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    Emerging connectivity of programmed cell death pathways and its physiological implications
    Bedoui, S ; Herold, MJ ; Strasser, A (Nature Research, 2020-11)
    The removal of functionally dispensable, infected or potentially neoplastic cells is driven by programmed cell death (PCD) pathways, highlighting their important roles in homeostasis, host defence against pathogens, cancer and a range of other pathologies. Several types of PCD pathways have been described, including apoptosis, necroptosis and pyroptosis; they employ distinct molecular and cellular processes and differ in their outcomes, such as the capacity to trigger inflammatory responses. Recent genetic and biochemical studies have revealed remarkable flexibility in the use of these PCD pathways and indicate a considerable degree of plasticity in their molecular regulation; for example, despite having a primary role in inducing pyroptosis, inflammatory caspases can also induce apoptosis, and conversely, apoptotic stimuli can trigger pyroptosis. Intriguingly, this flexibility is most pronounced in cellular responses to infection, while apoptosis is the dominant cell death process through which organisms prevent the development of cancer. In this Review, we summarize the mechanisms of the different types of PCD and describe the physiological and pathological processes that engage crosstalk between these pathways, focusing on infections and cancer. We discuss the intriguing notion that the different types of PCD could be seen as a single, coordinated cell death system, in which the individual pathways are highly interconnected and can flexibly compensate for one another.
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    Display of Native Antigen on cDC1 That Have Spatial Access to Both T and B Cells Underlies Efficient Humoral Vaccination.
    Kato, Y ; Steiner, TM ; Park, H-Y ; Hitchcock, RO ; Zaid, A ; Hor, JL ; Devi, S ; Davey, GM ; Vremec, D ; Tullett, KM ; Tan, PS ; Ahmet, F ; Mueller, SN ; Alonso, S ; Tarlinton, DM ; Ploegh, HL ; Kaisho, T ; Beattie, L ; Manton, JH ; Fernandez-Ruiz, D ; Shortman, K ; Lahoud, MH ; Heath, WR ; Caminschi, I (American Association of Immunologists, 2020-10-01)
    Follicular dendritic cells and macrophages have been strongly implicated in presentation of native Ag to B cells. This property has also occasionally been attributed to conventional dendritic cells (cDC) but is generally masked by their essential role in T cell priming. cDC can be divided into two main subsets, cDC1 and cDC2, with recent evidence suggesting that cDC2 are primarily responsible for initiating B cell and T follicular helper responses. This conclusion is, however, at odds with evidence that targeting Ag to Clec9A (DNGR1), expressed by cDC1, induces strong humoral responses. In this study, we reveal that murine cDC1 interact extensively with B cells at the border of B cell follicles and, when Ag is targeted to Clec9A, can display native Ag for B cell activation. This leads to efficient induction of humoral immunity. Our findings indicate that surface display of native Ag on cDC with access to both T and B cells is key to efficient humoral vaccination.
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    HBO1 (KAT7) Does Not Have an Essential Role in Cell Proliferation, DNA Replication, or Histone 4 Acetylation in Human Cells
    Kueh, AJ ; Eccles, S ; Tang, L ; Garnham, AL ; May, RE ; Herold, MJ ; Smyth, GK ; Voss, AK ; Thomas, T (American Society for Microbiology, 2020-02-01)
    HBO1 (MYST2/KAT7) is essential for histone 3 lysine 14 acetylation (H3K14ac) but is dispensable for H4 acetylation and DNA replication in mouse tissues. In contrast, previous studies using small interfering RNA (siRNA) knockdown in human cell lines have suggested that HBO1 is essential for DNA replication. To determine if HBO1 has distinctly different roles in immortalized human cell lines and normal mouse cells, we performed siRNA knockdown of HBO1. In addition, we used CRISPR/Cas9 to generate 293T, MCF7, and HeLa cell lines lacking HBO1. Using both techniques, we show that HBO1 is essential for all H3K14ac in human cells and is unlikely to have a direct effect on H4 acetylation and only has minor effects on cell proliferation. Surprisingly, the loss of HBO1 and H3K14ac in HeLa cells led to the secondary loss of almost all H4 acetylation after 4 weeks. Thus, HBO1 is dispensable for DNA replication and cell proliferation in immortalized human cells. However, while cell proliferation proceeded without HBO1 and H3K14ac, HBO1 gene deletion led to profound changes in cell adhesion, particularly in 293T cells. Consistent with this phenotype, the loss of HBO1 in both 293T and HeLa principally affected genes mediating cell adhesion, with comparatively minor effects on other cellular processes.
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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.