-
Články
- Časopisy
- Kurzy
- Témy
- Kongresy
- Videa
- Podcasty
Microevolution of in Macrophages Restores Filamentation in a Nonfilamentous Mutant
Pathogenic microbes often evolve complex traits to adapt to their respective hosts, and this evolution is ongoing: for example, microorganisms are developing resistance to antimicrobial compounds in the clinical setting. The ability of the common human pathogenic fungus, Candida albicans, to switch from yeast to hyphal (filamentous) growth is considered a central virulence attribute. For example, hyphal formation allows C. albicans to escape from macrophages following phagocytosis. A well-investigated signaling network integrates different environmental cues to induce and maintain hyphal growth. In fact, deletion of two central transcription factors in this network results in a mutant that is both nonfilamentous and avirulent. We used experimental evolution to study the adaptation capability of this mutant by continuous co-incubation within macrophages. We found that this selection regime led to a relatively rapid re-connection of signaling between environmental cues and the hyphal growth program. Indeed, the evolved mutant regained the ability to filament and its virulence in vivo. This bypass of central transcription factors was based on a single nucleotide exchange in a gene encoding a component of the general transcription regulation machinery. Our results show that even a complex regulatory network, such as the transcriptional network which governs hyphal growth, can be remodeled via microevolution.
Vyšlo v časopise: Microevolution of in Macrophages Restores Filamentation in a Nonfilamentous Mutant. PLoS Genet 10(12): e32767. doi:10.1371/journal.pgen.1004824
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004824Souhrn
Pathogenic microbes often evolve complex traits to adapt to their respective hosts, and this evolution is ongoing: for example, microorganisms are developing resistance to antimicrobial compounds in the clinical setting. The ability of the common human pathogenic fungus, Candida albicans, to switch from yeast to hyphal (filamentous) growth is considered a central virulence attribute. For example, hyphal formation allows C. albicans to escape from macrophages following phagocytosis. A well-investigated signaling network integrates different environmental cues to induce and maintain hyphal growth. In fact, deletion of two central transcription factors in this network results in a mutant that is both nonfilamentous and avirulent. We used experimental evolution to study the adaptation capability of this mutant by continuous co-incubation within macrophages. We found that this selection regime led to a relatively rapid re-connection of signaling between environmental cues and the hyphal growth program. Indeed, the evolved mutant regained the ability to filament and its virulence in vivo. This bypass of central transcription factors was based on a single nucleotide exchange in a gene encoding a component of the general transcription regulation machinery. Our results show that even a complex regulatory network, such as the transcriptional network which governs hyphal growth, can be remodeled via microevolution.
Zdroje
1. PfallerMA, DiekemaDJ (2007) Epidemiology of invasive candidiasis: a persistent public health problem. Clin Microbiol Rev 20 : 133–163.
2. KumamotoCA, VincesMD (2005) Contributions of hyphae and hypha-co-regulated genes to Candida albicans virulence. Cell Microbiol 7 : 1546–1554.
3. EneIV, BrunkeS, BrownAJ, HubeB (2014) Metabolism in Fungal Pathogenesis. Cold Spring Harb Perspect Med
4. KvaalCA, SrikanthaT, SollDR (1997) Misexpression of the white-phase-specific gene WH11 in the opaque phase of Candida albicans affects switching and virulence. Infect Immun 65 : 4468–4475.
5. MayerFL, WilsonD, HubeB (2013) Candida albicans pathogenicity mechanisms. Virulence 4 : 119–128.
6. van de VeerdonkFL, PlantingaTS, HoischenA, SmeekensSP, JoostenLA, et al. (2011) STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis. N Engl J Med 365 : 54–61.
7. van EnckevortFH, NeteaMG, HermusAR, SweepCG, MeisJF, et al. (1999) Increased susceptibility to systemic candidiasis in interleukin-6 deficient mice. Med Mycol 37 : 419–426.
8. WhiteTC, PfallerMA, RinaldiMG, SmithJ, ReddingSW (1997) Stable azole drug resistance associated with a substrain of Candida albicans from an HIV-infected patient. Oral Dis 3 Suppl 1: S102–109.
9. Rustchenko-BulgacEP, ShermanF, HicksJB (1990) Chromosomal rearrangements associated with morphological mutants provide a means for genetic variation of Candida albicans. J Bacteriol 172 : 1276–1283.
10. ShinJH, ParkMR, SongJW, ShinDH, JungSI, et al. (2004) Microevolution of Candida albicans strains during catheter-related candidemia. J Clin Microbiol 42 : 4025–4031.
11. TsongAE, TuchBB, LiH, JohnsonAD (2006) Evolution of alternative transcriptional circuits with identical logic. Nature 443 : 415–420.
12. TuchBB, GalgoczyDJ, HerndayAD, LiH, JohnsonAD (2008) The evolution of combinatorial gene regulation in fungi. PLoS Biol 6: e38.
13. ForcheA, MageePT, SelmeckiA, BermanJ, MayG (2009) Evolution in Candida albicans populations during a single passage through a mouse host. Genetics 182 : 799–811.
14. SudberyPE (2011) Growth of Candida albicans hyphae. Nat Rev Microbiol 9 : 737–748.
15. JacobsenID, WilsonD, WächtlerB, BrunkeS, NaglikJR, et al. (2012) Candida albicans dimorphism as a therapeutic target. Expert Rev Anti Infect Ther 10 : 85–93.
16. FillerSG, SheppardDC (2006) Fungal invasion of normally non-phagocytic host cells. PLoS Pathog 2: e129.
17. WächtlerB, WilsonD, HaedickeK, DalleF, HubeB (2011) From attachment to damage: defined genes of Candida albicans mediate adhesion, invasion and damage during interaction with oral epithelial cells. PLoS One 6: e17046.
18. WellingtonM, KoselnyK, SutterwalaFS, KrysanDJ (2014) Candida albicans triggers NLRP3-mediated pyroptosis in macrophages. Eukaryot Cell 13 : 329–340.
19. UwamahoroN, Verma-GaurJ, ShenHH, QuY, LewisR, et al. (2014) The pathogen Candida albicans hijacks pyroptosis for escape from macrophages. MBio 5: e00003–00014.
20. LorenzMC, BenderJA, FinkGR (2004) Transcriptional response of Candida albicans upon internalization by macrophages. Eukaryot Cell 3 : 1076–1087.
21. GowNA, van de VeerdonkFL, BrownAJ, NeteaMG (2011) Candida albicans morphogenesis and host defence: discriminating invasion from colonization. Nat Rev Microbiol 10 : 112–122.
22. LoHJ, KöhlerJR, DiDomenicoB, LoebenbergD, CacciapuotiA, et al. (1997) Nonfilamentous C. albicans mutants are avirulent. Cell 90 : 939–949.
23. StoldtVR, SonnebornA, LeukerCE, ErnstJF (1997) Efg1p, an essential regulator of morphogenesis of the human pathogen Candida albicans, is a member of a conserved class of bHLH proteins regulating morphogenetic processes in fungi. Embo J 16 : 1982–1991.
24. DoedtT, KrishnamurthyS, BockmühlDP, TebarthB, StempelC, et al. (2004) APSES proteins regulate morphogenesis and metabolism in Candida albicans. Mol Biol Cell 15 : 3167–3180.
25. MartinSW, KonopkaJB (2004) Lipid raft polarization contributes to hyphal growth in Candida albicans. Eukaryot Cell 3 : 675–684.
26. Merson-DaviesLA, OddsFC (1989) A morphology index for characterization of cell shape in Candida albicans. J Gen Microbiol 135 : 3143–3152.
27. MartinR, MoranGP, JacobsenID, HeykenA, DomeyJ, et al. (2011) The Candida albicans-specific gene EED1 encodes a key regulator of hyphal extension. PLoS One 6: e18394.
28. ZhaoX, OhSH, ChengG, GreenCB, NuessenJA, et al. (2004) ALS3 and ALS8 represent a single locus that encodes a Candida albicans adhesin; functional comparisons between Als3p and Als1p. Microbiology 150 : 2415–2428.
29. NobileCJ, FoxEP, NettJE, SorrellsTR, MitrovichQM, et al. (2012) A recently evolved transcriptional network controls biofilm development in Candida albicans. Cell 148 : 126–138.
30. BrownDHJr, GiusaniAD, ChenX, KumamotoCA (1999) Filamentous growth of Candida albicans in response to physical environmental cues and its regulation by the unique CZF1 gene. Mol Microbiol 34 : 651–662.
31. BanerjeeM, ThompsonDS, LazzellA, CarlislePL, PierceC, et al. (2008) UME6, a novel filament-specific regulator of Candida albicans hyphal extension and virulence. Mol Biol Cell 19 : 1354–1365.
32. ZavrelM, MajerO, KuchlerK, RuppS (2012) Transcription factor Efg1 shows a haploinsufficiency phenotype in modulating the cell wall architecture and immunogenicity of Candida albicans. Eukaryot Cell 11 : 129–140.
33. GowNA, HubeB (2012) Importance of the Candida albicans cell wall during commensalism and infection. Curr Opin Microbiol 15 : 406–412.
34. EismanB, Alonso-MongeR, RomanE, AranaD, NombelaC, et al. (2006) The Cek1 and Hog1 mitogen-activated protein kinases play complementary roles in cell wall biogenesis and chlamydospore formation in the fungal pathogen Candida albicans. Eukaryot Cell 5 : 347–358.
35. Navarro-GarciaF, Alonso-MongeR, RicoH, PlaJ, SentandreuR, et al. (1998) A role for the MAP kinase gene MKC1 in cell wall construction and morphological transitions in Candida albicans. Microbiology 144 (Pt 2) 411–424.
36. RomanE, NombelaC, PlaJ (2005) The Sho1 adaptor protein links oxidative stress to morphogenesis and cell wall biosynthesis in the fungal pathogen Candida albicans. Mol Cell Biol 25 : 10611–10627.
37. BrunoVM, WangZ, MarjaniSL, EuskirchenGM, MartinJ, et al. (2010) Comprehensive annotation of the transcriptome of the human fungal pathogen Candida albicans using RNA-seq. Genome Res 20 : 1451–1458.
38. MartinR, Albrecht-EckardtD, BrunkeS, HubeB, HünnigerK, et al. (2013) A core filamentation response network in Candida albicans is restricted to eight genes. PLoS One 8: e58613.
39. PierceJV, DignardD, WhitewayM, KumamotoCA (2013) Normal adaptation of Candida albicans to the murine gastrointestinal tract requires Efg1p-dependent regulation of metabolic and host defense genes. Eukaryot Cell 12 : 37–49.
40. SamaranayakeYH, CheungBP, YauJY, YeungSK, SamaranayakeLP (2013) Human serum promotes Candida albicans biofilm growth and virulence gene expression on silicone biomaterial. PLoS One 8: e62902.
41. HopeH, SchmauchC, ArkowitzRA, BassilanaM (2010) The Candida albicans ELMO homologue functions together with Rac1 and Dck1, upstream of the MAP Kinase Cek1, in invasive filamentous growth. Mol Microbiol 76 : 1572–1590.
42. BraunBR, KadoshD, JohnsonAD (2001) NRG1, a repressor of filamentous growth in C.albicans, is down-regulated during filament induction. Embo J 20 : 4753–4761.
43. MuradAM, LengP, StraffonM, WishartJ, MacaskillS, et al. (2001) NRG1 represses yeast-hypha morphogenesis and hypha-specific gene expression in Candida albicans. Embo J 20 : 4742–4752.
44. ForcheA, AbbeyD, PisithkulT, WeinzierlMA, RingstromT, et al. (2011) Stress alters rates and types of loss of heterozygosity in Candida albicans. MBio 2.
45. ForcheA, SteinbachM, BermanJ (2009) Efficient and rapid identification of Candida albicans allelic status using SNP-RFLP. FEMS Yeast Res 9 : 1061–1069.
46. FonziWA, IrwinMY (1993) Isogenic strain construction and gene mapping in Candida albicans. Genetics 134 : 717–728.
47. MuradAM, LeePR, BroadbentID, BarelleCJ, BrownAJ (2000) CIp10, an efficient and convenient integrating vector for Candida albicans. Yeast 16 : 325–327.
48. InglisDO, ArnaudMB, BinkleyJ, ShahP, SkrzypekMS, et al. (2012) The Candida genome database incorporates multiple Candida species: multispecies search and analysis tools with curated gene and protein information for Candida albicans and Candida glabrata. Nucleic Acids Res 40: D667–674.
49. HoyerLL (2001) The ALS gene family of Candida albicans. Trends Microbiol 9 : 176–180.
50. KuchinS, YeghiayanP, CarlsonM (1995) Cyclin-dependent protein kinase and cyclin homologs SSN3 and SSN8 contribute to transcriptional control in yeast. Proc Natl Acad Sci U S A 92 : 4006–4010.
51. NelsonC, GotoS, LundK, HungW, SadowskiI (2003) Srb10/Cdk8 regulates yeast filamentous growth by phosphorylating the transcription factor Ste12. Nature 421 : 187–190.
52. NolenB, TaylorS, GhoshG (2004) Regulation of protein kinases; controlling activity through activation segment conformation. Mol Cell 15 : 661–675.
53. ReussO, VikA, KolterR, MorschhauserJ (2004) The SAT1 flipper, an optimized tool for gene disruption in Candida albicans. Gene 341 : 119–127.
54. SelmeckiAM, DulmageK, CowenLE, AndersonJB, BermanJ (2009) Acquisition of aneuploidy provides increased fitness during the evolution of antifungal drug resistance. PLoS Genet 5: e1000705.
55. LiuH, KöhlerJ, FinkGR (1994) Suppression of hyphal formation in Candida albicans by mutation of a STE12 homolog. Science 266 : 1723–1726.
56. BockmühlDP, ErnstJF (2001) A potential phosphorylation site for an A-type kinase in the Efg1 regulator protein contributes to hyphal morphogenesis of Candida albicans. Genetics 157 : 1523–1530.
57. LebererE, HarcusD, BroadbentID, ClarkKL, DignardD, et al. (1996) Signal transduction through homologs of the Ste20p and Ste7p protein kinases can trigger hyphal formation in the pathogenic fungus Candida albicans. Proc Natl Acad Sci U S A 93 : 13217–13222.
58. JungWH, StatevaLI (2003) The cAMP phosphodiesterase encoded by CaPDE2 is required for hyphal development in Candida albicans. Microbiology 149 : 2961–2976.
59. CastillaR, PasseronS, CantoreML (1998) N-acetyl-D-glucosamine induces germination in Candida albicans through a mechanism sensitive to inhibitors of cAMP-dependent protein kinase. Cell Signal 10 : 713–719.
60. KlengelT, LiangWJ, ChaloupkaJ, RuoffC, SchröppelK, et al. (2005) Fungal adenylyl cyclase integrates CO2 sensing with cAMP signaling and virulence. Curr Biol 15 : 2021–2026.
61. RomanE, Alonso-MongeR, GongQ, LiD, CalderoneR, et al. (2009) The Cek1 MAPK is a short-lived protein regulated by quorum sensing in the fungal pathogen Candida albicans. FEMS Yeast Res 9 : 942–955.
62. Davis-HannaA, PiispanenAE, StatevaLI, HoganDA (2008) Farnesol and dodecanol effects on the Candida albicans Ras1-cAMP signalling pathway and the regulation of morphogenesis. Mol Microbiol 67 : 47–62.
63. LuY, SuC, WangA, LiuH (2011) Hyphal development in Candida albicans requires two temporally linked changes in promoter chromatin for initiation and maintenance. PLoS Biol 9: e1001105.
64. ZakikhanyK, NaglikJR, Schmidt-WesthausenA, HollandG, SchallerM, et al. (2007) In vivo transcript profiling of Candida albicans identifies a gene essential for interepithelial dissemination. Cell Microbiol 9 : 2938–2954.
65. Navarro-GarciaF, EismanB, FiuzaSM, NombelaC, PlaJ (2005) The MAP kinase Mkc1p is activated under different stress conditions in Candida albicans. Microbiology 151 : 2737–2749.
66. Galán-DiezM, AranaDM, Serrano-GomezD, KremerL, CasasnovasJM, et al. (2010) Candida albicans beta-glucan exposure is controlled by the fungal CEK1-mediated mitogen-activated protein kinase pathway that modulates immune responses triggered through dectin-1. Infect Immun 78 : 1426–1436.
67. SchweizerA, RuppS, TaylorBN, RollinghoffM, SchröppelK (2000) The TEA/ATTS transcription factor CaTec1p regulates hyphal development and virulence in Candida albicans. Mol Microbiol 38 : 435–445.
68. ClearyIA, LazzellAL, MonteagudoC, ThomasDP, SavilleSP (2012) BRG1 and NRG1 form a novel feedback circuit regulating Candida albicans hypha formation and virulence. Mol Microbiol 85 : 557–573.
69. ZeidlerU, LettnerT, LassnigC, MüllerM, LajkoR, et al. (2009) UME6 is a crucial downstream target of other transcriptional regulators of true hyphal development in Candida albicans. FEMS Yeast Res 9 : 126–142.
70. DavisD, WilsonRB, MitchellAP (2000) RIM101-dependent and-independent pathways govern pH responses in Candida albicans. Mol Cell Biol 20 : 971–978.
71. WimalasenaTT, EnjalbertB, GuillemetteT, PlumridgeA, BudgeS, et al. (2008) Impact of the unfolded protein response upon genome-wide expression patterns, and the role of Hac1 in the polarized growth, of Candida albicans. Fungal Genet Biol 45 : 1235–1247.
72. SharkeyLL, McNemarMD, Saporito-IrwinSM, SypherdPS, FonziWA (1999) HWP1 functions in the morphological development of Candida albicans downstream of EFG1, TUP1, and RBF1. J Bacteriol 181 : 5273–5279.
73. SelmeckiA, Gerami-NejadM, PaulsonC, ForcheA, BermanJ (2008) An isochromosome confers drug resistance in vivo by amplification of two genes, ERG11 and TAC1. Mol Microbiol 68 : 624–641.
74. ArbourM, EppE, HoguesH, SellamA, LacroixC, et al. (2009) Widespread occurrence of chromosomal aneuploidy following the routine production of Candida albicans mutants. FEMS Yeast Res 9 : 1070–1077.
75. ChengS, NguyenMH, ZhangZ, JiaH, HandfieldM, et al. (2003) Evaluation of the roles of four Candida albicans genes in virulence by using gene disruption strains that express URA3 from the native locus. Infect Immun 71 : 6101–6103.
76. SundstromP, CutlerJE, StaabJF (2002) Reevaluation of the role of HWP1 in systemic candidiasis by use of Candida albicans strains with selectable marker URA3 targeted to the ENO1 locus. Infect Immun 70 : 3281–3283.
77. SharkeyLL, LiaoWL, GhoshAK, FonziWA (2005) Flanking direct repeats of hisG alter URA3 marker expression at the HWP1 locus of Candida albicans. Microbiology 151 : 1061–1071.
78. MyersLC, KornbergRD (2000) Mediator of transcriptional regulation. Annu Rev Biochem 69 : 729–749.
79. LewisBA, ReinbergD (2003) The mediator coactivator complex: functional and physical roles in transcriptional regulation. J Cell Sci 116 : 3667–3675.
80. RaithathaS, SuTC, LourencoP, GotoS, SadowskiI (2012) Cdk8 regulates stability of the transcription factor Phd1 to control pseudohyphal differentiation of Saccharomyces cerevisiae. Mol Cell Biol 32 : 664–674.
81. SchüllerJ, LehmingN (2003) The cyclin in the RNA polymerase holoenzyme is a target for the transcriptional repressor Tup1p in Saccharomyces cerevisiae. J Mol Microbiol Biotechnol 5 : 199–205.
82. GreenSR, JohnsonAD (2004) Promoter-dependent roles for the Srb10 cyclin-dependent kinase and the Hda1 deacetylase in Tup1-mediated repression in Saccharomyces cerevisiae. Mol Biol Cell 15 : 4191–4202.
83. KuchinS, CarlsonM (1998) Functional relationships of Srb10-Srb11 kinase, carboxy-terminal domain kinase CTDK-I, and transcriptional corepressor Ssn6-Tup1. Mol Cell Biol 18 : 1163–1171.
84. ParkSH, KohSS, ChunJH, HwangHJ, KangHS (1999) Nrg1 is a transcriptional repressor for glucose repression of STA1 gene expression in Saccharomyces cerevisiae. Mol Cell Biol 19 : 2044–2050.
85. ChangYW, HowardSC, HermanPK (2004) The Ras/PKA signaling pathway directly targets the Srb9 protein, a component of the general RNA polymerase II transcription apparatus. Mol Cell 15 : 107–116.
86. BrunkeS, SeiderK, FischerD, JacobsenI, KasperL, et al. (2014) Brunke S, Seider K, Fischer D, Jacobsen ID, Kasper L, et al. (2014) One Small Step for a Yeast - Microevolution within Macrophages Renders Candida glabrata Hypervirulent Due to a Single Point Mutation. PLoS Pathog 10 (10) e1004478 doi:10.1371/journal.ppat.1004478
87. MayerFL, WilsonD, JacobsenID, MiramónP, GrosseK, et al. (2012) The novel Candida albicans transporter Dur31 Is a multi-stage pathogenicity factor. PLoS Pathog 8: e1002592.
88. LivakKJ, SchmittgenTD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔCT Method. Methods 25 : 402–408.
89. KongY (2011) Btrim: a fast, lightweight adapter and quality trimming program for next-generation sequencing technologies. Genomics 98 : 152–153.
90. TrapnellC, PachterL, SalzbergSL (2009) TopHat: discovering splice junctions with RNA-Seq. Bioinformatics 25 : 1105–1111.
91. RobinsonMD, McCarthyDJ, SmythGK (2010) edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26 : 139–140.
92. AndersS, HuberW (2010) Differential expression analysis for sequence count data. Genome Biol 11: R106.
93. FaziusE, ShelestV, ShelestE (2011) SiTaR: a novel tool for transcription factor binding site prediction. Bioinformatics 27 : 2806–2811.
94. Van der AuweraGA, MauricioOC, HatlC, PoplinR, del AngelG, et al. (2013) From FastQ Data to High-Confidence Variant Calls: The Genome Analysis Toolkit Best Practices Pipeline. Current Protocols in Bioinformatics 11.10.1–11.10.33.
95. LiH, DurbinR (2009) Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25 : 1754–1760.
96. SieversF, WilmA, DineenD, GibsonTJ, KarplusK, et al. (2011) Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega. Mol Syst Biol 7 : 539.
97. OssowskiS, SchneebergerK, ClarkRM, LanzC, WarthmannN, et al. (2008) Sequencing of natural strains of Arabidopsis thaliana with short reads. Genome Res 18 : 2024–2033.
98. AkoulitchevS, ChuikovS, ReinbergD (2000) TFIIH is negatively regulated by cdk8-containing mediator complexes. Nature 407 : 102–106.
Štítky
Genetika Reprodukčná medicína
Článek Large-scale Metabolomic Profiling Identifies Novel Biomarkers for Incident Coronary Heart DiseaseČlánek Notch Signaling Mediates the Age-Associated Decrease in Adhesion of Germline Stem Cells to the NicheČlánek Phosphorylation of Mitochondrial Polyubiquitin by PINK1 Promotes Parkin Mitochondrial TetheringČlánek Natural Variation Is Associated With Genome-Wide Methylation Changes and Temperature SeasonalityČlánek Overlapping and Non-overlapping Functions of Condensins I and II in Neural Stem Cell DivisionsČlánek Unisexual Reproduction Drives Meiotic Recombination and Phenotypic and Karyotypic Plasticity inČlánek Tetraspanin (TSP-17) Protects Dopaminergic Neurons against 6-OHDA-Induced Neurodegeneration inČlánek ABA-Mediated ROS in Mitochondria Regulate Root Meristem Activity by Controlling Expression inČlánek Mutations in Global Regulators Lead to Metabolic Selection during Adaptation to Complex EnvironmentsČlánek The Evolution of Sex Ratio Distorter Suppression Affects a 25 cM Genomic Region in the Butterfly
Článok vyšiel v časopisePLOS Genetics
Najčítanejšie tento týždeň
2014 Číslo 12- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
-
Všetky články tohto čísla
- Stratification by Smoking Status Reveals an Association of Genotype with Body Mass Index in Never Smokers
- Genome Wide Meta-analysis Highlights the Role of Genetic Variation in in the Regulation of Circulating Serum Chemerin
- Occupancy of Mitochondrial Single-Stranded DNA Binding Protein Supports the Strand Displacement Mode of DNA Replication
- Distinct Genealogies for Plasmids and Chromosome
- Large-scale Metabolomic Profiling Identifies Novel Biomarkers for Incident Coronary Heart Disease
- Non-coding RNAs Prevent the Binding of the MSL-complex to Heterochromatic Regions
- Plasmid Flux in ST131 Sublineages, Analyzed by Plasmid Constellation Network (PLACNET), a New Method for Plasmid Reconstruction from Whole Genome Sequences
- Epigenome-Guided Analysis of the Transcriptome of Plaque Macrophages during Atherosclerosis Regression Reveals Activation of the Wnt Signaling Pathway
- The Inventiveness of Nature: An Interview with Werner Arber
- Mediation Analysis Demonstrates That -eQTLs Are Often Explained by -Mediation: A Genome-Wide Analysis among 1,800 South Asians
- Generation of Antigenic Diversity in by Structured Rearrangement of Genes During Mitosis
- A Massively Parallel Pipeline to Clone DNA Variants and Examine Molecular Phenotypes of Human Disease Mutations
- Genetic Analysis of the Cardiac Methylome at Single Nucleotide Resolution in a Model of Human Cardiovascular Disease
- Genetic Analysis of Circadian Responses to Low Frequency Electromagnetic Fields in
- The Dissection of Meiotic Chromosome Movement in Mice Using an Electroporation Technique
- Altered Chromatin Occupancy of Master Regulators Underlies Evolutionary Divergence in the Transcriptional Landscape of Erythroid Differentiation
- Syd/JIP3 and JNK Signaling Are Required for Myonuclear Positioning and Muscle Function
- Notch Signaling Mediates the Age-Associated Decrease in Adhesion of Germline Stem Cells to the Niche
- Mutation of Leads to Blurred Tonotopic Organization of Central Auditory Circuits in Mice
- The IKAROS Interaction with a Complex Including Chromatin Remodeling and Transcription Elongation Activities Is Required for Hematopoiesis
- RAN-Binding Protein 9 is Involved in Alternative Splicing and is Critical for Male Germ Cell Development and Male Fertility
- Enhanced Longevity by Ibuprofen, Conserved in Multiple Species, Occurs in Yeast through Inhibition of Tryptophan Import
- Phosphorylation of Mitochondrial Polyubiquitin by PINK1 Promotes Parkin Mitochondrial Tethering
- Recurrent Loss of Specific Introns during Angiosperm Evolution
- Natural Variation Is Associated With Genome-Wide Methylation Changes and Temperature Seasonality
- SEEDSTICK is a Master Regulator of Development and Metabolism in the Arabidopsis Seed Coat
- Overlapping and Non-overlapping Functions of Condensins I and II in Neural Stem Cell Divisions
- Unisexual Reproduction Drives Meiotic Recombination and Phenotypic and Karyotypic Plasticity in
- Tetraspanin (TSP-17) Protects Dopaminergic Neurons against 6-OHDA-Induced Neurodegeneration in
- ABA-Mediated ROS in Mitochondria Regulate Root Meristem Activity by Controlling Expression in
- Mutations in Global Regulators Lead to Metabolic Selection during Adaptation to Complex Environments
- Global Analysis of Photosynthesis Transcriptional Regulatory Networks
- Mucolipin Co-deficiency Causes Accelerated Endolysosomal Vacuolation of Enterocytes and Failure-to-Thrive from Birth to Weaning
- Controlling Pre-leukemic Thymocyte Self-Renewal
- How Malaria Parasites Avoid Running Out of Ammo
- Echoes of the Past: Hereditarianism and
- Deep Reads: Strands in the History of Molecular Genetics
- Keep on Laying Eggs Mama, RNAi My Reproductive Aging Blues Away
- Analysis of a Plant Complex Resistance Gene Locus Underlying Immune-Related Hybrid Incompatibility and Its Occurrence in Nature
- Epistatic Adaptive Evolution of Human Color Vision
- Increased and Imbalanced dNTP Pools Symmetrically Promote Both Leading and Lagging Strand Replication Infidelity
- Genetic Basis of Haloperidol Resistance in Is Complex and Dose Dependent
- Genome-Wide Analysis of DNA Methylation Dynamics during Early Human Development
- Interaction between Conjugative and Retrotransposable Elements in Horizontal Gene Transfer
- The Evolution of Sex Ratio Distorter Suppression Affects a 25 cM Genomic Region in the Butterfly
- is Required for Adult Maintenance of Dopaminergic Neurons in the Ventral Substantia Nigra
- PRL1, an RNA-Binding Protein, Positively Regulates the Accumulation of miRNAs and siRNAs in Arabidopsis
- Genetic Control of Contagious Asexuality in the Pea Aphid
- Early Mesozoic Coexistence of Amniotes and Hepadnaviridae
- Local and Systemic Regulation of Plant Root System Architecture and Symbiotic Nodulation by a Receptor-Like Kinase
- Gene Pathways That Delay Reproductive Senescence
- The Evolution of Fungal Metabolic Pathways
- Maf1 Is a Novel Target of PTEN and PI3K Signaling That Negatively Regulates Oncogenesis and Lipid Metabolism
- Formation of Linear Amplicons with Inverted Duplications in Requires the MRE11 Nuclease
- Identification of Rare Causal Variants in Sequence-Based Studies: Methods and Applications to , a Gene Involved in Cohen Syndrome and Autism
- Rrp12 and the Exportin Crm1 Participate in Late Assembly Events in the Nucleolus during 40S Ribosomal Subunit Biogenesis
- The Mutations in the ATP-Binding Groove of the Rad3/XPD Helicase Lead to -Cockayne Syndrome-Like Phenotypes
- Topoisomerase I Plays a Critical Role in Suppressing Genome Instability at a Highly Transcribed G-Quadruplex-Forming Sequence
- A Cbx8-Containing Polycomb Complex Facilitates the Transition to Gene Activation during ES Cell Differentiation
- Transcriptional Frameshifting Rescues Type VI Secretion by the Production of Two Length Variants from the Prematurely Interrupted Gene
- Association Mapping across Numerous Traits Reveals Patterns of Functional Variation in Maize
- Genome-Wide Analysis of -Regulated and Phased Small RNAs Underscores the Importance of the ta-siRNA Pathway to Maize Development
- Dissemination of Cephalosporin Resistance Genes between Strains from Farm Animals and Humans by Specific Plasmid Lineages
- The Tau Tubulin Kinases TTBK1/2 Promote Accumulation of Pathological TDP-43
- Germline Signals Deploy NHR-49 to Modulate Fatty-Acid β-Oxidation and Desaturation in Somatic Tissues of
- Microevolution of in Macrophages Restores Filamentation in a Nonfilamentous Mutant
- Vangl2-Regulated Polarisation of Second Heart Field-Derived Cells Is Required for Outflow Tract Lengthening during Cardiac Development
- Chondrocytes Transdifferentiate into Osteoblasts in Endochondral Bone during Development, Postnatal Growth and Fracture Healing in Mice
- A ABC Transporter Regulates Lifespan
- RA and FGF Signalling Are Required in the Zebrafish Otic Vesicle to Pattern and Maintain Ventral Otic Identities
- , and Reprogram Thymocytes into Self-Renewing Cells
- The miR9863 Family Regulates Distinct Alleles in Barley to Attenuate NLR Receptor-Triggered Disease Resistance and Cell-Death Signaling
- Detection of Pleiotropy through a Phenome-Wide Association Study (PheWAS) of Epidemiologic Data as Part of the Environmental Architecture for Genes Linked to Environment (EAGLE) Study
- Extensive Copy-Number Variation of Young Genes across Stickleback Populations
- The and Genetic Modules Interact to Regulate Ciliogenesis and Ciliary Microtubule Patterning in
- Analysis of the Genome, Transcriptome and Secretome Provides Insight into Its Pioneer Colonization Strategies of Wood
- PLOS Genetics
- Archív čísel
- Aktuálne číslo
- Informácie o časopise
Najčítanejšie v tomto čísle- Tetraspanin (TSP-17) Protects Dopaminergic Neurons against 6-OHDA-Induced Neurodegeneration in
- Maf1 Is a Novel Target of PTEN and PI3K Signaling That Negatively Regulates Oncogenesis and Lipid Metabolism
- The IKAROS Interaction with a Complex Including Chromatin Remodeling and Transcription Elongation Activities Is Required for Hematopoiesis
- Echoes of the Past: Hereditarianism and
Prihlásenie#ADS_BOTTOM_SCRIPTS#Zabudnuté hesloZadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.
- Časopisy