Adaptation of codon usage to tRNA I34 modification controls translation kinetics and proteome landscape
Autoři:
Xueliang Lyu aff001; Qian Yang aff002; Lin Li aff003; Yunkun Dang aff004; Zhipeng Zhou aff002; She Chen aff002; Yi Liu aff002
Působiště autorů:
State Key Laboratory of Agricultural Microbiology, College of Plant Science and Technology, Huazhong Agricultural University, Wuhan, Hubei, China
aff001; Department of Physiology, The University of Texas Southwestern Medical Center,Harry Hines Blvd., Dallas, Texas, United States of America
aff002; National Institute of Biological Sciences, Changping District, Beijing, China
aff003; State Key Laboratory for Conservation and Utilization of Bio-Resources and Center for Life Science, School of Life Sciences, Yunnan University, Kunming, China
aff004; College of Life Sciences and Technology, Huazhong Agricultural University, Wuhan, Hubei, China
aff005
Vyšlo v časopise:
Adaptation of codon usage to tRNA I34 modification controls translation kinetics and proteome landscape. PLoS Genet 16(6): e32767. doi:10.1371/journal.pgen.1008836
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pgen.1008836
Souhrn
Codon usage bias is a universal feature of all genomes and plays an important role in regulating protein expression levels. Modification of adenosine to inosine at the tRNA anticodon wobble position (I34) by adenosine deaminases (ADATs) is observed in all eukaryotes and has been proposed to explain the correlation between codon usage and tRNA pool. However, how the tRNA pool is affected by I34 modification to influence codon usage-dependent gene expression is unclear. Using Neurospora crassa as a model system, by combining molecular, biochemical and bioinformatics analyses, we show that silencing of adat2 expression severely impaired the I34 modification levels for the ADAT-related tRNAs, resulting in major ADAT-related tRNA profile changes and reprogramming of translation elongation kinetics on ADAT-related codons. adat2 silencing also caused genome-wide codon usage-biased ribosome pausing on mRNAs and proteome landscape changes, leading to selective translational repression or induction of different mRNAs. The induced expression of CPC-1, the Neurospora ortholog of yeast GCN4p, mediates the transcriptional response after adat2 silencing and amino acid starvation. Together, our results demonstrate that the tRNA I34 modification by ADAT plays a major role in driving codon usage-biased translation to shape proteome landscape.
Klíčová slova:
Anticodons – Eukaryota – Gene expression – Messenger RNA – Neurospora – Protein translation – Ribosomes – Transfer RNA
Zdroje
1. Phizicky EM, Hopper AK (2010) tRNA biology charges to the front. Genes Dev 24: 1832–1860. doi: 10.1101/gad.1956510 20810645
2. El Yacoubi B, Bailly M, de Crecy-Lagard V (2012) Biosynthesis and function of posttranscriptional modifications of transfer RNAs. Annu Rev Genet 46: 69–95. doi: 10.1146/annurev-genet-110711-155641 22905870
3. Torres AG, Batlle E, Ribas de Pouplana L (2014) Role of tRNA modifications in human diseases. Trends Mol Med 20: 306–314. doi: 10.1016/j.molmed.2014.01.008 24581449
4. Chan CT, Pang YL, Deng W, Babu IR, Dyavaiah M, et al. (2012) Reprogramming of tRNA modifications controls the oxidative stress response by codon-biased translation of proteins. Nat Commun 3: 937. doi: 10.1038/ncomms1938 22760636
5. Chionh YH, McBee M, Babu IR, Hia F, Lin W, et al. (2016) tRNA-mediated codon-biased translation in mycobacterial hypoxic persistence. Nat Commun 7: 13302. doi: 10.1038/ncomms13302 27834374
6. Deng W, Babu IR, Su D, Yin S, Begley TJ, et al. (2015) Trm9-Catalyzed tRNA Modifications Regulate Global Protein Expression by Codon-Biased Translation. PLoS Genet 11: e1005706. doi: 10.1371/journal.pgen.1005706 26670883
7. Gerber AP, Keller W (1999) An adenosine deaminase that generates inosine at the wobble position of tRNAs. Science 286: 1146–1149. doi: 10.1126/science.286.5442.1146 10550050
8. Wolf J, Gerber AP, Keller W (2002) tadA, an essential tRNA-specific adenosine deaminase from Escherichia coli. EMBO J 21: 3841–3851. doi: 10.1093/emboj/cdf362 12110595
9. Gerber AP, Keller W (2001) RNA editing by base deamination: more enzymes, more targets, new mysteries. Trends Biochem Sci 26: 376–384. doi: 10.1016/s0968-0004(01)01827-8 11406411
10. Rafels-Ybern A, Torres AG, Grau-Bove X, Ruiz-Trillo I, Ribas de Pouplana L (2018) Codon adaptation to tRNAs with Inosine modification at position 34 is widespread among Eukaryotes and present in two Bacterial phyla. RNA Biol 15: 500–507. doi: 10.1080/15476286.2017.1358348 28880718
11. Rafels-Ybern À, Torres AG, Camacho N, Herencia-Ropero A, Roura Frigolé H, et al. (2018) The expansion of Inosine at the wobble position of tRNAs, and its role in the evolution of proteomes. Molecular biology and evolution 36: 650–662.
12. Juhling F, Morl M, Hartmann RK, Sprinzl M, Stadler PF, et al. (2009) tRNAdb 2009: compilation of tRNA sequences and tRNA genes. Nucleic Acids Res 37: D159–162. doi: 10.1093/nar/gkn772 18957446
13. Torres AG, Pineyro D, Filonava L, Stracker TH, Batlle E, et al. (2014) A-to-I editing on tRNAs: biochemical, biological and evolutionary implications. FEBS Lett 588: 4279–4286. doi: 10.1016/j.febslet.2014.09.025 25263703
14. Ikemura T (1985) Codon usage and tRNA content in unicellular and multicellular organisms. Mol Biol Evol 2: 13–34. doi: 10.1093/oxfordjournals.molbev.a040335 3916708
15. Sharp PM, Tuohy TM, Mosurski KR (1986) Codon usage in yeast: cluster analysis clearly differentiates highly and lowly expressed genes. Nucleic Acids Res 14: 5125–5143. doi: 10.1093/nar/14.13.5125 3526280
16. Comeron JM (2004) Selective and mutational patterns associated with gene expression in humans: influences on synonymous composition and intron presence. Genetics 167: 1293–1304. doi: 10.1534/genetics.104.026351 15280243
17. Plotkin JB, Kudla G (2011) Synonymous but not the same: the causes and consequences of codon bias. Nat Rev Genet 12: 32–42. doi: 10.1038/nrg2899 21102527
18. Xu Y, Ma PJ, Shah P, Rokas A, Liu Y, et al. (2013) Non-optimal codon usage is a mechanism to achieve circadian clock conditionality. Nature 495: 116–120. doi: 10.1038/nature11942 23417065
19. Zhou M, Guo J, Cha J, Chae M, Chen S, et al. (2013) Non-optimal codon usage affects expression, structure and function of clock protein FRQ. Nature 495: 111–115. doi: 10.1038/nature11833 23417067
20. Hense W, Anderson N, Hutter S, Stephan W, Parsch J, et al. (2010) Experimentally increased codon bias in the Drosophila Adh gene leads to an increase in larval, but not adult, alcohol dehydrogenase activity. Genetics 184: 547–555. doi: 10.1534/genetics.109.111294 19966063
21. Lampson BL, Pershing NL, Prinz JA, Lacsina JR, Marzluff WF, et al. (2013) Rare codons regulate KRas oncogenesis. Curr Biol 23: 70–75. doi: 10.1016/j.cub.2012.11.031 23246410
22. Zhou Z, Dang Y, Zhou M, Li L, Yu CH, et al. (2016) Codon usage is an important determinant of gene expression levels largely through its effects on transcription. Proc Natl Acad Sci U S A 113: E6117–E6125. doi: 10.1073/pnas.1606724113 27671647
23. Fu J, Dang Y, Counter C, Liu Y (2018) Codon usage regulates human KRAS expression at both transcriptional and translational levels. J Biol Chem 293: 17929–17940. doi: 10.1074/jbc.RA118.004908 30275015
24. Gingold H, Pilpel Y (2011) Determinants of translation efficiency and accuracy. Mol Syst Biol 7: 481. doi: 10.1038/msb.2011.14 21487400
25. Quax TEF, Claassens NJ, Soll D, van der Oost J (2015) Codon bias as a means to fine-tune gene expression. Molecular Cell 59: 149–161. doi: 10.1016/j.molcel.2015.05.035 26186290
26. Gamble CE, Brule CE, Dean KM, Fields S, Grayhack EJ (2016) Adjacent Codons Act in Concert to Modulate Translation Efficiency in Yeast. Cell 166: 679–690. doi: 10.1016/j.cell.2016.05.070 27374328
27. Bulmer M (1987) Coevolution of codon usage and transfer RNA abundance. Nature 325: 728–730. doi: 10.1038/325728a0 2434856
28. Moriyama EN, Powell JR (1997) Codon usage bias and tRNA abundance in Drosophila. J Mol Evol 45: 514–523. doi: 10.1007/pl00006256 9342399
29. Gingold H, Tehler D, Christoffersen NR, Nielsen MM, Asmar F, et al. (2014) A dual program for translation regulation in cellular proliferation and differentiation. Cell 158: 1281–1292. doi: 10.1016/j.cell.2014.08.011 25215487
30. Torrent M, Chalancon G, de Groot NS, Wuster A, Madan Babu M (2018) Cells alter their tRNA abundance to selectively regulate protein synthesis during stress conditions. Sci Signal 11: eaat6409. doi: 10.1126/scisignal.aat6409 30181241
31. Yu CH, Dang Y, Zhou Z, Wu C, Zhao F, et al. (2015) Codon Usage Influences the Local Rate of Translation Elongation to Regulate Co-translational Protein Folding. Mol Cell 59: 744–754. doi: 10.1016/j.molcel.2015.07.018 26321254
32. Zhao F, Yu CH, Liu Y (2017) Codon usage regulates protein structure and function by affecting translation elongation speed in Drosophila cells. Nucleic Acids Res 45: 8484–8492. doi: 10.1093/nar/gkx501 28582582
33. Weinberg DE, Shah P, Eichhorn SW, Hussmann JA, Plotkin JB, et al. (2016) Improved Ribosome-Footprint and mRNA Measurements Provide Insights into Dynamics and Regulation of Yeast Translation. Cell Rep 14: 1787–1799. doi: 10.1016/j.celrep.2016.01.043 26876183
34. Yang Q, Yu C, Zhao Z, Dang D, Wu C, et al. (2019) eRF1 mediates codon usage effects on mRNA translation efficiency through premature termination at rare codons. Nucleic Acids Res 47: 9243–9258. doi: 10.1093/nar/gkz710 31410471
35. Novoa EM, Pavon-Eternod M, Pan T, Ribas de Pouplana L (2012) A role for tRNA modifications in genome structure and codon usage. Cell 149: 202–213. doi: 10.1016/j.cell.2012.01.050 22464330
36. Bass BL (2002) RNA editing by adenosine deaminases that act on RNA. Annual review of biochemistry 71: 817–846. doi: 10.1146/annurev.biochem.71.110601.135501 12045112
37. Radford A, Parish JH (1997) The genome and genes of Neurospora crassa. Fungal Genet Biol 21: 258–266. doi: 10.1006/fgbi.1997.0979 9290240
38. Zhou M, Wang T, Fu J, Xiao G, Liu Y (2015) Nonoptimal codon usage influences protein structure in intrinsically disordered regions. Mol Microbiol 97: 974–987. doi: 10.1111/mmi.13079 26032251
39. Zhou Z, Dang Y, Zhou M, Yuan H, Liu Y (2018) Codon usage biases co-evolve with transcription termination machinery to suppress premature cleavage and polyadenylation. Elife 7.
40. Frumkin I, Lajoie MJ, Gregg CJ, Hornung G, Church GM, et al. (2018) Codon usage of highly expressed genes affects proteome-wide translation efficiency. Proceedings of the National Academy of Sciences 115: E4940–E4949.
41. Goodarzi H, Nguyen HCB, Zhang S, Dill BD, Molina H, et al. (2016) Modulated Expression of Specific tRNAs Drives Gene Expression and Cancer Progression. Cell 165: 1416–1427. doi: 10.1016/j.cell.2016.05.046 27259150
42. Jeacock L, Faria J, Horn D (2018) Codon usage bias controls mRNA and protein abundance in trypanosomatids. Elife 7: e32496. doi: 10.7554/eLife.32496 29543155
43. Li Y, Zhou H (2009) tRNAs as regulators in gene expression. Science in China Series C: Life Sciences 52: 245–252. doi: 10.1007/s11427-009-0039-y 19294349
44. Nelson AR, Henkin TM, Agris PF (2006) tRNA regulation of gene expression: interactions of an mRNA 5′-UTR with a regulatory tRNA. Rna 12: 1254–1261. doi: 10.1261/rna.29906 16741230
45. Raina M, Ibba M (2014) tRNAs as regulators of biological processes. Frontiers in genetics 5: 171. doi: 10.3389/fgene.2014.00171 24966867
46. Schwartz MH, Wang H, Pan JN, Clark WC, Cui S, et al. (2018) Microbiome characterization by high-throughput transfer RNA sequencing and modification analysis. Nature communications 9: 5353. doi: 10.1038/s41467-018-07675-z 30559359
47. Bornelöv S, Selmi T, Flad S, Dietmann S, Frye M (2019) Codon usage optimization in pluripotent embryonic stem cells. Genome biology 20: 119. doi: 10.1186/s13059-019-1726-z 31174582
48. Bennetzen JL, Hall BD (1982) Codon selection in yeast. J Biol Chem 257: 3026–3031. 7037777
49. Cheng P, He Q, He QY, Wang LX, Liu Y (2005) Regulation of the Neurospora circadian clock by an RNA helicase. Genes & Development 19: 234–241.
50. Ebbole DJ, Paluh JL, Plamann M, Sachs MS, Yanofsky C (1991) cpc-1, the general regulatory gene for genes of amino acid biosynthesis in Neurospora crassa, is differentially expressed during the asexual life cycle. Mol Cell Biol 11: 928–934. doi: 10.1128/mcb.11.2.928 1824959
51. Sachs MS, Yanofsky C (1991) Developmental expression of genes involved in conidiation and amino acid biosynthesis in Neurospora crassa. Dev Biol 148: 117–128. doi: 10.1016/0012-1606(91)90322-t 1834495
52. Wang Z, Sachs MS (1997) Arginine-specific regulation mediated by the Neurospora crassa arg-2 upstream open reading frame in a homologous, cell-free in vitro translation system. J Biol Chem 272: 255–261. doi: 10.1074/jbc.272.1.255 8995256
53. Wang Z, Gaba A, Sachs MS (1999) A highly conserved mechanism of regulated ribosome stalling mediated by fungal arginine attenuator peptides that appears independent of the charging status of arginyl-tRNAs. J Biol Chem 274: 37565–37574. doi: 10.1074/jbc.274.53.37565 10608810
54. Hood HM, Neafsey DE, Galagan J, Sachs MS (2009) Evolutionary roles of upstream open reading frames in mediating gene regulation in fungi. Annu Rev Microbiol 63: 385–409. doi: 10.1146/annurev.micro.62.081307.162835 19514854
55. Wei J, Zhang Y, Ivanov IP, Sachs MS (2013) The stringency of start codon selection in the filamentous fungus Neurospora crassa. J Biol Chem 288: 9549–9562. doi: 10.1074/jbc.M112.447177 23396971
56. Wu C, Amrani N, Jacobson A, Sachs MS (2007) The use of fungal in vitro systems for studying translational regulation. Methods Enzymol 429: 203–225. doi: 10.1016/S0076-6879(07)29010-X 17913625
57. Ingolia NT, Ghaemmaghami S, Newman JR, Weissman JS (2009) Genome-wide analysis in vivo of translation with nucleotide resolution using ribosome profiling. Science 324: 218–223. doi: 10.1126/science.1168978 19213877
58. Ingolia NT, Lareau LF, Weissman JS (2011) Ribosome profiling of mouse embryonic stem cells reveals the complexity and dynamics of mammalian proteomes. Cell 147: 789–802. doi: 10.1016/j.cell.2011.10.002 22056041
59. Dittmar KA, Sorensen MA, Elf J, Ehrenberg M, Pan T (2005) Selective charging of tRNA isoacceptors induced by amino-acid starvation. Embo Reports 6: 151–157. doi: 10.1038/sj.embor.7400341 15678157
60. Riba A, Di Nanni N, Mittal N, Arhné E, Schmidt A, et al. (2019) Protein synthesis rates and ribosome occupancies reveal determinants of translation elongation rates. Proceedings of the National Academy of Sciences 116: 15023–15032.
61. Sharma AK, Sormanni P, Ahmed N, Ciryam P, Friedrich UA, et al. (2019) A chemical kinetic basis for measuring translation initiation and elongation rates from ribosome profiling data. PLoS Comput Biol 15: e1007070. doi: 10.1371/journal.pcbi.1007070 31120880
62. Hinnebusch AG (2005) Translational regulation of GCN4 and the general amino acid control of yeast. Annu Rev Microbiol 59: 407–450. doi: 10.1146/annurev.micro.59.031805.133833 16153175
63. Buchan JR, Parker R (2009) Eukaryotic stress granules: the ins and outs of translation. Mol Cell 36: 932–941. doi: 10.1016/j.molcel.2009.11.020 20064460
64. Huang G, Chen S, Li S, Cha J, Long C, et al. (2007) Protein kinase A and casein kinases mediate sequential phosphorylation events in the circadian negative feedback loop. Genes Dev 21: 3283–3295. doi: 10.1101/gad.1610207 18079175
65. dos Reis M, Savva R, Wernisch L (2004) Solving the riddle of codon usage preferences: a test for translational selection. Nucleic Acids Res 32: 5036–5044. doi: 10.1093/nar/gkh834 15448185
66. Paluh JL, Orbach MJ, Legerton TL, Yanofsky C (1988) The cross-pathway control gene of Neurospora crassa, cpc-1, encodes a protein similar to GCN4 of yeast and the DNA-binding domain of the oncogene v-jun-encoded protein. Proc Natl Acad Sci U S A 85: 3728–3732. doi: 10.1073/pnas.85.11.3728 2967496
67. Paluh JL, Yanofsky C (1991) Characterization of Neurospora CPC1, a bZIP DNA-binding protein that does not require aligned heptad leucines for dimerization. Mol Cell Biol 11: 935–944. doi: 10.1128/mcb.11.2.935 1824960
68. Tian C, Kasuga T, Sachs MS, Glass NL (2007) Transcriptional profiling of cross pathway control in Neurospora crassa and comparative analysis of the Gcn4 and CPC1 regulons. Eukaryot Cell 6: 1018–1029. doi: 10.1128/EC.00078-07 17449655
69. Carsiotis M, Jones RF, Wesseling AC (1974) Cross-pathway regulation: histidine-mediated control of histidine, tryptophan, and arginine biosynthetic enzymes in Neurospora crassa. Journal of bacteriology 119: 893–898. 4368540
70. Hinnebusch AG (1990) Transcriptional and translational regulation of gene expression in the general control of amino-acid biosynthesis in Saccharomyces cerevisiae. Progress in nucleic acid research and molecular biology: Elsevier. pp. 195–240.
71. Hinnebusch AG, Natarajan K (2002) Gcn4p, a master regulator of gene expression, is controlled at multiple levels by diverse signals of starvation and stress. Eukaryotic Cell 1: 22–32. doi: 10.1128/ec.01.1.22-32.2002 12455968
72. Luo Z, Freitag M, Sachs MS (1995) Translational regulation in response to changes in amino acid availability in Neurospora crassa. Mol Cell Biol 15: 5235–5245. doi: 10.1128/mcb.15.10.5235 7565672
73. Ivanov IP, Wei J, Caster SZ, Smith KM, Michel AM, et al. (2017) Translation initiation from conserved non-AUG codons provides additional layers of regulation and coding capacity. MBio 8: e00844–00817. doi: 10.1128/mBio.00844-17 28655822
74. Kanehisa M. The KEGG database; 2002. Wiley Online Library. pp. 91–100.
75. Qiu H, Hu C, Anderson J, Bjork GR, Sarkar S, et al. (2000) Defects in tRNA processing and nuclear export induce GCN4 translation independently of phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2. Mol Cell Biol 20: 2505–2516. doi: 10.1128/mcb.20.7.2505-2516.2000 10713174
76. Dong H, Nilsson L, Kurland CG (1996) Co-variation of tRNA abundance and codon usage in Escherichia coli at different growth rates. J Mol Biol 260: 649–663. doi: 10.1006/jmbi.1996.0428 8709146
77. Wu CC, Zinshteyn B, Wehner KA, Green R (2019) High-resolution ribosome profiling defines discrete ribosome elongation states and translational regulation during cellular stress. Mol Cell 73: 959–970 e955. doi: 10.1016/j.molcel.2018.12.009 30686592
78. Chou HJ, Donnard E, Gustafsson HT, Garber M, Rando OJ (2017) Transcriptome-wide analysis of roles for tRNA modifications in translational regulation. Mol Cell 68: 978–992 e974. doi: 10.1016/j.molcel.2017.11.002 29198561
79. Lindqvist LM, Tandoc K, Topisirovic I, Furic L (2018) Cross-talk between protein synthesis, energy metabolism and autophagy in cancer. Current Opinion in Genetics & Development 48: 104–111.
80. Goffena J, Lefcort F, Zhang Y, Lehrmann E, Chaverra M, et al. (2018) Elongator and codon bias regulate protein levels in mammalian peripheral neurons. Nat Commun 9: 889. doi: 10.1038/s41467-018-03221-z 29497044
81. Dittmar KA, Goodenbour JM, Pan T (2006) Tissue-specific differences in human transfer RNA expression. PLoS Genet 2: e221. doi: 10.1371/journal.pgen.0020221 17194224
82. Pavon-Eternod M, Gomes S, Geslain R, Dai Q, Rosner MR, et al. (2009) tRNA over-expression in breast cancer and functional consequences. Nucleic Acids Res 37: 7268–7280. doi: 10.1093/nar/gkp787 19783824
83. Endres L, Dedon PC, Begley TJ (2015) Codon-biased translation can be regulated by wobble-base tRNA modification systems during cellular stress responses. RNA Biol 12: 603–614. doi: 10.1080/15476286.2015.1031947 25892531
84. Xue Z, Ye Q, Anson SR, Yang J, Xiao G, et al. (2014) Transcriptional interference by antisense RNA is required for circadian clock function. Nature 514: 650–653. doi: 10.1038/nature13671 25132551
85. Garceau N, Liu Y, Loros JJ, Dunlap JC (1997) Alternative initiation of translation and time-specific phosphorylation yield multiple forms of the essential clock protein FREQUENCY. Cell 89: 469–476. doi: 10.1016/s0092-8674(00)80227-5 9150146
86. Sabi R, Volvovitch Daniel R, Tuller T (2016) stAIcalc: tRNA adaptation index calculator based on species-specific weights. Bioinformatics 33: 589–591.
87. Chou H-J, Donnard E, Gustafsson HT, Garber M, Rando OJ (2017) Transcriptome-wide analysis of roles for tRNA modifications in translational regulation. Molecular cell 68: 978–992. e974. doi: 10.1016/j.molcel.2017.11.002 29198561
88. Nedialkova DD, Leidel SA (2015) Optimization of codon translation rates via tRNA modifications maintains proteome integrity. Cell 161: 1606–1618. doi: 10.1016/j.cell.2015.05.022 26052047
89. Nicholas J, Nicholas T (2017) Transcriptome-wide measurement of translation by ribosome profiling. Methods.
90. Ingolia NT, Brar GA, Rouskin S, McGeachy AM, Weissman JS (2012) The ribosome profiling strategy for monitoring translation in vivo by deep sequencing of ribosome-protected mRNA fragments. Nat Protoc 7: 1534–1550. doi: 10.1038/nprot.2012.086 22836135
91. Brar GA, Yassour M, Friedman N, Regev A, Ingolia NT, et al. (2012) High-resolution view of the yeast meiotic program revealed by ribosome profiling. Science 335: 552–557. doi: 10.1126/science.1215110 22194413
92. Zinshteyn B, Gilbert WV (2013) Loss of a conserved tRNA anticodon modification perturbs cellular signaling. PLoS Genet 9: e1003675. doi: 10.1371/journal.pgen.1003675 23935536
93. Lachenbruch PA, Mickey MR (1968) Estimation of error rates in discriminant analysis. Technometrics 10: 1–11.
Článek vyšel v časopise
PLOS Genetics
2020 Číslo 6
- S diagnostikou Parkinsonovy nemoci může nově pomoci AI nástroj pro hodnocení mrkacího reflexu
- Proč při poslechu některé muziky prostě musíme tančit?
- Chůze do schodů pomáhá prodloužit život a vyhnout se srdečním chorobám
- Metamizol jako analgetikum první volby: kdy, pro koho, jak a proč?
- „Jednohubky“ z klinického výzkumu – 2024/44
Nejčtenější v tomto čísle
- Osteocalcin promotes bone mineralization but is not a hormone
- AXR1 affects DNA methylation independently of its role in regulating meiotic crossover localization
- Super-resolution imaging of RAD51 and DMC1 in DNA repair foci reveals dynamic distribution patterns in meiotic prophase
- Steroid hormones regulate genome-wide epigenetic programming and gene transcription in human endometrial cells with marked aberrancies in endometriosis
