/ob) mice reduced white adipose tissue mass and prevented hepatic lipid accumulation but induced insulin resistance and dyslipidemia. This study indicates a dual role of Nrf2 during metabolic dysregulation-increasing lipid accumulation in liver and white adipose tissue but preventing lipid accumulation in obese mice. © 2014 The Obesity Society.

ACE ID genotype and the muscle strength and size response to unilateral resistance training.

PubMed

Pescatello, Linda S; Kostek, Matthew A; Gordish-Dressman, Heather; Thompson, Paul D; Seip, Richard L; Price, Thomas B; Angelopoulos, Theodore J; Clarkson, Priscilla M; Gordon, Paul M; Moyna, Niall M; Visich, Paul S; Zoeller, Robert F; Devaney, Joseph M; Hoffman, Eric P

2006-06-01

To examine associations among the angiotensin I-converting enzyme (ACE) insertion (I)/deletion (D) polymorphism and the response to a 12-wk (2 d.wk) unilateral, upper-arm resistance training (RT) program in the trained (T, nondominant) and untrained (UT, dominant) arms. Subjects were 631 (mean+/-SEM, 24.2+/-0.2 yr) white (80%) men (42%) and women (58%). The ACE ID genotype was in Hardy-Weinberg equilibrium with frequencies of 23.1, 46.1, and 30.8% for ACE II, ID, and DD, respectively (chi=1.688, P=0.430). Maximum voluntary contraction (MVC) and one-repetition maximum (1RM) assessed peak elbow flexor muscle strength. Magnetic resonance imaging measured biceps muscle cross-sectional area (CSA). Multiple variable and repeated-measures ANCOVA tested whether muscle strength and size differed at baseline and pre- to post-RT among T and UT and ACE ID genotype. Baseline muscle strength and size were greater in UT than T (P<0.001) and did not differ among ACE ID genotype in either arm (P >or= 0.05). In T, MVC increases were greater for ACE II/ID (22%) than DD (17%) (P<0.05), whereas 1RM (51%) and CSA (19%) gains were not different among ACE ID genotype pre- to post-RT (P >or= 0.05). In UT, MVC increased among ACE II/ID (7%) (P<0.001) but was similar among ACE DD (2%) pre- to post-RT (P >or= 0.05). In UT, 1RM (11%) and CSA (2%) increases were greater for ACE DD/ID than ACE II (1RM, 7%; CSA, -0.1%) (P<0.05). ACE ID genotype explained approximately 1% of the MVC response to RT in T and approximately 2% of MVC, 2% of 1RM, and 4% of CSA response in UT (P<0.05). ACE ID genotype is associated with the contralateral effects of unilateral RT, perhaps more so than with the muscle strength and size adaptations that result from RT.

Oxytocin improves behavioral and electrophysiological deficits in a novel Shank3-deficient rat.

PubMed

Harony-Nicolas, Hala; Kay, Maya; Hoffmann, Johann du; Klein, Matthew E; Bozdagi-Gunal, Ozlem; Riad, Mohammed; Daskalakis, Nikolaos P; Sonar, Sankalp; Castillo, Pablo E; Hof, Patrick R; Shapiro, Matthew L; Baxter, Mark G; Wagner, Shlomo; Buxbaum, Joseph D

2017-01-31

Mutations in the synaptic gene SHANK3 lead to a neurodevelopmental disorder known as Phelan-McDermid syndrome (PMS). PMS is a relatively common monogenic and highly penetrant cause of autism spectrum disorder (ASD) and intellectual disability (ID), and frequently presents with attention deficits. The underlying neurobiology of PMS is not fully known and pharmacological treatments for core symptoms do not exist. Here, we report the production and characterization of a Shank3 -deficient rat model of PMS, with a genetic alteration similar to a human SHANK3 mutation. We show that Shank3 -deficient rats exhibit impaired long-term social recognition memory and attention, and reduced synaptic plasticity in the hippocampal-medial prefrontal cortex pathway. These deficits were attenuated with oxytocin treatment. The effect of oxytocin on reversing non-social attention deficits is a particularly novel finding, and the results implicate an oxytocinergic contribution in this genetically defined subtype of ASD and ID, suggesting an individualized therapeutic approach for PMS.

TOP1MT deficiency promotes GC invasion and migration via the enhancements of LDHA expression and aerobic glycolysis.

PubMed

Wang, Hongqiang; Zhou, Rui; Sun, Li; Xia, Jianling; Yang, Xuchun; Pan, Changqie; Huang, Na; Shi, Min; Bin, Jianping; Liao, Yulin; Liao, Wangjun

2017-11-01

Aerobic glycolysis plays an important role in cancer progression. New target genes regulating cancer aerobic glycolysis must be explored to improve patient prognosis. Mitochondrial topoisomerase I ( TOP1MT ) deficiency suppresses glucose oxidative metabolism but enhances glycolysis in normal cells. Here, we examined the role of TOP1MT in gastric cancer (GC) and attempted to determine the underlying mechanism. Using in vitro and in vivo experiments and analyzing the clinicopathological characteristics of patients with GC, we found that TOP1MT expression was lower in GC samples than in adjacent nonmalignant tissues. TOP1MT knockdown significantly promoted GC migration and invasion in vitro and in vivo Importantly, TOP1MT silencing increased glucose consumption, lactate production, glucose transporter 1 expression and the epithelial-mesenchymal transition (EMT) in GC. Additionally, regulation of glucose metabolism induced by TOP1MT was significantly associated with lactate dehydrogenase A (LDHA) expression. A retrospective analysis of clinical data from 295 patients with GC demonstrated that low TOP1MT expression was associated with lymph node metastasis, recurrence and high mortality rates. TOP1MT deficiency enhanced glucose aerobic glycolysis by stimulating LDHA to promote GC progression. © 2017 The authors.

Evaluation of ID-PaGIA syphilis antibody test.

PubMed

Naaber, Paul; Makoid, Ene; Aus, Anneli; Loivukene, Krista; Poder, Airi

2009-01-01

Laboratory diagnosis of syphilis is usually accomplished by serology. There are currently a large number of different commercial treponemal tests available that vary in format, sensitivity and specificity. To evaluate the ID-PaGIA Syphilis Antibody Test as an alternative to other specific treponemal tests for primary screening or confirmation of diagnosis. Serum samples from healthy adults (n = 100) were used for detection of specificity of ID-PaGIA. To evaluate sensitivity of ID-PaGIA serum samples (n = 101) from patients with confirmed or suspected syphilis were tested for syphilis antibodies with FTA-Abs IgM, ID-PaGIA, ELISA IgM and TPHA tests. No false-positive results were found with ID-PaGIA. Sensitivity of various treponemal tests was the following: FTA-Abs IgM: 95.5%, ID-PaGIA and ELISA IgM: 94%, and TPHA 75%. The positive and negative predictive values of ID-PaGIA were 100 and 89.5%, respectively. Compared with other treponemal tests ID-PaGIA has excellent sensitivity and specificity.

Deoxycytidine and deoxythymidine treatment for thymidine kinase 2 deficiency

PubMed Central

Lopez-Gomez, Carlos; Levy, Rebecca J; Sanchez-Quintero, Maria J; Juanola-Falgarona, Marti; Barca, Emanuele; Garcia-Diaz, Beatriz; Tadesse, Saba; Garone, Caterina; Hirano, Michio

2017-01-01

Objective Thymidine kinase 2 (TK2), a critical enzyme in the mitochondrial pyrimidine salvage pathway, is essential for mitochondrial DNA (mtDNA) maintenance. Mutations in the nuclear gene TK2 cause TK2 deficiency, which manifests predominantly in children as myopathy with mtDNA depletion. Molecular bypass therapy with the TK2 products, dCMP and dTMP, prolongs the lifespan of Tk2-deficient (Tk2-/-) mice by 2-3 fold. Because we observed rapid catabolism of the deoxynucleoside monophosphates to deoxythymidine (dT) and deoxycytidine (dC), we hypothesized that: 1) deoxynucleosides might be the major active agents and 2) inhibition of deoxycytidine deamination might enhance dTMP+dCMP therapy. Methods To test these hypotheses, we assessed two therapies in Tk2-/- mice: 1) dT+dC and 2) co-administration of the deaminase inhibitor, tetrahydrouridine (THU), with dTMP+dCMP. Results We observed that dC+dT delayed disease onset, prolonged lifespan of Tk2-deficient mice, and restored mtDNA copy number as well as respiratory chain enzyme activities and levels. In contrast, dCMP+dTMP+THU therapy decreased lifespan of Tk2-/- animals compared to dCMP+dTMP. Interpretation Our studies demonstrate that deoxynucleoside substrate enhancement is a novel therapy, which may ameliorate TK2 deficiency in patients. PMID:28318037

[Vitamin B12 Deficiency in Type 2 Diabetes Mellitus].

PubMed

Tavares Bello, Carlos; Capitão, Ricardo Miguel; Sequeira Duarte, João; Azinheira, Jorge; Vasconcelos, Carlos

2017-10-31

Type 2 diabetes mellitus is a common disease, affecting up to 13.1% of the Portuguese population. In addition to the known micro and macrovascular complications, drug side effects constitute a major concern, leading to changes in the treatment guidelines, which favor safety over efficacy. Metformin is the first-line pharmacological treatment for most patients with type 2 diabetes mellitus; however, it has been associated with vitamin B12 deficiency in up to 30% of treated patients. The authors describe the prevalence of vitamin B12 deficiency in a diabetic population and explore the possible underlying factors. Retrospective, observational study. Clinical and laboratory data of type 2 diabetes mellitus patients whose vitamin B12 status was evaluated in the last decade (2005 - 2016) were analyzed. Patients with known malabsorptive syndromes or having undergone bariatric surgery were excluded from the study. Statistical analysis of the data was done and the results were considered statistically significant at p values < 0.05. The study included a total of 1007 patients (58% women) with a mean age of 66.4 ± 12.2 years and 11 ± 10.4 years of type 2 diabetes mellitus duration. These patients had a high prevalence of complications: diabetic renal disease 47.7%, neuropathy 9.2%, retinopathy 14.9%, coronary artery disease 8.4%, cerebrovascular disease 10.9%, and peripheral arterial disease 5.5%. Vitamin B12 deficiency (< 174 ng / dL) was present in 21.4% of the population and this subgroup was older (68.4 vs 65.8 years, p = 0.006), had a longer type 2 diabetes mellitus duration (13.35 vs 10.36 years; p = 0.001), higher prevalence of retinopathy (20.9% vs 13.3%; p = 0.005) and thyroid dysfunction (34% vs 23.7%; p = 0.002). Vitamin B12 deficiency was also more frequent in patients treated with metformin (24.7% vs 15.8%; p = 0.017), antiplatelet agents (25.4% vs 16.2%, p < 0.001), and calcium channel blockers (26.8% vs 18.2%; p = 0.001). After adjustment for possible

Anemia and Iron Deficiency in Vietnamese Children, 6 to 11 Years Old.

PubMed

Le Nguyen Bao, Khanh; Tran Thuy, Nga; Nguyen Huu, Chinh; Khouw, Ilse; Deurenberg, Paul

2016-07-01

In a population sample of 385 children, 6 to 11 years old, venous blood parameters-hemoglobin (Hb), ferritin, red blood cell count (RBC), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), C-reactive protein (CRP), and α1-acid glycoprotein (AGP)-were determined to get insight into the iron status. The prevalence of anemia was 11.4%; 5.6% had iron deficiency (ID), whereas 0.4% had ID anemia. Correction for inflammation based on CRP and AGP did not markedly change the overall prevalence of ID and ID anemia. Stunted children had lower Hb and ferritin values compared with nonstunted children, and thin children had lower values compared with normal-weight or overweight and obese children. Many nonanemic children had alert values for RBC, MCV, MCH, and MCHC. It is concluded that although the prevalence of anemia is of the magnitude of a mild public health problem, the iron status of many nonanemic children is borderline, as indicated by a high number of children with low values for red blood cytology. © 2016 APJPH.

Iron Deficiency with or without Anemia Impairs Prepulse Inhibition of the Startle Reflex

PubMed Central

Pisansky, Marc T.; Wickham, Robert J.; Su, Jianjun; Fretham, Stephanie; Yuan, Li-Lian; Sun, Mu; Gewirtz, Jonathan C.; Georgieff, Michael K.

2013-01-01

Iron deficiency (ID) during early life causes long-lasting detrimental cognitive sequelae, many of which are linked to alterations in hippocampus function, dopamine synthesis, and the modulation of dopaminergic circuitry by the hippocampus. These same features have been implicated in the origins of schizophrenia, a neuropsychiatric disorder with significant cognitive impairments. Deficits in sensorimotor gating represent a reliable endophenotype of schizophrenia that can be measured by prepulse inhibition (PPI) of the acoustic startle reflex. Using two rodent model systems, we investigated the influence of early-life ID on PPI in adulthood. To isolate the role of hippocampal iron in PPI, our mouse model utilized a timed (embryonic day 18.5), hippocampus-specific knockout of Slc11a2, a gene coding an important regulator of cellular iron uptake, the divalent metal transport type 1 protein (DMT-1). Our second model used a classic rat dietary-based global ID during gestation, a condition that closely mimics human gestational ID anemia (IDA). Both models exhibited impaired PPI in adulthood. Furthermore, our DMT-1 knockout model displayed reduced long-term potentiation (LTP) and elevated paired pulse facilitation (PPF), electrophysiological results consistent with previous findings in the IDA rat model. These results, in combination with previous findings demonstrating impaired hippocampus functioning and altered dopaminergic and glutamatergic neurotransmission, suggest that iron availability within the hippocampus is critical for the neurodevelopmental processes underlying sensorimotor gating. Ultimately, evidence of reduced PPI in both of our models may offer insights into the roles of fetal ID and the hippocampus in the pathophysiology of schizophrenia. PMID:23733517

Dose-Response Analysis of Developmental Iodide Deficiency: Reductions in Thyroid Hormones and Impaired Hippocampal Synaptic Transmission

EPA Science Inventory

Iodide is an essential nutrient for thyroid hormone synthesis and severe iodide deficiency (ID) during early development is associated with neurological impairments. Several environmental contaminants can perturb the thyroid axis and this perturbation may be more acute under cond...

Deoxycytidine and Deoxythymidine Treatment for Thymidine Kinase 2 Deficiency.

PubMed

Lopez-Gomez, Carlos; Levy, Rebecca J; Sanchez-Quintero, Maria J; Juanola-Falgarona, Martí; Barca, Emanuele; Garcia-Diaz, Beatriz; Tadesse, Saba; Garone, Caterina; Hirano, Michio

2017-05-01

Thymidine kinase 2 (TK2), a critical enzyme in the mitochondrial pyrimidine salvage pathway, is essential for mitochondrial DNA (mtDNA) maintenance. Mutations in the nuclear gene, TK2, cause TK2 deficiency, which manifests predominantly in children as myopathy with mtDNA depletion. Molecular bypass therapy with the TK2 products, deoxycytidine monophosphate (dCMP) and deoxythymidine monophosphate (dTMP), prolongs the life span of Tk2-deficient (Tk2 -/- ) mice by 2- to 3-fold. Because we observed rapid catabolism of the deoxynucleoside monophosphates to deoxythymidine (dT) and deoxycytidine (dC), we hypothesized that: (1) deoxynucleosides might be the major active agents and (2) inhibition of deoxycytidine deamination might enhance dTMP+dCMP therapy. To test these hypotheses, we assessed two therapies in Tk2 -/- mice: (1) dT+dC and (2) coadministration of the deaminase inhibitor, tetrahydrouridine (THU), with dTMP+dCMP. We observed that dC+dT delayed disease onset, prolonged life span of Tk2-deficient mice and restored mtDNA copy number as well as respiratory chain enzyme activities and levels. In contrast, dCMP+dTMP+THU therapy decreased life span of Tk2 -/- animals compared to dCMP+dTMP. Our studies demonstrate that deoxynucleoside substrate enhancement is a novel therapy, which may ameliorate TK2 deficiency in patients. Ann Neurol 2017;81:641-652. © 2017 American Neurological Association.

R&D100: IC ID

ScienceCinema

Hamlet, Jason; Pierson, Lyndon; Bauer, Todd

2018-06-25

Supply chain security to detect, deter, and prevent the counterfeiting of networked and stand-alone integrated circuits (ICs) is critical to cyber security. Sandia National Laboratory researchers have developed IC ID to leverage Physically Unclonable Functions (PUFs) and strong cryptographic authentication to create a unique fingerprint for each integrated circuit. IC ID assures the authenticity of ICs to prevent tampering or malicious substitution.

Tissue-autonomous promotion of palisade cell development by phototropin 2 in Arabidopsis.

PubMed

Kozuka, Toshiaki; Kong, Sam-Geun; Doi, Michio; Shimazaki, Ken-ichiro; Nagatani, Akira

2011-10-01

Light is an important environmental information source that plants use to modify their growth and development. Palisade parenchyma cells in leaves develop cylindrical shapes in response to blue light; however, the photosensory mechanism for this response has not been elucidated. In this study, we analyzed the palisade cell response in phototropin-deficient mutants. First, we found that two different light-sensing mechanisms contributed to the response in different proportions depending on the light intensity. One response observed under lower intensities of blue light was mediated exclusively by a blue light photoreceptor, phototropin 2 (PHOT2). Another response was elicited under higher intensities of light in a phototropin-independent manner. To determine the tissue in which PHOT2 perceives the light stimulus to regulate the response, green fluorescent protein (GFP)-tagged PHOT2 (P2G) was expressed under the control of tissue-specific promoters in the phot1 phot2 mutant background. The results revealed that the expression of P2G in the mesophyll, but not in the epidermis, promoted palisade cell development. Furthermore, a constitutively active C-terminal kinase fragment of PHOT2 fused to GFP (P2CG) promoted the development of cylindrical palisade cells in the proper direction without the directional cue provided by light. Hence, in response to blue light, PHOT2 promotes the development of cylindrical palisade cells along a predetermined axis in a tissue-autonomous manner.

The FAK–Arp2/3 interaction promotes leading edge advance and haptosensing by coupling nascent adhesions to lamellipodia actin

PubMed Central

Swaminathan, Vinay; Fischer, R. S.; Waterman, Clare M.

2016-01-01

Cell migration is initiated in response to biochemical or physical cues in the environment that promote actin-mediated lamellipodial protrusion followed by the formation of nascent integrin adhesions (NAs) within the protrusion to drive leading edge advance. Although FAK is known to be required for cell migration through effects on focal adhesions, its role in NA formation and lamellipodial dynamics is unclear. Live-cell microscopy of FAK−/− cells with expression of phosphorylation deficient or a FERM-domain mutant deficient in Arp2/3 binding revealed a requirement for FAK in promoting the dense formation, transient stabilization, and timely turnover of NA within lamellipodia to couple actin-driven protrusion to adhesion and advance of the leading edge. Phosphorylation on Y397 of FAK promotes dense NA formation but is dispensable for transient NA stabilization and leading edge advance. In contrast, transient NA stabilization and advance of the cell edge requires FAK–Arp2/3 interaction, which promotes Arp2/3 localization to NA and reduces FAK activity. Haptosensing of extracellular matrix (ECM) concentration during migration requires the interaction between FAK and Arp2/3, whereas FAK phosphorylation modulates mechanosensing of ECM stiffness during spreading. Taken together, our results show that mechanistically separable functions of FAK in NA are required for cells to distinguish distinct properties of their environment during migration. PMID:26842895

41 CFR 101-26.803-2 - Reporting quality deficiencies.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 41 Public Contracts and Property Management 2 2012-07-01 2012-07-01 false Reporting quality... product quality deficiency condition, an information copy should be sent to the following address: General... future procurements. (j) Additional information regarding reporting of quality deficiences may be...

41 CFR 101-26.803-2 - Reporting quality deficiencies.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 41 Public Contracts and Property Management 2 2011-07-01 2007-07-01 true Reporting quality... product quality deficiency condition, an information copy should be sent to the following address: General... future procurements. (j) Additional information regarding reporting of quality deficiences may be...

Atg5-mediated autophagy deficiency in proximal tubules promotes cell cycle G2/M arrest and renal fibrosis.

PubMed

Li, Huiyan; Peng, Xuan; Wang, Yating; Cao, Shirong; Xiong, Liping; Fan, Jinjin; Wang, Yihan; Zhuang, Shougang; Yu, Xueqing; Mao, Haiping

2016-09-01

Macroautophagy/autophagy protects against cellular stress. Renal sublethal injury-triggered tubular epithelial cell cycle arrest at G2/M is associated with interstitial fibrosis. However, the role of autophagy in renal fibrosis is elusive. Here, we hypothesized that autophagy activity in tubular epithelial cells is pivotal for inhibition of cell cycle G2/M arrest and subsequent fibrogenic response. In both renal epithelial cells stimulated by angiotensin II (AGT II) and the murine kidney after unilateral ureteral obstruction (UUO), we observed that occurrence of autophagy preceded increased production of COL1 (collagen, type I). Pharmacological enhancement of autophagy by rapamycin suppressed COL1 accumulation and renal fibrosis. In contrast, genetic ablation of autophagy by proximal tubular epithelial cell-specific deletion of Atg5, with reduction of the LC3-II protein level and degradation of SQSTM1/p62, showed marked cell cycle arrest at the G2/M phase, robust COL1 deposition, and severe interstitial fibrosis in a UUO model, as compared with wild-type mice. In vitro, AGT II exposure triggered autophagy preferentially in the G1/S phase, and increased COL1 expression in the G2/M phase in renal epithelial cells. Stimulation of Atg5-deficient primary proximal tubular cells with AGT II also resulted in elevated G2/M arrest and COL1 production. Pharmacological or genetic inhibition of autophagy increased AGT II-mediated G2/M arrest. Enhanced expression of ATG5, but not the autophagy-deficient ATG5 mutant K130R, rescued the G2/M arrest, suggesting the regulation of cell cycle progression by ATG5 is autophagy dependent. In conclusion, Atg5-mediated autophagy in proximal epithelial cells is a critical host-defense mechanism that prevents renal fibrosis by blocking G2/M arrest.

Depletion in LpA-I:A-II particles enhances HDL-mediated endothelial protection in familial LCAT deficiency[S

PubMed Central

Gomaraschi, Monica; Ossoli, Alice; Castelnuovo, Samuela; Simonelli, Sara; Pavanello, Chiara; Balzarotti, Gloria; Arca, Marcello; Di Costanzo, Alessia; Sampietro, Tiziana; Vaudo, Gaetano; Baldassarre, Damiano; Veglia, Fabrizio; Franceschini, Guido; Calabresi, Laura

2017-01-01

The aim of this study was to evaluate the vasoprotective effects of HDL isolated from carriers of LCAT deficiency, which are characterized by a selective depletion of LpA-I:A-II particles and predominance of preβ migrating HDL. HDLs were isolated from LCAT-deficient carriers and tested in vitro for their capacity to promote NO production and to inhibit vascular cell adhesion molecule-1 (VCAM-1) expression in cultured endothelial cells. HDLs from carriers were more effective than control HDLs in promoting eNOS activation with a gene-dose-dependent effect (PTrend = 0.048). As a consequence, NO production induced by HDL from carriers was significantly higher than that promoted by control HDL (1.63 ± 0.24-fold vs. 1.34 ± 0.07-fold, P = 0.031). HDLs from carriers were also more effective than control HDLs in inhibiting the expression of VCAM-1 (homozygotes, 65.0 ± 8.6%; heterozygotes, 53.1 ± 7.2%; controls, 44.4 ± 4.1%; PTrend = 0.0003). The increased efficiency of carrier HDL was likely due to the depletion in LpA-I:A-II particles. The in vitro findings might explain why carriers of LCAT deficiency showed flow-mediated vasodilation and plasma-soluble cell adhesion molecule concentrations comparable to controls, despite low HDL-cholesterol levels. These results indicate that selective depletion of apoA-II-containing HDL, as observed in carriers of LCAT deficiency, leads to an increased capacity of HDL to stimulate endothelial NO production, suggesting that changes in HDL apolipoprotein composition may be the target of therapeutic interventions designed to improve HDL functionality. PMID:28351888

Evaluation of Association of ADRA2A rs553668 and ACE I/D Gene Polymorphisms with Obesity Traits in the Setapak Population, Malaysia.

PubMed

Shunmugam, Vicneswari; Say, Yee-How

2016-02-01

α-adrenergic receptor 2A (ADRA2A) and angiotensin-converting enzyme (ACE) genes have been variably associated with obesity and its related phenotypes in different populations worldwide. This cross-sectional study aims to investigate the association of adrenergic receptor α2A (ADRA2A) rs553668 and angiotensin-converting enzyme (ACE) I/D single nucleotide polymorphisms (SNPs) with obesity traits (body mass index-BMI; waist-hip ratio-WHR; total body fat percentage - TBF) in a Malaysian population. Demographic and clinical variables were initially collected from 230 subjects via convenience sampling among residents and workers in Setapak, Malaysia, but in the end only 214 multi-ethnic Malaysians (99 males; 45 Malays, 116 ethnic Chinese, and 53 ethnic Indians) were available for statistical analysis. Genotyping was performed by polymerase chain reaction using DNA extracted from mouthwash samples. The overall minor allele frequencies (MAFs) for ADRA2A rs553668 and ACE I/D were 0.55 and 0.56, respectively. Allele distribution of ACE I/D was significantly associated with ethnicity and WHR class. Logistic regression analysis showed that subjects with the ACE II genotype and I allele were, respectively, 2.15 and 1.55 times more likely to be centrally obese, but when adjusted for age and ethnicity, this association was abolished. Covariate analysis controlling for age, gender, and ethnicity also showed similar results, where subjects carrying the II genotype or I allele did not have significantly higher WHR. Combinatory genotype and allele analysis for ADRA2A rs553668 and ACE I/D showed that subjects with both ADRA2A rs553668 GG and ACE I/D II genotypes had significant lowest WHR compared to other genotype combinations. The ACE II genotype might be a protective factor against central adiposity risk among the Malaysian population when in combination with the ADRA2A rs553668 GG genotype.

Effectiveness of fortification of corn flour-derived products with hydrogen-reduced elemental iron on iron-deficiency anaemia in children and adolescents in southern Brazil.

PubMed

Miglioranza, Lúcia H S; Breganó, José Wander; Dichi, Isaias; Matsuo, Tiemi; Dichi, Jane Bandeira; Barbosa, Décio Sabbatini

2009-02-01

To find the ideal combination of Fe fortifier and its food vehicle is an essential measure in developing countries. However, its cost also plays an important role. In the present study, the effect on blood parameter values of corn flour-derived products fortified with powdered elemental Fe in the form of H2-reduced Fe was investigated in children and adolescents. One hundred and sixty-two individuals (eighty-six boys and seventy-six girls) from public educational centres in Londrina, Paraná (southern Brazil) participated in the study. Fe-deficiency anaemia (IDA) was defined when Hb and serum ferritin values fell below 12 g/dl and 20 microg/l, respectively; Fe deficiency (ID) was considered when serum ferritin was below 20 microg/l. The prevalence of ID and IDA decreased from 18.0 % and 14.9 %, values found at the beginning of the study, to respectively 5.6 % and 1.2 % after 6 months. Changes from altered to normal values occurred more often than normal to altered values with transferrin saturation (14.2 % v. 6.8 %; P < 0.04) and ferritin (12.4 % v. 0 %; P < 0.001). Hb, transferrin saturation and ferritin showed differences between normal and altered parameters after 6 months (P < 0.001). A pronounced reduction in the prevalence of ID and IDA was observed in children and adolescents following 6 months' ingestion of corn flour-derived products enriched with elemental Fe.

A Novel Mutation in OTX2 Causes Combined Pituitary Hormone Deficiency, Bilateral Microphthalmia, and Agenesis of the Left Internal Carotid Artery.

PubMed

Shimada, Aya; Takagi, Masaki; Nagashima, Yuka; Miyai, Kentaro; Hasegawa, Yukihiro

2016-01-01

Mutations in OTX2 cause hypopituitarism, ranging from isolated growth hormone deficiency to combined pituitary hormone deficiency (CPHD), which are commonly detected in association with severe eye abnormalities, including anophthalmia or microphthalmia. Pituitary phenotypes of OTX2 mutation carriers are highly variable; however, ACTH deficiency during the neonatal period is not common in previous reports. We report a novel missense OTX2 (R89P) mutation in a CPHD patient with severe hypoglycemia in the neonatal period due to ACTH deficiency, bilateral microphthalmia, and agenesis of the left internal carotid artery (ICA). We identified a novel heterozygous mutation in OTX2 (c.266G>C, p.R89P). R89P OTX2 showed markedly reduced transcriptional activity of HESX1 and POU1F1 reporters compared with wild-type OTX2. A dominant negative effect was noted only in the transcription analysis with POU1F1 promoter. Electrophoretic mobility shift assay experiments showed that R89P OTX2 abrogated DNA-binding ability. OTX2 mutations can cause ACTH deficiency in the neonatal period. Our study also shows that OTX2 mutations are associated with agenesis of the ICA. To the best of our knowledge, this is the first report of a transcription factor gene mutation, which was identified due to agenesis of the ICA of a patient with CPHD. This study extends our understanding of the phenotypic features, molecular mechanism, and developmental course associated with mutations in OTX2. © 2016 S. Karger AG, Basel.

ID-based encryption scheme with revocation

NASA Astrophysics Data System (ADS)

Othman, Hafizul Azrie; Ismail, Eddie Shahril

2017-04-01

In 2015, Meshram proposed an efficient ID-based cryptographic encryption based on the difficulty of solving discrete logarithm and integer-factoring problems. The scheme was pairing free and claimed to be secure against adaptive chosen plaintext attacks (CPA). Later, Tan et al. proved that the scheme was insecure by presenting a method to recover the secret master key and to obtain prime factorization of modulo n. In this paper, we propose a new pairing-free ID-based encryption scheme with revocation based on Meshram's ID-based encryption scheme, which is also secure against Tan et al.'s attacks.

Prevalence and prognostic implications of anaemia and iron deficiency in Tanzanian patients with heart failure.

PubMed

Makubi, Abel; Hage, Camilla; Lwakatare, Johnson; Mmbando, Bruno; Kisenge, Peter; Lund, Lars H; Rydén, Lars; Makani, Julie

2015-04-01

To determine the prevalence, correlates and prognostic implications of anaemia and iron deficiency (ID) in patients with heart failure (HF) in Tanzania. This was a cross-sectional and prospective observational study conducted at Muhimbili National Hospital in Dar es Salaam, Tanzania. Patients were ≥ 18 years of age, with HF defined according to the Framingham criteria. The primary outcome was anaemia and the secondary outcome was a composite of hospitalisation for HF or all-cause mortality. A total of 401 HF patients (median age 56 years, IQR 41-67 years; women 51%) were included. The prevalence of anaemia was 57%. The overall prevalence of ID was 49% distributed as 69% versus 21% in subjects with and without anaemia (p < 0.001). Normocytic anaemia was seen in 18% of the patients while none had macrocytic anaemia. The risk of having anaemia was positively associated with residency outside Dar es Salaam (OR 1.72 (95% CI 1.02 to 2.89); p = 0.038), atrial fibrillation (4.12 (1.60 to 10.61); p=0.003), LVEF < 45% (2.70 (1.57 to 4.67); p < 0.001) and negatively (ORs per unit decrease) with creatinine clearance (0.98 (0.97 to 0.99); p = 0.012) and total cholesterol (0.78 (0.63 to 0.98); p = 0.029). One-year survival free from a composite endpoint was 70%. The presence of ID anaemia increased the likelihood for an event (HR 2.67; 95% CI 1.39 to 5.07; p = 0.003), while anaemia without ID did not influence the risk. ID anaemia was common in Tanzanian patients with HF and was independently associated with the risk for hospitalisation or death. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Thiamine transporter-2 deficiency: outcome and treatment monitoring.

PubMed

Ortigoza-Escobar, Juan Darío; Serrano, Mercedes; Molero, Marta; Oyarzabal, Alfonso; Rebollo, Mónica; Muchart, Jordi; Artuch, Rafael; Rodríguez-Pombo, Pilar; Pérez-Dueñas, Belén

2014-06-23

The clinical characteristics distinguishing treatable thiamine transporter-2 deficiency (ThTR2) due to SLC19A3 genetic defects from the other devastating causes of Leigh syndrome are sparse. We report the clinical follow-up after thiamine and biotin supplementation in four children with ThTR2 deficiency presenting with Leigh and biotin-thiamine-responsive basal ganglia disease phenotypes. We established whole-blood thiamine reference values in 106 non-neurological affected children and monitored thiamine levels in SLC19A3 patients after the initiation of treatment. We compared our results with those of 69 patients with ThTR2 deficiency after a review of the literature. At diagnosis, the patients were aged 1 month to 17 years, and all of them showed signs of acute encephalopathy, generalized dystonia, and brain lesions affecting the dorsal striatum and medial thalami. One patient died of septicemia, while the remaining patients evidenced clinical and radiological improvements shortly after the initiation of thiamine. Upon follow-up, the patients received a combination of thiamine (10-40 mg/kg/day) and biotin (1-2 mg/kg/day) and remained stable with residual dystonia and speech difficulties. After establishing reference values for the different age groups, whole-blood thiamine quantification was a useful method for treatment monitoring. ThTR2 deficiency is a reversible cause of acute dystonia and Leigh encephalopathy in the pediatric years. Brain lesions affecting the dorsal striatum and medial thalami may be useful in the differential diagnosis of other causes of Leigh syndrome. Further studies are needed to validate the therapeutic doses of thiamine and how to monitor them in these patients.

Fetal Iron Deficiency and Genotype Influence Emotionality in Infant Rhesus Monkeys123

PubMed Central

Golub, Mari S; Hogrefe, Casey E

2015-01-01

Background: Anemia during the third trimester of fetal development affects one-third of the pregnancies in the United States and has been associated with postnatal behavioral outcomes. This study examines how fetal iron deficiency (ID) interacts with the fetal monoamine oxidase A (MAOA) genotype. MAOA metabolizes monoamine neurotransmitters. MAOA polymorphisms in humans affect temperament and modify the influence of early adverse environments on later behavior. Objective: The aim of the study was to advance translation of developmental ID research in animal models by taking into account genetic factors that influence outcomes in human populations. Methods: Male infant rhesus monkeys 3–4 mo old born to mothers fed an ID (10 ppm iron) diet were compared with controls (100 ppm iron). Infant monkeys with high- or low-transcription rate MAOA polymorphisms were equally distributed between diet groups. Behavioral responses to a series of structured experiences were recorded during a 25-h separation of the infants from their mothers. Results: Infant monkeys with low-transcription MAOA polymorphisms more clearly demonstrated the following ID effects suggested in earlier studies: a 4% smaller head circumference, a 39% lower cortisol response to social separation, a 129% longer engagement with novel visual stimuli, and 33% lesser withdrawal in response to a human intruder. The high MAOA genotype ID monkeys demonstrated other ID effects: less withdrawal and emotionality after social separation and lower “fearful” ratings. Conclusion: MAOA × ID interactions support the role of monoamine neurotransmitters in prenatal ID effects in rhesus monkeys and the potential involvement of common human polymorphisms in determining the pattern of neurobehavioral effects produced by inadequate prenatal nutrition. PMID:25733484

Spectrum of neurological and survival outcomes in pyruvate dehydrogenase complex (PDC) deficiency: lack of correlation with genotype.

PubMed

DeBrosse, Suzanne D; Okajima, Kazuki; Zhang, Shulin; Nakouzi, Ghunwa; Schmotzer, Christine L; Lusk-Kopp, Marilyn; Frohnapfel, Mary Beth; Grahame, George; Kerr, Douglas S

2012-11-01

Pyruvate dehydrogenase complex (PDC) deficiency is a relatively common mitochondrial disorder that primarily presents with neurological manifestations and lactic acidemia. We analyzed the clinical outcomes and neurological features of 59 consented symptomatic subjects (27 M, 32 F), who were confirmed to have PDC deficiency with defined mutations in one of the genes of PDC (PDHA1, n = 53; PDHB, n = 4; DLAT, n = 2), including 47 different mutations, of which 22 were novel, and for whom clinical records and/or structured interviews were obtained. 39% of these subjects (23/59) have died. Of these, 91% (21/23) died before age 4 years, 61% (14/23) before 1 year, and 43% (10/23) before 3 months. 56% of males died compared with 25% of females. Causes of death included severe lactic acidosis, respiratory failure, and infection. In subjects surviving past 6 months, a broad range of intellectual outcomes was observed. Of 42 subjects whose intellectual abilities were professionally evaluated, 19% had normal or borderline intellectual ability (CQ/IQ ≥ 70), 10% had mild intellectual disability (ID) (CQ/IQ 55-69), 17% had moderate ID (CQ/IQ 40-54), 24% had severe ID (CQ/IQ 25-39) and 33% had profound ID (CQ/IQ<25). Assessment by parents was comparable. Of 10 subjects who reached age 12 years, 9 had had professional IQ assessments, and only 4 had IQs ≥ 70 (only 2 of these 4 had assessments after age 12 years). The average outcome for females was severe-to-profound ID, whereas that of males was mild-to-moderate ID. Of subjects for whom specific neurological data were available, the majority had hypotonia (89%), and hypertonia or mixed hyper-/hypotonia (49%) were common. Seizures (57%), microcephaly (49%), and structural brain abnormalities including ventriculomegaly (67%) and agenesis, dysgenesis, or hypoplasia of the corpus callosum (55%) were common. Leigh syndrome was found in only 35%. Structural brain abnormalities were more common in females, and Leigh syndrome was more

Hyaluronidase 2 Deficiency Causes Increased Mesenchymal Cells, Congenital Heart Defects, and Heart Failure.

PubMed

Chowdhury, Biswajit; Xiang, Bo; Liu, Michelle; Hemming, Richard; Dolinsky, Vernon W; Triggs-Raine, Barbara

2017-01-01

Hyaluronan (HA) is required for endothelial-to-mesenchymal transition and normal heart development in the mouse. Heart abnormalities in hyaluronidase 2 (HYAL2)-deficient ( Hyal2 - /- ) mice and humans suggested removal of HA is also important for normal heart development. We have performed longitudinal studies of heart structure and function in Hyal2 -/- mice to determine when, and how, HYAL2 deficiency leads to these abnormalities. Echocardiography revealed atrial enlargement, atrial tissue masses, and valvular thickening at 4 weeks of age, as well as diastolic dysfunction that progressed with age, in Hyal2 -/- mice. These abnormalities were associated with increased HA, vimentin-positive cells, and fibrosis in Hyal2 -/- compared with control mice. Based on the severity of heart dysfunction, acute and chronic groups of Hyal2 -/- mice that died at an average of 12 and 25 weeks respectively, were defined. Increased HA levels and mesenchymal cells, but not vascular endothelial growth factor in Hyal2 -/- embryonic hearts, suggest that HYAL2 is important to inhibit endothelial-to-mesenchymal transition. Consistent with this, in wild-type embryos, HYAL2 and HA were readily detected, and HA levels decreased with age. These data demonstrate that disruption of normal HA catabolism in Hyal2 -/- mice causes increased HA, which may promote endothelial-to-mesenchymal transition and proliferation of mesenchymal cells. Excess endothelial-to-mesenchymal transition, resulting in increased mesenchymal cells, is the likely cause of morphological heart abnormalities in both humans and mice. In mice, these abnormalities result in progressive and severe diastolic dysfunction, culminating in heart failure. © 2016 The Authors.

Level-2 Milestone 3244: Deploy Dawn ID Machine for Initial Science Runs

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

Fox, D

2009-09-21

This report documents the delivery, installation, integration, testing, and acceptance of the Dawn system, ASC L2 milestone 3244: Deploy Dawn ID Machine for Initial Science Runs, due September 30, 2009. The full text of the milestone is included in Attachment 1. The description of the milestone is: This milestone will be a result of work started three years ago with the planning for a multi-petaFLOPS UQ-focused platform (Sequoia) and will be satisfied when a smaller ID version of the final system is delivered, installed, integrated, tested, accepted, and deployed at LLNL for initial science runs in support of SSP mission.more » The deliverable for this milestone will be a LA petascale computing system (named Dawn) usable for code development and scaling necessary to ensure effective use of a final Sequoia platform (expected in 2011-2012), and for urgent SSP program needs. Allocation and scheduling of Dawn as an LA system will likely be performed informally, similar to what has been used for BlueGene/L. However, provision will be made to allow for dedicated access times for application scaling studies across the entire Dawn resource. The milestone was completed on April 1, 2009, when science runs began running on the Dawn system. The following sections describe the Dawn system architecture, current status, installation and integration time line, and testing and acceptance process. A project plan is included as Attachment 2. Attachment 3 is a letter certifying the handoff of the system to a nuclear weapons stockpile customer. Attachment 4 presents the results of science runs completed on the system.« less

Vitek 2 ANC card versus BBL Crystal Anaerobe and RapID ANA II for identification of clinical anaerobic bacteria.

PubMed

Blairon, Laurent; Maza, Mengi L; Wybo, Ingrid; Piérard, Denis; Dediste, Anne; Vandenberg, Olivier

2010-08-01

The Vitek 2 Anaerobe and Corynebacterium Identification Card (ANC) was recently evaluated in a multicentre study. In the present work, this system was compared with the BBL Crystal Anaerobe and RapID ANA II panels. These kits were tested using 196 strains of anaerobes that had been previously identified by gas-liquid chromatography. Identification to the species or to the genus level was 75.0%, 81.1% and 70.9% for Crystal, RapID and Vitek, respectively. Vitek ANC failed to provide any identification in 20.4% of the strains, but it had fewer misidentifications than RapID. The confidence factors provided on the results report of each kit were not always correlated with a lower risk of major errors, with the exception of Vitek 2 in which a confidence factor higher than 0.86 excluded the risk of misidentification in more than 87% of isolates. The lower rate of identification by the Vitek and Crystal panels is mostly due the lower ability of these systems to identify the Clostridia. Overall, the three panels are comparable but need improvement to a better accuracy. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

Beneficial effects of postnatal choline supplementation on long-Term neurocognitive deficit resulting from fetal-Neonatal iron deficiency.

PubMed

Kennedy, Bruce C; Tran, Phu V; Kohli, Maulika; Maertens, Jamie J; Gewirtz, Jonathan C; Georgieff, Michael K

2018-01-15

Early-life iron deficiency is a common nutrient condition worldwide and can result in cognitive impairment in adulthood despite iron treatment. In rodents, prenatal choline supplementation can diminish long-term hippocampal gene dysregulation and neurocognitive deficits caused by iron deficiency. Since fetal iron status is generally unknown in humans, we determined whether postnatal choline supplementation exerts similar beneficial effects. Male rat pups were made iron deficient (ID) by providing pregnant and nursing dams an ID diet (3-6ppm Fe) from gestational day (G) 3 through postnatal day (P) 7, and an iron-sufficient (IS) diet (200ppm Fe) thereafter. Control pups were provided IS diet throughout. Choline (5ppm) was given to half the nursing dams and weanlings in each group from P11-P30. P65 rat cognitive performance was assessed by novel object recognition (NOR). Real-time PCR was performed to validate expression levels of synaptic plasticity genes known to be dysregulated by early-life iron deficiency. Postnatal choline supplementation prevented impairment of NOR memory in formerly iron-deficient (FID) adult rats but impaired NOR memory in IS controls. Gene expression analysis revealed a recovery of 4 out of 10 dysregulated genes compared to 8 of the same 10 genes that we previously demonstrated to recover following prenatal choline supplementation. Recognition memory deficits induced by early-life iron deficiency can be prevented by postnatal choline supplementation and disrupted expression of a subset of synaptic plasticity genes can be ameliorated. The positive response to postnatal choline represents a potential adjunctive therapeutic supplement to treat iron-deficient anemic children in order to spare long-term neurodevelopmental deficits. Copyright © 2017. Published by Elsevier B.V.

Prevalence of iron deficiency on ICU discharge and its relation with fatigue: a multicenter prospective study.

PubMed

Lasocki, Sigismond; Chudeau, Nicolas; Papet, Thibaut; Tartiere, Deborah; Roquilly, Antoine; Carlier, Laurence; Mimoz, Olivier; Seguin, Philippe; Malledant, Yannick; Asehnoune, Karim; Hamel, Jean François

2014-09-30

Prevalence of iron deficiency (ID) at intensive care (ICU) admission is around 25 to 40%. Blood losses are important during ICU stay, leading to iron losses, but prevalence of ID at ICU discharge is unknown. ID has been associated with fatigue and muscular weakness, and may thus impair post-ICU rehabilitation. This study assessed ID prevalence at ICU discharge, day 28 (D28) and six months (M6) after and its relation with fatigue. We conducted this prospective, multicenter observational study at four University hospitals ICUs. Anemic (hemoglobin (Hb) less than 13 g/dL in male and less than 12 g/dL in female) critically ill adult patients hospitalized for at least five days had an iron profile taken at discharge, D28 and M6. ID was defined as ferritin less than 100 ng/L or less than 300 ng/L together with a transferrin saturation less than 20%. Fatigue was assessed by numerical scale and the Multidimensional Fatigue Inventory-20 questionnaire at D28 and M6 and muscular weakness by a hand grip test at ICU discharge. Among 107 patients (men 77%, median (IQR) age 63 (48 to 73) years) who had a complete iron profile at ICU discharge, 9 (8.4%) had ID. At ICU discharge, their hemoglobin concentration (9.5 (87.7 to 10.3) versus 10.2 (92.2 to 11.7) g/dL, P =0.09), hand grip strength (52.5 (30 to 65) versus 49.5 (15.5 to 67.7)% of normal value, P =0.61) and visual analog scale fatigue scale (57 (40 to 80) versus 60 (47.5 to 80)/100, P =0.82) were not different from non-ID patients. At D28 (n =80 patients) and M6 (n =78 patients), ID prevalence increased (to 25 and 35% respectively) while anemia prevalence decreased (from 100% to 80 and 25% respectively, P <0.0001). ID was associated with increased fatigue at D28, after adjustment for main confounding factors, including anemia (regression coefficient (95%CI), 3.19 (0.74 to 5.64), P =0.012). At M6, this association disappeared. The prevalence of ID increases from 8% at discharge to 35% six months after prolonged ICU stay (more

Cigarette smoke exposure promotes arterial thrombosis and vessel remodeling after vascular injury in apolipoprotein E-deficient mice.

PubMed

Schroeter, Marco R; Sawalich, Matthias; Humboldt, Tim; Leifheit, Maren; Meurrens, Kris; Berges, An; Xu, Haiyan; Lebrun, Stefan; Wallerath, Thomas; Konstantinides, Stavros; Schleef, Raymond; Schaefer, Katrin

2008-01-01

Cigarette smoking is a major risk factor for the development of cardiovascular disease. However, in terms of the vessel wall, the underlying pathomechanisms of cigarette smoking are incompletely understood, partly due to a lack of adequate in vivo models. Apolipoprotein E-deficient mice were exposed to filtered air (sham) or to cigarette mainstream smoke at a total particulate matter (TPM) concentration of 600 microg/l for 1, 2, 3, or 4 h, for 5 days/week. After exposure for 10 +/- 1 weeks, arterial thrombosis and neointima formation at the carotid artery were induced using 10% ferric chloride. Mice exposed to mainstream smoke exhibited shortened time to thrombotic occlusion (p < 0.01) and lower vascular patency rates (p < 0.001). Morphometric and immunohistochemical analysis of neointimal lesions demonstrated that mainstream smoke exposure increased the amount of alpha-actin-positive smooth muscle cells (p < 0.05) and dose-dependently increased the intima-to-media ratio (p < 0.05). Additional analysis of smooth muscle cells in vitro suggested that 10 microg TPM/ml increased cell proliferation without affecting viability or apoptosis, whereas higher concentrations (100 and 500 microg TPM/ml) appeared to be cytotoxic. Taken together, these findings suggest that cigarette smoking promotes arterial thrombosis and modulates the size and composition of neointimal lesions after arterial injury in apolipoprotein E-deficient mice. Copyright 2008 S. Karger AG, Basel.

Magnetic and dielectric properties in the UHF frequency band of half-dense Ni-Zn-Co ferrites ceramics with Fe-excess and Fe-deficiency

NASA Astrophysics Data System (ADS)

Mattei, Jean-Luc; Souriou, David; Chevalier, Alexis

2018-02-01

This work investigates electromagnetic properties of half-dense ceramics with compositions Ni0.5Zn0.3Co0.2FeyO4-δ where y = 1.98 (Iron deficient, noted ID) or y = 2.3 (Iron in excess, noted IE). IE and ID materials are obtained by chemical coprecipitation route. The obtained nano-sized powders are pressed and annealed at two temperatures (800 °C, 900 °C), so has to obtain half-massive ceramics. Ferrous and ferric ions coexist in the crystalline structures, but the former in a less extend for ID ferrite. The concomitant influences of Fe2+ and Fe3+ on the dielectric and magnetic losses (ε″/ε‧ and μ″/μ‧, respectively) are considered at frequency up to 6 GHz. The permeability dispersion changes from relaxation-like to resonance-like with the decrease in ferrous ions. In reason of the relaxing-like behavior of Fe2+, and because of a relatively high amount in Fe2+, IE sample shows lower total losses (magnetic and dielectric) than ID sample. These conclusions applied for TA = 900 °C. At frequencies above 700 MHz, the total loss values (IE and ID samples) are prohibitive for antenna downsizing whatever is the firing temperature value (800 °C and 900 °C). Whereas at frequencies below 700 MHz Ni0.5Zn0.3Co0.2Fe2.3O4+δ may leads to better antenna performances than Ni0.5Zn0.3Co0.2Fe1.98O4-δ.

Oral versus intravenous iron therapy in patients with inflammatory bowel disease and iron deficiency with and without anemia in Germany - a real-world evidence analysis.

PubMed

Stein, Jürgen; Haas, Jennifer Scarlet; Ong, Siew Hwa; Borchert, Kathrin; Hardt, Thomas; Lechat, Elmira; Nip, Kerry; Foerster, Douglas; Braun, Sebastian; Baumgart, Daniel C

2018-01-01

Iron-deficiency anemia and iron deficiency are common comorbidities associated with inflammatory bowel disease (IBD) resulting in impaired quality of life and high health care costs. Intravenous iron has shown clinical benefit compared to oral iron therapy. This study aimed to compare health care outcomes and costs after oral vs intravenous iron treatment for IBD patients with iron deficiency or iron deficiency anemia (ID/A) in Germany. IBD patients with ID/A were identified by ICD-10-GM codes and newly commenced iron treatment via ATC codes in 2013 within the InGef (formerly Health Risk Institute) research claims database. Propensity score matching was performed to balance both treatment groups. Non-observable covariates were adjusted by applying the difference-in-differences (DID) approach. In 2013, 589 IBD patients with ID/A began oral and 442 intravenous iron treatment. After matching, 380 patients in each treatment group were analyzed. The intravenous group had fewer all-cause hospitalizations (37% vs 48%) and ID/A-related hospitalizations (5% vs 14%) than the oral iron group. The 1-year preobservation period comparison revealed significant health care cost differences between both groups. After adjusting for cost differences by DID method, total health care cost savings in the intravenous iron group were calculated to be €367. While higher expenditure for medication (€1,876) was observed in the intravenous iron group, the inpatient setting achieved most cost savings (€1,887). IBD patients receiving intravenous iron were less frequently hospitalized and incurred lower total health care costs compared to patients receiving oral iron. Higher expenditures for pharmaceuticals were compensated by cost savings in other domains.

The SNPforID Assay as a Supplementary Method in Kinship and Trace Analysis

PubMed Central

Schwark, Thorsten; Meyer, Patrick; Harder, Melanie; Modrow, Jan-Hendrick; von Wurmb-Schwark, Nicole

2012-01-01

Objective Short tandem repeat (STR) analysis using commercial multiplex PCR kits is the method of choice for kinship testing and trace analysis. However, under certain circumstances (deficiency testing, mutations, minute DNA amounts), STRs alone may not suffice. Methods We present a 50-plex single nucleotide polymorphism (SNP) assay based on the SNPs chosen by the SNPforID consortium as an additional method for paternity and for trace analysis. The new assay was applied to selected routine paternity and trace cases from our laboratory. Results and Conclusions Our investigation shows that the new SNP multiplex assay is a valuable method to supplement STR analysis, and is a powerful means to solve complicated genetic analyses. PMID:22851934

Oxytocin improves behavioral and electrophysiological deficits in a novel Shank3-deficient rat

PubMed Central

Harony-Nicolas, Hala; Kay, Maya; du Hoffmann, Johann; Klein, Matthew E; Bozdagi-Gunal, Ozlem; Riad, Mohammed; Daskalakis, Nikolaos P; Sonar, Sankalp; Castillo, Pablo E; Hof, Patrick R; Shapiro, Matthew L; Baxter, Mark G; Wagner, Shlomo; Buxbaum, Joseph D

2017-01-01

Mutations in the synaptic gene SHANK3 lead to a neurodevelopmental disorder known as Phelan-McDermid syndrome (PMS). PMS is a relatively common monogenic and highly penetrant cause of autism spectrum disorder (ASD) and intellectual disability (ID), and frequently presents with attention deficits. The underlying neurobiology of PMS is not fully known and pharmacological treatments for core symptoms do not exist. Here, we report the production and characterization of a Shank3-deficient rat model of PMS, with a genetic alteration similar to a human SHANK3 mutation. We show that Shank3-deficient rats exhibit impaired long-term social recognition memory and attention, and reduced synaptic plasticity in the hippocampal-medial prefrontal cortex pathway. These deficits were attenuated with oxytocin treatment. The effect of oxytocin on reversing non-social attention deficits is a particularly novel finding, and the results implicate an oxytocinergic contribution in this genetically defined subtype of ASD and ID, suggesting an individualized therapeutic approach for PMS. DOI: http://dx.doi.org/10.7554/eLife.18904.001 PMID:28139198

Effect of ingredients on sensory profile of idli.

PubMed

Durgadevi, Manoharan; Shetty, Prathapkumar H

2014-09-01

Idli is a traditional fermented food and is consumed in India and Srilanka. The objective of the present study is to select the ingredients for optimum desirable product characteristics and to identify the optimum ratios of ingredients and fermentation time with respect to sensory attributes using Response Surface Methodology (RSM). The sensory attributes included were color, appearance, texture, taste and overall quality. Preliminary trials were conducted using five variants of rice and common black gram dhal before framing a model using Central Composite Rotatable Design (CCRD). From the study it was found that a desirable score of 0.7439 was obtained for sensory attributes of idli made with the ratio of 3: 1.475 for IR20 idli rice and ADT3 variety black gram (with husk removed after soaking) fermented for 10.2 h. Principal Component Analysis (PCA) helped to discriminate the samples and attributes within the data matrix, depending upon their inter relationships.

Prevalence and factors promoting the occurrence of vitamin D deficiency in the elderly.

PubMed

Wyskida, Magdalena; Wieczorowska-Tobis, Katarzyna; Chudek, Jerzy

2017-03-13

Vitamin D deficiency affects a large part of the population of elderly people, especially women, who live in moderate climate countries due to a reduced amount of vitamin D in the diet (small sea fish consumption) and reduced content of 7-dehydrocholesterol, which causes decreased skin synthesis. The lowest seasonal concentration of 25(OH)D3 is usually observed during winter and spring. Sun exposure influences 25(OH)D3 concentration more strongly in men than in women. Sociodemographic factors that increase the risk of vitamin D deficiency in the elderly include poor environmental conditions, low economic status, lower educational level, drug exposure (smoking), reduced physical activity, overall poor health and obesity, which causes reduced skin exposure to sunlight. The use of medications or supplements that contain vitamin D and staying in a nursing home that employ such supplementation are factors that prevent deficiency. Significant prevalence of diseases of the gastrointestinal tract may contribute to cholecalciferol and ergocalciferol malabsorption or impair their liver transformation. In addition, the high incidence of chronic kidney disease in old age reduces processing hydroxylation of vitamin D and the formation of active metabolites. Vitamin D deficiency can not only cause bone mineralization disorders, but also increase incidence of cardiovascular diseases, cancers, type 2 diabetes and depression. The aim of this study was to summarize current knowledge about the risk factors of vitamin D deficiency development in the elderly population.

Improvement of liver injury and survival by JNK2 and iNOS deficiency in liver transplants from cardiac death mice.

PubMed

Liu, Qinlong; Rehman, Hasibur; Krishnasamy, Yasodha; Schnellmann, Rick G; Lemasters, John J; Zhong, Zhi

2015-07-01

Inclusion of liver grafts from cardiac death donors (CDD) would increase the availability of donor livers but is hampered by a higher risk of primary non-function. Here, we seek to determine mechanisms that contribute to primary non-function of liver grafts from CDD with the goal to develop strategies for improved function and outcome, focusing on c-Jun-N-terminal kinase (JNK) activation and mitochondrial depolarization, two known mediators of graft failure. Livers explanted from wild-type, inducible nitric oxide synthase knockout (iNOS(-/-)), JNK1(-/-) or JNK2(-/-) mice after 45-min aorta clamping were implanted into wild-type recipients. Mitochondrial depolarization was detected by intravital confocal microscopy in living recipients. After transplantation of wild-type CDD livers, graft iNOS expression and 3-nitrotyrosine adducts increased, but hepatic endothelial NOS expression was unchanged. Graft injury and dysfunction were substantially higher in CDD grafts than in non-CDD grafts. iNOS deficiency and inhibition attenuated injury and improved function and survival of CDD grafts. JNK1/2 and apoptosis signal-regulating kinase-1 activation increased markedly in wild-type CDD grafts, which was blunted by iNOS deficiency. JNK inhibition and JNK2 deficiency, but not JNK1 deficiency, decreased injury and improved function and survival of CDD grafts. Mitochondrial depolarization and binding of phospho-JNK2 to Sab, a mitochondrial protein linked to the mitochondrial permeability transition, were higher in CDD than in non-CDD grafts. iNOS deficiency, JNK inhibition and JNK2 deficiency all decreased mitochondrial depolarization and blunted ATP depletion in CDD grafts. JNK inhibition and deficiency did not decrease 3-nitrotyrosine adducts in CDD grafts. The iNOS-JNK2-Sab pathway promotes CDD graft failure via increased mitochondrial depolarization, and is an attractive target to improve liver function and survival in CDD liver transplantation recipients. Copyright © 2015

Tissue-Autonomous Promotion of Palisade Cell Development by Phototropin 2 in Arabidopsis[W

PubMed Central

Kozuka, Toshiaki; Kong, Sam-Geun; Doi, Michio; Shimazaki, Ken-ichiro; Nagatani, Akira

2011-01-01

Light is an important environmental information source that plants use to modify their growth and development. Palisade parenchyma cells in leaves develop cylindrical shapes in response to blue light; however, the photosensory mechanism for this response has not been elucidated. In this study, we analyzed the palisade cell response in phototropin-deficient mutants. First, we found that two different light-sensing mechanisms contributed to the response in different proportions depending on the light intensity. One response observed under lower intensities of blue light was mediated exclusively by a blue light photoreceptor, phototropin 2 (PHOT2). Another response was elicited under higher intensities of light in a phototropin-independent manner. To determine the tissue in which PHOT2 perceives the light stimulus to regulate the response, green fluorescent protein (GFP)–tagged PHOT2 (P2G) was expressed under the control of tissue-specific promoters in the phot1 phot2 mutant background. The results revealed that the expression of P2G in the mesophyll, but not in the epidermis, promoted palisade cell development. Furthermore, a constitutively active C-terminal kinase fragment of PHOT2 fused to GFP (P2CG) promoted the development of cylindrical palisade cells in the proper direction without the directional cue provided by light. Hence, in response to blue light, PHOT2 promotes the development of cylindrical palisade cells along a predetermined axis in a tissue-autonomous manner. PMID:21972260

Towards Holistic Heart Failure Management-How to Tackle the Iron Deficiency Epidemic?

PubMed

Van Aelst, Lucas N L; Mazure, Dominiek; Cohen-Solal, Alain

2017-08-01

Heart failure (HF) is a common, costly, disabling, and deadly clinical syndrome and often associated with one or several co-morbidities complicating its treatment or worsening its symptoms. During the last decade, iron deficiency (ID) got recognized as a frequent, debilitating yet easily treatable co-morbidity in HF. In this review, we focus on new evidence that emerged during the last 5 years and discuss the epidemiology, the causes, and the clinical consequences of ID in HF. Apart from replenishing iron stores, intravenous iron improves patients' symptoms, perceived quality of life (QoL), exercise capacity, and hospitalization rates. These beneficial effects cannot be attributed to oral iron, as increased hepcidin levels, typical in inflammatory states such as HF, preclude resorption of iron from the gut. Intravenous iron is the only valid treatment option for ID in HF. However, there are several burning research questions and gaps in evidence remaining in this research field.

Thiamine transporter-2 deficiency: outcome and treatment monitoring

PubMed Central

2014-01-01

Background The clinical characteristics distinguishing treatable thiamine transporter-2 deficiency (ThTR2) due to SLC19A3 genetic defects from the other devastating causes of Leigh syndrome are sparse. Methods We report the clinical follow-up after thiamine and biotin supplementation in four children with ThTR2 deficiency presenting with Leigh and biotin-thiamine-responsive basal ganglia disease phenotypes. We established whole-blood thiamine reference values in 106 non-neurological affected children and monitored thiamine levels in SLC19A3 patients after the initiation of treatment. We compared our results with those of 69 patients with ThTR2 deficiency after a review of the literature. Results At diagnosis, the patients were aged 1 month to 17 years, and all of them showed signs of acute encephalopathy, generalized dystonia, and brain lesions affecting the dorsal striatum and medial thalami. One patient died of septicemia, while the remaining patients evidenced clinical and radiological improvements shortly after the initiation of thiamine. Upon follow-up, the patients received a combination of thiamine (10–40 mg/kg/day) and biotin (1–2 mg/kg/day) and remained stable with residual dystonia and speech difficulties. After establishing reference values for the different age groups, whole-blood thiamine quantification was a useful method for treatment monitoring. Conclusions ThTR2 deficiency is a reversible cause of acute dystonia and Leigh encephalopathy in the pediatric years. Brain lesions affecting the dorsal striatum and medial thalami may be useful in the differential diagnosis of other causes of Leigh syndrome. Further studies are needed to validate the therapeutic doses of thiamine and how to monitor them in these patients. PMID:24957181

Iron Deficiency Is a Determinant of Functional Capacity and Health-related Quality of Life 30 Days After an Acute Coronary Syndrome.

PubMed

Meroño, Oona; Cladellas, Mercè; Ribas-Barquet, Núria; Poveda, Paula; Recasens, Lluis; Bazán, Víctor; García-García, Cosme; Ivern, Consol; Enjuanes, Cristina; Orient, Salvador; Vila, Joan; Comín-Colet, Josep

2017-05-01

Iron deficiency (ID) is a prevalent condition in patients with ischemic heart disease and heart failure. Little is known about the impact of ID on exercise capacity and quality of life (QoL) in the recovery phase after an acute coronary syndrome (ACS). Iron status and its impact on exercise capacity and QoL were prospectively evaluated in 244 patients 30 days after the ACS. QoL was assessed by the standard EuroQoL-5 dimensions, EuroQoL visual analogue scale, and Heart-QoL questionnaires. Exercise capacity was analyzed by treadmill/6-minute walk tests. The effect of ID on cardiovascular mortality and readmission rate was also investigated. A total of 46% of the patients had ID. These patients had lower exercise times (366±162 vs 462±155seconds; P<.001), metabolic consumption rates (7.9±2.9 vs 9.3±2.6 METS; P=.003), and EuroQoL-5 dimensions (0.76±0.25 vs 0.84±0.16), visual analogue scale (66±16 vs 72±17), and Heart-QoL (1.9±0.6 vs 2.2±0.6) scores (P<.05). ID independently predicted lower exercise times (OR, 2.9; 95%CI, 1.1-7.6; P=.023) and worse QoL (OR, 1.9; 95%CI, 1.1-3.3; P<.001) but had no effect on cardiovascular morbidity or mortality. ID, a prevalent condition in ACS patients, results in a poorer mid-term functional recovery, as measured by exercise capacity and QoL. Copyright © 2016 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

Quercetin promotes proliferation and differentiation of oligodendrocyte precursor cells after oxygen/glucose deprivation-induced injury.

PubMed

Wu, Xiuxiang; Qu, Xuebin; Zhang, Qiang; Dong, Fuxing; Yu, Hongli; Yan, Chen; Qi, Dashi; Wang, Meng; Liu, Xuan; Yao, Ruiqin

2014-04-01

The aim of this study was to investigate quercetin's (Qu) ability to promote proliferation and differentiation of oligodendrocyte precursor cells (OPCs) under oxygen/glucose deprivation (OGD)-induced injury in vitro. The results showed that after OGD, OPCs survival rate was significantly increased by Qu as measured by Cell Counting Kit-8. Furthermore, Qu treatment reduced apoptosis of OPCs surveyed by Hoechst 33258 nuclear staining. Qu at 9 and 27 μM promoted the proliferation of OPCs the most by Brdu and Olig2 immunocytochemical staining after OGD 3 days. Also, Qu treatment for 8 days after OGD, the differentiation of OPCs to oligodendrocyte was detected by immunofluorescence staining showing that O4, Olig2, and myelin basic protein (MBP) positive cells were significantly increased compared to control group. Additionally, the protein levels of Olig2 and MBP of OPCs were quantified using western blot and mRNA levels of Olig2 and Inhibitor of DNA binding 2 (Id2) were measured by RT-PCR. Western blot showed a significant increase in Olig2 and MBP expression levels compared with controls after OGD and Qu treatment with a linear does-response curve from 3 to 81 μM. After treatment with Qu compared to its control group, Olig2 mRNA level was significantly up-regulated, whereas Id2 mRNA level was down-regulated. In conclusion, Qu at 3-27 μM can promote the proliferation and differentiation of OPCs after OGD injury and may regulate the activity of Olig2 and Id2.

GM2 Activator Deficiency Caused by a Homozygous Exon 2 Deletion in GM2A.

PubMed

Hall, Patricia L; Laine, Regina; Alexander, John J; Ankala, Arunkanth; Teot, Lisa A; Lidov, Hart G W; Anselm, Irina

2018-01-01

GM2 activator (GM2A) deficiency (OMIM 613109) is a rare lysosomal storage disorder, with onset typically in infancy or early childhood. Clinically, it is almost indistinguishable from Tay-Sachs disease (OMIM 272800) or Sandhoff disease (OMIM 268800); however, traditionally available biochemical screening tests will most likely reveal normal results. We report a 2-year-old male with initially normal development until the age of 9 months, when he presented with developmental delay and regression. Workup at that time was unrevealing; at 15 months, he had abnormal brain MRI findings and a cherry red spot on ophthalmological examination. Family history and all laboratory studies were uninformative. The combination of a cherry red spot and developmental regression was strongly suggestive of a lysosomal storage disorder. Sequence analysis of GM2A did not reveal any pathogenic variants; however, exon 2 of GM2A could not be amplified by PCR, raising suspicion for a large, homozygous deletion. Subsequent copy number analysis confirmed a homozygous deletion of exon 2 in GM2A. This is the first reported case of GM2A deficiency being caused by a whole exon deletion. We describe previously unreported electron microscopy findings in this disease, thus expanding the clinical and variant spectrum for GM2 activator deficiency. These findings demonstrate the increased degree of suspicion required for diagnosis of this rare disorder. Brief Summary: This case of GM2 activator deficiency was caused by a homozygous deletion in GM2A, demonstrating the need to include exon level copy number analysis in any workup to fully exclude this disorder.

Potential Association of IL1B Polymorphism With Iron Deficiency Risk in Childhood Helicobacter pylori Infection.

PubMed

Chen, Szu-Ta; Ni, Yen-Hsuan; Liu, Shing-Hwa

2018-02-01

Helicobacter pylori infection occurs predominantly in childhood. Host immune response gene polymorphism is reported to affect the susceptibility to H pylori infection and the outcome of H pylori-related gastric cancer. Not all H pylori-infected patients, however, exhibit iron deficiency (ID). The relationship between host genetic polymorphisms and ID mediated by H pylori infection is not well understood. Subjects (n = 644) from the general population of age 10 to 18 years were divided into 2 groups based on serology testing for anti-H pylori IgG: seropositive study group; and seronegative control group. Five single nucleotide polymorphisms (SNPs) in IL1B (rs1143627 and rs16944), IL8 (rs4073), IL10 (rs1800896), and ABO (rs505922), were genotyped and the iron status of the 2 groups was compared. The seroprevalence rate for H pylori was 10.7% in this study. Infected subjects were significantly older and had lower serum iron levels than uninfected subjects (P = 0.0195 and 0.0059, respectively). Multivariate analysis revealed a significantly higher frequency of the T allele of rs505922 (odds ratio [OR] = 6.128; P < 0.001) and lower frequency of the T allele of rs1143627 (OR = 0.846; P = 0.014) in seropositive subjects. Among 59 seropositive subjects, the T allele frequency of rs1143627 was significantly higher in those with ID (OR = 3.156; P = 0.043), compared with those without ID. ABO (rs505922) and IL1B (rs1143627) may affect H pylori infection susceptibility, and IL1B (rs1143627) may also influence ID risk in infected children.

Oral versus intravenous iron therapy in patients with inflammatory bowel disease and iron deficiency with and without anemia in Germany – a real-world evidence analysis

PubMed Central

Haas, Jennifer Scarlet; Ong, Siew Hwa; Borchert, Kathrin; Hardt, Thomas; Lechat, Elmira; Nip, Kerry; Foerster, Douglas; Braun, Sebastian; Baumgart, Daniel C

2018-01-01

Background Iron-deficiency anemia and iron deficiency are common comorbidities associated with inflammatory bowel disease (IBD) resulting in impaired quality of life and high health care costs. Intravenous iron has shown clinical benefit compared to oral iron therapy. Aim This study aimed to compare health care outcomes and costs after oral vs intravenous iron treatment for IBD patients with iron deficiency or iron deficiency anemia (ID/A) in Germany. Methods IBD patients with ID/A were identified by ICD-10-GM codes and newly commenced iron treatment via ATC codes in 2013 within the InGef (formerly Health Risk Institute) research claims database. Propensity score matching was performed to balance both treatment groups. Non-observable covariates were adjusted by applying the difference-in-differences (DID) approach. Results In 2013, 589 IBD patients with ID/A began oral and 442 intravenous iron treatment. After matching, 380 patients in each treatment group were analyzed. The intravenous group had fewer all-cause hospitalizations (37% vs 48%) and ID/A-related hospitalizations (5% vs 14%) than the oral iron group. The 1-year preobservation period comparison revealed significant health care cost differences between both groups. After adjusting for cost differences by DID method, total health care cost savings in the intravenous iron group were calculated to be €367. While higher expenditure for medication (€1,876) was observed in the intravenous iron group, the inpatient setting achieved most cost savings (€1,887). Conclusion IBD patients receiving intravenous iron were less frequently hospitalized and incurred lower total health care costs compared to patients receiving oral iron. Higher expenditures for pharmaceuticals were compensated by cost savings in other domains. PMID:29440920

Installation, commissioning and performance of IDs installed at ALBA

NASA Astrophysics Data System (ADS)

Campmany, J.; Marcos, J.; Massana, V.; Becheri, F.; Gigante, J. V.; Colldelram, C.; Ribó, Ll

2013-03-01

The new synchrotron light source ALBA is currently starting regular operation. Up to 6 beamlines are using light produced by Insertion Devices. There are up to four types of IDs: 2 Apple-II undulators (EU62 and EU71) operating at low energies, one conventional wiggler (MPW80) operating in the range of 2 - 20 keV, two in-vacuum undulators (IVU21) operating in the range 5 - 30 keV and a superconducting wiggler (SCW30) operating in the range of (up to) 40 keV. The main IDs characteristics, their influence on the beam dynamics and a first characterization of their light will be presented.

CYP2R1 mutations causing vitamin D-deficiency rickets.

PubMed

Thacher, Tom D; Levine, Michael A

2017-10-01

CYP2R1 is the principal hepatic 25-hydroxylase responsible for the hydroxylation of parent vitamin D to 25-hydroxyvitamin D [25(OH)D]. Serum concentrations of 25(OH)D reflect vitamin D status, because 25(OH)D is the major circulating metabolite of vitamin D. The 1α-hydroxylation of 25(OH)D in the kidney by CYP27B1 generates the fully active vitamin D metabolite, 1,25-dihydroxyvitamin D (1,25(OH) 2 D). The human CYP2R1 gene, located at 11p15.2, has five exons, coding for an enzyme with 501 amino acids. In Cyp2r1-/- knockout mice, serum 25(OH)D levels were reduced by more than 50% compared wild-type mice. Genetic polymorphisms of CYP2R1 account for some of the individual variability of circulating 25(OH)D values in the population. We review the evidence that inactivating mutations in CYP2R1 can lead to a novel form of vitamin D-deficiency rickets resulting from impaired 25-hydroxylation of vitamin D. We sequenced the promoter, exons and intron-exon flanking regions of the CYP2R1 gene in members of 12 Nigerian families with rickets in more than one family member. We found missense mutations (L99P and K242N) in affected members of 2 of 12 families. The L99P mutation had previously been reported as a homozygous defect in an unrelated child of Nigerian origin with rickets. In silico analyses predicted impaired CYP2R1 folding or reduced interaction with substrate vitamin D by L99P and K242N mutations, respectively. In vitro studies of the mutant CYP2R1 proteins in HEK293 cells confirmed normal expression levels but completely absent or markedly reduced 25-hydroxylase activity by the L99P and K242N mutations, respectively. Heterozygous subjects had more moderate biochemical and clinical features of vitamin D deficiency than homozygous subjects. After an oral bolus dose of 50,000 IU of vitamin D 2 or vitamin D 3 , heterozygous subjects had lower increases in serum 25(OH)D than control subjects, and homozygous subjects had minimal increases, supporting a semidominant

Guinea Pig ID-Like Families of SINEs

PubMed Central

Kass, David H.; Schaetz, Brian A.; Beitler, Lindsey; Bonney, Kevin M.; Jamison, Nicole; Wiesner, Cathy

2009-01-01

Previous studies have indicated a paucity of SINEs within the genomes of the guinea pig and nutria, representatives of the Hystricognathi suborder of rodents. More recent work has shown that the guinea pig genome contains a large number of B1 elements, expanding to various levels among different rodents. In this work we utilized A–B PCR and screened GenBank with sequences from isolated clones to identify potentially uncharacterized SINEs within the guinea pig genome, and identified numerous sequences with a high degree of similarity (>92%) specific to the guinea pig. The presence of A-tails and flanking direct repeats associated with these sequences supported the identification of a full-length SINE, with a consensus sequence notably distinct from other rodent SINEs. Although most similar to the ID SINE, it clearly was not derived from the known ID master gene (BC1), hence we refer to this element as guinea pig ID-like (GPIDL). Using the consensus to screen the guinea pig genomic database (Assembly CavPor2) with Ensembl BlastView, we estimated at least 100,000 copies, which contrasts markedly to just over 100 copies of ID elements. Additionally we provided evidence of recent integrations of GPIDL as two of seven analyzed conserved GPIDL-containing loci demonstrated presence/absence variants in Cavia porcellus and C. aperea. Using intra-IDL PCR and sequence analyses we also provide evidence that GPIDL is derived from a hystricognath-specific SINE family. These results demonstrate that this SINE family continues to contribute to the dynamics of genomes of hystricognath rodents. PMID:19232383

Guinea pig ID-like families of SINEs.

PubMed

Kass, David H; Schaetz, Brian A; Beitler, Lindsey; Bonney, Kevin M; Jamison, Nicole; Wiesner, Cathy

2009-05-01

Previous studies have indicated a paucity of SINEs within the genomes of the guinea pig and nutria, representatives of the Hystricognathi suborder of rodents. More recent work has shown that the guinea pig genome contains a large number of B1 elements, expanding to various levels among different rodents. In this work we utilized A-B PCR and screened GenBank with sequences from isolated clones to identify potentially uncharacterized SINEs within the guinea pig genome, and identified numerous sequences with a high degree of similarity (>92%) specific to the guinea pig. The presence of A-tails and flanking direct repeats associated with these sequences supported the identification of a full-length SINE, with a consensus sequence notably distinct from other rodent SINEs. Although most similar to the ID SINE, it clearly was not derived from the known ID master gene (BC1), hence we refer to this element as guinea pig ID-like (GPIDL). Using the consensus to screen the guinea pig genomic database (Assembly CavPor2) with Ensembl BlastView, we estimated at least 100,000 copies, which contrasts markedly to just over 100 copies of ID elements. Additionally we provided evidence of recent integrations of GPIDL as two of seven analyzed conserved GPIDL-containing loci demonstrated presence/absence variants in Cavia porcellus and C. aperea. Using intra-IDL PCR and sequence analyses we also provide evidence that GPIDL is derived from a hystricognath-specific SINE family. These results demonstrate that this SINE family continues to contribute to the dynamics of genomes of hystricognath rodents.

Genetics Home Reference: adenosine deaminase 2 deficiency

MedlinePlus

... not fully understand how a loss of this enzyme's function leads to the features of ADA2 deficiency. They speculate that a lack of this enzyme may disrupt the balance between pro-inflammatory and ...

Vitamin D deficiency: a new risk factor for type 2 diabetes?.

PubMed

Mezza, T; Muscogiuri, G; Sorice, G P; Prioletta, A; Salomone, E; Pontecorvi, A; Giaccari, A

2012-01-01

Recent compelling evidence suggests a role of vitamin D deficiency in the pathogenesis of insulin resistance and insulin secretion derangements, with a consequent possible interference with type 2 diabetes mellitus. The mechanism of this link is incompletely understood. In fact, vitamin D deficiency is usually detected in obesity in which insulin resistance is also a common finding. The coexistence of insulin resistance and vitamin D deficiency has generated several hypotheses. Some cross-sectional and prospective studies have suggested that vitamin D deficiency may play a role in worsening insulin resistance; others have identified obesity as a risk factor predisposing individuals to exhibit both vitamin D deficiency and insulin resistance. The available data from intervention studies are largely confounded, and inadequate considerations of seasonal effects on 25(OH)D concentrations are also a common design flaw in many studies. On the contrary, there is strong evidence that obesity might cause both vitamin D deficiency and insulin resistance, leaving open the possibility that vitamin D and diabetes are not related at all. Although it might seem premature to draw firm conclusions on the role of vitamin D supplementation in reducing insulin resistance and preventing type 2 diabetes, this manuscript will review the circumstances leading to vitamin D deficiency and how such a deficiency can eventually independently affect insulin sensitivity. Copyright © 2012 S. Karger AG, Basel.

Nrf2 Deficiency Exacerbates Obesity-Induced Oxidative Stress, Neurovascular Dysfunction, Blood-Brain Barrier Disruption, Neuroinflammation, Amyloidogenic Gene Expression, and Cognitive Decline in Mice, Mimicking the Aging Phenotype.

PubMed

Tarantini, Stefano; Valcarcel-Ares, M Noa; Yabluchanskiy, Andriy; Tucsek, Zsuzsanna; Hertelendy, Peter; Kiss, Tamas; Gautam, Tripti; Zhang, Xin A; Sonntag, William E; de Cabo, Rafael; Farkas, Eszter; Elliott, Michael H; Kinter, Michael T; Deak, Ferenc; Ungvari, Zoltan; Csiszar, Anna

2018-06-14

Obesity has deleterious effects on cognitive function in the elderly adults. In mice, aging exacerbates obesity-induced oxidative stress, microvascular dysfunction, blood-brain barrier (BBB) disruption, and neuroinflammation, which compromise cognitive health. However, the specific mechanisms through which aging and obesity interact to remain elusive. Previously, we have shown that Nrf2 signaling plays a critical role in microvascular resilience to obesity and that aging is associated with progressive Nrf2 dysfunction, promoting microvascular impairment. To test the hypothesis that Nrf2 deficiency exacerbates cerebromicrovascular dysfunction induced by obesity Nrf2+/+ and Nrf2-/-, mice were fed an adipogenic high-fat diet (HFD). Nrf2 deficiency significantly exacerbated HFD-induced oxidative stress and cellular senescence, impairment of neurovascular coupling responses, BBB disruption, and microglia activation, mimicking the aging phenotype. Obesity in Nrf2-/- mice elicited complex alterations in the amyloidogenic gene expression profile, including upregulation of amyloid precursor protein. Nrf2 deficiency and obesity additively reduced long-term potentiation in the CA1 area of the hippocampus. Collectively, Nrf2 dysfunction exacerbates the deleterious effects of obesity, compromising cerebromicrovascular and brain health by impairing neurovascular coupling mechanisms, BBB integrity and synaptic function and promoting neuroinflammation. These results support a possible role for age-related Nrf2 dysfunction in the pathogenesis of vascular cognitive impairment and Alzheimer's disease.

Transhydrogenase Promotes the Robustness and Evolvability of E. coli Deficient in NADPH Production

PubMed Central

Chou, Hsin-Hung; Marx, Christopher J.; Sauer, Uwe

2015-01-01

Metabolic networks revolve around few metabolites recognized by diverse enzymes and involved in myriad reactions. Though hub metabolites are considered as stepping stones to facilitate the evolutionary expansion of biochemical pathways, changes in their production or consumption often impair cellular physiology through their system-wide connections. How does metabolism endure perturbations brought immediately by pathway modification and restore hub homeostasis in the long run? To address this question we studied laboratory evolution of pathway-engineered Escherichia coli that underproduces the redox cofactor NADPH on glucose. Literature suggests multiple possibilities to restore NADPH homeostasis. Surprisingly, genetic dissection of isolates from our twelve evolved populations revealed merely two solutions: (1) modulating the expression of membrane-bound transhydrogenase (mTH) in every population; (2) simultaneously consuming glucose with acetate, an unfavored byproduct normally excreted during glucose catabolism, in two subpopulations. Notably, mTH displays broad phylogenetic distribution and has also played a predominant role in laboratory evolution of Methylobacterium extorquens deficient in NADPH production. Convergent evolution of two phylogenetically and metabolically distinct species suggests mTH as a conserved buffering mechanism that promotes the robustness and evolvability of metabolism. Moreover, adaptive diversification via evolving dual substrate consumption highlights the flexibility of physiological systems to exploit ecological opportunities. PMID:25715029

Iodine deficiency in Egyptian autistic children and their mothers: relation to disease severity.

PubMed

Hamza, Rasha T; Hewedi, Doaa H; Sallam, Mahmoud T

2013-10-01

Because autism may be a disease of early fetal brain development, maternal hypothyroxinemia (HT) in early pregnancy secondary to iodine deficiency (ID) may be related to etiology of autism. The aim of the study was to assess the iodine nutritional status in Egyptian autistic children and their mothers and its relationship with disease characteristics. Fifty autistic children and their mothers were studied in comparison to 50 controls. All subjects were subjected to clinical evaluation, measurement of urinary iodine (UI), free triiodothyronine (fT3), free tetraiodothyronine (fT4) and thyroid-stimulating hormone (TSH) along with measurement of thyroid volume (TV). In addition, electroencephalography (EEG) and intelligence quotient (IQ) assessment were done for all autistic children. Of autistic children and their mothers, 54% and 58%, respectively, were iodine deficient. None of the control children or their mothers was iodine deficient. UI was lower among autistic patients (p <0.001) and their mothers (p <0.001). Childhood Autism Rating Scale (CARS) score correlated negatively with UI (r = -0.94, p <0.001). Positive correlations were detected between autistic patients and their mothers regarding UI (r = 0.88, p <0.001), fT3 (r = 0.79, p = 0.03), fT4 (r = 0.91, p <0.001) and TSH (r = 0.69, p = 0.04). Autism had a significant risk for association with each of low UI (OR: 9.5, 95% CI: 2.15-33.8, p = 0.02) and intake of noniodized salt (OR: 6.82, 95% CI = 1.36-34.27, p = 0.031). ID is prevalent in Egyptian autistic children and their mothers and was inversely related to disease severity and could be related to its etiology. Copyright © 2013 IMSS. Published by Elsevier Inc. All rights reserved.

Absolute and functional iron deficiency in professional athletes during training and recovery.

PubMed

Reinke, Simon; Taylor, William R; Duda, Georg N; von Haehling, Stephan; Reinke, Petra; Volk, Hans-Dieter; Anker, Stefan D; Doehner, Wolfram

2012-04-19

Iron deficiency (ID) is one of the most important metabolic dysfunctions. Athletic performance depends on oxygen transport and mitochondrial efficiency, thus on optimal iron balance. We hypothesised that physical extremes result in ID in elite athletes and that the short recovery period may be insufficient to allow a lasting replenishment of iron reserves. Iron metabolism was examined in 20 elite rowing athletes and 10 professional soccer players at the end of a competitive season, after recuperation and during pre-season training. Absolute ID values were defined as ferritin <30 μg/L, functional ID as ferritin 30-99 μg/L or 100-299 μg/L+transferrin saturation <20%. At the end of season, 27% of all athletes had absolute ID and 70% showed functional ID. Absolute iron depletion was not generally restored after recuperation and observed at all time points in 14% of the athletes. Although athletes with initially low ferritin levels showed a slight increase during recuperation (p<0.09), these increases remained within borderline levels. Furthermore, 10% showed borderline haemoglobin levels, suggestive of mild anaemia, as defined by the World Health Organisation. A significant proportion of professional athletes have ID, independent of the training mode. Although recuperation seems to allow a certain recovery of iron storage, particularly in athletes with initially low ferritin levels, this retrieval was insufficient to fully normalise reduced iron levels. Therefore, iron status should be carefully monitored during the various training and competitive periods in elite athletes. An adequate iron supplementation may be needed to maintain balanced iron stores. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Scaffold protein enigma homolog 1 overcomes the repression of myogenesis activation by inhibitor of DNA binding 2

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

Nakatani, Miyuki; Ito, Jumpei; Japan Society for the Promotion of Science, Tokyo, 102-0083

Enigma Homolog 1 (ENH1) is a scaffold protein for signaling proteins and transcription factors. Previously, we reported that ENH1 overexpression promotes the differentiation of C2C12 myoblasts. However, the molecular mechanism underlying the role of ENH1 in the C2C12 cells differentiation remains elusive. ENH1 was shown to inhibit the proliferation of neuroblastoma cells by sequestering Inhibitor of DNA binding protein 2 (Id2) in the cytosol. Id2 is a repressor of basic Helix-Loop-Helix transcription factors activity and prevents myogenesis. Here, we found that ENH1 overcome the Id2 repression of C2C12 cells myogenic differentiation and that ENH1 overexpression promotes mice satellite cells activation, the firstmore » step toward myogenic differentiation. In addition, we show that ENH1 interacted with Id2 in C2C12 cells and mice satellite cells. Collectively, our results suggest that ENH1 plays an important role in the activation of myogenesis through the repression of Id2 activity. -- Highlights: •Enigma Homolog 1 (ENH1) is a scaffold protein. •ENH1 binds to inhibitor of DNA binding 2 (Id2) in myoblasts. •ENH1 overexpression overcomes the Id2's repression of myogenesis. •The Id2-ENH1 complex play an important role in the activation of myogenesis.« less

STAG2 promotes error correction in mitosis by regulating kinetochore-microtubule attachments.

PubMed

Kleyman, Marianna; Kabeche, Lilian; Compton, Duane A

2014-10-01

Mutations in the STAG2 gene are present in ∼20% of tumors from different tissues of origin. STAG2 encodes a subunit of the cohesin complex, and tumors with loss-of-function mutations are usually aneuploid and display elevated frequencies of lagging chromosomes during anaphase. Lagging chromosomes are a hallmark of chromosomal instability (CIN) arising from persistent errors in kinetochore-microtubule (kMT) attachment. To determine whether the loss of STAG2 increases the rate of formation of kMT attachment errors or decreases the rate of their correction, we examined mitosis in STAG2-deficient cells. STAG2 depletion does not impair bipolar spindle formation or delay mitotic progression. Instead, loss of STAG2 permits excessive centromere stretch along with hyperstabilization of kMT attachments. STAG2-deficient cells display mislocalization of Bub1 kinase, Bub3 and the chromosome passenger complex. Importantly, strategically destabilizing kMT attachments in tumor cells harboring STAG2 mutations by overexpression of the microtubule-destabilizing enzymes MCAK (also known as KIF2C) and Kif2B decreased the rate of lagging chromosomes and reduced the rate of chromosome missegregation. These data demonstrate that STAG2 promotes the correction of kMT attachment errors to ensure faithful chromosome segregation during mitosis. © 2014. Published by The Company of Biologists Ltd.

Telomerase Reverse Transcriptase Deficiency Prevents Neointima Formation Through Chromatin Silencing of E2F1 Target Genes.

PubMed

Endorf, Elizabeth B; Qing, Hua; Aono, Jun; Terami, Naoto; Doyon, Geneviève; Hyzny, Eric; Jones, Karrie L; Findeisen, Hannes M; Bruemmer, Dennis

2017-02-01

Aberrant proliferation of smooth muscle cells (SMC) in response to injury induces pathological vascular remodeling during atherosclerosis and neointima formation. Telomerase is rate limiting for tissue renewal and cell replication; however, the physiological role of telomerase in vascular diseases remains to be determined. The goal of the present study was to determine whether telomerase reverse transcriptase (TERT) affects proliferative vascular remodeling and to define the molecular mechanism by which TERT supports SMC proliferation. We first demonstrate high levels of TERT expression in replicating SMC of atherosclerotic and neointimal lesions. Using a model of guidewire-induced arterial injury, we demonstrate decreased neointima formation in TERT-deficient mice. Studies in SMC isolated from TERT-deficient and TERT overexpressing mice with normal telomere length established that TERT is necessary and sufficient for cell proliferation. TERT deficiency did not induce a senescent phenotype but resulted in G1 arrest albeit hyperphosphorylation of the retinoblastoma protein. This proliferative arrest was associated with stable silencing of the E2F1-dependent S-phase gene expression program and not reversed by ectopic overexpression of E2F1. Finally, chromatin immunoprecipitation and accessibility assays revealed that TERT is recruited to E2F1 target sites and promotes chromatin accessibility for E2F1 by facilitating the acquisition of permissive histone modifications. These data indicate a previously unrecognized role for TERT in neointima formation through epigenetic regulation of proliferative gene expression in SMC. © 2016 American Heart Association, Inc.

Proton Pump Inhibitor and Histamine-2 Receptor Antagonist Use and Iron Deficiency.

PubMed

Lam, Jameson R; Schneider, Jennifer L; Quesenberry, Charles P; Corley, Douglas A

2017-03-01

Proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs) suppress gastric acid production, which can inhibit iron absorption. However, few data exist regarding whether these medications increase the risk of clinical iron deficiency. A community-based case-control study evaluated the association between acid-suppressing medication use and the subsequent risk of iron deficiency. It contrasted 77,046 patients with new iron deficiency diagnoses (January 1999-December 2013), with 389,314 controls. Medication exposures, outcomes, and potential confounders used electronic databases. We excluded patients with pre-existing risk factors for iron deficiency. Associations were estimated using conditional logistic regression. Among cases, 2343 (3.0%) received a prior ≥2-year supply of PPIs and 1063 (1.4%) received H2RAs (without PPI use). Among controls, 3354 (0.9%) received a prior ≥2-year supply of PPIs and 2247 (0.6%) H2RAs. Both ≥2 years of PPIs (adjusted odds ratio, 2.49; 95% confidence interval, 2.35-2.64) and ≥2 years of H2RAs (odds ratio, 1.58; 95% CI, 1.46-1.71) were associated with an increased subsequent risk for iron deficiency. Among PPI users, the associations were stronger for higher daily doses (>1.5 vs <0.75 PPI pills/d; P value interaction = .004) and decreased after medication discontinuation (P-trend < .001). Some of the strongest associations were among persons taking >1.5 pills per day for at least 10 years (odds ratio, 4.27; 95% CI, 2.53-7.21). No similar strong associations were found for other commonly used prescription medications. Among patients without known risk factors for iron deficiency, gastric acid inhibitor use for ≥2 years was associated with an increased subsequent risk of iron deficiency. The risk increased with increasing potency of acid inhibition and decreased after medication discontinuation. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

Effects on vitamin A deficiency in children of periodic high-dose supplements and of fortified oil promotion in a deficient area of the Philippines.

PubMed

Mason, John B; Ramirez, Maria A; Fernandez, Chona M; Pedro, Regina; Lloren, Tina; Saldanha, Lisa; Deitchler, Megan; Eisele, T

2011-09-01

Regular semi-annual distribution of high-dose (200,000 IU) vitamin A capsules (VACs) to children 1 - 5 years of age (previously identified as underweight), in Leyte Province, the Philippines, was compared to providing extra VACs to give three-monthly dosing, and to vitamin A-fortified cooking oil (VAFO) promotion (with continued VACs every 6 months). Serum retinol (SR) was measured at baseline and after 12 or 18 months (for VAFO). No sustained increase in SR was determined from the three-month VAC dosing regimen, and the prevalence of vitamin A deficiency (VAD) as assessed by SR (< 20 mcg / dL) remained around 30 % (in line with national survey estimates over the previous 15 years). The major difference found was that 18 months of VAFO (of which 9 months had sustained promotion) was associated with reducing the prevalence of VAD to < 10 %. The effective fortification and lack of effect of semi-annual VAC results are in line with previous studies; testing with dosing of VAC every three months is a new intervention. The results imply that promotion of fortified oil would reduce VAD in these conditions; whether it can replace or needs to be added to semi-annual VAC dosing remains to be determined. A phased changeover to reliance on fortified commodities (including oil) with careful monitoring of VAD trends is indicated.

The inhibitor of differentiation-1 (Id1) enables lung cancer liver colonization through activation of an EMT program in tumor cells and establishment of the pre-metastatic niche.

PubMed

Castañón, Eduardo; Soltermann, Alex; López, Inés; Román, Marta; Ecay, Margarita; Collantes, María; Redrado, Miriam; Baraibar, Iosune; López-Picazo, José María; Rolfo, Christian; Vidal-Vanaclocha, Fernando; Raez, Luis; Weder, Walter; Calvo, Alfonso; Gil-Bazo, Ignacio

2017-08-28

Id1 promotes carcinogenesis and metastasis, and predicts prognosis of non-small cell lung cancer (NSCLC)-adenocarcionoma patients. We hypothesized that Id1 may play a critical role in lung cancer colonization of the liver by affecting both tumor cells and the microenvironment. Depleted levels of Id1 in LLC (Lewis lung carcinoma cells, LLC shId1) significantly reduced cell proliferation and migration in vitro. Genetic loss of Id1 in the host tissue (Id1 -/- mice) impaired liver colonization and increased survival of Id1 -/- animals. Histologically, the presence of Id1 in tumor cells of liver metastasis was responsible for liver colonization. Microarray analysis comparing liver tumor nodules from Id1 +/+ mice and Id1 -/- mice injected with LLC control cells revealed that Id1 loss reduces the levels of EMT-related proteins, such as vimentin. In tissue microarrays containing 532 NSCLC patients' samples, we found that Id1 significantly correlated with vimentin and other EMT-related proteins. Id1 loss decreased the levels of vimentin, integrinβ1, TGFβ1 and snail, both in vitro and in vivo. Therefore, Id1 enables both LLC and the host microenvironment for an effective liver colonization, and may represent a novel therapeutic target to avoid NSCLC liver metastasis. Copyright © 2017 Elsevier B.V. All rights reserved.

Plectin deficiency in liver cancer cells promotes cell migration and sensitivity to sorafenib treatment.

PubMed

Cheng, Chiung-Chi; Chao, Wei-Ting; Liao, Chen-Chun; Tseng, Yu-Hui; Lai, Yen-Chang Clark; Lai, Yih-Shyong; Hsu, Yung-Hsiang; Liu, Yi-Hsiang

2018-01-02

Plectin involved in activation of kinases in cell signaling pathway and plays important role in cell morphology and migration. Plectin knockdown promotes cell migration by activating focal adhesion kinase and Rac1-GTPase activity in liver cells. Sorafenib is a multi-targeting tyrosine kinase inhibitor that improves patient survival on hepatocellular carcinoma. The aim of this study is to investigate the correlation between the expression of plectin and cell migration as well as the sensitivity of hepatoma cell lines exposing to sorafenib. Hepatoma cell lines PLC/PRF/5 and HepG2 were used to examine the level of plectin expression and cell migration in comparison with Chang liver cell line. In addition, sensitivity of the 3 cell lines to sorafenib treatment was also measured. Expression of plectin was lower in PLC/PRF/5 and HepG2 hepatoma cells than that of Chang liver cells whereas HepG2 and PLC/PRF/5 cells exhibit higher rate of cell migration in trans-well migration assay. Immunohistofluorecent staining on E-cadherin revealed the highest rate of collective cell migration in HepG2 cells and the lowest was found in Chang liver cells. Likewise, HepG2 cell line was most sensitive to sorafenib treatment and Chang liver cells exhibited the least sensitivity. The drug sensitivity to sorafenib treatment showed inverse correlation with the expression of plectin. We suggest that plectin deficiency and increased E-cadherin in hepatoma cells were associated with higher rates of cell motility, collective cell migration as well as higher drug sensitivity to sorafenib treatment.

Genetic deficiency of indoleamine 2,3-dioxygenase promotes gut microbiota-mediated metabolic health.

PubMed

Laurans, Ludivine; Venteclef, Nicolas; Haddad, Yacine; Chajadine, Mouna; Alzaid, Fawaz; Metghalchi, Sarvenaz; Sovran, Bruno; Denis, Raphael G P; Dairou, Julien; Cardellini, Marina; Moreno-Navarrete, Jose-Maria; Straub, Marjolene; Jegou, Sarah; McQuitty, Claire; Viel, Thomas; Esposito, Bruno; Tavitian, Bertrand; Callebert, Jacques; Luquet, Serge H; Federici, Massimo; Fernandez-Real, José Manuel; Burcelin, Remy; Launay, Jean-Marie; Tedgui, Alain; Mallat, Ziad; Sokol, Harry; Taleb, Soraya

2018-06-25

The association between altered gut microbiota, intestinal permeability, inflammation and cardiometabolic diseases is becoming increasingly clear but remains poorly understood 1,2 . Indoleamine 2,3-dioxygenase is an enzyme induced in many types of immune cells, including macrophages in response to inflammatory stimuli, and catalyzes the degradation of tryptophan along the kynurenine pathway. Indoleamine 2,3-dioxygenase activity is better known for its suppression of effector T cell immunity and its activation of regulatory T cells 3,4 . However, high indoleamine 2,3-dioxygenase activity predicts worse cardiovascular outcome 5-9 and may promote atherosclerosis and vascular inflammation 6 , suggesting a more complex role in chronic inflammatory settings. Indoleamine 2,3-dioxygenase activity is also increased in obesity 10-13 , yet its role in metabolic disease is still unexplored. Here, we show that obesity is associated with an increase of intestinal indoleamine 2,3-dioxygenase activity, which shifts tryptophan metabolism from indole derivative and interleukin-22 production toward kynurenine production. Indoleamine 2,3-dioxygenase deletion or inhibition improves insulin sensitivity, preserves the gut mucosal barrier, decreases endotoxemia and chronic inflammation, and regulates lipid metabolism in liver and adipose tissues. These beneficial effects are due to rewiring of tryptophan metabolism toward a microbiota-dependent production of interleukin-22 and are abrogated after treatment with a neutralizing anti-interleukin-22 antibody. In summary, we identify an unexpected function of indoleamine 2,3-dioxygenase in the fine tuning of intestinal tryptophan metabolism with major consequences on microbiota-dependent control of metabolic disease, which suggests indoleamine 2,3-dioxygenase as a potential therapeutic target.

Familial discoid lupus erythematosus associated with heterozygote C2 deficiency.

PubMed

Belin, D C; Bordwell, B J; Einarson, M E; McLean, R H; Weinstein, A; Yunis, E J; Rothfield, N F

1980-08-01

Two siblings with chronic discoid lupus erythematosus and several family members were found with heterozygous C2 deficiency. An association with histocompatibility markers HLA-B18 and HLA-Dw2 was demonstrated, and the slow allotype of factor B was present. Linkage studies in this family suggested a close linkage between the C2 deficiency gene and genes coding for B18, Dw2, and BfS antigens. One HLA-ACB/DBf recombinant was observed showing closer linkage between HLA-D and Bf than between HLA-B and Bf.

SigmoID: a user-friendly tool for improving bacterial genome annotation through analysis of transcription control signals

PubMed Central

Damienikan, Aliaksandr U.

2016-01-01

The majority of bacterial genome annotations are currently automated and based on a ‘gene by gene’ approach. Regulatory signals and operon structures are rarely taken into account which often results in incomplete and even incorrect gene function assignments. Here we present SigmoID, a cross-platform (OS X, Linux and Windows) open-source application aiming at simplifying the identification of transcription regulatory sites (promoters, transcription factor binding sites and terminators) in bacterial genomes and providing assistance in correcting annotations in accordance with regulatory information. SigmoID combines a user-friendly graphical interface to well known command line tools with a genome browser for visualising regulatory elements in genomic context. Integrated access to online databases with regulatory information (RegPrecise and RegulonDB) and web-based search engines speeds up genome analysis and simplifies correction of genome annotation. We demonstrate some features of SigmoID by constructing a series of regulatory protein binding site profiles for two groups of bacteria: Soft Rot Enterobacteriaceae (Pectobacterium and Dickeya spp.) and Pseudomonas spp. Furthermore, we inferred over 900 transcription factor binding sites and alternative sigma factor promoters in the annotated genome of Pectobacterium atrosepticum. These regulatory signals control putative transcription units covering about 40% of the P. atrosepticum chromosome. Reviewing the annotation in cases where it didn’t fit with regulatory information allowed us to correct product and gene names for over 300 loci. PMID:27257541

A survey of children affected by ectomermal dysplasia syndromes shows an increased prevalence of atopic disorders and immune deficiency

USDA-ARS?s Scientific Manuscript database

Ectodermal dysplasia (ED) syndromes are rare genetic disorders that affect the development of tissues derived from the embryonic ectoderm. Studies and anecdotal experience have indicated that atopic disorders (AD) and immune deficiencies (ID) may be associated with ED in children. Some ED genotypes ...

The missed opportunities to diagnose and treat iron deficiency in patients hospitalized with heart failure.

PubMed

Silverberg, Donald S; Schwartz, Doron; Schwartz, Idit; Ben Assa, Eyal

2013-10-03

Iron Deficiency (ID) is common in heart failure (HF), and is an independent contributor to mortality and morbidity. We examined whether patients with previously known HF who were recently hospitalized, had previous treatment for ID, were investigated for it at the time of hospitalization, and, if ID was found, were prescribed iron on discharge. We examined the records of 76 consecutive patients admitted to our hospital medical wards with a primary diagnosis of HF. Anemia (Hb<12 g/dl) was found in 42/76 patients (55.3%). In 55/76 patients (72.4%) there was no iron workup, in 6 (7.9%) an incomplete iron workup with serum iron, transferrin or ferritin lacking and in 15/76 (19.7%) a complete iron workup. If ID was defined as either a serum ferritin of <100 μg/l or a serum ferritin of 100-299 μg/l and a %Transferrin Saturation of <20% it was found in 12/15 (80%) of those with a complete workup; in 9 of 10 (90%) of the anemic patients and in 3 of 5 (60%) of those non-anemic patients. At discharge 11/15 (73.3%) of those with a complete iron workup were given iron, 10 orally and 1 IV. In those 6 with an incomplete workup 2 were started on oral iron (33.3%) and in those without any workup, 1 of 55 (1.8%) was given oral iron. ID is common in hospitalized HF patients but is usually not sought after by physicians at the time of admission. However if detected the physicians usually treated it. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Proxy indicators for identifying iron deficiency among anemic vegetarians in an area prevalent for thalassemia and hemoglobinopathies.

PubMed

Wongprachum, Kasama; Sanchaisuriya, Kanokwan; Sanchaisuriya, Pattara; Siridamrongvattana, Sirivara; Manpeun, Suwanna; Schlep, Frank P

2012-01-01

The study aimed to determine the proportion of iron deficiency (ID) anemia (IDA) among vegans in northeast Thailand and to explore whether mathematical formulas derived from red blood cell (RBC) indices are applicable for IDA screening in the study population. Blood samples from 234 individuals (age 6-45 years) living in a vegan community were taken. Complete blood cell count, serum ferritin, hemoglobin profiles and DNA analysis for α-thalassemia were determined. Anemia was defined using the WHO criteria adjusted for age and sex. Serum ferritin <15 ng/ml was considered as ID. A number of mathematical formulas derived from RBC indices were applied to screen ID among anemic individuals. Anemia was found in 41.5% (95% CI = 35.1-48.1%) of the study participants. The overall proportion of thalassemia and hemoglobinopathies was 56.4% (95% CI = 49.8-62.9%). Of the anemic participants, 45.4% had ID. Based on the receiver-operating characteristic curve analysis, 4 formulas were applicable for predicting ID among anemic individuals (highest sensitivity of 86.4%). The proposed formulas might be used as proxy indicators for the identification of ID among anemic children and adult vegans if more sophisticated laboratory determinations are not available due to limited financial resources. Copyright © 2012 S. Karger AG, Basel.

Iron deficiency is associated with food insecurity in pregnant females in the United States: National Health and Nutrition Examination Survey 1999-2010.

PubMed

Park, Clara Y; Eicher-Miller, Heather A

2014-12-01

Food-insecure pregnant females may be at greater risk of iron deficiency (ID) because nutrition needs increase and more resources are needed to secure food during pregnancy. This may result in a higher risk of infant low birth weight and possibly cognitive impairment in the neonate. The relationships of food insecurity and poverty income ratio (PIR) with iron intake and ID among pregnant females in the United States were investigated using National Health and Nutrition Examination Survey 1999-2010 data (n=1,045). Food security status was classified using the US Food Security Survey Module. One 24-hour dietary recall and a 30-day supplement recall were used to assess iron intake. Ferritin, soluble transferrin receptor, or total body iron classified ID. Difference of supplement intake prevalence, difference in mean iron intake, and association of ID and food security status or PIR were assessed using χ(2) analysis, Student t test, and logistic regression analysis (adjusted for age, race, survey year, PIR/food security status, education, parity, trimester, smoking, C-reactive protein level, and health insurance coverage), respectively. Mean dietary iron intake was similar among groups. Mean supplemental and total iron intake were lower, whereas odds of ID, classified by ferritin status, were 2.90 times higher for food-insecure pregnant females compared with food-secure pregnant females. Other indicators of ID were not associated with food security status. PIR was not associated with iron intake or ID. Food insecurity status may be a better indicator compared with income status to identify populations at whom to direct interventions aimed at improving access and education regarding iron-rich foods and supplements. Copyright © 2014 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.

Deficiency of the protein-tyrosine phosphatase DEP-1/PTPRJ promotes matrix metalloproteinase-9 expression in meningioma cells.

PubMed

Petermann, Astrid; Stampnik, Yvonn; Cui, Yan; Morrison, Helen; Pachow, Doreen; Kliese, Nadine; Mawrin, Christian; Böhmer, Frank-D

2015-05-01

Brain-invasive growth of a subset of meningiomas is associated with less favorable prognosis. The molecular mechanisms causing invasiveness are only partially understood, however, the expression of matrix metalloproteinases (MMPs) has been identified as a contributing factor. We have previously found that loss of density enhanced phosphatase-1 (DEP-1, also designated PTPRJ), a transmembrane protein-tyrosine phosphatase, promotes meningioma cell motility and invasive growth in an orthotopic xenotransplantation model. We have now analyzed potential alterations of the expression of genes involved in motility control, caused by DEP-1 loss in meningioma cell lines. DEP-1 depleted cells exhibited increased expression of mRNA encoding MMP-9, and the growth factors EGF and FGF-2. The increase of MMP-9 expression in DEP-1 depleted cells was also readily detectable at the protein level by zymography. MMP-9 upregulation was sensitive to chemical inhibitors of growth factor signal transduction. Conversely, MMP-9 mRNA levels could be stimulated with growth factors (e.g. EGF) and inflammatory cytokines (e.g. TNFα). Increase of MMP-9 expression by DEP-1 depletion, or growth factor/cytokine stimulation qualitatively correlated with increased invasiveness in vitro scored as transmigration through matrigel-coated membranes. The studies suggest induction of MMP-9 expression promoted by DEP-1 deficiency, or potentially by growth factors and inflammatory cytokines, as a mechanism contributing to meningioma brain invasiveness.

Inhibition of FOXO1/3 promotes vascular calcification.

PubMed

Deng, Liang; Huang, Lu; Sun, Yong; Heath, Jack M; Wu, Hui; Chen, Yabing

2015-01-01

Vascular calcification is a characteristic feature of atherosclerosis, diabetes mellitus, and end-stage renal disease. We have demonstrated that activation of protein kinase B (AKT) upregulates runt-related transcription factor 2 (Runx2), a key osteogenic transcription factor that is crucial for calcification of vascular smooth muscle cells (VSMC). Using mice with SMC-specific deletion of phosphatase and tensin homolog (PTEN), a major negative regulator of AKT, the present studies uncovered a novel molecular mechanism underlying PTEN/AKT/FOXO (forkhead box O)-mediated Runx2 upregulation and VSMC calcification. SMC-specific PTEN deletion mice were generated by crossing PTEN floxed mice with SM22α-Cre transgenic mice. The PTEN deletion resulted in sustained activation of AKT that upregulated Runx2 and promoted VSMC calcification in vitro and arterial calcification ex vivo. Runx2 knockdown did not affect proliferation but blocked calcification of the PTEN-deficient VSMC, suggesting that PTEN deletion promotes Runx2-depedent VSMC calcification that is independent of proliferation. At the molecular level, PTEN deficiency increased the amount of Runx2 post-transcriptionally by inhibiting Runx2 ubiquitination. AKT activation increased phosphorylation of FOXO1/3 that led to nuclear exclusion of FOXO1/3. FOXO1/3 knockdown in VSMC phenocopied the PTEN deficiency, demonstrating a novel function of FOXO1/3, as a downstream signaling of PTEN/AKT, in regulating Runx2 ubiquitination and VSMC calcification. Using heterozygous SMC-specific PTEN-deficient mice and atherogenic ApoE(-/-) mice, we further demonstrated AKT activation, FOXO phosphorylation, and Runx2 ubiquitination in vascular calcification in vivo. Our studies have determined a new causative effect of SMC-specific PTEN deficiency on vascular calcification and demonstrated that FOXO1/3 plays a crucial role in PTEN/AKT-modulated Runx2 ubiquitination and VSMC calcification. © 2014 American Heart Association, Inc.

Combination of electron beam irradiation and thermal treatment to enhance the shelf-life of traditional Indian fermented food (Idli)

NASA Astrophysics Data System (ADS)

Mulmule, Manoj D.; Shimmy, Shankar M.; Bambole, Vaishali; Jamdar, Sahayog N.; Rawat, K. P.; Sarma, K. S. S.

2017-02-01

Idli, a steam-cooked breakfast food item consumed in India, is famous as a staple food for its spongy texture and unique fermented taste. Idli preparation is a time consuming process; although instant Idli pre-mixes as powder or batter are available in the market, they do not have the distinctive taste and aroma similar to the Idli prepared at home. Hence ready-to-eat (RTE) form of this food is in demand. Therefore, an attempt was made to prepare RTE Idli bearing similar taste as home-cooked Idli with an extended shelf-life of up to two months at an ambient temperature using Electron Beam Irradiation (EBI) at dosages 2.5 kGy, 5 kGy and 7.5 kGy and combination processing comprised of EBI dosage at 2.5 kGy and thermal treatment (80 °C for 20 min). The treated Idli's were microbiologically and sensorially evaluated at storage periods of zero day, 14 days, 30 days and 60 days. Idli's irradiated at 7.5 kGy and subjected to combination processing at 2.5 kGy and thermal treatment were shelf-stable for 60 days. 2.5 kGy and 5 kGy radiation dosages alone were not sufficient to preserve Idli samples for more than 14 days. Undesirable change in sensory properties of Idli was observed at an EBI dosage of 7.5 kGy. Sensory properties of combination processed Idli's were found to undergo minor change over the storage period. The present work suggests that lowest radiation dosage in combination with thermal treatment could be useful to achieve the extended shelf-life without considerably impairing the organoleptic quality of Ready-to-Eat Idli.

The FAK-Arp2/3 interaction promotes leading edge advance and haptosensing by coupling nascent adhesions to lamellipodia actin.

PubMed

Swaminathan, Vinay; Fischer, R S; Waterman, Clare M

2016-04-01

Cell migration is initiated in response to biochemical or physical cues in the environment that promote actin-mediated lamellipodial protrusion followed by the formation of nascent integrin adhesions (NAs) within the protrusion to drive leading edge advance. Although FAK is known to be required for cell migration through effects on focal adhesions, its role in NA formation and lamellipodial dynamics is unclear. Live-cell microscopy of FAK(-/-)cells with expression of phosphorylation deficient or a FERM-domain mutant deficient in Arp2/3 binding revealed a requirement for FAK in promoting the dense formation, transient stabilization, and timely turnover of NA within lamellipodia to couple actin-driven protrusion to adhesion and advance of the leading edge. Phosphorylation on Y397 of FAK promotes dense NA formation but is dispensable for transient NA stabilization and leading edge advance. In contrast, transient NA stabilization and advance of the cell edge requires FAK-Arp2/3 interaction, which promotes Arp2/3 localization to NA and reduces FAK activity. Haptosensing of extracellular matrix (ECM) concentration during migration requires the interaction between FAK and Arp2/3, whereas FAK phosphorylation modulates mechanosensing of ECM stiffness during spreading. Taken together, our results show that mechanistically separable functions of FAK in NA are required for cells to distinguish distinct properties of their environment during migration. © 2016 Swaminathan et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

Retrospective natural history of thymidine kinase 2 deficiency.

PubMed

Garone, Caterina; Taylor, Robert W; Nascimento, Andrés; Poulton, Joanna; Fratter, Carl; Domínguez-González, Cristina; Evans, Julie C; Loos, Mariana; Isohanni, Pirjo; Suomalainen, Anu; Ram, Dipak; Hughes, M Imelda; McFarland, Robert; Barca, Emanuele; Lopez Gomez, Carlos; Jayawant, Sandeep; Thomas, Neil D; Manzur, Adnan Y; Kleinsteuber, Karin; Martin, Miguel A; Kerr, Timothy; Gorman, Grainne S; Sommerville, Ewen W; Chinnery, Patrick F; Hofer, Monika; Karch, Christoph; Ralph, Jeffrey; Cámara, Yolanda; Madruga-Garrido, Marcos; Domínguez-Carral, Jana; Ortez, Carlos; Emperador, Sonia; Montoya, Julio; Chakrapani, Anupam; Kriger, Joshua F; Schoenaker, Robert; Levin, Bruce; Thompson, John L P; Long, Yuelin; Rahman, Shamima; Donati, Maria Alice; DiMauro, Salvatore; Hirano, Michio

2018-03-30

Thymine kinase 2 (TK2) is a mitochondrial matrix protein encoded in nuclear DNA and phosphorylates the pyrimidine nucleosides: thymidine and deoxycytidine. Autosomal recessive TK2 mutations cause a spectrum of disease from infantile onset to adult onset manifesting primarily as myopathy. To perform a retrospective natural history study of a large cohort of patients with TK2 deficiency. The study was conducted by 42 investigators across 31 academic medical centres. We identified 92 patients with genetically confirmed diagnoses of TK2 deficiency: 67 from literature review and 25 unreported cases. Based on clinical and molecular genetics findings, we recognised three phenotypes with divergent survival: (1) infantile-onset myopathy (42.4%) with severe mitochondrial DNA (mtDNA) depletion, frequent neurological involvement and rapid progression to early mortality (median post-onset survival (POS) 1.00, CI 0.58 to 2.33 years); (2) childhood-onset myopathy (40.2%) with mtDNA depletion, moderate-to-severe progression of generalised weakness and median POS at least 13 years; and (3) late-onset myopathy (17.4%) with mild limb weakness at onset and slow progression to respiratory insufficiency with median POS of 23 years. Ophthalmoparesis and facial weakness are frequent in adults. Muscle biopsies show multiple mtDNA deletions often with mtDNA depletion. In TK2 deficiency, age at onset, rate of weakness progression and POS are important variables that define three clinical subtypes. Nervous system involvement often complicates the clinical course of the infantile-onset form while extraocular muscle and facial involvement are characteristic of the late-onset form. Our observations provide essential information for planning future clinical trials in this disorder. © 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.

Enhanced ID Pit Sizing Using Multivariate Regression Algorithm

NASA Astrophysics Data System (ADS)

Krzywosz, Kenji

2007-03-01

EPRI is funding a program to enhance and improve the reliability of inside diameter (ID) pit sizing for balance-of plant heat exchangers, such as condensers and component cooling water heat exchangers. More traditional approaches to ID pit sizing involve the use of frequency-specific amplitude or phase angles. The enhanced multivariate regression algorithm for ID pit depth sizing incorporates three simultaneous input parameters of frequency, amplitude, and phase angle. A set of calibration data sets consisting of machined pits of various rounded and elongated shapes and depths was acquired in the frequency range of 100 kHz to 1 MHz for stainless steel tubing having nominal wall thickness of 0.028 inch. To add noise to the acquired data set, each test sample was rotated and test data acquired at 3, 6, 9, and 12 o'clock positions. The ID pit depths were estimated using a second order and fourth order regression functions by relying on normalized amplitude and phase angle information from multiple frequencies. Due to unique damage morphology associated with the microbiologically-influenced ID pits, it was necessary to modify the elongated calibration standard-based algorithms by relying on the algorithm developed solely from the destructive sectioning results. This paper presents the use of transformed multivariate regression algorithm to estimate ID pit depths and compare the results with the traditional univariate phase angle analysis. Both estimates were then compared with the destructive sectioning results.

Healthy living according to adults with intellectual disabilities: towards tailoring health promotion initiatives.

PubMed

Kuijken, N M J; Naaldenberg, J; Nijhuis-van der Sanden, M W; van Schrojenstein-Lantman de Valk, H M J

2016-03-01

A healthy lifestyle can prevent several health problems experienced by adults with intellectual disabilities (ID). For the development of effective and usable health promoting interventions for people with ID, the perspective of the intended audience should be taken into account. The aim of this qualitative study was to gain insight into the perspectives of people with mild to moderate ID on healthy living. Qualitative study. Five semi-structured focus groups were conducted with a total of 21 adults with mild to moderate ID in the Netherlands. Discussions focused on three main themes: (1) perceptions of own health, (2) what participants consider as healthy living and (3) factors experienced to be related to the ability to live healthily. Interviews were analysed thematically resulting in two main domains: (1) perceptions of what is healthy and unhealthy and (2) factors that participants experience to be related to their ability to live healthily. For participants, healthy living entails more than healthy food and exercising: feeling healthy, happiness and level of independence are perceived as important as well. Factors experienced to relate to their ability to live healthily were (a lack of) motivation, support from others and environmental factors such as available health education, (a lack of) facilities and a(n) (dis)advantageous location of work or residence. This qualitative study shows that adults with mild to moderate ID have a good understanding of what being healthy and living healthily constitute. As they face several difficulties in their attempts to live healthily, existing health promotion programmes for people with ID must be tailored to individual preferences and motivations and adapted for individual physical disabilities. Moreover, because of their dependency on others, tailoring should also be focused on the resources and hindering factors in their physical and social environment. © 2015 MENCAP and International Association of the Scientific

Promoting effect of foliage sprayed zinc sulfate on accumulation of sugar and phenolics in berries of Vitis vinifera cv. Merlot growing on zinc deficient soil.

PubMed

Song, Chang-Zheng; Liu, Mei-Ying; Meng, Jiang-Fei; Chi, Ming; Xi, Zhu-Mei; Zhang, Zhen-Wen

2015-02-02

The effect of foliage sprayed zinc sulfate on berry development of Vitis vinifera cv. Merlot growing on arid zone Zn-deficient soils was investigated over two consecutive seasons, 2013 and 2014. Initial zinc concentration in soil and vines, photosynthesis at three berry developmental stages, berry weight, content of total soluble solids, titratable acidity, phenolics and expression of phenolics biosynthetic pathway genes throughout the stages were measured. Foliage sprayed zinc sulfate showed promoting effects on photosynthesis and berry development of vines and the promotion mainly occurred from veraison to maturation. Zn treatments enhanced the accumulation of total soluble solids, total phenols, flavonoids, flavanols, tannins and anthocyanins in berry skin, decreasing the concentration of titratable acidity. Furthermore, foliage sprayed zinc sulfate could significantly influence the expression of phenolics biosynthetic pathway genes throughout berry development, and the results of expression analysis supported the promotion of Zn treatments on phenolics accumulation. This research is the first comprehensive and detailed study about the effect of foliage sprayed Zn fertilizer on grape berry development, phenolics accumulation and gene expression in berry skin, providing a basis for improving the quality of grape and wine in Zn-deficient areas.

Marginal Iodine Deficiency Affects Dendritic Spine Development by Disturbing the Function of Rac1 Signaling Pathway on Cytoskeleton.

PubMed

Min, Hui; Dong, Jing; Wang, Yi; Wang, Yuan; Yu, Ye; Shan, Zhongyan; Xi, Qi; Teng, Weiping; Chen, Jie

2017-01-01

Iodine deficiency (ID)-induced thyroid hormone (TH) insufficient during development leads to impairments of brain function, such as learning and memory. Marginal ID has been defined as subtle insufficiency of TH, characterized as low thyroxine (T 4 ) levels, whether marginal ID potentially had adverse effects on the development of hippocampus and the underlying mechanisms remain unclear. Thus, in the present study, we established Wistar rat models with ID diet during pregnancy and lactation. The effects of marginal ID on long-term potentiation (LTP) were investigated in the hippocampal CA1 region. To study the development of dendritic spines in pyramidal cells, Golgi-Cox staining was conducted on postnatal day (PN) 7, PN14, PN21, and PN28. The activation of Rac1 signaling pathway, which is essential for dendritic spine development by regulating actin cytoskeleton, was also investigated. Our results showed that marginal ID slightly reduced the field-excitatory postsynaptic potential (f-EPSP) slope and the population spike (PS) amplitude. Besides, the density of dendritic spines during the critical period of rat postnatal development was mildly decreased, and we found no significant change of spine morphology in marginal ID group. We also observed decreased activation of the Rac1 signaling pathway in pups subjected to maternal marginal ID. Our study may support the hypothesis that decreased T 4 induced by marginal ID results in slight impairments of LTP and leads to mild damage of dendritic spine development, which may be due to abnormal regulation of Rac1 signaling pathway on cytoskeleton.

A Paleolithic-type diet results in iodine deficiency: a 2-year randomized trial in postmenopausal obese women.

PubMed

Manousou, S; Stål, M; Larsson, C; Mellberg, C; Lindahl, B; Eggertsen, R; Hulthén, L; Olsson, T; Ryberg, M; Sandberg, S; Nyström, H F

2018-01-01

Different diets are used for weight loss. A Paleolithic-type diet (PD) has beneficial metabolic effects, but two of the largest iodine sources, table salt and dairy products, are excluded. The objectives of this study were to compare 24-h urinary iodine concentration (24-UIC) in subjects on PD with 24-UIC in subjects on a diet according to the Nordic Nutrition Recommendations (NNR) and to study if PD results in a higher risk of developing iodine deficiency (ID), than NNR diet. A 2-year prospective randomized trial in a tertiary referral center where healthy postmenopausal overweight or obese women were randomized to either PD (n=35) or NNR diet (n=35). Dietary iodine intake, 24-UIC, 24-h urinary iodine excretion (24-UIE), free thyroxin (FT4), free triiodothyronine (FT3) and thyrotropin (TSH) were measured at baseline, 6 and 24 months. Completeness of urine sampling was monitored by para-aminobenzoic acid and salt intake by urinary sodium. At baseline, median 24-UIC (71.0 μg/l) and 24-UIE (134.0 μg/d) were similar in the PD and NNR groups. After 6 months, 24-UIC had decreased to 36.0 μg/l (P=0.001) and 24-UIE to 77.0 μg/d (P=0.001) in the PD group; in the NNR group, levels were unaltered. FT4, TSH and FT3 were similar in both groups, except for FT3 at 6 months being lower in PD than in NNR group. A PD results in a higher risk of developing ID, than a diet according to the NNR. Therefore, we suggest iodine supplementation should be considered when on a PD.

Role of hypoxia-inducible factor-1 in transcriptional activation of ceruloplasmin by iron deficiency

NASA Technical Reports Server (NTRS)

Mukhopadhyay, C. K.; Mazumder, B.; Fox, P. L.

2000-01-01

A role of the copper protein ceruloplasmin (Cp) in iron metabolism is suggested by its ferroxidase activity and by the tissue iron overload in hereditary Cp deficiency patients. In addition, plasma Cp increases markedly in several conditions of anemia, e.g. iron deficiency, hemorrhage, renal failure, sickle cell disease, pregnancy, and inflammation. However, little is known about the cellular and molecular mechanism(s) involved. We have reported that iron chelators increase Cp mRNA expression and protein synthesis in human hepatocarcinoma HepG2 cells. Furthermore, we have shown that the increase in Cp mRNA is due to increased rate of transcription. We here report the results of new studies designed to elucidate the molecular mechanism underlying transcriptional activation of Cp by iron deficiency. The 5'-flanking region of the Cp gene was cloned from a human genomic library. A 4774-base pair segment of the Cp promoter/enhancer driving a luciferase reporter was transfected into HepG2 or Hep3B cells. Iron deficiency or hypoxia increased luciferase activity by 5-10-fold compared with untreated cells. Examination of the sequence showed three pairs of consensus hypoxia-responsive elements (HREs). Deletion and mutation analysis showed that a single HRE was necessary and sufficient for gene activation. The involvement of hypoxia-inducible factor-1 (HIF-1) was shown by gel-shift and supershift experiments that showed HIF-1alpha and HIF-1beta binding to a radiolabeled oligonucleotide containing the Cp promoter HRE. Furthermore, iron deficiency (and hypoxia) did not activate Cp gene expression in Hepa c4 hepatoma cells deficient in HIF-1beta, as shown functionally by the inactivity of a transfected Cp promoter-luciferase construct and by the failure of HIF-1 to bind the Cp HRE in nuclear extracts from these cells. These results are consistent with in vivo findings that iron deficiency increases plasma Cp and provides a molecular mechanism that may help to understand these

Iron deficiency in female pattern hair loss, chronic telogen effluvium, and control groups.

PubMed

Olsen, Elise A; Reed, Katherine B; Cacchio, Patrick B; Caudill, Leslie

2010-12-01

The literature suggests that iron deficiency (ID) may play a role in female pattern hair loss (FPHL) or in chronic telogen effluvium (CTE). We sought to determine if ID is more common in women with FPHL and/or CTE than in control subjects without hair loss. This was a controlled study of 381 Caucasian women aged 18 years or older with FPHL or CTE seen in the Duke University Hair Disorders Clinic, Durham, NC, and 76 Caucasian women aged 18 years or older from the university environs who had no history or physical findings of hair loss (control subjects). All participants had to have at least a serum ferritin and hemoglobin reading and history of menopausal status. When ferritin less than or equal to 15 μg/L was used as the definition, ID occurred in 12.4%, 12.1%, and 29.8% of premenopausal women with FPHL (n = 170), CTE (n = 58), and control subjects (n = 47), respectively, and in 1.7%, 10.5%, and 6.9% of postmenopausal women with FPHL (n = 115), CTE (n = 38), and control subjects (n = 29), respectively. When ferritin less than or equal to 40 μg/L was used as the definition, ID occurred in 58.8%, 63.8%, and 72.3% of premenopausal women with FPHL, CTE, and control subjects, respectively, and in 26.1%, 36.8%, and 20.7% of postmenopausal women with FPHL, CTE, and control subjects, respectively. There was no statistically significant increase in the incidence of ID in premenopausal or postmenopausal women with FPHL or CTE versus control subjects. The effect of correction of ID on hair loss is unknown. ID is common in women but not increased in patients with FPHL or CTE compared with control subjects. Copyright © 2010 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

Inpatient iron deficiency detection and management: how do general physicians and gastroenterologists perform in a tertiary care hospital?

PubMed

Fazal, Muhammad W; Andrews, Jane M; Thomas, Josephine; Saffouri, Eliana

2017-08-01

Iron deficiency (ID) is often an indicator of underlying pathology. Early detection and treatment avoids long-term morbidity and allows for prompt iron repletion, avoiding ID anaemia (IDA) and the need for blood transfusion. To evaluate the management of ID in two internal medicine units (general medical (GM) and gastroenterology (GE)) in a large metropolitan hospital and compare it to international guidelines. All consecutive inpatient admissions in the GM and GE units were retrospectively reviewed until 40 patients in each service were identified with anaemia and/or microcytic hypochromic blood counts. Patient records and electronic discharge summaries were then reviewed to assess the recognition, investigation and management of these abnormalities. Overall, only 60% (48/80) of the cases of microcytic hypochromic picture and/or anaemia were recognised. Cases were more likely to be detected under the GE unit, 77.5% (31/40) versus 42% (17/40) in GM (P < 0.002). Of the 31 recognised GE cases, 28 (90%) were investigated further with iron studies and/or endoscopic procedures. ID was confirmed in nearly half (5/11) of those tested; however, only 2 of 5 received iron replacement. Among GM patients, only 11 of the 17 recognised cases (64%) were investigated further. Iron studies were performed in all 11, confirming IDA in 4 (36%), all of whom received intravenous iron. A faecal human haemoglobin test was performed in two GM patients and one GE patient. There remains significant room for improvement in the recognition, investigation and management of ID in hospital practice in Australia. © 2017 Royal Australasian College of Physicians.

Biofortification of riboflavin and folate in idli batter, based on fermented cereal and pulse, by Lactococcus lactis N8 and Saccharomyces boulardii SAA655.

PubMed

Chandrasekar Rajendran, S C; Chamlagain, B; Kariluoto, S; Piironen, V; Saris, P E J

2017-06-01

Lactococcus lactis N8 and Saccharomyces boulardii SAA655 were investigated for their ability to synthesize B-vitamins (riboflavin and folate) and their functional role as microbial starters in idli fermentation. In this study, ultra-high performance liquid chromatography and microbiological assay were used to determine the total riboflavin and folate content respectively. Increased levels of folate were evident in both L. lactis N8 and S. boulardii SAA655 cultivated medium. Enhanced riboflavin levels were found only in S. boulardii SAA655 grown medium, whereas decreased riboflavin level was found in L. lactis N8 cultivated medium. To evaluate the functional role of microbial starter strains, L. lactis N8 and S. boulardii SAA655 were incorporated individually and in combination into idli batter, composed of wet grounded rice and black gram. For the experiments, naturally fermented idli batter was considered as control. The results indicated that natural idli fermentation did not enhance the riboflavin level and depleted folate levels by half. In comparison with control, L. lactis N8 and S. boulardii SAA655 incorporated idli batter (individually and in combination) increased riboflavin and folate levels by 40-90%. Apart from compensating the folate loss caused by natural fermentation, S. boulardii SAA655 fermented idli batter individually and in combination with L. lactis N8 also showed the highest leavening character. Moreover, the microbial starter incorporation did not significantly influence the pH of idli batter. Incorporation of L. lactis N8 and S. boulardii SAA655 can evidently enhance the functional and technological characteristics of idli batter. UN General Assembly declared 2016 the International Year of pulses emphasizing the importance of legumes as staple food. Furthermore, this is the first experimental report of in situ biofortifcation of riboflavin and folate using microbes in pulse based fermented staple food. The current study suggests possible

Toward operation of series IDs at BL43LXU of SPring-8

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

Baron, A. Q. R.; Tanaka, T.; Soutome, K.

2016-07-27

This paper discusses two issues relating to using 3 small gap insertion devices in series at BL43LXU of SPring-8 to make a uniquely powerful source in the 15-26 keV region of the x-ray spectrum. The issues discussed are (1) damage to the covers of the downstream IDs by radiation from the upstream IDs and (2) proper steering of the electron beam to get the best photon beam properties. After tests in several configurations, including one where an ID was run without an impedance-reducing cover, the damage issue was solved by installing a distributed absorber in the most downstream ID. Themore » steering issues were mostly resolved by the introduction of appropriate corrector magnets and feedback. The paper is written from the viewpoint of an interested beamline scientist impressed with the cooperation of different groups to make a source for new science possible.« less

alpha-L-iduronidase, beta-D-glucuronidase, and 2-sulfo-L-iduronate 2-sulfatase: preparation and characterization of radioactive substrates from heparin.

PubMed

Hopwood, J J

1979-03-01

Radioactive disaccharide substrates for alpha-L-iduronidase, beta-D-glucuronidase, and 2-sulfo-L-iduronate 2-sulfatase have been prepared from heparin by deaminative cleavage followed by reduction with NaBT4. Six disaccharides were isolated from this reaction mixture and identified. Acid hydrolysis of the major disaccharide, O-(alpha-L-idopyranosyluronic acid 2-sulfate)-(1 linked to 4)-(2,5-anhydro-D-mannitol-l-t 6-sulfate (IdAs--Ms), produced 48% of O-(alpha-L-idopyranosyluronic acid)-(1 linked to 4)-(2,5-anhydro-D-mannitol-l-t 6-sulfate) (IdA--Ms) and 25% of O-(alpha-L-idopyranosyluronic acid)-(1 linked to 4)-2,5-anhydro-D-mannitol-l-t. The most-sensitive substrate for determining alpha-L-iduronidase activity was IdA--Ms which, when incubated with leucocyte and skin-fibroblast homogenates prepared from patients having a deficiency of alpha-L-iduronidase (Mucopolysaccharidosis Type I; MPS-I), was hydrolysed to yield 2,5-anhydro-D-mannitol-l-t 6-sulfate at a rate 50-times less than that found for normal control-preparations. Similarly, O-(beta-D-glucopyranosyluronic acid)-(1 linked to 4)-(2,5-anhydro-D-mannitol-l-t 6-sulfate) was degraded by whole-cell homogenates prepared from beta-D-glucuronidase-deficient (Mucopolysaccharidosis, Type VII) fibroblasts, to yield 2,5-anhydro-D-mannitol-l-t 5-sulfate at a rate 60-times less that that found for MPS-I and normal control-preparations. IdAs--Ms was degraded by 2-sulfo-L-iduronate 2-sulfatase at a rate more than 45-times greater than that found for O-(alpha-L-idopyranosyluronic acid 2-sulfate)-(1 linked to 4)-2,5-anhydro-D-mannitol-l-t. C-6 Sulfation of the anhydro-D-mannitol-l-t residue is an important structural determinant in the mechanism of action of both alpha-L-iduronidase and 2-sulfo-L-iduronate 2-sulfatase on disaccharide substrates.

Microbe-ID: an open source toolbox for microbial genotyping and species identification

PubMed Central

Tabima, Javier F.; Everhart, Sydney E.; Larsen, Meredith M.; Weisberg, Alexandra J.; Kamvar, Zhian N.; Tancos, Matthew A.; Smart, Christine D.; Chang, Jeff H.

2016-01-01

Development of tools to identify species, genotypes, or novel strains of invasive organisms is critical for monitoring emergence and implementing rapid response measures. Molecular markers, although critical to identifying species or genotypes, require bioinformatic tools for analysis. However, user-friendly analytical tools for fast identification are not readily available. To address this need, we created a web-based set of applications called Microbe-ID that allow for customizing a toolbox for rapid species identification and strain genotyping using any genetic markers of choice. Two components of Microbe-ID, named Sequence-ID and Genotype-ID, implement species and genotype identification, respectively. Sequence-ID allows identification of species by using BLAST to query sequences for any locus of interest against a custom reference sequence database. Genotype-ID allows placement of an unknown multilocus marker in either a minimum spanning network or dendrogram with bootstrap support from a user-created reference database. Microbe-ID can be used for identification of any organism based on nucleotide sequences or any molecular marker type and several examples are provided. We created a public website for demonstration purposes called Microbe-ID (microbe-id.org) and provided a working implementation for the genus Phytophthora (phytophthora-id.org). In Phytophthora-ID, the Sequence-ID application allows identification based on ITS or cox spacer sequences. Genotype-ID groups individuals into clonal lineages based on simple sequence repeat (SSR) markers for the two invasive plant pathogen species P. infestans and P. ramorum. All code is open source and available on github and CRAN. Instructions for installation and use are provided at https://github.com/grunwaldlab/Microbe-ID. PMID:27602267

Microbe-ID: an open source toolbox for microbial genotyping and species identification.

PubMed

Tabima, Javier F; Everhart, Sydney E; Larsen, Meredith M; Weisberg, Alexandra J; Kamvar, Zhian N; Tancos, Matthew A; Smart, Christine D; Chang, Jeff H; Grünwald, Niklaus J

2016-01-01

Development of tools to identify species, genotypes, or novel strains of invasive organisms is critical for monitoring emergence and implementing rapid response measures. Molecular markers, although critical to identifying species or genotypes, require bioinformatic tools for analysis. However, user-friendly analytical tools for fast identification are not readily available. To address this need, we created a web-based set of applications called Microbe-ID that allow for customizing a toolbox for rapid species identification and strain genotyping using any genetic markers of choice. Two components of Microbe-ID, named Sequence-ID and Genotype-ID, implement species and genotype identification, respectively. Sequence-ID allows identification of species by using BLAST to query sequences for any locus of interest against a custom reference sequence database. Genotype-ID allows placement of an unknown multilocus marker in either a minimum spanning network or dendrogram with bootstrap support from a user-created reference database. Microbe-ID can be used for identification of any organism based on nucleotide sequences or any molecular marker type and several examples are provided. We created a public website for demonstration purposes called Microbe-ID (microbe-id.org) and provided a working implementation for the genus Phytophthora (phytophthora-id.org). In Phytophthora-ID, the Sequence-ID application allows identification based on ITS or cox spacer sequences. Genotype-ID groups individuals into clonal lineages based on simple sequence repeat (SSR) markers for the two invasive plant pathogen species P. infestans and P. ramorum. All code is open source and available on github and CRAN. Instructions for installation and use are provided at https://github.com/grunwaldlab/Microbe-ID.

Security analysis for biometric data in ID documents

NASA Astrophysics Data System (ADS)

Schimke, Sascha; Kiltz, Stefan; Vielhauer, Claus; Kalker, Ton

2005-03-01

In this paper we analyze chances and challenges with respect to the security of using biometrics in ID documents. We identify goals for ID documents, set by national and international authorities, and discuss the degree of security, which is obtainable with the inclusion of biometric into documents like passports. Starting from classical techniques for manual authentication of ID card holders, we expand our view towards automatic methods based on biometrics. We do so by reviewing different human biometric attributes by modality, as well as by discussing possible techniques for storing and handling the particular biometric data on the document. Further, we explore possible vulnerabilities of potential biometric passport systems. Based on the findings of that discussion we will expand upon two exemplary approaches for including digital biometric data in the context of ID documents and present potential risks attack scenarios along with technical aspects such as capacity and robustness.

2'-5' Oligoadenylate synthetase-like 1 (OASL1) deficiency in mice promotes an effective anti-tumor immune response by enhancing the production of type I interferons.

PubMed

Sim, Chan Kyu; Cho, Yeon Sook; Kim, Byung Soo; Baek, In-Jeoung; Kim, Young-Joon; Lee, Myeong Sup

2016-06-01

Type I interferon (IFN-I) plays a critical role in antiviral and antitumor defense. In our previous studies, we showed that IFN-I-inducible 2'-5' oligoadenylate synthetase-like 1 (OASL1) negatively regulates IFN-I production upon viral infection by specifically inhibiting translation of the IFN-I-regulating master transcription factor, interferon regulatory factor 7 (IRF7). In this study, we investigated whether OASL1 plays a negative role in the anti-tumor immune response by using OASL1-deficient (Oasl1 (-/-)) mice and transplantable syngeneic tumor cell models. We found that Oasl1 (-/-) mice demonstrate enhanced resistance to lung metastatic tumors and subcutaneously implanted tumors compared to wild-type (WT) mice. Additionally, we found that cytotoxic effector cells such as CD8(+) T cells (including tumor antigen-specific CD8(+) T cells) and NK cells as well as CD8α(+) DCs (the major antigen cross-presenting cells) were much more frequent (>fivefold) in the Oasl1 (-/-) mouse tumors. Furthermore, the cytotoxic effector cells in Oasl1 (-/-) mouse tumors seemed to be more functionally active. However, the proportion of immunosuppressive myeloid-derived suppressor cells within hematopoietic cells and of regulatory T cells within CD4(+) T cells in Oasl1 (-/-) mouse tumors did not differ significantly from that of WT mice. Tumor-challenged Oasl1 (-/-) mice expressed increased levels of IFN-I and IRF7 protein in the growing tumor, indicating that the enhanced antitumor immune response observed in Oasl1 (-/-) mice was caused by higher IFN-I production in Oasl1 (-/-) mice. Collectively, these results show that OASL1 deficiency promotes the antitumor immune response, and thus, OASL1 could be a good therapeutic target for treating tumors.

Comparison of Perinatal Risk Factors Associated with Autism Spectrum Disorder (ASD), Intellectual Disability (ID), and Co-Occurring ASD and ID

ERIC Educational Resources Information Center

Schieve, Laura A.; Clayton, Heather B.; Durkin, Maureen S.; Wingate, Martha S.; Drews-Botsch, Carolyn

2015-01-01

While studies report associations between perinatal outcomes and both autism spectrum disorder (ASD) and intellectual disability (ID), there has been little study of ASD with versus without co-occurring ID. We compared perinatal risk factors among 7547 children in the 2006-2010 Autism and Developmental Disability Monitoring Network classified as…

Biolog(TM) ID as compared to 16S ribosomal RNA ID for environmental isolates from the deep subsurface

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

McKinsey, P.C.

2000-05-05

The U.S. Dept of Energy (DOE) Subsurface Microbial Culture Collection (SMCC) contains nearly 10,000 strains of microorganisms isolated from terrestrial subsurface environments. Many of the aerobic, gram-negative, chemoheterotrophs isolated from the DOE Savannah River Site (SRS) have previously been identified by phylogenetic analysis of 16S ribosomal RNA (rRNA) gene nucleotide sequences. These SMCC isolates are currently being examined using Biolog GN Microplates and the Biolog Microstation System in order to gain knowledge of their metabolic capabilities and to compare Biolog IDs with 16S IDs. To accommodate the particular needs of these subsurface isolates, which are often incapable of growing undermore » high-nutrient conditions, Biolog's recommendations for inoculating isolates into Biolog GN Microplates have been altered. The isolates are grown on low nutrient media, sodium thioglycolate (3mM) is added to the culture media to inhibit capsule formation, and a low density of bacteria is inoculated into the microplate. Using these altered inoculation criteria, 60 percent of these SMCC isolates have a Biolog genus ID that matches the 16S rRNA ID. These results indicate that the Biolog System can be a good means of identifying unusual environmental isolates, even when recommended inoculation procedures are altered to accommodate particular isolate needs.« less

Vitamin D deficiency contributes directly to the acute respiratory distress syndrome (ARDS).

PubMed

Dancer, Rachel C A; Parekh, Dhruv; Lax, Sian; D'Souza, Vijay; Zheng, Shengxing; Bassford, Chris R; Park, Daniel; Bartis, D G; Mahida, Rahul; Turner, Alice M; Sapey, Elizabeth; Wei, Wenbin; Naidu, Babu; Stewart, Paul M; Fraser, William D; Christopher, Kenneth B; Cooper, Mark S; Gao, Fang; Sansom, David M; Martineau, Adrian R; Perkins, Gavin D; Thickett, David R

2015-07-01

Vitamin D deficiency has been implicated as a pathogenic factor in sepsis and intensive therapy unit mortality but has not been assessed as a risk factor for acute respiratory distress syndrome (ARDS). Causality of these associations has never been demonstrated. To determine if ARDS is associated with vitamin D deficiency in a clinical setting and to determine if vitamin D deficiency in experimental models of ARDS influences its severity. Human, murine and in vitro primary alveolar epithelial cell work were included in this study. Vitamin D deficiency (plasma 25(OH)D levels <50 nmol/L) was ubiquitous in patients with ARDS and present in the vast majority of patients at risk of developing ARDS following oesophagectomy. In a murine model of intratracheal lipopolysaccharide challenge, dietary-induced vitamin D deficiency resulted in exaggerated alveolar inflammation, epithelial damage and hypoxia. In vitro, vitamin D has trophic effects on primary human alveolar epithelial cells affecting >600 genes. In a clinical setting, pharmacological repletion of vitamin D prior to oesophagectomy reduced the observed changes of in vivo measurements of alveolar capillary damage seen in deficient patients. Vitamin D deficiency is common in people who develop ARDS. This deficiency of vitamin D appears to contribute to the development of the condition, and approaches to correct vitamin D deficiency in patients at risk of ARDS should be developed. UKCRN ID 11994. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Thioredoxin Reductase 2 (TXNRD2) mutation associated with familial glucocorticoid deficiency (FGD).

PubMed

Prasad, Rathi; Chan, Li F; Hughes, Claire R; Kaski, Juan P; Kowalczyk, Julia C; Savage, Martin O; Peters, Catherine J; Nathwani, Nisha; Clark, Adrian J L; Storr, Helen L; Metherell, Louise A

2014-08-01

Classic ACTH resistance, due to disruption of ACTH signaling, accounts for the majority of cases of familial glucocorticoid deficiency (FGD). Recently FGD cases caused by mutations in the mitochondrial antioxidant, nicotinamide nucleotide transhydrogenase, have highlighted the importance of redox regulation in steroidogenesis. We hypothesized that other components of mitochondrial antioxidant systems would be good candidates in the etiology of FGD. Whole-exome sequencing was performed on three related patients, and segregation of putative causal variants confirmed by Sanger sequencing of all family members. A TXNRD2-knockdown H295R cell line was created to investigate redox homeostasis. The study was conducted on patients from three pediatric centers in the United Kingdom. Seven individuals from a consanguineous Kashmiri kindred, six of whom presented with FGD between 0.1 and 10.8 years, participated in the study. There were no interventions. Identification and functional interrogation of a novel homozygous mutation segregating with the disease trait were measured. A stop gain mutation, p.Y447X in TXNRD2, encoding the mitochondrial selenoprotein thioredoxin reductase 2 (TXNRD2) was identified and segregated with disease in this extended kindred. RT-PCR and Western blotting revealed complete absence of TXNRD2 in patients homozygous for the mutation. TXNRD2 deficiency leads to impaired redox homeostasis in a human adrenocortical cell line. In contrast to the Txnrd2-knockout mouse model, in which embryonic lethality as a consequence of hematopoietic and cardiac defects is described, absence of TXNRD2 in humans leads to glucocorticoid deficiency. This is the first report of a homozygous mutation in any component of the thioredoxin antioxidant system leading to inherited disease in humans.

Crybb2 deficiency impairs fertility in female mice

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

Gao, Qian; Sun, Li-Li; Department of Laboratory Diagnosis, Changhai Hospital, Second Military Medical University, Shanghai 200433

Highlights: • Crybb2 deletion impaired female fertility. • Crybb2 deletion dramatically affected the production of reproduction-related hormones and hormone response. • Crybb2 deletion impaired follicular development and inhibited the proliferation of granulosa cells. • Crybb2 deletion promoted follicular atresia and apoptosis in granulosa cells. - Abstract: Beta-B2-crystallin (CRYBB2), encoded by Crybb2 gene, is a major protein in the mammalian eye lens that plays an important role in maintaining the transparency of the ocular lens. However, CRYBB2 also plays important roles in many extra-lenticular tissues and organs such as the retina, brain and testis. Our previous studies demonstrated that male Crybb2more » deficient (Crybb2{sup −/−}) mice have reduced fertility compared with wild-type (WT) mice, while female Crybb2{sup −/−} mice exhibited reduced ovary weights and shorter estrous cycle percentages. Here we specifically investigated the role of CRYBB2 in the female reproductive system. Our studies revealed that ovaries from female Crybb2{sup −/−} mice exhibited significantly reduced numbers of primordial, secondary and pre-ovulatory follicles when compared with WT mice, while the rate of atretic follicles was also increased. Additionally, fewer eggs were collected from the oviduct of Crybb2{sup −/−} female mice after superovulation. Estrogen levels were higher in the metestrus and diestrus cycles of female Crybb2{sup −/−} mice, while progesterone levels were lower in diestrus cycles. Furthermore, the expression of survival and cell cycle genes, Bcl-2, Cdk4 and Ccnd2, were significantly decreased in granulosa cells isolated from female Crybb2{sup −/−} mice, consistent with the predominant expression of CRYBB2 in ovarian granulosa cells. Our results reveal a critical role for CRYBB2 in female fertility and specific effects on the proliferation and survival status of ovarian granulosa cells.« less

Plasticity of DNA methylation and gene expression under zinc deficiency in Arabidopsis roots.

PubMed

Chen, Xiaochao; Schönberger, Brigitte; Menz, Jochen; Ludewig, Uwe

2018-05-25

DNA methylation is a heritable chromatin modification that maintains chromosome stability, regulates transposon silencing and appears to be involved in gene expression in response to environmental conditions. Environmental stress alters DNA methylation patterns that are correlated with gene expression differences. Here, genome-wide differential DNA-methylation was identified upon prolonged Zn deficiency, leading to hypo- and hyper-methylated chromosomal regions. Preferential CpG methylation changes occurred in gene promoters and gene bodies, but did not overlap with transcriptional start sites. Methylation changes were also prominent in transposable elements. By contrast, non-CG methylation differences were exclusively found in promoters of protein coding genes and in transposable elements. Strongly Zn deficiency-induced genes and their promoters were mostly non-methylated, irrespective of Zn supply. Differential DNA methylation in the CpG and CHG, but not in the CHH context, was found close to a few up-regulated Zn-deficiency genes. However, the transcriptional Zn-deficiency response in roots appeared little correlated with associated DNA methylation changes in promoters or gene bodies. Furthermore, under Zn deficiency, developmental defects were identified in an Arabidopsis mutant lacking non-CpG methylation. The root methylome thus responds specifically to a micro-nutrient deficiency and is important for efficient Zn utilization at low availability, but the relationship of differential methylation and differentially expressed genes is surprisingly poor.

The Recombinant Inhibitor of DNA Binding Id2 Forms Multimeric Structures via the Helix-Loop-Helix Domain and the Nuclear Export Signal.

PubMed

Roschger, Cornelia; Schubert, Mario; Regl, Christof; Andosch, Ancuela; Marquez, Augusto; Berger, Thomas; Huber, Christian G; Lütz-Meindl, Ursula; Cabrele, Chiara

2018-04-07

The inhibitor of DNA binding and cell differentiation 2 (Id2) is a helix-loop-helix (HLH) protein that acts as negative dominant regulator of basic-HLH transcription factors during development and in cancer. The structural properties of Id2 have been investigated so far by using synthetic or recombinant fragments reproducing single domains (N-terminus, HLH, C-terminus): the HLH domain tends to dimerize into a four-helix bundle, whereas the flanking regions are flexible. In this work, the intact protein was expressed in E. coli , solubilized from inclusion bodies with urea, purified and dissolved in water at pH~4. Under these conditions, Id2 was obtained with both cysteine residues disulfide-bonded to β-mercaptoethanol that was present during the solubilization process. Moreover, it existed in a self-assembled state, in which the N-terminus remained highly flexible, while the HLH domain and, surprisingly, part of the C-terminus, which corresponds to the nuclear export signal (NES), both were involved in slowly tumbling, rigid structures. The protein oligomers also formed twisted fibrils that were several micrometers long and up to 80 nm thick. These results show that self-assembly decreases the backbone flexibility of those two protein regions (HLH and NES) that are important for interaction with basic-HLH transcription factors or for nucleocytoplasmic shuttling.

The evolution of cellular deficiency in GATA2 mutation

PubMed Central

Dickinson, Rachel E.; Milne, Paul; Jardine, Laura; Zandi, Sasan; Swierczek, Sabina I.; McGovern, Naomi; Cookson, Sharon; Ferozepurwalla, Zaveyna; Langridge, Alexander; Pagan, Sarah; Gennery, Andrew; Heiskanen-Kosma, Tarja; Hämäläinen, Sari; Seppänen, Mikko; Helbert, Matthew; Tholouli, Eleni; Gambineri, Eleonora; Reykdal, Sigrún; Gottfreðsson, Magnús; Thaventhiran, James E.; Morris, Emma; Hirschfield, Gideon; Richter, Alex G.; Jolles, Stephen; Bacon, Chris M.; Hambleton, Sophie; Haniffa, Muzlifah; Bryceson, Yenan; Allen, Carl; Prchal, Josef T.; Dick, John E.; Bigley, Venetia

2014-01-01

Constitutive heterozygous GATA2 mutation is associated with deafness, lymphedema, mononuclear cytopenias, infection, myelodysplasia (MDS), and acute myeloid leukemia. In this study, we describe a cross-sectional analysis of 24 patients and 6 relatives with 14 different frameshift or substitution mutations of GATA2. A pattern of dendritic cell, monocyte, B, and natural killer (NK) lymphoid deficiency (DCML deficiency) with elevated Fms-like tyrosine kinase 3 ligand (Flt3L) was observed in all 20 patients phenotyped, including patients with Emberger syndrome, monocytopenia with Mycobacterium avium complex (MonoMAC), and MDS. Four unaffected relatives had a normal phenotype indicating that cellular deficiency may evolve over time or is incompletely penetrant, while 2 developed subclinical cytopenias or elevated Flt3L. Patients with GATA2 mutation maintained higher hemoglobin, neutrophils, and platelets and were younger than controls with acquired MDS and wild-type GATA2. Frameshift mutations were associated with earlier age of clinical presentation than substitution mutations. Elevated Flt3L, loss of bone marrow progenitors, and clonal myelopoiesis were early signs of disease evolution. Clinical progression was associated with increasingly elevated Flt3L, depletion of transitional B cells, CD56bright NK cells, naïve T cells, and accumulation of terminally differentiated NK and CD8+ memory T cells. These studies provide a framework for clinical and laboratory monitoring of patients with GATA2 mutation and may inform therapeutic decision-making. PMID:24345756

ID'ing innate and innate-like lymphoid cells.

PubMed

Verykokakis, Mihalis; Zook, Erin C; Kee, Barbara L

2014-09-01

The immune system can be divided into innate and adaptive components that differ in their rate and mode of cellular activation, with innate immune cells being the first responders to invading pathogens. Recent advances in the identification and characterization of innate lymphoid cells have revealed reiterative developmental programs that result in cells with effector fates that parallel those of adaptive lymphoid cells and are tailored to effectively eliminate a broad spectrum of pathogenic challenges. However, activation of these cells can also be associated with pathologies such as autoimmune disease. One major distinction between innate and adaptive immune system cells is the constitutive expression of ID proteins in the former and inducible expression in the latter. ID proteins function as antagonists of the E protein transcription factors that play critical roles in lymphoid specification as well as B- and T-lymphocyte development. In this review, we examine the transcriptional mechanisms controlling the development of innate lymphocytes, including natural killer cells and the recently identified innate lymphoid cells (ILC1, ILC2, and ILC3), and innate-like lymphocytes, including natural killer T cells, with an emphasis on the known requirements for the ID proteins. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Novel ID-based anti-collision approach for RFID

NASA Astrophysics Data System (ADS)

Zhang, De-Gan; Li, Wen-Bin

2016-09-01

Novel correlation ID-based (CID) anti-collision approach for RFID under the banner of the Internet of Things (IOT) has been presented in this paper. The key insights are as follows: according to the deterministic algorithms which are based on the binary search tree, we propose a method to increase the association between tags so that tags can initiatively send their own ID under certain trigger conditions, at the same time, we present a multi-tree search method for querying. When the number of tags is small, by replacing the actual ID with the temporary ID, it can greatly reduce the number of times that the reader reads and writes to tag's ID. Active tags send data to the reader by the way of modulation binary pulses. When applying this method to the uncertain ALOHA algorithms, the reader can determine the locations of the empty slots according to the position of the binary pulse, so it can avoid the decrease in efficiency which is caused by reading empty slots when reading slots. Theory and experiment show that this method can greatly improve the recognition efficiency of the system when applied to either the search tree or the ALOHA anti-collision algorithms.

Clinical management of iron deficiency anemia in adults: Systemic review on advances in diagnosis and treatment.

PubMed

De Franceschi, Lucia; Iolascon, Achille; Taher, Ali; Cappellini, Maria Domenica

2017-07-01

Global burden disease studies point out that one of the top cause-specific anemias is iron deficiency (ID). Recent advances in knowledge of iron homeostasis have shown that fragile patients are a new target population in which the correction of ID might impact their morbidity, mortality and quality of life. We did a systematic review using specific search strategy, carried out the review of PubMed database, Cochrane Database of systemic reviews and international guidelines on diagnosis and clinical management of ID from 2010 to 2016. The International guidelines were limited to those with peer-review process and published in journal present in citation index database. The eligible studies show that serum ferritin and transferrin saturation are the key tests in early decision-making process to identify iron deficiency anemia (IDA). The clinician has to carefully consider fragile and high-risk subset of patients such as elders or individuals with chronic diseases (i.e chronic kidney disease, inflammatory bowel disease, chronic heart failure). Treatment is based on iron supplementation. Infusion route should be preferentially considered in frail patients especially in the view of new iron available formulations. The available evidences indicate that (i) recurrent IDA should always be investigated, considering uncommon causes; (ii) IDA might worse the performance and the clinical outcome of fragile and high-risk patients and require an intensive treatment. Copyright © 2017 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

Mitochondrial PKC-ε deficiency promotes I/R-mediated myocardial injury via GSK3β-dependent mitochondrial permeability transition pore opening.

PubMed

Wang, Shijun; Zhang, Feng; Zhao, Gang; Cheng, Yong; Wu, Ting; Wu, Bing; Zhang, You-En

2017-09-01

Mitochondrial fission is critically involved in cardiomyocyte apoptosis, which has been considered as one of the leading causes of ischaemia/reperfusion (I/R)-induced myocardial injury. In our previous works, we demonstrate that aldehyde dehydrogenase-2 (ALDH2) deficiency aggravates cardiomyocyte apoptosis and cardiac dysfunction. The aim of this study was to elucidate whether ALDH2 deficiency promotes mitochondrial injury and cardiomyocyte death in response to I/R stress and the underlying mechanism. I/R injury was induced by aortic cross-clamping for 45 min. followed by unclamping for 24 hrs in ALDH2 knockout (ALDH2 -/- ) and wild-type (WT) mice. Then myocardial infarct size, cell apoptosis and cardiac function were examined. The protein kinase C (PKC) isoform expressions and their mitochondrial translocation, the activity of dynamin-related protein 1 (Drp1), caspase9 and caspase3 were determined by Western blot. The effects of N-acetylcysteine (NAC) or PKC-δ shRNA treatment on glycogen synthase kinase-3β (GSK-3β) activity and mitochondrial permeability transition pore (mPTP) opening were also detected. The results showed that ALDH2 -/- mice exhibited increased myocardial infarct size and cardiomyocyte apoptosis, enhanced levels of cleaved caspase9, caspase3 and phosphorylated Drp1. Mitochondrial PKC-ε translocation was lower in ALDH2 -/- mice than in WT mice, and PKC-δ was the opposite. Further data showed that mitochondrial PKC isoform ratio was regulated by cellular reactive oxygen species (ROS) level, which could be reversed by NAC pre-treatment under I/R injury. In addition, PKC-ε inhibition caused activation of caspase9, caspase3 and Drp1Ser 616 in response to I/R stress. Importantly, expression of phosphorylated GSK-3β (inactive form) was lower in ALDH2 -/- mice than in WT mice, and both were increased by NAC pre-treatment. I/R-induced mitochondrial translocation of GSK-3β was inhibited by PKC-δ shRNA or NAC pre-treatment. In addition

Vitamin D deficiency is associated with type 2 diabetes mellitus in HIV infection.

PubMed

Szep, Zsofia; Guaraldi, Giovanni; Shah, Samir S; Lo Re, Vincent; Ratcliffe, Sarah J; Orlando, Gabriella; Carli, Federica; Rossi, Rosario; Rochira, Vincenzo; Tebas, Pablo

2011-02-20

Metabolic complications, including type 2 diabetes mellitus and metabolic syndrome, are increasingly recognized among HIV-infected individuals. Low vitamin D levels increase the risk of type 2 diabetes mellitus, and vitamin D supplementation has been shown to decrease the risk of type 2 diabetes mellitus in patients without HIV infection. The primary objective was to determine whether vitamin D deficiency (serum 25-hyrdoxyvitamin D <20 ng/ml) was associated with type 2 diabetes mellitus among HIV-infected patients. Our secondary objective was to determine whether vitamin D deficiency was associated with metabolic syndrome in HIV. We conducted a cross-sectional study among participants enrolled in the prospective Modena (Italy) HIV Metabolic Clinic Cohort. Clinical and laboratory data, including history of type 2 diabetes mellitus, fasting blood glucose, components of metabolic syndrome, and 25-hydroxyvitamin D levels, were obtained for all participants. After adjusting for vitamin D supplementation, sex, age, body mass index, and hepatitis C virus co-infection, vitamin D deficiency was associated with type 2 diabetes mellitus [adjusted odds ratio (OR) 1.85; 95% confidence interval (CI) 1.03-3.32; P = 0.038]. The association between vitamin D deficiency and metabolic syndrome was not significant after adjusting for vitamin D supplementation, sex, age and body mass index (adjusted OR 1.32; 95% CI 1.00-1.75; P = 0.053). Our study demonstrates an association between vitamin D deficiency and type 2 diabetes mellitus. Clinical trials are needed to better characterize the association between vitamin D deficiency and type 2 diabetes mellitus in HIV infection and to evaluate whether vitamin D is able to prevent or delay the onset of type 2 diabetes mellitus.

Increasing brain serotonin corrects CO2 chemosensitivity in methyl-CpG-binding protein 2 (Mecp2)-deficient mice

PubMed Central

Toward, Marie A.; Abdala, Ana P.; Knopp, Sharon J.; Paton, Julian F. R.; Bissonnette, John M.

2013-01-01

Mice deficient in the transcription factor methyl-CpG-binding protein 2 (Mecp2), a mouse model of Rett syndrome, display reduced CO2 chemosensitivity, which may contribute to their breathing abnormalities. In addition, patients with Rett syndrome and male mice that are null for Mecp2 show reduced levels of brain serotonin (5-HT). Serotonin is known to play a role in central chemosensitivity, and we hypothesized that increasing the availability of 5-HT in this mouse model would improve their respiratory response to CO2. Here we determined the apnoeic threshold in heterozygous Mecp2-deficient female mice and examined the effects of blocking 5-HT reuptake on the CO2 response in Mecp2-null male mice. Studies were performed in B6.129P2(C)-Mecp2τm1.1Bird null males and heterozygous females. In an in situ preparation, seven of eight Mecp2-deficient heterozygous females showed arrest of phrenic nerve activity when arterial CO2 was lowered to 3%, whereas the wild-types maintained phrenic nerve amplitude at 53 ± 3% of maximal. In vivo plethysmography studies were used to determine CO2 chemosensitivity in null males. These mice were exposed sequentially to 1, 3 and 5% CO2. The percentage increase in minute ventilation in response to increased inspired CO2 was less in Mecp2−/y than in Mecp2+/y mice. Pretreatment with citalopram, a selective 5-HT reuptake inhibitor (2.5 mg kg−1 I.P.), 40 min prior to CO2 exposure, in Mecp2−/y mice resulted in an improvement in CO2 chemosensitivity to wild-type levels. These results suggest that decreased 5-HT in Mecp2-deficient mice reduces CO2 chemosensitivity, and restoring 5-HT levels can reverse this effect. PMID:23180809

RB1 deficiency in triple-negative breast cancer induces mitochondrial protein translation.

PubMed

Jones, Robert A; Robinson, Tyler J; Liu, Jeff C; Shrestha, Mariusz; Voisin, Veronique; Ju, YoungJun; Chung, Philip E D; Pellecchia, Giovanna; Fell, Victoria L; Bae, SooIn; Muthuswamy, Lakshmi; Datti, Alessandro; Egan, Sean E; Jiang, Zhe; Leone, Gustavo; Bader, Gary D; Schimmer, Aaron; Zacksenhaus, Eldad

2016-10-03

Triple-negative breast cancer (TNBC) includes basal-like and claudin-low subtypes for which no specific treatment is currently available. Although the retinoblastoma tumor-suppressor gene (RB1) is frequently lost together with TP53 in TNBC, it is not directly targetable. There is thus great interest in identifying vulnerabilities downstream of RB1 that can be therapeutically exploited. Here, we determined that combined inactivation of murine Rb and p53 in diverse mammary epithelial cells induced claudin-low-like TNBC with Met, Birc2/3-Mmp13-Yap1, and Pvt1-Myc amplifications. Gene set enrichment analysis revealed that Rb/p53-deficient tumors showed elevated expression of the mitochondrial protein translation (MPT) gene pathway relative to tumors harboring p53 deletion alone. Accordingly, bioinformatic, functional, and biochemical analyses showed that RB1-E2F complexes bind to MPT gene promoters to regulate transcription and control MPT. Additionally, a screen of US Food and Drug Administration-approved (FDA-approved) drugs identified the MPT antagonist tigecycline (TIG) as a potent inhibitor of Rb/p53-deficient tumor cell proliferation. TIG preferentially suppressed RB1-deficient TNBC cell proliferation, targeted both the bulk and cancer stem cell fraction, and strongly attenuated xenograft growth. It also cooperated with sulfasalazine, an FDA-approved inhibitor of cystine xCT antiporter, in culture and xenograft assays. Our results suggest that RB1 deficiency promotes cancer cell proliferation in part by enhancing mitochondrial function and identify TIG as a clinically approved drug for RB1-deficient TNBC.

RB1 deficiency in triple-negative breast cancer induces mitochondrial protein translation

PubMed Central

Jones, Robert A.; Robinson, Tyler J.; Liu, Jeff C.; Shrestha, Mariusz; Voisin, Veronique; Ju, YoungJun; Chung, Philip E.D.; Pellecchia, Giovanna; Fell, Victoria L.; Bae, SooIn; Muthuswamy, Lakshmi; Egan, Sean E.; Jiang, Zhe; Leone, Gustavo; Bader, Gary D.; Schimmer, Aaron

2016-01-01

Triple-negative breast cancer (TNBC) includes basal-like and claudin-low subtypes for which no specific treatment is currently available. Although the retinoblastoma tumor-suppressor gene (RB1) is frequently lost together with TP53 in TNBC, it is not directly targetable. There is thus great interest in identifying vulnerabilities downstream of RB1 that can be therapeutically exploited. Here, we determined that combined inactivation of murine Rb and p53 in diverse mammary epithelial cells induced claudin-low–like TNBC with Met, Birc2/3-Mmp13-Yap1, and Pvt1-Myc amplifications. Gene set enrichment analysis revealed that Rb/p53-deficient tumors showed elevated expression of the mitochondrial protein translation (MPT) gene pathway relative to tumors harboring p53 deletion alone. Accordingly, bioinformatic, functional, and biochemical analyses showed that RB1-E2F complexes bind to MPT gene promoters to regulate transcription and control MPT. Additionally, a screen of US Food and Drug Administration–approved (FDA-approved) drugs identified the MPT antagonist tigecycline (TIG) as a potent inhibitor of Rb/p53-deficient tumor cell proliferation. TIG preferentially suppressed RB1-deficient TNBC cell proliferation, targeted both the bulk and cancer stem cell fraction, and strongly attenuated xenograft growth. It also cooperated with sulfasalazine, an FDA-approved inhibitor of cystine xCT antiporter, in culture and xenograft assays. Our results suggest that RB1 deficiency promotes cancer cell proliferation in part by enhancing mitochondrial function and identify TIG as a clinically approved drug for RB1-deficient TNBC. PMID:27571409

The incidence of gastrointestinal pathology and subsequent anemia in young men presenting with iron deficiency without anemia.

PubMed

Carter, Dan; Bardan, Eytan; Derazne, Estela; Tzur, Dorit; Avidan, Benjamin

2016-10-01

The etiology of iron deficiency (ID) without anemia in young men is unclear, and there are no evidence-based recommendations for the required gastrointestinal (GI) evaluation. The aims of this study were to examine the incidence of significant GI pathology and the development of anemia during the follow-up of young men presenting with ID, but without anemia. All young men (18-30 years) who served in the Israel Defense Forces during the years 2005-2013 and had at least a single laboratory test indicative of ID without anemia were followed until the diagnosis of significant GI pathology or discharge from military service. The study population included 2061 young men (mean age 20.7±1.8). During follow-up of 3150 person years, significant GI pathologies were diagnosed in 39 patients: inflammatory bowel disease in 25 (1.2%), celiac disease in 8 (0.4%), and peptic disease in 4 (0.1%). No cases of GI-related cancer were diagnosed. ID anemia developed during follow-up in 203 (9.8%). Lower baseline hemoglobin levels, lower ferritin levels, and younger age at diagnosis were more common among those who developed anemia. The development of anemia was a predisposing factor for the diagnosis of GI pathology (risk ratio=3.60, 95% confidence interval 1.34-8.32, P=0.012). Significant GI pathology is very uncommon in young men presenting with ID. Overt anemia developed in close to 10% of the study cohort. Therefore, we advise simple GI evaluation (celiac serology, C-reactive protein or fecal calprotectin, and urease breath test) as well as follow-up in this population.

Inhibitor of differentiation 1 transcription factor promotes metabolic reprogramming in hepatocellular carcinoma cells

PubMed Central

Sharma, Bal Krishan; Kolhe, Ravindra; Black, Stephen M.; Keller, Jonathan R.; Mivechi, Nahid F.; Satyanarayana, Ande

2016-01-01

Reprograming of metabolism is one of the central hallmarks of cancer. The majority of cancer cells depend on high rates of glycolysis and glutaminolysis for their growth and survival. A number of oncogenes and tumor suppressors have been connected to the regulation of altered glucose and glutamine metabolism in cancer cells. For example, the oncogene c-Myc plays vital roles in cancer cell metabolic adaptation by directly regulating various genes that participate in aerobic glycolysis and glutaminolysis. Inhibitor of differentiation 1 (Id1) is a helix-loop-helix transcription factor that plays important roles in cell proliferation, differentiation, and cell fate determination. Overexpression of Id1 causes intestinal adenomas and thymic lymphomas in mice, suggesting that Id1 could function as an oncogene. Despite it being an oncogene, whether Id1 plays any prominent role in cancer cell metabolic reprograming is unknown. Here, we demonstrate that Id1 is strongly expressed in human and mouse liver tumors and in hepatocellular carcinoma (HCC) cell lines, whereas its expression is very low or undetectable in normal liver tissues. In HCC cells, Id1 expression is regulated by the MAPK/ERK pathway at the transcriptional level. Knockdown of Id1 suppressed aerobic glycolysis and glutaminolysis, suggesting that Id1 promotes a metabolic shift toward aerobic glycolysis. At the molecular level, Id1 mediates its metabolic effects by regulating the expression levels of c-Myc. Knockdown of Id1 resulted in down-regulation (∼75%) of c-Myc, whereas overexpression of Id1 strongly induced (3-fold) c-Myc levels. Interestingly, knockdown of c-Myc resulted in down-regulation (∼60%) of Id1, suggesting a positive feedback-loop regulatory mechanism between Id1 and c-Myc. Under anaerobic conditions, both Id1 and c-Myc are down-regulated (50–70%), and overexpression of oxygen-insensitive hypoxia-inducible factor 1α (Hif1α) or its downstream target Mxi1 resulted in a significant reduction

Simultaneous occurrence of hereditary C6 and C2 deficiency in a French-Canadian family.

PubMed

Delâge, J M; Lehner-Netsch, G; Lafleur, R; Simard, J; Brun, G; Prochazka, E

1979-06-01

The sera of four sisters were found to lack the sixth component of complement (C6) and the serum of one was also partially deficient in the second component (C2). Two other blood relatives were found to be heterozygous for both deficiencies, while only one sibling had normal values. The father of these eight siblings was heterozygous for C2D and C6D and in the third generation, six children were heterozygous for C6 deficiency was treated for chronic active brucel-transmitted; the C6 deficiency was not linked to the HLA system, while the C2-deficiency segregated with the haplotype A10,B18. The proband, homozygous for C6 deficiency was treated for chronic active Brucellosis and in another sibling with C6 deficiency, toxoplasmosis was diagnosed. Neither bleeding disorders nor a tendency to collagen diseases have been observed and the opsonic activity was normal in the sera of all family members.

Simultaneous occurrence of hereditary C6 and C2 deficiency in a French-Canadian family.

PubMed Central

Delâge, J M; Lehner-Netsch, G; Lafleur, R; Simard, J; Brun, G; Prochazka, E

1979-01-01

The sera of four sisters were found to lack the sixth component of complement (C6) and the serum of one was also partially deficient in the second component (C2). Two other blood relatives were found to be heterozygous for both deficiencies, while only one sibling had normal values. The father of these eight siblings was heterozygous for C2D and C6D and in the third generation, six children were heterozygous for C6 deficiency was treated for chronic active brucel-transmitted; the C6 deficiency was not linked to the HLA system, while the C2-deficiency segregated with the haplotype A10,B18. The proband, homozygous for C6 deficiency was treated for chronic active Brucellosis and in another sibling with C6 deficiency, toxoplasmosis was diagnosed. Neither bleeding disorders nor a tendency to collagen diseases have been observed and the opsonic activity was normal in the sera of all family members. PMID:468307

Increased Ca2+ signaling through CaV1.2 promotes bone formation and prevents estrogen deficiency–induced bone loss

PubMed Central

Cao, Chike; Barnett, Adam S.; Mirando, Anthony J.; Rouse, Douglas; Mun, Se Hwan; Park-Min, Kyung-Hyun; McNulty, Amy L.; Karner, Courtney M.; Hilton, Matthew J.

2017-01-01

While the prevalence of osteoporosis is growing rapidly with population aging, therapeutic options remain limited. Here, we identify potentially novel roles for CaV1.2 L-type voltage–gated Ca2+ channels in osteogenesis and exploit a transgenic gain-of-function mutant CaV1.2 to stem bone loss in ovariectomized female mice. We show that endogenous CaV1.2 is expressed in developing bone within proliferating chondrocytes and osteoblasts. Using primary BM stromal cell (BMSC) cultures, we found that Ca2+ influx through CaV1.2 activates osteogenic transcriptional programs and promotes mineralization. We used Prx1-, Col2a1-, or Col1a1-Cre drivers to express an inactivation-deficient CaV1.2 mutant in chondrogenic and/or osteogenic precursors in vivo and found that the resulting increased Ca2+ influx markedly thickened bone not only by promoting osteogenesis, but also by inhibiting osteoclast activity through increased osteoprotegerin secretion from osteoblasts. Activating the CaV1.2 mutant in osteoblasts at the time of ovariectomy stemmed bone loss. Together, these data highlight roles for CaV1.2 in bone and demonstrate the potential dual anabolic and anticatabolic therapeutic actions of tissue-specific CaV1.2 activation in osteoblasts. PMID:29202453

Helicobacter pylori infection and low dietary iron alter behavior, induce iron deficiency anemia, and modulate hippocampal gene expression in female C57BL/6 mice

PubMed Central

Burns, Monika; Amaya, Aldo; Bodi, Caroline; Ge, Zhongming; Bakthavatchalu, Vasudevan; Ennis, Kathleen; Wang, Timothy C.; Georgieff, Michael

2017-01-01

Helicobacter pylori (H.pylori), a bacterial pathogen, is a causative agent of gastritis and peptic ulcer disease and is a strong risk factor for development of gastric cancer. Environmental conditions, such as poor dietary iron resulting in iron deficiency anemia (IDA), enhance H.pylori virulence and increases risk for gastric cancer. IDA affects billions of people worldwide, and there is considerable overlap between regions of high IDA and high H.pylori prevalence. The primary aims of our study were to evaluate the effect of H.pylori infection on behavior, iron metabolism, red blood cell indices, and behavioral outcomes following comorbid H. pylori infection and dietary iron deficiency in a mouse model. C57BL/6 female mice (n = 40) were used; half were placed on a moderately iron deficient (ID) diet immediately post-weaning, and the other half were maintained on an iron replete (IR) diet. Half were dosed with H.pylori SS1 at 5 weeks of age, and the remaining mice were sham-dosed. There were 4 study groups: a control group (-Hp, IR diet) as well as 3 experimental groups (-Hp, ID diet; +Hp, IR diet; +Hp,ID diet). All mice were tested in an open field apparatus at 8 weeks postinfection. Independent of dietary iron status, H.pylori -infected mice performed fewer exploratory behaviors in the open field chamber than uninfected mice (p<0.001). Hippocampal gene expression of myelination markers and dopamine receptor 1 was significantly downregulated in mice on an ID diet (both p<0.05), independent of infection status. At 12 months postinfection, hematocrit (Hct) and hemoglobin (Hgb) concentration were significantly lower in +Hp, ID diet mice compared to all other study groups. H.pylori infection caused IDA in mice maintained on a marginal iron diet. The mouse model developed in this study is a useful model to study the neurologic, behavioral, and hematologic impact of the common human co-morbidity of H. pylori infection and IDA. PMID:28355210

Triggering Receptor Expressed on Myeloid Cells 2 Deficiency Alters Acute Macrophage Distribution and Improves Recovery after Traumatic Brain Injury.

PubMed

Saber, Maha; Kokiko-Cochran, Olga; Puntambekar, Shweta S; Lathia, Justin D; Lamb, Bruce T

2017-01-15

Traumatic brain injury (TBI) affects 1.7 million persons annually in the United States (Centers for Disease Control and Prevention). There is increasing evidence that persons exposed to TBI have increased risk of the development of multiple neurodegenerative conditions, including Alzheimer disease (AD). TBI triggers a strong neuroinflammatory response characterized by astrogliosis, activation of microglia, and infiltration of peripheral monocytes. Recent evidence suggests that alterations in innate immunity promote neurodegeneration. This includes genetic studies demonstrating that mutations in triggering receptor expressed on myeloid cells 2 (TREM2) is associated with a higher risk for not only AD but also multiple neurodegenerative diseases. To examine whether TREM2 deficiency affects pathological outcomes of TBI, Trem2 knockout (Trem2 -/- ) and C57BL/6J (B6) mice were given a lateral fluid percussion injury (FPI) and sacrificed at 3 and 120 days post-injury (DPI) to look at both acute and chronic consequences of TREM2 deficiency. Notably, at 3 DPI, B6 mice exposed to TBI exhibited increased expression of TREM2 in the brain. Further, Trem2 -/- mice exposed to TBI exhibited enhanced macrophage activation near the lesion, but significantly less macrophage activation away from the lesion when compared with B6 mice exposed to TBI. In addition, at 120 DPI, Trem2 -/- mice exposed to TBI demonstrated reduced hippocampal atrophy and rescue of TBI-induced behavioral changes when compared with B6 mice exposed to TBI. Taken together, this study suggests that TREM2 deficiency influences both acute and chronic responses to TBI, leading to an altered macrophage response at early time points, and improved pathological and functional outcomes at later time points.

Replication and Comparison of the Newly Proposed ADOS-2, Module 4 Algorithm in ASD without ID: A Multi-site Study

PubMed Central

Pugliese, Cara E.; Kenworthy, Lauren; Bal, Vanessa Hus; Wallace, Gregory L; Yerys, Benjamin E; Maddox, Brenna B.; White, Susan W.; Popal, Haroon; Armour, Anna Chelsea; Miller, Judith; Herrington, John D.; Schultz, Robert T.; Martin, Alex; Anthony, Laura Gutermuth

2015-01-01

Recent updates have been proposed to the Autism Diagnostic Observation Schedule-2 Module 4 diagnostic algorithm. This new algorithm, however, has not yet been validated in an independent sample without intellectual disability (ID). This multi-site study compared the original and revised algorithms in individuals with ASD without ID. The revised algorithm demonstrated increased sensitivity, but lower specificity in the overall sample. Estimates were highest for females, individuals with a verbal IQ below 85 or above 115, and ages 16 and older. Best practice diagnostic procedures should include the Module 4 in conjunction with other assessment tools. Balancing needs for sensitivity and specificity depending on the purpose of assessment (e.g., clinical vs. research) and demographic characteristics mentioned above will enhance its utility. PMID:26385796

Replication and Comparison of the Newly Proposed ADOS-2, Module 4 Algorithm in ASD Without ID: A Multi-site Study.

PubMed

Pugliese, Cara E; Kenworthy, Lauren; Bal, Vanessa Hus; Wallace, Gregory L; Yerys, Benjamin E; Maddox, Brenna B; White, Susan W; Popal, Haroon; Armour, Anna Chelsea; Miller, Judith; Herrington, John D; Schultz, Robert T; Martin, Alex; Anthony, Laura Gutermuth

2015-12-01

Recent updates have been proposed to the Autism Diagnostic Observation Schedule-2 Module 4 diagnostic algorithm. This new algorithm, however, has not yet been validated in an independent sample without intellectual disability (ID). This multi-site study compared the original and revised algorithms in individuals with ASD without ID. The revised algorithm demonstrated increased sensitivity, but lower specificity in the overall sample. Estimates were highest for females, individuals with a verbal IQ below 85 or above 115, and ages 16 and older. Best practice diagnostic procedures should include the Module 4 in conjunction with other assessment tools. Balancing needs for sensitivity and specificity depending on the purpose of assessment (e.g., clinical vs. research) and demographic characteristics mentioned above will enhance its utility.

Inhibition of muscle-specific gene expression by Id3: requirement of the C-terminal region of the protein for stable expression and function.

PubMed

Chen, B; Han, B H; Sun, X H; Lim, R W

1997-01-15

We have examined the role of an Id-like protein, Id3 (also known as HLH462), in the regulation of muscle-specific gene expression. Id proteins are believed to block expression of muscle-specific genes by preventing the dimerization between ubiquitous bHLH proteins (E proteins) and myogenic bHLH proteins such as MyoD. Consistent with its putative role as an inhibitor of differentiation, Id3 mRNA was detected in proliferating skeletal muscle cells, was further induced by basic fibroblast growth factor (bFGF) and was down-regulated in differentiated muscle cultures. Overexpression of Id3 efficiently inhibited the MyoD-mediated activation of the muscle-specific creatine kinase (MCK) reporter gene. Deletion analysis indicated that the C-terminal 15 amino acids of Id3 are critical for the full inhibitory activity while deleting up to 42 residues from the C-terminus of the related protein, Id2, did not affect its ability to inhibit the MCK reporter gene. Chimeric protein containing the N-terminal region of Id3 and the C-terminus of Id2 was also non-functional in transfected cells. In contrast, wild-type Id3, the C-terminal mutants, and the Id3/Id2 chimera could all interact with the E-protein E47in vitro. Additional studies indicated that truncation of the Id3 C-terminus might have adversely affected the expression level of the mutant proteins but the Id3/Id2 chimera was stably expressed. Taken together, our results revealed a more complex requirement for the expression and proper function of the Id family proteins than was hitherto expected.

Inhibition of muscle-specific gene expression by Id3: requirement of the C-terminal region of the protein for stable expression and function.

PubMed Central

Chen, B; Han, B H; Sun, X H; Lim, R W

1997-01-01

We have examined the role of an Id-like protein, Id3 (also known as HLH462), in the regulation of muscle-specific gene expression. Id proteins are believed to block expression of muscle-specific genes by preventing the dimerization between ubiquitous bHLH proteins (E proteins) and myogenic bHLH proteins such as MyoD. Consistent with its putative role as an inhibitor of differentiation, Id3 mRNA was detected in proliferating skeletal muscle cells, was further induced by basic fibroblast growth factor (bFGF) and was down-regulated in differentiated muscle cultures. Overexpression of Id3 efficiently inhibited the MyoD-mediated activation of the muscle-specific creatine kinase (MCK) reporter gene. Deletion analysis indicated that the C-terminal 15 amino acids of Id3 are critical for the full inhibitory activity while deleting up to 42 residues from the C-terminus of the related protein, Id2, did not affect its ability to inhibit the MCK reporter gene. Chimeric protein containing the N-terminal region of Id3 and the C-terminus of Id2 was also non-functional in transfected cells. In contrast, wild-type Id3, the C-terminal mutants, and the Id3/Id2 chimera could all interact with the E-protein E47in vitro. Additional studies indicated that truncation of the Id3 C-terminus might have adversely affected the expression level of the mutant proteins but the Id3/Id2 chimera was stably expressed. Taken together, our results revealed a more complex requirement for the expression and proper function of the Id family proteins than was hitherto expected. PMID:9016574

Epigenetic repression of regulator of G-protein signaling 2 promotes androgen-independent prostate cancer cell growth.

PubMed

Wolff, Dennis W; Xie, Yan; Deng, Caishu; Gatalica, Zoran; Yang, Mingjie; Wang, Bo; Wang, Jincheng; Lin, Ming-Fong; Abel, Peter W; Tu, Yaping

2012-04-01

G-protein-coupled receptor (GPCR)-stimulated androgen-independent activation of androgen receptor (AR) contributes to acquisition of a hormone-refractory phenotype by prostate cancer. We previously reported that regulator of G-protein signaling (RGS) 2, an inhibitor of GPCRs, inhibits androgen-independent AR activation (Cao et al., Oncogene 2006;25:3719-34). Here, we show reduced RGS2 protein expression in human prostate cancer specimens compared to adjacent normal or hyperplastic tissue. Methylation-specific PCR analysis and bisulfite sequencing indicated that methylation of the CpG island in the RGS2 gene promoter correlated with RGS2 downregulation in prostate cancer. In vitro methylation of this promoter suppressed reporter gene expression in transient transfection studies, whereas reversal of this promoter methylation with 5-aza-2'-deoxycytidine (5-Aza-dC) induced RGS2 reexpression in androgen-independent prostate cancer cells and inhibited their growth under androgen-deficient conditions. Interestingly, the inhibitory effect of 5-Aza-dC was significantly reduced by an RGS2-targeted short hairpin RNA, indicating that reexpressed RGS2 contributed to this growth inhibition. Restoration of RGS2 levels by ectopic expression in androgen-independent prostate cancer cells suppressed growth of xenografts in castrated mice. Thus, RGS2 promoter hypermethylation represses its expression and unmasks a latent pathway for AR transactivation in prostate cancer cells. Targeting this reversible process may provide a new strategy for suppressing prostate cancer progression by reestablishing its androgen sensitivity. Copyright © 2011 UICC.

Impact of Fetal-Neonatal Iron Deficiency on Recognition Memory at 2 Months of Age.

PubMed

Geng, Fengji; Mai, Xiaoqin; Zhan, Jianying; Xu, Lin; Zhao, Zhengyan; Georgieff, Michael; Shao, Jie; Lozoff, Betsy

2015-12-01

To assess the effects of fetal-neonatal iron deficiency on recognition memory in early infancy. Perinatal iron deficiency delays or disrupts hippocampal development in animal models and thus may impair related neural functions in human infants, such as recognition memory. Event-related potentials were used in an auditory recognition memory task to compare 2-month-old Chinese infants with iron sufficiency or deficiency at birth. Fetal-neonatal iron deficiency was defined 2 ways: high zinc protoporphyrin/heme ratio (ZPP/H > 118 μmol/mol) or low serum ferritin (<75 μg/L) in cord blood. Late slow wave was used to measure infant recognition of mother's voice. Event related potentials patterns differed significantly for fetal-neonatal iron deficiency as defined by high cord ZPP/H but not low ferritin. Comparing 35 infants with iron deficiency (ZPP/H > 118 μmol/mol) to 92 with lower ZPP/H (iron-sufficient), only infants with iron sufficiency showed larger late slow wave amplitude for stranger's voice than mother's voice in frontal-central and parietal-occipital locations, indicating the recognition of mother's voice. Infants with iron sufficiency showed electrophysiological evidence of recognizing their mother's voice, whereas infants with fetal-neonatal iron deficiency did not. Their poorer auditory recognition memory at 2 months of age is consistent with effects of fetal-neonatal iron deficiency on the developing hippocampus. Copyright © 2015 Elsevier Inc. All rights reserved.

RETRACTED: Association between the ACE I/D gene polymorphism and T2DN susceptibility: The risk of T2DM developing into T2DN in the Asian population.

PubMed

Zhong, Weiqiang; Jiang, Zongpei; Zhou, Tian-Biao

2015-12-01

This article has been included in a multiple retraction: Weiqiang Zhong, Zongpei Jiang, and Tian-Biao Zhou Association between the ACE I/D gene polymorphism and T2DN susceptibility: The risk of T2DM developing into T2DN in the Asian population Journal of Renin-Angiotensin-Aldosterone System 1470320314566019, first published on January 26, 2015 doi: 10.1177/1470320314566019 This article has been retracted at the request of the Editors and the Publisher. After conducting a thorough investigation, SAGE found that the submitting authors of a number of papers published in the Journal of the Renin-Angiotensin Aldosterone System ( JRAAS) (listed below) had supplied fabricated contact details for their nominated reviewers. The Editors accepted these papers based on the reports supplied by the individuals using these fake reviewer email accounts. After concluding that the peer review process was therefore seriously compromised, SAGE and the journal Editors have decided to retract all affected articles. Online First articles (these articles will not be published in an issue) Wenzhuang Tang, Tian-Biao Zhou, and Zongpei Jiang Association of the angiotensinogen M235T gene polymorphism with risk of diabetes mellitus developing into diabetic nephropathy Journal of Renin-Angiotensin-Aldosterone System 1470320314563426, first published on December 18, 2014 doi: 10.1177/1470320314563426 Tian-Biao Zhou, Hong-Yan Li, Zong-Pei Jiang, Jia-Fan Zhou, Miao-Fang Huang, and Zhi-Yang Zhou Role of renin-angiotensin-aldosterone system inhibitors in radiation nephropathy Journal of Renin-Angiotensin-Aldosterone System 1470320314563424, first published on December 18, 2014 doi: 10.1177/1470320314563424 Weiqiang Zhong, Zongpei Jiang, and Tian-Biao Zhou Association between the ACE I/D gene polymorphism and T2DN susceptibility: The risk of T2DM developing into T2DN in the Asian population Journal of Renin-Angiotensin-Aldosterone System 1470320314566019, first published on January 26, 2015 doi: 10

Metabolic pathways promoting intrahepatic fatty acid accumulation in methionine and choline deficiency: implications for the pathogenesis of steatohepatitis.

PubMed

Macfarlane, David P; Zou, Xiantong; Andrew, Ruth; Morton, Nicholas M; Livingstone, Dawn E W; Aucott, Rebecca L; Nyirenda, Moffat J; Iredale, John P; Walker, Brian R

2011-02-01

The pathological mechanisms that distinguish simple steatosis from steatohepatitis (or NASH, with consequent risk of cirrhosis and hepatocellular cancer) remain incompletely defined. Whereas both a methionine- and choline-deficient diet (MCDD) and a choline-deficient diet (CDD) lead to hepatic triglyceride accumulation, MCDD alone is associated with hepatic insulin resistance and inflammation (steatohepatitis). We used metabolic tracer techniques, including stable isotope ([¹³C₄]palmitate) dilution and mass isotopomer distribution analysis (MIDA) of [¹³C₂]acetate, to define differences in intrahepatic fatty acid metabolism that could explain the contrasting effect of MCDD and CDD on NASH in C57Bl6 mice. Compared with control-supplemented (CS) diet, liver triglyceride pool sizes were similarly elevated in CDD and MCDD groups (24.37 ± 2.4, 45.94 ± 3.9, and 43.30 ± 3.5 μmol/liver for CS, CDD, and MCDD, respectively), but intrahepatic neutrophil infiltration and plasma alanine aminotransferase (31 ± 3, 48 ± 4, 231 ± 79 U/l, P < 0.05) were elevated only in MCDD mice. However, despite loss of peripheral fat in MCDD mice, neither the rate of appearance of palmitate (27.2 ± 3.5, 26.3 ± 2.3, and 28.3 ± 3.5 μmol·kg⁻¹·min⁻¹) nor the contribution of circulating fatty acids to the liver triglyceride pool differed between groups. Unlike CDD, MCDD had a defect in hepatic triglyceride export that was confirmed using intravenous tyloxapol (142 ± 21, 122 ± 15, and 80 ± 7 mg·kg⁻¹·h⁻¹, P < 0.05). Moreover, hepatic de novo lipogenesis was significantly elevated in the MCDD group only (1.4 ± 0.3, 2.3 ± 0.4, and 3.4 ± 0.4 μmol/day, P < 0.01). These findings suggest that important alterations in hepatic fatty acid metabolism may promote the development of steatohepatitis. Similar mechanisms may predispose to hepatocyte damage in human NASH.

Chronic arsenic intoxication diagnostic score (CAsIDS).

PubMed

Dani, Sergio Ulhoa; Walter, Gerhard Franz

2018-01-01

Arsenic and its compounds are well-established, potent, environmentally widespread and persistent toxicants with metabolic, genotoxic, mutagenic, teratogenic, epigenetic and carcinogenic effects. Arsenic occurs naturally in the Earth's crust, but anthropogenic arsenic emissions have surmounted the emissions from important natural sources such as volcanism. Inorganic arsenicals exhibit acute and chronic toxicities in virtually all cell types and tissues, and hence arsenic intoxication affects multiple systems. Whereas acute arsenic intoxication is rare and relatively easy to diagnose, chronic arsenic intoxication (CAsI) is common but goes often misdiagnosed. Based on a review of the literature as well as our own clinical experience, we propose a chronic arsenic intoxication diagnostic score (CAsIDS). A distinctive feature of CAsIDS is the use of bone arsenic load as an essential criterion for the individual risk assessment of chronic arsenic intoxication, combined with a systemic clinical assessment. We present clinical examples where CAsIDS is applied for the diagnosis of CAsI, review the main topics of the toxicity of arsenic in different cell and organ systems and discuss the therapy and prevention of disease caused or aggravated by chronic arsenic intoxication. CAsIDS can help physicians establish the diagnosis of CAsI and associated conditions. Copyright © 2017 John Wiley & Sons, Ltd.

76 FR 28306 - Amendment of Class D and Class E Airspace; Idaho Falls, ID

Federal Register 2010, 2011, 2012, 2013, 2014

2011-05-17

...-0023; Airspace Docket No. 11-ANM-2] Amendment of Class D and Class E Airspace; Idaho Falls, ID AGENCY... D and Class E airspace at Idaho Falls, ID, by changing the name of the airport to Idaho Falls... Performance (RNP) standard instrument approach procedures at Idaho Falls Regional Airport. This improves the...

The impact of iron deficiency and anaemia on exercise capacity and outcomes in patients with chronic heart failure. Results from the Studies Investigating Co-morbidities Aggravating Heart Failure.

PubMed

Ebner, Nicole; Jankowska, Ewa A; Ponikowski, Piotr; Lainscak, Mitja; Elsner, Sebastian; Sliziuk, Veronika; Steinbeck, Lisa; Kube, Jennifer; Bekfani, Tarek; Scherbakov, Nadja; Valentova, Miroslava; Sandek, Anja; Doehner, Wolfram; Springer, Jochen; Anker, Stefan D; von Haehling, Stephan

2016-02-15

Anaemia and iron deficiency (ID) are important co-morbidities in patients with chronic heart failure (HF) and both may lead to reduced exercise capacity. We enrolled 331 out-patients with stable chronic HF (mean age: 64 ± 11 years, 17% female, left ventricular ejection fraction [LVEF] 35 ± 13%, body mass index [BMI] 28.5 ± 5.2 kg/m(2), New York Heart Association [NYHA] class 2.2 ± 0.7, chronic kidney disease 35%, glomerular filtration rate 61.7 ± 20.1 mL/min). Anaemia was defined according to World Health Organization criteria (haemoglobin [Hb] < 13 g/dL in men, < 12 g/dL in women). ID was defined as serum ferritin < 100 μg/L or ferritin < 300 μg/L with transferrin saturation (TSAT) < 20%. Exercise capacity was assessed as peak oxygen consumption (peak VO2) by spiroergometry and 6-minute walk test (6MWT). A total of 91 (27%) patients died from any cause during a mean follow-up of 18 months. At baseline, 98 (30%) patients presented with anaemia and 149 (45%) patients presented with ID. We observed a significant reduction in exercise capacity in parallel to decreasing Hb levels (r = 0.24, p < 0.001). In patients with anaemia and ID (n = 63, 19%), exercise capacity was significantly lower than in patients with ID or anaemia only. Cox regression analysis showed that after adjusting for NYHA, age, hsCRP and creatinine anaemia is an independent predictor of mortality in patients with HF (hazard ratio [HR]: 0.56, 95% confidence interval [CI]: 0.33-0.97, p = 0.04). The impact of anaemia on reduced exercise capacity and on mortality is stronger than that of ID. Anaemia remained an independent predictor of death after adjusting for clinically relevant variables. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Identification of an active ID-like group of SINEs in the mouse

PubMed Central

Kass, David H; Jamison, Nicole

2007-01-01

The mouse genome consists of five known families of SINEs: B1, B2, B4/RSINE, ID, and MIR. Using RT-PCR we identified a germ-line transcript that demonstrates 92.7% sequence identity to ID (excluding primer sequence), yet a BLAST search identified numerous matches of 100% sequence identity. We analyzed four of these elements for their presence in orthologous genes in strains and subspecies of M. musculus as well as other species of Mus using a PCR-based assay. All four analyzed elements were either identified only in M. musculus or exclusively in both M. musculus and M. domesticus indicative of recent integrations. In conjunction with the identification of transcripts, we present an active ID-like group of elements that is not derived from the proposed BC1 master gene of ID elements. A BLAST of the rat genome indicated that these elements were not in the rat. Therefore, this family of SINEs has recently evolved, and since thus far has mainly been observed in M. musculus, we then refer to this family as MMIDL. PMID:17572061

Identification of an active ID-like group of SINEs in the mouse.

PubMed

Kass, David H; Jamison, Nicole

2007-09-01

The mouse genome consists of five known families of SINEs: B1, B2, B4/RSINE, ID, and MIR. Using RT-PCR we identified a germ-line transcript that demonstrates 92.7% sequence identity to ID (excluding primer sequence), yet a BLAST search identified numerous matches of 100% sequence identity. We analyzed four of these elements for their presence in orthologous genes in strains and subspecies of Mus musculus as well as other species of Mus using a PCR-based assay. All four analyzed elements were identified either only in M. musculus or exclusively in both M. musculus and M. domesticus, indicative of recent integrations. In conjunction with the identification of transcripts, we present an active ID-like group of elements that is not derived from the proposed BC1 master gene of ID elements. A BLAST of the rat genome indicated that these elements were not in the rat. Therefore, this family of SINEs has recently evolved, and since it has thus far been observed mainly in M. musculus, we refer to this family as MMIDL.

Ethylene response factor AtERF72 negatively regulates Arabidopsis thaliana response to iron deficiency.

PubMed

Liu, Wei; Li, Qiwei; Wang, Yi; Wu, Ting; Yang, Yafei; Zhang, Xinzhong; Han, Zhenhai; Xu, Xuefeng

2017-09-23

Ethylene regulates the plant's response to stress caused by iron (Fe) deficiency. However, specific roles of ERF proteins in response to Fe deficiency remain poorly understood. Here, we investigated the role of ERF72 in response to iron deficiency in Arabidopsis thaliana. In this study, the levels of the ethylene response factor AtERF72 increased in leaves and roots induced under the iron deficient conditions. erf72 mutant plants showed increased growth compared to wild type (WT) when grown in iron deficient medium for 5 d. erf72 mutants had increased root H + velocity and the ferric reductase activity, and increase in the expression of the iron deficiency response genes iron-regulated transporter 1 (IRT1) and H + -ATPase (HA2) levels in iron deficient conditions. Compared to WT plants, erf72 mutants retained healthy chloroplast structure with significantly higher Fe and Mg content, and decreased chlorophyll degradation gene pheophorbide a oxygenase (PAO) and chlorophyllase (CLH1) expression when grown in iron deficient media. Yeast one-hybrid analysis showed that ERF72 could directly bind to the promoter regions of iron deficiency responses genes IRT1, HA2 and CLH1. Based on our results, we suggest that ethylene released from plants under iron deficiency stress can activate the expression of ERF72, which responds to iron deficiency in the negative regulation. Copyright © 2017 Elsevier Inc. All rights reserved.

Robust Speech Processing & Recognition: Speaker ID, Language ID, Speech Recognition/Keyword Spotting, Diarization/Co-Channel/Environmental Characterization, Speaker State Assessment

DTIC Science & Technology

2015-10-01

Scoring, Gaussian Backend , etc.) as shown in Fig. 39. The methods in this domain also emphasized the ability to perform data purification for both...investigation using the same infrastructure was undertaken to explore Lombard effect “flavor” detection for improved speaker ID. The study The presence of...dimension selection and compared to a common N-gram frequency based selection. 2.1.2: Exploration on NN/DBN backend : Since Deep Neural Networks (DNN) have

Lamp-2 deficiency prevents high-fat diet-induced obese diabetes via enhancing energy expenditure

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

Yasuda-Yamahara, Mako; Kume, Shinji, E-mail: skume@belle.shiga-med.ac.jp; Yamahara, Kosuke

Autophagy process is essential for maintaining intracellular homeostasis and consists of autophagosome formation and subsequent fusion with lysosome for degradation. Although the role of autophagosome formation in the pathogenesis of diabetes has been recently documented, the role of the latter process remains unclear. This study analyzed high-fat diet (HFD)-fed mice lacking lysosome-associated membrane protein-2 (lamp-2), which is essential for the fusion with lysosome and subsequent degradation of autophagosomes. Although lamp-2 deficient mice showed little alteration in glucose metabolism under normal diet feeding, they showed a resistance against high-fat diet (HFD)-induced obesity, hyperinsulinemic hyperglycemia and tissues lipid accumulation, accompanied with highermore » energy expenditure. The expression levels of thermogenic genes in brown adipose tissue were significantly increased in HFD-fed lamp-2-deficient mice. Of some serum factors related to energy expenditure, the serum level of fibroblast growth factor (FGF) 21 and its mRNA expression level in the liver were significantly higher in HFD-fed lamp-2-deficient mice in an ER stress-, but not PPARα-, dependent manner. In conclusion, a lamp-2-depenedent fusion and degradation process of autophagosomes is involved in the pathogenesis of obese diabetes, providing a novel insight into autophagy and diabetes. - Highlights: • Lamp-2 is essential for autophagosome fusion with lysosome and its degradation. • Lamp-2 deficiency lead to a resistance to diet-induced obese diabetes in mice. • Lamp-2 deficiency increased whole body energy expenditure under HFD-feeding. • Lamp-2 deficiency elevated the serum level of FGF21 under HFD-feeding.« less

The Transferability of Health Promotion and Education Approaches Between Non-communicable Diseases and Communicable Diseases—an Analysis of Evidence

PubMed Central

McQueen, David V.; Manoncourt, Erma; Cartier, Yuri N.; Dinca, Irina; Nurm, Ülla-Karin

2014-01-01

Background There is a seeming lack within the public health fields of both research and practice of information sharing across so-called “silos of work”. Many professionals in the public health fields dealing with infectious diseases (IDs) are unaware of the programs and approaches taken by their colleagues in the non-communicable diseases (NCDs) arena, and vice versa. A particular instance of this is in the understanding and application of health promotion approaches. This is a problem that needs to be addressed with the goal of producing the most efficient and effective health promotion approaches to the prevention and control of diseases in general. Objectives This project examined health promotion approaches to the prevention of NCDs that could be used in the prevention of IDs. Methods A knowledge synthesis and translation perspective was undertaken. We screened and analyzed a wide range of sources that were considered relevant, with particular emphasis on systematic reviews, published articles and the grey literature. Results The analysis revealed a diverse health promotion knowledge base for application to IDs. Comprehensive health promotion models were found to be useful. Findings suggest that there are profound similarities for health promotion approaches in both NCDs and IDs. Conclusions: This study revealed gaps in knowledge synthesis to translation. The need for development of intervention and implementation research is considered. PMID:29546085

DD Genotype of ACE I/D Polymorphism Might Confer Protection against Dental Caries in Polish Children.

PubMed

Olszowski, Tomasz; Adler, Grażyna; Janiszewska-Olszowska, Joanna; Safranow, Krzysztof; Chlubek, Dariusz

2015-01-01

The aim of the study was to examine the frequencies of the genotypes and alleles of ACE insertion/deletion (I/D) polymorphism and their association with dental caries in a sample of Polish children. The study subjects were 120 children with dental caries experience (cases) and 41 caries-free individuals (controls). The genotyping was performed using polymerase chain reaction. The genotype distributions of ACE I/D polymorphism were not statistically different between carious and control children. However, we found a borderline overrepresentation of the II + ID genotypes versus the DD genotype in the carious compared to the control group (69.2% and 51.2%, respectively, p = 0.057). Logistic regression analysis adjusted for age and sex revealed that I allele carriage was a significant predictor of dental caries susceptibility (OR = 2.14, 95% CI = 1.02-4.49, p = 0.041). In conclusion, the DD genotype of ACE I/D polymorphism might be protective against dental caries in Polish children. © 2015 S. Karger AG, Basel.

Nrf2 target genes are induced under marginal selenium-deficiency

PubMed Central

Müller, Mike; Banning, Antje; Brigelius-Flohé, Regina

2010-01-01

A suboptimal selenium supply appears to prevail in Europe. The current study, therefore, was focused on the changes in gene expression under a suboptimal selenium intake. Previous microarray analyses in the colon of mice fed either a selenium-adequate or a moderately deficient diet revealed a change in genes of several pathways. Severe selenium-deficiency has been found previously to influence Nrf2-regulated genes of the adaptive response. Since the previous pathway analyses were done with a program not searching for Nrf2 target genes, respective genes were manually selected and confirmed by qPCR. qPCR revealed an induction of phase II (Nqo1, Gsts, Sult1b1 and Ugt1a6) and antioxidant enzymes (Hmox1, Mt2, Prdx1, Srxn1, Sod1 and Gclc) under the selenium-poor diet, which is considered to compensate for the loss of selenoproteins. The strongest effects were observed in the duodenum where preferentially genes for antioxidant enzymes were up-regulated. These also include the mRNA of the selenoproteins TrxR1 and GPx2 that would enable their immediate translation upon selenium refeeding. The down-regulation of Gsk3β in moderate selenium-deficiency observed in the previous paper provides a possible explanation for the activation of the Nrf2 pathway, because inhibition of GSK3β results in the nuclear accumulation of Nrf2. PMID:21189866

Spinal cord injury-induced immune deficiency syndrome enhances infection susceptibility dependent on lesion level

PubMed Central

Brommer, Benedikt; Engel, Odilo; Kopp, Marcel A.; Watzlawick, Ralf; Müller, Susanne; Prüss, Harald; Chen, Yuying; DeVivo, Michael J.; Finkenstaedt, Felix W.; Dirnagl, Ulrich; Liebscher, Thomas; Meisel, Andreas

2016-01-01

Pneumonia is the leading cause of death after acute spinal cord injury and is associated with poor neurological outcome. In contrast to the current understanding, attributing enhanced infection susceptibility solely to the patient’s environment and motor dysfunction, we investigate whether a secondary functional neurogenic immune deficiency (spinal cord injury-induced immune deficiency syndrome, SCI-IDS) may account for the enhanced infection susceptibility. We applied a clinically relevant model of experimental induced pneumonia to investigate whether the systemic SCI-IDS is functional sufficient to cause pneumonia dependent on spinal cord injury lesion level and investigated whether findings are mirrored in a large prospective cohort study after human spinal cord injury. In a mouse model of inducible pneumonia, high thoracic lesions that interrupt sympathetic innervation to major immune organs, but not low thoracic lesions, significantly increased bacterial load in lungs. The ability to clear the bacterial load from the lung remained preserved in sham animals. Propagated immune susceptibility depended on injury of central pre-ganglionic but not peripheral postganglionic sympathetic innervation to the spleen. Thoracic spinal cord injury level was confirmed as an independent increased risk factor of pneumonia in patients after motor complete spinal cord injury (odds ratio = 1.35, P < 0.001) independently from mechanical ventilation and preserved sensory function by multiple regression analysis. We present evidence that spinal cord injury directly causes increased risk for bacterial infection in mice as well as in patients. Besides obvious motor and sensory paralysis, spinal cord injury also induces a functional SCI-IDS (‘immune paralysis’), sufficient to propagate clinically relevant infection in an injury level dependent manner. PMID:26754788

Transgene expression of Drosophila melanogaster nucleoside kinase reverses mitochondrial thymidine kinase 2 deficiency.

PubMed

Krishnan, Shuba; Zhou, Xiaoshan; Paredes, João A; Kuiper, Raoul V; Curbo, Sophie; Karlsson, Anna

2013-02-15

A strategy to reverse the symptoms of thymidine kinase 2 (TK2) deficiency in a mouse model was investigated. The nucleoside kinase from Drosophila melanogaster (Dm-dNK) was expressed in TK2-deficient mice that have been shown to present with a severe phenotype caused by mitochondrial DNA depletion. The Dm-dNK(+/-) transgenic mice were shown to be able to rescue the TK2-deficient mice. The Dm-dNK(+/-)TK2(-/-) mice were normal as judged by growth and behavior during the observation time of 6 months. The Dm-dNK-expressing mice showed a substantial increase in thymidine-phosphorylating activity in investigated tissues. The Dm-dNK expression also resulted in highly elevated dTTP pools. The dTTP pool alterations did not cause specific mitochondrial DNA mutations or deletions when 6-month-old mice were analyzed. The mitochondrial DNA was also detected at normal levels. In conclusion, the Dm-dNK(+/-)TK2(-/-) mouse model illustrates how dTMP synthesized in the cell nucleus can compensate for loss of intramitochondrial dTMP synthesis in differentiated tissue. The data presented open new possibilities to treat the severe symptoms of TK2 deficiency.

Disruption of the potassium channel regulatory subunit KCNE2 causes iron-deficient anemia

PubMed Central

Salsbury, Grace; Cambridge, Emma L.; McIntyre, Zoe; Arends, Mark J.; Karp, Natasha A.; Isherwood, Christopher; Shannon, Carl; Hooks, Yvette; Ramirez-Solis, Ramiro; Adams, David J.; White, Jacqueline K.; Speak, Anneliese O.

2014-01-01

Iron homeostasis is a dynamic process that is tightly controlled to balance iron uptake, storage, and export. Reduction of dietary iron from the ferric to the ferrous form is required for uptake by solute carrier family 11 (proton-coupled divalent metal ion transporters), member 2 (Slc11a2) into the enterocytes. Both processes are proton dependent and have led to the suggestion of the importance of acidic gastric pH for the absorption of dietary iron. Potassium voltage-gated channel subfamily E, member 2 (KCNE2), in combination with potassium voltage-gated channel, KQT-like subfamily, member 1 (KCNQ1), form a gastric potassium channel essential for gastric acidification. Deficiency of either Kcne2 or Kcnq1 results in achlorhydia, gastric hyperplasia, and neoplasia, but the impact on iron absorption has not, to our knowledge, been investigated. Here we report that Kcne2-deficient mice, in addition to the previously reported phenotypes, also present with iron-deficient anemia. Interestingly, impaired function of KCNQ1 results in iron-deficient anemia in Jervell and Lange-Nielsen syndrome patients. We speculate that impaired function of KCNE2 could result in the same clinical phenotype. PMID:25127743

An online ID identification system for liquefied-gas cylinder plant

NASA Astrophysics Data System (ADS)

He, Jin; Ding, Zhenwen; Han, Lei; Zhang, Hao

2017-11-01

An automatic ID identification system for gas cylinders' online production was developed based on the production conditions and requirements of the Technical Committee for Standardization of Gas Cylinders. A cylinder ID image acquisition system was designed to improve the image contrast of ID regions on gas cylinders against the background. Then the ID digits region was located by the CNN template matching algorithm. Following that, an adaptive threshold method based on the analysis of local average grey value and standard deviation was proposed to overcome defects of non-uniform background in the segmentation results. To improve the single digit identification accuracy, two BP neural networks were trained respectively for the identification of all digits and the easily confusable digits. If the single digit was classified as one of confusable digits by the former BP neural network, it was further tested by the later one, and the later result was taken as the final identification result of this single digit. At last, the majority voting was adopted to decide the final identification result for the 6-digit cylinder ID. The developed system was installed on a production line of a liquefied-petroleum-gas cylinder plant and worked in parallel with the existing weighing step on the line. Through the field test, the correct identification rate for single ID digit was 94.73%, and none of the tested 2000 cylinder ID was misclassified through the majority voting.

Prostaglandin E2 is critical for the development of niacin-deficiency-induced photosensitivity via ROS production

NASA Astrophysics Data System (ADS)

Sugita, Kazunari; Ikenouchi-Sugita, Atsuko; Nakayama, Yasuko; Yoshioka, Haruna; Nomura, Takashi; Sakabe, Jun-Ichi; Nakahigashi, Kyoko; Kuroda, Etsushi; Uematsu, Satoshi; Nakamura, Jun; Akira, Shizuo; Nakamura, Motonobu; Narumiya, Shuh; Miyachi, Yoshiki; Tokura, Yoshiki; Kabashima, Kenji

2013-10-01

Pellagra is a photosensitivity syndrome characterized by three ``D's'': diarrhea, dermatitis, and dementia as a result of niacin deficiency. However, the molecular mechanisms of photosensitivity dermatitis, the hallmark abnormality of this syndrome, remain unclear. We prepared niacin deficient mice in order to develop a murine model of pellagra. Niacin deficiency induced photosensitivity and severe diarrhea with weight loss. In addition, niacin deficient mice exhibited elevated expressions of COX-2 and PGE syntheses (Ptges) mRNA. Consistently, photosensitivity was alleviated by a COX inhibitor, deficiency of Ptges, or blockade of EP4 receptor signaling. Moreover, enhanced PGE2 production in niacin deficiency was mediated via ROS production in keratinocytes. In line with the above murine findings, human skin lesions of pellagra patients confirmed the enhanced expression of Ptges. Niacin deficiency-induced photosensitivity was mediated through EP4 signaling in response to increased PGE2 production via induction of ROS formation.

Ankyrin Repeat Domain Protein 2 and Inhibitor of DNA Binding 3 Cooperatively Inhibit Myoblast Differentiation by Physical Interaction*

PubMed Central

Mohamed, Junaith S.; Lopez, Michael A.; Cox, Gregory A.; Boriek, Aladin M.

2013-01-01

Ankyrin repeat domain protein 2 (ANKRD2) translocates from the nucleus to the cytoplasm upon myogenic induction. Overexpression of ANKRD2 inhibits C2C12 myoblast differentiation. However, the mechanism by which ANKRD2 inhibits myoblast differentiation is unknown. We demonstrate that the primary myoblasts of mdm (muscular dystrophy with myositis) mice (pMBmdm) overexpress ANKRD2 and ID3 (inhibitor of DNA binding 3) proteins and are unable to differentiate into myotubes upon myogenic induction. Although suppression of either ANKRD2 or ID3 induces myoblast differentiation in mdm mice, overexpression of ANKRD2 and inhibition of ID3 or vice versa is insufficient to inhibit myoblast differentiation in WT mice. We identified that ANKRD2 and ID3 cooperatively inhibit myoblast differentiation by physical interaction. Interestingly, although MyoD activates the Ankrd2 promoter in the skeletal muscles of wild-type mice, SREBP-1 (sterol regulatory element binding protein-1) activates the same promoter in the skeletal muscles of mdm mice, suggesting the differential regulation of Ankrd2. Overall, we uncovered a novel pathway in which SREBP-1/ANKRD2/ID3 activation inhibits myoblast differentiation, and we propose that this pathway acts as a critical determinant of the skeletal muscle developmental program. PMID:23824195

Evaluation of 1.0 mm i.d. column performances on ultra high pressure liquid chromatography instrumentation.

PubMed

Lestremau, François; Wu, Di; Szücs, Roman

2010-07-23

The present study focuses on the evaluation of 1.0 mm i.d. (internal diameter) columns on a commercial Ultra-High Pressure system. These systems have been developed specifically to operate columns with small volumes, typically 2.1 mm i.d., by reducing extra-column volume dispersion. The use of columns with smaller i.d. results in a reduced solvent consumption and required sample volume. The evaluation of the columns was carried out with samples containing neutral and pharmaceutical compounds. In isocratic mode, the extra-column volume produced additional band broadening leading to poor performances compared to equivalent 2.1 mm i.d. columns. By increasing the length of the column, the influence of the extra-column bandspreading could be reduced and 75,000 plates were obtained when four columns were coupled. In gradient mode, the effect of the extra-column contribution on efficiency was limited and about 80% of the performance of the 2.1 mm i.d. columns was obtained. Optimum conditions in gradient mode were further investigated by changing flow rate, gradient time and column length. A different approach of the calculation of peak capacity was also considered for the comparison of the influence of these different parameters. Copyright (c) 2010 Elsevier B.V. All rights reserved.