58 research outputs found
Calcifediol is a safe and effective metabolite for raising vitamin D status and improving growth and feed conversion in rainbow trout
The vitamin D endocrine system is required for the transcriptional regulation of a myriad of vertebrate genes including those involved in bone health, growth, nutrient metabolism and immunity. The requirements of salmonids for vitamin D are amongst the highest for any aquaculture species. With nuances, the metabolism of the pre-vitamin cholecalciferol (D3) via calcifediol (25-OH-D3), required to produce the physiologically active hormone calcitriol (1,25-OH-D3) is conserved in fish. The composition of modern aquafeeds, growth in seawater and production challenges, such as disease, may result in the suboptimal biochemical activation of vitamin D hormone in fish.
A 91-day experimental feeding trial was used to test the safety and efficacy of calcifediol for the supply of vitamin D to rainbow trout with an initial body weight of 57.6 g. A practical diet containing cholecalciferol within recommended levels (5240 IU) was supplemented with either 69.8, 687 or 6854 μg/kg calcifediol. The efficacy of calcifediol was determined by the assessment of zootechnical performance and the appearance of vitamin D metabolites in the blood. The safety of the dietary interventions was assessed from generic health indices, examination of gross pathologies, hematology, and blood chemistry.
Test fish increased body weight at least 5.6-fold to 323.5 g over the experimental feeding period. The supplementation of 687 or 6854 μg/kg calcifediol resulted in significant improvements in growth rate and feed conversion (FCR). Whilst not detectable in control fish, calcifediol increased linearly according to dietary levels in the blood and to a lesser extent in the white muscle. The increases of calcifediol in the blood were accompanied by saturable increases of circulating active vitamin D. At the end of the 91-day feeding period, survival was 100%, no gross pathologies relating to the diets were observed, and health indices, hematology, and blood chemistry, including calcium and phosphorus, were not significantly altered.
The supplementation of calcifediol to practical diets containing recommended levels of cholecalciferol improves zootechnical performance and ensures that maximal levels of active vitamin D are present in the blood to meet physiological demands. With a lack of significant effects on health indices, hematology, and blood chemistry, including calcium and phosphorus, the tested high doses of calcifediol are concluded to be safe for salmonids
Genome-wide computational identification of WG/GW Argonaute-binding proteins in Arabidopsis
Domains in Arabidopsis proteins NRPE1 and SPT5-like, composed almost exclusively of repeated motifs in which only WG or GW sequences and an overall amino-acid preference are conserved, have been experimentally shown to bind multiple molecules of Argonaute (AGO) protein(s). Domain swapping between the WG/GW domains of NRPE1 and the human protein GW182 showed a conserved function. As classical sequence alignment methods are poorly-adapted to detect such weakly-conserved motifs, we have developed a tool to carry out a systematic analysis to identify genes potentially encoding AGO-binding GW/WG proteins. Here, we describe exhaustive analysis of the Arabidopsis genome for all regions potentially encoding proteins bearing WG/GW motifs and consider the possible role of some of them in AGO-dependent mechanisms. We identified 20 different candidate WG/GW genes, encoding proteins in which the predicted domains range from 92aa to 654aa. These mostly correspond to a limited number of families: RNA-binding proteins, transcription factors, glycine-rich proteins, translation initiation factors and known silencing-associated proteins such as SDE3. Recent studies have argued that the interaction between WG/GW-rich domains and AGO proteins is evolutionarily conserved. Here, we demonstrate by an in silico domain-swapping simulation between plant and mammalian WG/GW proteins that the biased amino-acid composition of the AGO-binding sites is conserved
Spare PRELI Gene Loci: Failsafe Chromosome Insurance?
LEA (late embryogenesis abundant) proteins encode conserved N-terminal mitochondrial signal domains and C-terminal (A/TAEKAK) motif repeats, long-presumed to confer cell resistance to stress and death cues. This prompted the hypothesis that LEA proteins are central to mitochondria mechanisms that connect bioenergetics with cell responses to stress and death signaling. In support of this hypothesis, recent studies have demonstrated that mammalian LEA protein PRELI can act as a biochemical hub, which upholds mitochondria energy metabolism, while concomitantly promoting B cell resistance to stress and induced death. Hence, it is important to define in vivo the physiological relevance of PRELI expression.Given the ubiquitous PRELI expression during mouse development, embryo lethality could be anticipated. Thus, conditional gene targeting was engineered by insertion of flanking loxP (flox)/Cre recognition sites on PRELI chromosome 13 (Chr 13) locus to abort its expression in a tissue-specific manner. After obtaining mouse lines with homozygous PRELI floxed alleles (PRELI(f/f)), the animals were crossed with CD19-driven Cre-recombinase transgenic mice to investigate whether PRELI inactivation could affect B-lymphocyte physiology and survival. Mice with homozygous B cell-specific PRELI deletion (CD19-Cre/Chr13 PRELI(-/-)) bred normally and did not show any signs of morbidity. Histopathology and flow cytometry analyses revealed that cell lineage identity, morphology, and viability were indistinguishable between wild type CD19-Cre/Chr13 PRELI(+/+) and CD19-Cre/Chr13 PRELI(-/-) deficient mice. Furthermore, B cell PRELI gene expression seemed unaffected by Chr13 PRELI gene targeting. However, identification of additional PRELI loci in mouse Chr1 and Chr5 provided an explanation for the paradox between LEA-dependent cytoprotection and the seemingly futile consequences of Chr 13 PRELI gene inactivation. Importantly, PRELI expression from spare gene loci appeared ample to surmount Chr 13 PRELI gene deficiency.These findings suggest that PRELI is a vital LEA B cell protein with failsafe genetics
The De Novo Cytosine Methyltransferase DRM2 Requires Intact UBA Domains and a Catalytically Mutated Paralog DRM3 during RNA–Directed DNA Methylation in Arabidopsis thaliana
Eukaryotic DNA cytosine methylation can be used to transcriptionally silence repetitive sequences, including transposons and retroviruses. This silencing is stable between cell generations as cytosine methylation is maintained epigenetically through DNA replication. The Arabidopsis thaliana Dnmt3 cytosine methyltransferase ortholog DOMAINS REARRANGED METHYLTRANSFERASE2 (DRM2) is required for establishment of small interfering RNA (siRNA) directed DNA methylation. In mammals PIWI proteins and piRNA act in a convergently evolved RNA–directed DNA methylation system that is required to repress transposon expression in the germ line. De novo methylation may also be independent of RNA interference and small RNAs, as in Neurospora crassa. Here we identify a clade of catalytically mutated DRM2 paralogs in flowering plant genomes, which in A.thaliana we term DOMAINS REARRANGED METHYLTRANSFERASE3 (DRM3). Despite being catalytically mutated, DRM3 is required for normal maintenance of non-CG DNA methylation, establishment of RNA–directed DNA methylation triggered by repeat sequences and accumulation of repeat-associated small RNAs. Although the mammalian catalytically inactive Dnmt3L paralogs act in an analogous manner, phylogenetic analysis indicates that the DRM and Dnmt3 protein families diverged independently in plants and animals. We also show by site-directed mutagenesis that both the DRM2 N-terminal UBA domains and C-terminal methyltransferase domain are required for normal RNA–directed DNA methylation, supporting an essential targeting function for the UBA domains. These results suggest that plant and mammalian RNA–directed DNA methylation systems consist of a combination of ancestral and convergent features
IDN2 and Its Paralogs Form a Complex Required for RNA–Directed DNA Methylation
IDN2/RDM12 has been previously identified as a component of the RNA–directed DNA methylation (RdDM) machinery in Arabidopsis thaliana, but how it functions in RdDM remains unknown. By affinity purification of IDN2, we co-purified two IDN2 paralogs IDP1 and IDP2 (IDN2 PARALOG 1 and 2). The coiled-coil domain between the XS and XH domains of IDN2 is essential for IDN2 homodimerization, whereas the IDN2 C-terminal XH domain but not the coiled-coil domain is required for IDN2 interaction with IDP1 and IDP2. By introducing the wild-type IDN2 sequence and its mutated derivatives into the idn2 mutant for complementation testing, we demonstrated that the previously uncharacterized IDN2 XH domain is required for the IDN2-IDP1/IDP2 complex formation as well as for IDN2 function. IDP1 is required for de novo DNA methylation, siRNA accumulation, and transcriptional gene silencing, whereas IDP2 has partially overlapping roles with IDP1. Unlike IDN2, IDP1 and IDP2 are incapable of binding double-stranded RNA, suggesting that the roles of IDP1 and IDP2 are different from those of IDN2 in the IDN2-IDP1/IDP2 complex and that IDP1 and IDP2 are essential for the functioning of the complex in RdDM
Prevalence and incidence of iron deficiency in European community-dwelling older adults : An observational analysis of the DO-HEALTH trial
Background and aim
Iron deficiency is associated with increased morbidity and mortality in older adults. However, data on its prevalence and incidence among older adults is limited. The aim of this study was to investigate the prevalence and incidence of iron deficiency in European community-dwelling older adults aged ≥ 70 years.
Methods
Secondary analysis of the DO-HEALTH trial, a 3-year clinical trial including 2157 community-dwelling adults aged ≥ 70 years from Austria, France, Germany, Portugal and Switzerland. Iron deficiency was defined as soluble transferrin receptor (sTfR) > 28.1 nmol/L. Prevalence and incidence rate (IR) of iron deficiency per 100 person-years were examined overall and stratified by sex, age group, and country. Sensitivity analysis for three commonly used definitions of iron deficiency (ferritin 1.5) were also performed.
Results
Out of 2157 participants, 2141 had sTfR measured at baseline (mean age 74.9 years; 61.5% women). The prevalence of iron deficiency at baseline was 26.8%, and did not differ by sex, but by age (35.6% in age group ≥ 80, 29.3% in age group 75–79, 23.2% in age group 70–74); P 1.5. Occurrences of iron deficiency were observed with IR per 100 person-years of 9.2 (95% CI 8.3–10.1) and did not significantly differ by sex or age group. The highest IR per 100 person-years was observed in Austria (20.8, 95% CI 16.1–26.9), the lowest in Germany (6.1, 95% CI 4.7–8.0). Regarding the other definitions of iron deficiency, the IR per 100 person-years was 4.5 (95% CI 4.0–4.9) for ferritin 1.5.
Conclusions
Iron deficiency is frequent among relatively healthy European older adults, with people aged ≥ 80 years and residence in Austria and Portugal associated with the highest risk
Plant ARGONAUTEs: Features, Functions and Unknowns
ARGONAUTEs (AGOs) are the effector proteins in eukaryotic small RNA(sRNA)–
based gene silencing pathways controlling gene expression and transposon activity. In
plants, AGOs regulate key biological processes such as development, response to
stress, genome structure and integrity, and pathogen defense. Canonical functions of
plant AGO–sRNA complexes include the endonucleolytic cleavage or translational
inhibition of target RNAs, and the methylation of target DNAs. Here, I provide a brief
update on the major features, molecular functions and biological roles of plant AGOs.
A special focus is given to the more recent discoveries related to emerging molecular
or biological functions of plant AGOs, as well as to the major unknowns in the plant
AGO field.This work
was supported by an Individual Fellowship from the European
Union’s Horizon 2020 research and innovation program under
the Marie Skłodowska-Curie grant agreement No. 655841 to A.C.Carbonell Olivares, A. (2017). Plant ARGONAUTEs: Features, Functions and Unknowns. En Plant Argonaute Proteins: Methods and Protocols. Springer Link. 1-21. https://doi.org/10.1007/978-1-4939-7165-7_1121Meister G (2013) Argonaute proteins: functional insights and emerging roles. Nat Rev Genet 14(7):447–459. doi: 10.1038/nrg3462Huntzinger E, Izaurralde E (2011) Gene silencing by microRNAs: contributions of translational repression and mRNA decay. Nat Rev Genet 12(2):99–110. doi: 10.1038/nrg2936Cerutti H, Casas-Mollano JA (2006) On the origin and functions of RNA-mediated silencing: from protists to man. Curr Genet 50(2):81–99. doi: 10.1007/s00294-006-0078-xFang X, Qi Y (2016) RNAi in plants: an argonaute-centered view. Plant Cell 28(2):272–285. doi: 10.1105/tpc1500920Kapoor M, Arora R, Lama T, Nijhawan A, Khurana JP, Tyagi AK, Kapoor S (2008) Genome-wide identification, organization and phylogenetic analysis of Dicer-like, Argonaute and RNA-dependent RNA polymerase gene families and their expression analysis during reproductive development and stress in rice. BMC Genomics 9:451. doi: 10.1186/1471-2164-9-451Morel JB, Godon C, Mourrain P, Beclin C, Boutet S, Feuerbach F, Proux F, Vaucheret H (2002) Fertile hypomorphic ARGONAUTE (ago1) mutants impaired in post-transcriptional gene silencing and virus resistance. Plant Cell 14(3):629–639. doi: 10.1105/tpc010358Yamasaki T, Kim EJ, Cerutti H, Ohama T (2016) Argonaute3 is a key player in miRNA-mediated target cleavage and translational repression in Chlamydomonas. Plant J 85(2):258–268. doi: 10.1111/tpj13107Schroda M (2006) RNA silencing in Chlamydomonas: mechanisms and tools. Curr Genet 49(2):69–84. doi: 10.1007/s00294-005-0042-1Arif MA, Frank W, Khraiwesh B (2013) Role of RNA interference (RNAi) in the moss Physcomitrella patens. Int J Mol Sci 14(1):1516–1540. doi: 10.3390/ijms14011516Zhang H, Xia R, Meyers BC, Walbot V (2015) Evolution, functions, and mysteries of plant ARGONAUTE proteins. Curr Opin Plant Biol 27:84–90. doi: 10.1016/jpbi201506011Chapman EJ, Carrington JC (2007) Specialization and evolution of endogenous small RNA pathways. Nat Rev Genet 8(11):884–896. doi: 10.1038/nrg2179Tolia NH, Joshua-Tor L (2007) Slicer and the argonautes. Nat Chem Biol 3(1):36–43. doi: 10.1038/nchembio848Song JJ, Smith SK, Hannon GJ, Joshua-Tor L (2004) Crystal structure of Argonaute and its implications for RISC slicer activity. Science 305(5689):1434–1437. doi: 10.1126/science1102514Nakanishi K, Weinberg DE, Bartel DP, Patel DJ (2012) Structure of yeast Argonaute with guide RNA. Nature 486(7403):368–374. doi: 10.1038/nature11211Montgomery TA, Howell MD, Cuperus JT, Li D, Hansen JE, Alexander AL, Chapman EJ, Fahlgren N, Allen E, Carrington JC (2008) Specificity of ARGONAUTE7-miR390 interaction and dual functionality in TAS3 trans-acting siRNA formation. Cell 133(1):128–141. doi: 10.1016/jcell200802033Mi S, Cai T, Hu Y, Chen Y, Hodges E, Ni F, Wu L, Li S, Zhou H, Long C, Chen S, Hannon GJ, Qi Y (2008) Sorting of small RNAs into Arabidopsis Argonaute complexes is directed by the 5′ terminal nucleotide. Cell 133(1):116–127. doi: 10.1016/jcell200802034Takeda A, Iwasaki S, Watanabe T, Utsumi M, Watanabe Y (2008) The mechanism selecting the guide strand from small RNA duplexes is different among argonaute proteins. Plant Cell Physiol 49(4):493–500. doi: 10.1093/pcp/pcn043Zhu H, Hu F, Wang R, Zhou X, Sze SH, Liou LW, Barefoot A, Dickman M, Zhang X (2011) Arabidopsis Argonaute10 specifically sequesters miR166/165 to regulate shoot apical meristem development. Cell 145(2):242–256. doi: 10.1016/jcell201103024Zhang X, Niu D, Carbonell A, Wang A, Lee A, Tun V, Wang Z, Carrington JC, Chang CE, Jin H (2014) ARGONAUTE PIWI domain and microRNA duplex structure regulate small RNA sorting in Arabidopsis. Nat Commun 5:5468. doi: 10.1038/ncomms6468Liu J, Carmell MA, Rivas FV, Marsden CG, Thomson JM, Song JJ, Hammond SM, Joshua-Tor L, Hannon GJ (2004) Argonaute2 is the catalytic engine of mammalian RNAi. Science 305(5689):1437–1441. doi: 10.1126/science1102513Sheng G, Zhao H, Wang J, Rao Y, Tian W, Swarts DC, van der Oost J, Patel DJ, Wang Y (2014) Structure-based cleavage mechanism of Thermus thermophilus Argonaute DNA guide strand-mediated DNA target cleavage. Proc Natl Acad Sci U S A 111(2):652–657. doi: 10.1073/pnas1321032111Baumberger N, Baulcombe DC (2005) Arabidopsis ARGONAUTE1 is an RNA slicer that selectively recruits microRNAs and short interfering RNAs. Proc Natl Acad Sci U S A 102(33):11928–11933. doi: 10.1073/pnas0505461102Qi Y, Denli AM, Hannon GJ (2005) Biochemical specialization within Arabidopsis RNA silencing pathways. Mol Cell 19(3):421–428. doi: 10.1016/jmolcel200506014Carbonell A, Fahlgren N, Garcia-Ruiz H, Gilbert KB, Montgomery TA, Nguyen T, Cuperus JT, Carrington JC (2012) Functional analysis of three Arabidopsis ARGONAUTES using slicer-defective mutants. Plant Cell 24(9):3613–3629. doi: 10.1105/tpc112099945Qi Y, He X, Wang XJ, Kohany O, Jurka J, Hannon GJ (2006) Distinct catalytic and non-catalytic roles of ARGONAUTE4 in RNA-directed DNA methylation. Nature 443(7114):1008–1012. doi: 10.1038/nature05198Ji L, Liu X, Yan J, Wang W, Yumul RE, Kim YJ, Dinh TT, Liu J, Cui X, Zheng B, Agarwal M, Liu C, Cao X, Tang G, Chen X (2011) ARGONAUTE10 and ARGONAUTE1 regulate the termination of floral stem cells through two microRNAs in Arabidopsis. PLoS Genet 7(3):e1001358. doi: 10.1371/journalpgen1001358Llave C, Xie Z, Kasschau KD, Carrington JC (2002) Cleavage of Scarecrow-like mRNA targets directed by a class of Arabidopsis miRNA. Science 297(5589):2053–2056. doi: 10.1126/science1076311Rhoades MW, Reinhart BJ, Lim LP, Burge CB, Bartel B, Bartel DP (2002) Prediction of plant microRNA targets. Cell 110(4):513–520. doi: 10.1016/S0092-8674(02)00863-2Mallory AC, Reinhart BJ, Jones-Rhoades MW, Tang G, Zamore PD, Barton MK, Bartel DP (2004) MicroRNA control of PHABULOSA in leaf development: importance of pairing to the microRNA 5′ region. EMBO J 23(16):3356–3364. doi: 10.1038/sjemboj7600340German MA, Pillay M, Jeong DH, Hetawal A, Luo S, Janardhanan P, Kannan V, Rymarquis LA, Nobuta K, German R, De Paoli E, Lu C, Schroth G, Meyers BC, Green PJ (2008) Global identification of microRNA-target RNA pairs by parallel analysis of RNA ends. Nat Biotechnol 26(8):941–946. doi: 10.1038/nbt1417Addo-Quaye C, Eshoo TW, Bartel DP, Axtell MJ (2008) Endogenous siRNA and miRNA targets identified by sequencing of the Arabidopsis degradome. Curr Biol 18(10):758–762. doi: 10.1016/jcub200804042Arribas-Hernandez L, Kielpinski LJ, Brodersen P (2016) mRNA decay of most Arabidopsis miRNA targets requires slicer activity of AGO1. Plant Physiol 171(4):2620–2632. doi: 10.1104/pp.16.00231Cuperus JT, Carbonell A, Fahlgren N, Garcia-Ruiz H, Burke RT, Takeda A, Sullivan CM, Gilbert SD, Montgomery TA, Carrington JC (2010) Unique functionality of 22-nt miRNAs in triggering RDR6-dependent siRNA biogenesis from target transcripts in Arabidopsis. Nat Struct Mol Biol 17(8):997–1003. doi: 10.1038/nsmb1866Montgomery TA, Yoo SJ, Fahlgren N, Gilbert SD, Howell MD, Sullivan CM, Alexander A, Nguyen G, Allen E, Ahn JH, Carrington JC (2008) AGO1-miR173 complex initiates phased siRNA formation in plants. Proc Natl Acad Sci U S A 105(51):20055–20062. doi: 10.1073/pnas0810241105Allen E, Xie Z, Gustafson AM, Carrington JC (2005) microRNA-directed phasing during trans-acting siRNA biogenesis in plants. Cell 121(2):207–221. doi: 10.1016/jcell200504004Yoshikawa M, Peragine A, Park MY, Poethig RS (2005) A pathway for the biogenesis of trans-acting siRNAs in Arabidopsis. Genes Dev 19(18):2164–2175. doi: 10.1101/gad1352605Rajagopalan R, Vaucheret H, Trejo J, Bartel DP (2006) A diverse and evolutionarily fluid set of microRNAs in Arabidopsis thaliana. Genes Dev 20(24):3407–3425. doi: 10.1101/gad1476406Arribas-Hernandez L, Marchais A, Poulsen C, Haase B, Hauptmann J, Benes V, Meister G, Brodersen P (2016) The slicer activity of ARGONAUTE1 Is required specifically for the phasing, not production, of trans-acting short interfering RNAs in Arabidopsis. Plant Cell 28(7):1563–1580. doi: 10.1105/tpc1600121Brodersen P, Sakvarelidze-Achard L, Bruun-Rasmussen M, Dunoyer P, Yamamoto YY, Sieburth L, Voinnet O (2008) Widespread translational inhibition by plant miRNAs and siRNAs. Science 320(5880):1185–1190. doi: 10.1126/science1159151Li S, Le B, Ma X, Li S, You C, Yu Y, Zhang B, Liu L, Gao L, Shi T, Zhao Y, Mo B, Cao X, Chen X (2016) Biogenesis of phased siRNAs on membrane-bound polysomes in Arabidopsis. Elife 5:e22750. doi: 10.7554/eLife22750Zeng Y, Yi R, Cullen BR (2003) MicroRNAs and small interfering RNAs can inhibit mRNA expression by similar mechanisms. Proc Natl Acad Sci U S A 100(17):9779–9784. doi: 10.1073/pnas1630797100Iwakawa HO, Tomari Y (2013) Molecular insights into microRNA-mediated translational repression in plants. Mol Cell 52(4):591–601. doi: 10.1016/jmolcel201310033Li S, Liu L, Zhuang X, Yu Y, Liu X, Cui X, Ji L, Pan Z, Cao X, Mo B, Zhang F, Raikhel N, Jiang L, Chen X (2013) MicroRNAs inhibit the translation of target mRNAs on the endoplasmic reticulum in Arabidopsis. Cell 153(3):562–574. doi: 10.1016/jcell201304005Li JF, Chung HS, Niu Y, Bush J, McCormack M, Sheen J (2013) Comprehensive protein-based artificial microRNA screens for effective gene silencing in plants. Plant Cell 25(5):1507–1522. doi: 10.1105/tpc113112235Liu MJ, SH W, JF W, Lin WD, YC W, Tsai TY, Tsai HL, SH W (2013) Translational landscape of photomorphogenic Arabidopsis. Plant Cell 25(10):3699–3710. doi: 10.1105/tpc113114769Aukerman MJ, Sakai H (2003) Regulation of flowering time and floral organ identity by a microRNA and its APETALA2-like target genes. Plant Cell 15(11):2730–2741. doi: 10.1105/tpc016238Chen X (2004) A microRNA as a translational repressor of APETALA2 in Arabidopsis flower development. Science 303(5666):2022–2025. doi: 10.1126/science1088060Gandikota M, Birkenbihl RP, Hohmann S, Cardon GH, Saedler H, Huijser P (2007) The miRNA156/157 recognition element in the 3′ UTR of the Arabidopsis SBP box gene SPL3 prevents early flowering by translational inhibition in seedlings. Plant J 49(4):683–693. doi: 10.1111/j1365-313X200602983xYang L, Wu G, Poethig RS (2012) Mutations in the GW-repeat protein SUO reveal a developmental function for microRNA-mediated translational repression in Arabidopsis. Proc Natl Acad Sci U S A 109(1):315–320. doi: 10.1073/pnas1114673109Mallory AC, Hinze A, Tucker MR, Bouche N, Gasciolli V, Elmayan T, Lauressergues D, Jauvion V, Vaucheret H, Laux T (2009) Redundant and specific roles of the ARGONAUTE proteins AGO1 and ZLL in development and small RNA-directed gene silencing. PLoS Genet 5(9):e1000646. doi: 10.1371/journalpgen1000646Hou CY, Lee WC, Chou HC, Chen AP, Chou SJ, Chen HM (2016) Global analysis of truncated RNA ends reveals new insights into ribosome stalling in plants. Plant Cell 28(10):2398–2416. doi: 10.1105/tpc1600295Rogers K, Chen X (2013) Biogenesis, turnover, and mode of action of plant microRNAs. Plant Cell 25(7):2383–2399. doi: 10.1105/tpc113113159Behm-Ansmant I, Rehwinkel J, Doerks T, Stark A, Bork P, Izaurralde E (2006) mRNA degradation by miRNAs and GW182 requires both CCR4:NOT deadenylase and DCP1:DCP2 decapping complexes. Genes Dev 20(14):1885–1898. doi: 10.1101/gad1424106Wu L, Fan J, Belasco JG (2006) MicroRNAs direct rapid deadenylation of mRNA. Proc Natl Acad Sci U S A 103(11):4034–4039. doi: 10.1073/pnas0510928103Schirle NT, MacRae IJ (2012) The crystal structure of human Argonaute2. Science 336(6084):1037–1040. doi: 10.1126/science1221551Pfaff J, Hennig J, Herzog F, Aebersold R, Sattler M, Niessing D, Meister G (2013) Structural features of Argonaute-GW182 protein interactions. Proc Natl Acad Sci U S A 110(40):E3770–E3779. doi: 10.1073/pnas1308510110Ma X, Kim EJ, Kook I, Ma F, Voshall A, Moriyama E, Cerutti H (2013) Small interfering RNA-mediated translation repression alters ribosome sensitivity to inhibition by cycloheximide in Chlamydomonas reinhardtii. Plant Cell 25(3):985–998. doi: 10.1105/tpc113109256Law JA, Jacobsen SE (2010) Establishing, maintaining and modifying DNA methylation patterns in plants and animals. Nat Rev Genet 11(3):204–220. doi: 10.1038/nrg2719Xie Z, Johansen LK, Gustafson AM, Kasschau KD, Lellis AD, Zilberman D, Jacobsen SE, Carrington JC (2004) Genetic and functional diversification of small RNA pathways in plants. PLoS Biol 2(5):E104. doi: 10.1371/journalpbio0020104Herr AJ, Jensen MB, Dalmay T, Baulcombe DC (2005) RNA polymerase IV directs silencing of endogenous DNA. Science 308(5718):118–120. doi: 10.1126/science1106910Kanno T, Huettel B, Mette MF, Aufsatz W, Jaligot E, Daxinger L, Kreil DP, Matzke M, Matzke AJ (2005) Atypical RNA polymerase subunits required for RNA-directed DNA methylation. Nat Genet 37(7):761–765. doi: 10.1038/ng1580Onodera Y, Haag JR, Ream T, Costa Nunes P, Pontes O, Pikaard CS (2005) Plant nuclear RNA polymerase IV mediates siRNA and DNA methylation-dependent heterochromatin formation. Cell 120(5):613–622. doi: 10.1016/jcell200502007Haag JR, Ream TS, Marasco M, Nicora CD, Norbeck AD, Pasa-Tolic L, Pikaard CS (2012) In vitro transcription activities of Pol IV, Pol V, and RDR2 reveal coupling of Pol IV and RDR2 for dsRNA synthesis in plant RNA silencing. Mol Cell 48(5):811–818. doi: 10.1016/jmolcel201209027Pontes O, Li CF, Costa Nunes P, Haag J, Ream T, Vitins A, Jacobsen SE, Pikaard CS (2006) The Arabidopsis chromatin-modifying nuclear siRNA pathway involves a nucleolar RNA processing center. Cell 126(1):79–92. doi: 10.1016/jcell200605031Li CF, Pontes O, El-Shami M, Henderson IR, Bernatavichute YV, Chan SW, Lagrange T, Pikaard CS, Jacobsen SE (2006) An ARGONAUTE4-containing nuclear processing center colocalized with Cajal bodies in Arabidopsis thaliana. Cell 126(1):93–106. doi: 10.1016/jcell200605032El-Shami M, Pontier D, Lahmy S, Braun L, Picart C, Vega D, Hakimi MA, Jacobsen SE, Cooke R, Lagrange T (2007) Reiterated WG/GW motifs form functionally and evolutionarily conserved ARGONAUTE-binding platforms in RNAi-related components. Genes Dev 21(20):2539–2544. doi: 10.1101/gad451207Li CF, Henderson IR, Song L, Fedoroff N, Lagrange T, Jacobsen SE (2008) Dynamic regulation of ARGONAUTE4 within multiple nuclear bodies in Arabidopsis thaliana. PLoS Genet 4(2):e27. doi: 10.1371/journalpgen0040027Bies-Etheve N, Pontier D, Lahmy S, Picart C, Vega D, Cooke R, Lagrange T (2009) RNA-directed DNA methylation requires an AGO4-interacting member of the SPT5 elongation factor family. EMBO Rep 10(6):649–654. doi: 10.1038/embor200931He XJ, Hsu YF, Zhu S, Wierzbicki AT, Pontes O, Pikaard CS, Liu HL, Wang CS, Jin H, Zhu JK (2009) An effector of RNA-directed DNA methylation in Arabidopsis is an ARGONAUTE 4- and RNA-binding protein. Cell 137(3):498–508. doi: 10.1016/jcell200904028Zhong X, Du J, Hale CJ, Gallego-Bartolome J, Feng S, Vashisht AA, Chory J, Wohlschlegel JA, Patel DJ, Jacobsen SE (2014) Molecular mechanism of action of plant DRM de novo DNA methyltransferases. Cell 157(5):1050–1060. doi: 10.1016/jcell201403056Cao X, Jacobsen SE (2002) Locus-specific control of asymmetric and CpNpG methylation by the DRM and CMT3 methyltransferase genes. Proc Natl Acad Sci U S A 99(Suppl 4):16491–16498. doi: 10.1073/pnas162371599Lahmy S, Pontier D, Bies-Etheve N, Laudie M, Feng S, Jobet E, Hale CJ, Cooke R, Hakimi MA, Angelov D, Jacobsen SE, Lagrange T (2016) Evidence for ARGONAUTE4-DNA interactions in RNA-directed DNA methylation in plants. Genes Dev 30(23):2565–2570. doi: 10.1101/gad289553116Zheng X, Zhu J, Kapoor A, Zhu JK (2007) Role of Arabidopsis AGO6 in siRNA accumulation, DNA methylation and transcriptional gene silencing. EMBO J 26(6):1691–1701. doi: 10.1038/sjemboj7601603Havecker ER, Wallbridge LM, Hardcastle TJ, Bush MS, Kelly KA, Dunn RM, Schwach F, Doonan JH, Baulcombe DC (2010) The Arabidopsis RNA-directed DNA methylation Argonautes functionally diverge based on their expression and interaction with target loci. Plant Cell 22(2):321–334. doi: 10.1105/tpc109072199Eun C, Lorkovic ZJ, Naumann U, Long Q, Havecker ER, Simon SA, Meyers BC, Matzke AJ, Matzke M (2011) AGO6 functions in RNA-mediated transcriptional gene silencing in shoot and root meristems in Arabidopsis thaliana. PLoS One 6(10):e25730. doi: 10.1371/journalpone0025730Duan CG, Zhang H, Tang K, Zhu X, Qian W, Hou YJ, Wang B, Lang Z, Zhao Y, Wang X, Wang P, Zhou J, Liang G, Liu N, Wang C, Zhu JK (2015) Specific but interdependent functions for Arabidopsis AGO4 and AGO6 in RNA-directed DNA methylation. EMBO J 34(5):581–592. doi: 10.15252/embj201489453McCue AD, Panda K, Nuthikattu S, Choudury SG, Thomas EN, Slotkin RK (2015) ARGONAUTE 6 bridges transposable element mRNA-derived siRNAs to the establishment of DNA methylation. EMBO J 34(1):20–35. doi: 10.15252/embj201489499Zhang Z, Liu X, Guo X, Wang XJ, Zhang X (2016) Arabidopsis AGO3 predominantly recruits 24-nt small RNAs to regulate epigenetic silencing. Nat Plants 2(5):16049. doi: 10.1038/nplants201649Wu J, Yang Z, Wang Y, Zheng L, Ye R, Ji Y, Zhao S, Ji S, Liu R, Xu L, Zheng H, Zhou Y, Zhang X, Cao X, Xie L, Wu Z, Qi Y, Li Y (2015) Viral-inducible Argonaute18 confers broad-spectrum virus resistance in rice by sequestering a host microRNA. Elife 4:05733. doi: 10.7554/eLife05733Wu J, Yang R, Yang Z, Yao S, Zhao S, Wang Y, Li P, Song X, Jin L, Zhou T, Lan Y, Xie L, Zhou X, Chu C, Qi Y, Cao X, Li Y (2017) ROS accumulation and antiviral defence control by microRNA528 in rice. Nat Plants 3:16203. doi: 10.1038/nplants2016203Wei W, Ba Z, Gao M, Wu Y, Ma Y, Amiard S, White CI, Rendtlew Danielsen JM, Yang YG, Qi Y (2012) A role for small RNAs in DNA double-strand break repair. Cell 149(1):101–112. doi: 10.1016/jcell201203002Oliver C, Santos JL, Pradillo M (2014) On the role of some ARGONAUTE proteins in meiosis and DNA repair in Arabidopsis thaliana. Front Plant Sci 5:177. doi: 10.3389/fpls201400177Ye R, Chen Z, Lian B, Rowley MJ, Xia N, Chai J, Li Y, He XJ, Wierzbicki AT, Qi Y (2016) A Dicer-independent route for biogenesis of siRNAs that direct DNA methylation in Arabidopsis. Mol Cell 61(2):222–235. doi: 10.1016/jmolcel201511015Dolata J, Bajczyk M, Bielewicz D, Niedojadlo K, Niedojadlo J, Pietrykowska H, Walczak W, Szweykowska-Kulinska Z, Jarmolowski A (2016) Salt stress reveals a new role for ARGONAUTE1 in miRNA biogenesis at the transcriptional and posttranscriptional levels. Plant Physiol 172(1):297–312. doi: 10.1104/pp1600830Singh RK, Gase K, Baldwin IT, Pandey SP (2015) Molecular evolution and diversification of the Argonaute family of proteins in plants. BMC Plant Biol 15(1):23. doi: 10.1186/s12870-014-0364-6Singh RK, Pandey SP (2015) Evolution of structural and functional diversification among plant Argonautes. Plant Signal Behav 10(10):e1069455. doi: 10.1080/1559232420151069455Bohmert K, Camus I, Bellini C, Bouchez D, Caboche M, Benning C (1998) AGO1 defines a novel locus of Arabidopsis controlling leaf development. EMBO J 17(1):170–180. doi: 10.1093/emboj/171170Kidner CA, Martienssen RA (2004) Spatially restricted microRNA directs leaf polarity through ARGONAUTE1. Nature 428(6978):81–84. doi: 10.1038/nature02366Sorin C, Bussell JD, Camus I, Ljung K, Kowalczyk M, Geiss G, McKhann H, Garcion C, Vaucheret H, Sandberg G, Bellini C (2005) Auxin and light control of adventitious rooting in Arabidopsis require ARGONAUTE1. Plant Cell 17(5):1343–1359. doi: 10.1105/tpc105031625Yang L, Huang W, Wang H, Cai R, Xu Y, Huang H (2006) Characterizations of a hypomorphic argonaute1 mutant reveal novel AGO1 functions in Arabidopsis lateral organ development. Plant Mol Biol 61(1-2):63–78. doi: 10.1007/s11103-005-5992-7Kidner CA, Martienssen RA (2005) The developmental role of microRNA in plants. Curr Opin Plant Biol 8(1):38–44. doi: 10.1016/jpbi200411008Wu L, Zhang Q, Zhou H, Ni F, Wu X, Qi Y (2009) Rice microRNA effector complexes and targets. Plant Cell 21(11):3421–3435. doi: 10.1105/tpc109070938Vaucheret H (2008) Plant ARGONAUTES. Trends Plant Sci 13(7):350–358. doi: 10.1016/jtplants200804007Hunter C, Sun H, Poethig RS (2003) The Arabidopsis heterochronic gene ZIPPY is an ARGONAUTE family member. Curr Biol 13(19):1734–1739Adenot X, Elmayan T, Lauressergues D, Boutet S, Bouche N, Gasciolli V, Vaucheret H (2006) DRB4-dependent TAS3 trans-acting siRNAs control leaf morphology through AGO7. Curr Biol 16(9):927–932. doi: 10.1016/jcub200603035Fahlgren N, Montgomery TA, Howell MD, Allen E, Dvorak SK, Alexander AL, Carrington JC (2006) Regulation of AUXIN RESPONSE FACTOR3 by TAS3 ta-siRNA affects developmental timing and patterning in Arabidopsis. Curr Biol 16(9):939–944. doi: 10.1016/jcub200603065Axtell MJ, Jan C, Rajagopalan R, Bartel DP (2006) A two-hit trigger for siRNA biogenesis in plants. Cell 127(3):565–577. doi: 10.1016/jcell200609032Hunter C, Willmann MR, Wu G, Yoshikawa M, de la Luz G-NM, Poethig SR (2006) Trans-acting siRNA-mediated repre
Prevalence and incidence of iron deficiency in European community-dwelling older adults: an observational analysis of the DO-HEALTH trial
Background and aim
Iron deficiency is associated with increased morbidity and mortality in older adults. However, data on its prevalence and incidence among older adults is limited. The aim of this study was to investigate the prevalence and incidence of iron deficiency in European community-dwelling older adults aged ≥ 70 years.
Methods
Secondary analysis of the DO-HEALTH trial, a 3-year clinical trial including 2157 community-dwelling adults aged ≥ 70 years from Austria, France, Germany, Portugal and Switzerland. Iron deficiency was defined as soluble transferrin receptor (sTfR) > 28.1 nmol/L. Prevalence and incidence rate (IR) of iron deficiency per 100 person-years were examined overall and stratified by sex, age group, and country. Sensitivity analysis for three commonly used definitions of iron deficiency (ferritin 1.5) were also performed.
Results
Out of 2157 participants, 2141 had sTfR measured at baseline (mean age 74.9 years; 61.5% women). The prevalence of iron deficiency at baseline was 26.8%, and did not differ by sex, but by age (35.6% in age group ≥ 80, 29.3% in age group 75–79, 23.2% in age group 70–74); P 1.5. Occurrences of iron deficiency were observed with IR per 100 person-years of 9.2 (95% CI 8.3–10.1) and did not significantly differ by sex or age group. The highest IR per 100 person-years was observed in Austria (20.8, 95% CI 16.1–26.9), the lowest in Germany (6.1, 95% CI 4.7–8.0). Regarding the other definitions of iron deficiency, the IR per 100 person-years was 4.5 (95% CI 4.0–4.9) for ferritin 1.5.
Conclusions
Iron deficiency is frequent among relatively healthy European older adults, with people aged ≥ 80 years and residence in Austria and Portugal associated with the highest risk
gem-Difluorocarbadisaccharides: Restoring the exo-Anomeric Effect
International audienceMolecular mimicry is an essential part of the development of drugs and molecular probes. In the chemical glycobiology field, although many glycomimetics have been developed in the past years, it has been considered that many failures in their use are related to the lack of the anomeric effects in these analogues. Additionally, the origin of the anomeric effects is still the subject of virulent scientific debates. Herein, by combining chemical synthesis, NMR methods, and theoretical calculations, we show that it is possible to restore the anomeric effect for an acetal when replacing one of the oxygen atoms by a CF2 group. This result provides key findings in chemical sciences. On the one hand, it strongly suggests the key relevance of the stereoelectronic component of the anomeric effect. On the other hand, the CF2 analogue adopts the natural glycoside conformation, which might provide new avenues for sugar-based drug design. Molecular mimicry is an essential part of the development of drugs and molecular probes. In the chemical glycobiology field, although many glycomimetics have been developed in the past years, it has been considered that many failures in their use are related to the lack of the anomeric effects in these analogues. Additionally, the origin of the anomeric effects is still the subject of virulent scientific debates. Herein, by combining chemical synthesis, NMR methods, and theoretical calculations, we show that it is possible to restore the anomeric effect for an acetal when replacing one of the oxygen atoms by a CF2 group. This result provides key findings in chemical sciences. On the one hand, it strongly suggests the key relevance of the stereoelectronic component of the anomeric effect. On the other hand, the CF2 analogue adopts the natural glycoside conformation, which might provide new avenues for sugar-based drug design
- …