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    HBO1 Is Required for H3K14 Acetylation and Normal Transcriptional Activity during Embryonic Development
    Kueh, AJ ; Dixon, MP ; Voss, AK ; Thomas, T (AMER SOC MICROBIOLOGY, 2011-02)
    We report here that the MYST histone acetyltransferase HBO1 (histone acetyltransferase bound to ORC; MYST2/KAT7) is essential for postgastrulation mammalian development. Lack of HBO1 led to a more than 90% reduction of histone 3 lysine 14 (H3K14) acetylation, whereas no reduction of acetylation was detected at other histone residues. The decrease in H3K14 acetylation was accompanied by a decrease in expression of the majority of genes studied. However, some genes, in particular genes regulating embryonic patterning, were more severely affected than "housekeeping" genes. Development of HBO1-deficient embryos was arrested at the 10-somite stage. Blood vessels, mesenchyme, and somites were disorganized. In contrast to previous studies that reported cell cycle arrest in HBO1-depleted cultured cells, no defects in DNA replication or cell proliferation were seen in Hbo1 mutant embryo primary fibroblasts or immortalized fibroblasts. Rather, a high rate of cell death and DNA fragmentation was observed in Hbo1 mutant embryos, resulting initially in the degeneration of mesenchymal tissues and ultimately in embryonic lethality. In conclusion, the primary role of HBO1 in development is that of a transcriptional activator, which is indispensable for H3K14 acetylation and for the normal expression of essential genes regulating embryonic development.
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    Gata-3 Negatively Regulates the Tumor-Initiating Capacity of Mammary Luminal Progenitor Cells and Targets the Putative Tumor Suppressor Caspase-14
    Asselin-Labat, M-L ; Sutherland, KD ; Vaillant, F ; Gyorki, DE ; Wu, D ; Holroyd, S ; Breslin, K ; Ward, T ; Shi, W ; Bath, ML ; Deb, S ; Fox, SB ; Smyth, GK ; Lindeman, GJ ; Visvader, JE (AMER SOC MICROBIOLOGY, 2011-11)
    The transcription factor Gata-3 is a definitive marker of luminal breast cancers and a key regulator of mammary morphogenesis. Here we have explored a role for Gata-3 in tumor initiation and the underlying cellular mechanisms using a mouse model of "luminal-like" cancer. Loss of a single Gata-3 allele markedly accelerated tumor progression in mice carrying the mouse mammary tumor virus promoter-driven polyomavirus middle T antigen (MMTV-PyMT mice), while overexpression of Gata-3 curtailed tumorigenesis. Through the identification of two distinct luminal progenitor cells in the mammary gland, we demonstrate that Gata-3 haplo-insufficiency increases the tumor-initiating capacity of these progenitors but not the stem cell-enriched population. Overexpression of a conditional Gata-3 transgene in the PyMT model promoted cellular differentiation and led to reduced tumor-initiating capacity as well as diminished angiogenesis. Transcript profiling studies identified caspase-14 as a novel downstream target of Gata-3, in keeping with its roles in differentiation and tumorigenesis. A strong association was evident between GATA-3 and caspase-14 expression in preinvasive ductal carcinoma in situ samples, where GATA-3 also displayed prognostic significance. Overall, these studies identify GATA-3 as an important regulator of tumor initiation through its ability to promote the differentiation of committed luminal progenitor cells.
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    Correction: Does Malaria Affect Placental Development? Evidence from In Vitro Models
    Umbers, AJ ; Stanisic, DI ; Ome, M ; Wangnapi, R ; Hanieh, S ; Unger, HW ; Robinson, LJ ; Lufele, E ; Baiwog, F ; Siba, PM ; King, CL ; Beeson, JG ; Mueller, I ; Aplin, JD ; Glazier, JD ; Rogerson, SJ ; Hviid, L (Public Library of Science (PLoS), 2013)
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    Undernutrition among children in South and South-East Asia
    Pasricha, S-R ; Biggs, B-A (WILEY, 2010-09)
    Undernutrition remains a major public health problem among children living in Asia. Although the burden is maximal among poorer, rural and Indigenous communities, the problem affects the majority in many Asian countries, especially in South Asia. In order to prevent the pervasive consequences of undernutrition, strategies that address this burden are required. Successful implementation of strategies may be limited by the complex aetiology of undernutrition, including the political setting. Rising food insecurity because of climate change, land use for biofuel production and the recent global financial crisis threaten to exacerbate childhood malnutrition. In this review, we describe the burden of undernutrition among Asian children and discuss contributing factors and potential solutions.
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    Vitamin B-12, folate, iron, and vitamin A concentrations in rural Indian children are associated with continued breastfeeding, complementary diet, and maternal nutrition
    Pasricha, S-R ; Shet, AS ; Black, JF ; Sudarshan, H ; Prashanth, NS ; Biggs, B-A (OXFORD UNIV PRESS, 2011-11)
    BACKGROUND: Determinants of vitamin B-12, folate, iron, and vitamin A concentrations in young children in rural south Asia are poorly understood. These micronutrients are crucial for the production of hemoglobin and have other important physiologic functions. OBJECTIVE: We sought to develop explanatory models for concentrations of vitamin B-12, folate, ferritin, and retinol binding protein (RBP) in children aged between 1 and 2 y in rural Karnataka, India. DESIGN: We performed a cross-sectional study in 12-23-mo-old toddlers who lived in 2 rural districts of Karnataka, India. For each child, data concerning dietary, food-security, and sociodemographic and maternal factors were obtained, and serum vitamin B-12, folate, ferritin, and RBP were measured. Multiple regression and structural equation modeling were applied to determine associations with micronutrient concentrations. RESULTS: Of 396 sampled children, 254 children (65.6%) had at least one micronutrient deficiency. With the use of multiple regression, continued breastfeeding was independently associated with the concentration of each micronutrient [(log) vitamin B-12: standardized coefficient of -0.30 (P < 0.001); folate: standardized coefficient of +0.20 (P < 0.001); (log) ferritin: standardized coefficient of -0.18 (P = 0.004); (log) RBP: standardized coefficient of-0.21 (P < 0.001)]. Children who continued to breastfeed received less nutrition from complementary foods and belonged to poorer families with higher food insecurity. A structural equation model for children's vitamin B-12 concentrations was developed that highlighted the interrelation between wealth, continued breastfeeding, complementary diet, and vitamin B-12 concentrations in children. CONCLUSIONS: Micronutrient deficiencies are common in this population. Rural Indian children between 1 and 2 y of age who continue to breastfeed should be especially targeted during micronutrient-supplementation programs. This trial was registered in the Australian and New Zealand Clinical Trials Registry as ACTRN12611000596909.
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    Effects of Daily Iron Supplementation in 2- to 5-Year-Old Children: Systematic Review and Meta-analysis
    Thompson, J ; Biggs, B-A ; Pasricha, S-R (American Academy of Pediatrics, 2013-04-01)
    BACKGROUND AND OBJECTIVES: Iron deficiency (ID) is the most common cause of anemia worldwide. The prevalence is highest among preschool-aged children. Iron is widely administered to children with or at risk for ID, but evidence of benefit among 2- to 5-year-old children has not been evaluated by systematic review. We summarize the evidence for the benefit and safety of daily iron supplementation with regard to hematologic, growth, and cognitive parameters in 2 to 5 year olds. METHODS: Electronic databases, regional databases, thesis repositories, gray literature, and references of studies and previous reviews were searched. We included randomized controlled trials that compared daily oral iron supplementation with control in 2 to 5 year olds. A random-effects meta-analysis was used to synthesize predefined outcomes reported by at least 2 studies. RESULTS: Of 9169 references, 15 studies met the inclusion criteria, none of which were at low risk of bias. Children receiving iron supplementation had a mean end point hemoglobin of 6.97 g/L (P < .00001; I(2) = 82%) greater than controls, whereas mean end point ferritin was 11.64 µg/L (P < .0001; I(2) = 48%) greater. No trials reported the effects of iron supplementation on ID or iron deficiency anemia, and only one reported on anemia. Limited evidence suggested that iron supplementation produced a small improvement in cognitive development but had no effect on physical growth. CONCLUSIONS: In 2 to 5 year olds, daily iron supplementation increases hemoglobin and ferritin. There is a concerning lack of data on the effect of iron supplementation on clinically important outcomes including anemia, ID anemia, ID, and cognitive development. Additional interventional studies in this age group are needed.
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    Effects of daily iron supplementation in primary-school-aged children: systematic review and meta-analysis of randomized controlled trials
    Low, M ; Farrell, A ; Biggs, B-A ; Pasricha, S-R (CMA-CANADIAN MEDICAL ASSOC, 2013-11-19)
    BACKGROUND: Anemia is an important public health and clinical problem. Observational studies have linked iron deficiency and anemia in children with many poor outcomes, including impaired cognitive development; however, iron supplementation, a widely used preventive and therapeutic strategy, is associated with adverse effects. Primary-school-aged children are at a critical stage in intellectual development, and optimization of their cognitive performance could have long-lasting individual and population benefits. In this study, we summarize the evidence for the benefits and safety of daily iron supplementation in primary-school-aged children. METHODS: We searched electronic databases (including MEDLINE and Embase) and other sources (July 2013) for randomized and quasi-randomized controlled trials involving daily iron supplementation in children aged 5-12 years. We combined the data using random effects meta-analysis. RESULTS: We identified 16 501 studies; of these, we evaluated 76 full-text papers and included 32 studies including 7089 children. Of the included studies, 31 were conducted in low- or middle-income settings. Iron supplementation improved global cognitive scores (standardized mean difference 0.50, 95% confidence interval [CI] 0.11 to 0.90, p = 0.01), intelligence quotient among anemic children (mean difference 4.55, 95% CI 0.16 to 8.94, p = 0.04) and measures of attention and concentration. Iron supplementation also improved age-adjusted height among all children and age-adjusted weight among anemic children. Iron supplementation reduced the risk of anemia by 50% and the risk of iron deficiency by 79%. Adherence in the trial settings was generally high. Safety data were limited. INTERPRETATION: Our analysis suggests that iron supplementation safely improves hematologic and nonhematologic outcomes among primary-school-aged children in low- or middle-income settings and is well-tolerated.
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    Proteomics and Deep Sequencing Comparison of Seasonally Active Venom Glands in the Platypus Reveals Novel Venom Peptides and Distinct Expression Profiles
    Wong, ESW ; Morgenstern, D ; Mofiz, E ; Gombert, S ; Morris, KM ; Temple-Smith, P ; Renfree, MB ; Whittington, CM ; King, GF ; Warren, WC ; Papenfuss, AT ; Belov, K (AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2012-11)
    The platypus is a venomous monotreme. Male platypuses possess a spur on their hind legs that is connected to glands in the pelvic region. They produce venom only during the breeding season, presumably to fight off conspecifics. We have taken advantage of this unique seasonal production of venom to compare the transcriptomes of in- and out-of-season venom glands, in conjunction with proteomic analysis, to identify previously undiscovered venom genes. Comparison of the venom glands revealed distinct gene expression profiles that are consistent with changes in venom gland morphology and venom volumes in and out of the breeding season. Venom proteins were identified through shot-gun sequenced venom proteomes of three animals using RNA-seq-derived transcripts for peptide-spectral matching. 5,157 genes were expressed in the venom glands, 1,821 genes were up-regulated in the in-season gland, and 10 proteins were identified in the venom. New classes of platypus-venom proteins identified included antimicrobials, amide oxidase, serpin protease inhibitor, proteins associated with the mammalian stress response pathway, cytokines, and other immune molecules. Five putative toxins have only been identified in platypus venom: growth differentiation factor 15, nucleobindin-2, CD55, a CXC-chemokine, and corticotropin-releasing factor-binding protein. These novel venom proteins have potential biomedical and therapeutic applications and provide insights into venom evolution.
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    Tumor Necrosis Factor (TNF) Signaling, but Not TWEAK (TNF-like Weak Inducer of Apoptosis)-triggered cIAP1 (Cellular Inhibitor of Apoptosis Protein 1) Degradation, Requires cIAP1 RING Dimerization and E2 Binding
    Feltham, R ; Moulin, M ; Vince, JE ; Mace, PD ; Wong, WW-L ; Anderton, H ; Day, CL ; Vaux, DL ; Silke, J (AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2010-06-04)
    Cellular inhibitor of apoptosis (cIAP) proteins, cIAP1 and cIAP2, are important regulators of tumor necrosis factor (TNF) superfamily (SF) signaling and are amplified in a number of tumor types. They are targeted by IAP antagonist compounds that are undergoing clinical trials. IAP antagonist compounds trigger cIAP autoubiquitylation and degradation. The TNFSF member TWEAK induces lysosomal degradation of TRAF2 and cIAPs, leading to elevated NIK levels and activation of non-canonical NF-kappaB. To investigate the role of the ubiquitin ligase RING domain of cIAP1 in these pathways, we used cIAP-deleted cells reconstituted with cIAP1 point mutants designed to interfere with the ability of the RING to dimerize or to interact with E2 enzymes. We show that RING dimerization and E2 binding are required for IAP antagonists to induce cIAP1 degradation and protect cells from TNF-induced cell death. The RING functions of cIAP1 are required for full TNF-induced activation of NF-kappaB, however, delayed activation of NF-kappaB still occurs in cIAP1 and -2 double knock-out cells. The RING functions of cIAP1 are also required to prevent constitutive activation of non-canonical NF-kappaB by targeting NIK for proteasomal degradation. However, in cIAP double knock-out cells TWEAK was still able to increase NIK levels demonstrating that NIK can be regulated by cIAP-independent pathways. Finally we show that, unlike IAP antagonists, TWEAK was able to induce degradation of cIAP1 RING mutants. These results emphasize the critical importance of the RING of cIAP1 in many signaling scenarios, but also demonstrate that in some pathways RING functions are not required.
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    In TNF-stimulated Cells, RIPK1 Promotes Cell Survival by Stabilizing TRAF2 and cIAP1, which Limits Induction of Non-canonical NF-κB and Activation of Caspase-8
    Gentle, IE ; Wong, WW-L ; Evans, JM ; Bankovacki, A ; Cook, WD ; Khan, NR ; Nachbur, U ; Rickard, J ; Anderton, H ; Moulin, M ; Lluis, JM ; Moujalled, DM ; Silke, J ; Vaux, DL (AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2011-04-15)
    RIPK1 is involved in signaling from TNF and TLR family receptors. After receptor ligation, RIPK1 not only modulates activation of both canonical and NIK-dependent NF-κB, but also regulates caspase-8 activation and cell death. Although overexpression of RIPK1 can cause caspase-8-dependent cell death, when RIPK1(-/-) cells are exposed to TNF and low doses of cycloheximide, they die more readily than wild-type cells, indicating RIPK1 has pro-survival as well as pro-apoptotic activities. To determine how RIPK1 promotes cell survival, we compared wild-type and RIPK1(-/-) cells treated with TNF. Although TRAF2 levels remained constant in TNF-treated wild-type cells, TNF stimulation of RIPK1(-/-) cells caused TRAF2 and cIAP1 to be rapidly degraded by the proteasome, which led to an increase in NIK levels. This resulted in processing of p100 NF-κB2 to p52, a decrease in levels of cFLIP(L), and activation of caspase-8, culminating in cell death. Therefore, the pro-survival effect of RIPK1 is mediated by stabilization of TRAF2 and cIAP1.