#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#
preLekára.sk / Odborné časopisy / PLOS Genetics / 2014 - 10

Recovery from an Acute Infection in Requires the GATA Transcription Factor ELT-2

English version České info

Infections by bacterial pathogens often produce substantial tissue damage and alter metabolism in the host that, if left unchecked, could be detrimental to overall fitness. The cellular and systemic responses that resolve these alterations in the host are not well defined. Here, we examine transcriptional networks in an animal host that are modulated during the resolution phase of an intestinal infection treated with an antibiotic. Up-regulation of genes involved in detoxification and cellular homeostasis during the resolution phase is controlled by the conserved endodermal GATA transcription factor ELT-2. GATA transcription factors are known to be involved in the development, differentiation, and function of a diverse array of metazoan tissue types. Therefore, our results ascribe a new role to GATA transcription factors in recovery from an acute infection. Fully characterizing the host response during resolution of an infection will lead to a better understanding of human health concerns related to recurrent infections, wound healing, autoimmune diseases, and chronic inflammatory disorders.

Vyšlo v časopise: Recovery from an Acute Infection in Requires the GATA Transcription Factor ELT-2. PLoS Genet 10(10): e32767. doi:10.1371/journal.pgen.1004609
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004609

Souhrn

Infections by bacterial pathogens often produce substantial tissue damage and alter metabolism in the host that, if left unchecked, could be detrimental to overall fitness. The cellular and systemic responses that resolve these alterations in the host are not well defined. Here, we examine transcriptional networks in an animal host that are modulated during the resolution phase of an intestinal infection treated with an antibiotic. Up-regulation of genes involved in detoxification and cellular homeostasis during the resolution phase is controlled by the conserved endodermal GATA transcription factor ELT-2. GATA transcription factors are known to be involved in the development, differentiation, and function of a diverse array of metazoan tissue types. Therefore, our results ascribe a new role to GATA transcription factors in recovery from an acute infection. Fully characterizing the host response during resolution of an infection will lead to a better understanding of human health concerns related to recurrent infections, wound healing, autoimmune diseases, and chronic inflammatory disorders.

Zdroje

1. Darby C (2005) Interactions with microbial pathogens. WormBook: 1–15.

2. TenorJL, McCormickBA, AusubelFM, AballayA (2004) Caenorhabditis elegans-based screen identifies Salmonella virulence factors required for conserved host-pathogen interactions. Curr Biol 14: 1018–1024.

3. TanMW, RahmeLG, SternbergJA, TompkinsRG, AusubelFM (1999) Pseudomonas aeruginosa killing of Caenorhabditis elegans used to identify P. aeruginosa virulence factors. Proc Natl Acad Sci U S A 96: 2408–2413.

4. GarsinDA, SifriCD, MylonakisE, QinX, SinghKV, et al. (2001) A simple model host for identifying Gram-positive virulence factors. Proc Natl Acad Sci U S A 98: 10892–10897.

5. Pukkila-WorleyR, AusubelFM (2012) Immune defense mechanisms in the Caenorhabditis elegans intestinal epithelium. Curr Opin Immunol 24: 3–9.

6. PartridgeFA, Gravato-NobreMJ, HodgkinJ (2010) Signal transduction pathways that function in both development and innate immunity. Dev Dyn 239: 1330–1336.

7. IrazoquiJE, UrbachJM, AusubelFM (2010) Evolution of host innate defence: insights from Caenorhabditis elegans and primitive invertebrates. Nat Rev Immunol 10: 47–58.

8. MeansTK, AballayA (2011) Models to study ancient host-pathogen interactions: lessons from Crete. EMBO reports 12: 5–7.

9. AballayA, YorgeyP, AusubelFM (2000) Salmonella typhimurium proliferates and establishes a persistent infection in the intestine of Caenorhabditis elegans. Curr Biol 10: 1539–1542.

10. LeroyM, MosserT, ManiereX, AlvarezDF, MaticI (2012) Pathogen-induced Caenorhabditis elegans developmental plasticity has a hormetic effect on the resistance to biotic and abiotic stresses. BMC evolutionary biology 12: 187.

11. HuangDW, ShermanBT, LempickiRA (2009) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nature protocols 4: 44–57.

12. KerryS, TeKippeM, GaddisNC, AballayA (2006) GATA transcription factor required for immunity to bacterial and fungal pathogens. PLoS One 1: e77.

13. MalloGV, KurzCL, CouillaultC, PujolN, GranjeaudS, et al. (2002) Inducible antibacterial defense system in C. elegans. Curr Biol 12: 1209–1214.

14. TroemelER, ChuSW, ReinkeV, LeeSS, AusubelFM, et al. (2006) p38 MAPK regulates expression of immune response genes and contributes to longevity in C. elegans. PLoS Genet 2: e183.

15. O'RourkeD, BabanD, DemidovaM, MottR, HodgkinJ (2006) Genomic clusters, putative pathogen recognition molecules, and antimicrobial genes are induced by infection of C. elegans with M. nematophilum. Genome Res 16: 1005–1016.

16. ShoreDE, RuvkunG (2013) A cytoprotective perspective on longevity regulation. Trends Cell Biol 23: 409–420.

17. XuC, LiCY, KongAN (2005) Induction of phase I, II and III drug metabolism/transport by xenobiotics. Archives of pharmacal research 28: 249–268.

18. ChavezV, Mohri-ShiomiA, GarsinDA (2009) Ce-Duox1/BLI-3 generates reactive oxygen species as a protective innate immune mechanism in Caenorhabditis elegans. Infect Immun 77: 4983–4989.

19. van der HoevenR, McCallumKC, GarsinDA (2012) Speculations on the activation of ROS generation in C. elegans innate immune signaling. Worm 1: 160–163.

20. SemX, RhenM (2012) Pathogenicity of Salmonella enterica in Caenorhabditis elegans relies on disseminated oxidative stress in the infected host. PLoS One 7: e45417.

21. BurmeisterC, LuersenK, HeinickA, HusseinA, DomagalskiM, et al. (2008) Oxidative stress in Caenorhabditis elegans: protective effects of the Omega class glutathione transferase (GSTO-1). FASEB journal: official publication of the Federation of American Societies for Experimental Biology 22: 343–354.

22. FukushigeT, HawkinsMG, McGheeJD (1998) The GATA-factor elt-2 is essential for formation of the Caenorhabditis elegans intestine. Dev Biol 198: 286–302.

23. McGheeJD, FukushigeT, KrauseMW, MinnemaSE, GoszczynskiB, et al. (2009) ELT-2 is the predominant transcription factor controlling differentiation and function of the C. elegans intestine, from embryo to adult. Dev Biol 327: 551–565.

24. McGheeJD (2013) The Caenorhabditis elegans intestine. Wiley interdisciplinary reviews Developmental biology 2: 347–367.

25. WattsJL (2009) Fat synthesis and adiposity regulation in Caenorhabditis elegans. Trends in endocrinology and metabolism: TEM 20: 58–65.

26. McFall-NgaiM, HadfieldMG, BoschTC, CareyHV, Domazet-LosoT, et al. (2013) Animals in a bacterial world, a new imperative for the life sciences. Proc Natl Acad Sci U S A 110: 3229–3236.

27. ShaoJ, HeK, WangH, HoWS, RenX, et al. (2013) Collaborative regulation of development but independent control of metabolism by two epidermis-specific transcription factors in Caenorhabditis elegans. The Journal of biological chemistry 288: 33411–33426.

28. ShapiraM, HamlinBJ, RongJ, ChenK, RonenM, et al. (2006) A conserved role for a GATA transcription factor in regulating epithelial innate immune responses. Proc Natl Acad Sci U S A 103: 14086–14091.

29. LeeSH, WongRR, ChinCY, LimTY, EngSA, et al. (2013) Burkholderia pseudomallei suppresses Caenorhabditis elegans immunity by specific degradation of a GATA transcription factor. Proc Natl Acad Sci U S A 110: 15067–15072.

30. KimDH, FeinbaumR, AlloingG, EmersonFE, GarsinDA, et al. (2002) A conserved p38 MAP kinase pathway in Caenorhabditis elegans innate immunity. Science 297: 623–626.

31. AballayA, DrenkardE, HilbunLR, AusubelFM (2003) Caenorhabditis elegans innate immune response triggered by Salmonella enterica requires intact LPS and is mediated by a MAPK signaling pathway. Curr Biol 13: 47–52.

32. McGhee JD (2007) The C. elegans intestine. WormBook: the online review of C elegans biology: 1–36.

33. McGheeJD, SleumerMC, BilenkyM, WongK, McKaySJ, et al. (2007) The ELT-2 GATA-factor and the global regulation of transcription in the C. elegans intestine. Dev Biol 302: 627–645.

34. ZhangP, JudyM, LeeSJ, KenyonC (2013) Direct and indirect gene regulation by a life-extending FOXO protein in C. elegans: roles for GATA factors and lipid gene regulators. Cell Metab 17: 85–100.

35. Glover-CutterKM, LinS, BlackwellTK (2013) Integration of the unfolded protein and oxidative stress responses through SKN-1/Nrf. PLoS Genet 9: e1003701.

36. HoevenR, McCallumKC, CruzMR, GarsinDA (2011) Ce-Duox1/BLI-3 generated reactive oxygen species trigger protective SKN-1 activity via p38 MAPK signaling during infection in C. elegans. PLoS Pathog 7: e1002453.

37. RiedelCG, DowenRH, LourencoGF, KirienkoNV, HeimbucherT, et al. (2013) DAF-16 employs the chromatin remodeller SWI/SNF to promote stress resistance and longevity. Nat Cell Biol 15: 491–501.

38. StyerKL, SinghV, MacoskoE, SteeleSE, BargmannCI, et al. (2008) Innate immunity in Caenorhabditis elegans is regulated by neurons expressing NPR-1/GPCR. Science 322: 460–464.

39. SunJ, SinghV, Kajino-SakamotoR, AballayA (2011) Neuronal GPCR controls innate immunity by regulating noncanonical unfolded protein response genes. Science 332: 729–732.

40. ReddyKC, AndersenEC, KruglyakL, KimDH (2009) A polymorphism in npr-1 is a behavioral determinant of pathogen susceptibility in C. elegans. Science 323: 382–384.

41. SunJ, LiuY, AballayA (2012) Organismal regulation of XBP-1-mediated unfolded protein response during development and immune activation. EMBO reports 13: 855–860.

42. SinghV, AballayA (2012) Endoplasmic reticulum stress pathway required for immune homeostasis is neurally controlled by arrestin-1. The Journal of biological chemistry 287: 33191–33197.

43. AnyanfulA, EasleyKA, BenianGM, KalmanD (2009) Conditioning protects C. elegans from lethal effects of enteropathogenic E. coli by activating genes that regulate lifespan and innate immunity. Cell Host Microbe 5: 450–462.

44. KawliT, TanMW (2008) Neuroendocrine signals modulate the innate immunity of Caenorhabditis elegans through insulin signaling. Nat Immunol 9: 1415–24.

45. EvansEA, KawliT, TanMW (2008) Pseudomonas aeruginosa suppresses host immunity by activating the DAF-2 insulin-like signaling pathway in Caenorhabditis elegans. PLoS Pathog 4: e1000175.

46. ZugastiO, EwbankJJ (2009) Neuroimmune regulation of antimicrobial peptide expression by a noncanonical TGF-beta signaling pathway in Caenorhabditis elegans epidermis. Nature immunology 10: 249–256.

47. BrennerS (1974) The genetics of Caenorhabditis elegans. Genetics 77: 71–94.

48. KamathRS, FraserAG, DongY, PoulinG, DurbinR, et al. (2003) Systematic functional analysis of the Caenorhabditis elegans genome using RNAi. Nature 421: 231–237.

49. BurtonEA, PendergastAM, AballayA (2006) The Caenorhabditis elegans ABL-1 tyrosine kinase is required for Shigella flexneri pathogenesis. Appl Environ Microbiol 72: 5043–5051.

50. HoisethSK, StockerBA (1981) Aromatic-dependent Salmonella typhimurium are non-virulent and effective as live vaccines. Nature 291: 238–239.

51. ValdiviaRH, FalkowS (1996) Bacterial genetics by flow cytometry: rapid isolation of Salmonella typhimurium acid-inducible promoters by differential fluorescence induction. Mol Microbiol 22: 367–378.

52. EngelmannI, GriffonA, TichitL, Montanana-SanchisF, WangG, et al. (2011) A comprehensive analysis of gene expression changes provoked by bacterial and fungal infection in C. elegans. PLoS One 6: e19055.

Štítky
Genetika Reprodukčná medicína
Článek An Deletion Is Highly Associated with a Juvenile-Onset Inherited Polyneuropathy in Leonberger and Saint Bernard Dogs
Článek Licensing of Yeast Centrosome Duplication Requires Phosphoregulation of Sfi1
Článek Oligoasthenoteratozoospermia and Infertility in Mice Deficient for miR-34b/c and miR-449 Loci
Článek Basement Membrane and Cell Integrity of Self-Tissues in Maintaining Immunological Tolerance
Článek The Kinesin AtPSS1 Promotes Synapsis and is Required for Proper Crossover Distribution in Meiosis
Článek Germline Mutations in Are Associated with Familial Gastric Cancer
Článek POT1a and Components of CST Engage Telomerase and Regulate Its Activity in
Článek Controlling Meiotic Recombinational Repair – Specifying the Roles of ZMMs, Sgs1 and Mus81/Mms4 in Crossover Formation
Článek Payoffs, Not Tradeoffs, in the Adaptation of a Virus to Ostensibly Conflicting Selective Pressures
Článek FHIT Suppresses Epithelial-Mesenchymal Transition (EMT) and Metastasis in Lung Cancer through Modulation of MicroRNAs
Článek Genome-Wide Mapping of Yeast RNA Polymerase II Termination
Článek Examination of Prokaryotic Multipartite Genome Evolution through Experimental Genome Reduction
Článek White Cells Facilitate Opposite- and Same-Sex Mating of Opaque Cells in
Článek BMP-FGF Signaling Axis Mediates Wnt-Induced Epidermal Stratification in Developing Mammalian Skin
Článek Genome-Wide Association Study of CSF Levels of 59 Alzheimer's Disease Candidate Proteins: Significant Associations with Proteins Involved in Amyloid Processing and Inflammation
Článek COE Loss-of-Function Analysis Reveals a Genetic Program Underlying Maintenance and Regeneration of the Nervous System in Planarians
Článek Fat-Dachsous Signaling Coordinates Cartilage Differentiation and Polarity during Craniofacial Development
Článek Identification of Genes Important for Cutaneous Function Revealed by a Large Scale Reverse Genetic Screen in the Mouse
Článek Sensors at Centrosomes Reveal Determinants of Local Separase Activity
Článek Genes Integrate and Hedgehog Pathways in the Second Heart Field for Cardiac Septation
Článek Systematic Dissection of Coding Exons at Single Nucleotide Resolution Supports an Additional Role in Cell-Specific Transcriptional Regulation
Článek HIPPO Pathway Members Restrict SOX2 to the Inner Cell Mass Where It Promotes ICM Fates in the Mouse Blastocyst
Článek Role of and in Development of Abdominal Epithelia Breaks Posterior Prevalence Rule
Článek The Formation of Endoderm-Derived Taste Sensory Organs Requires a -Dependent Expansion of Embryonic Taste Bud Progenitor Cells
Článek Role of STN1 and DNA Polymerase α in Telomere Stability and Genome-Wide Replication in Arabidopsis
Článek Keratin 76 Is Required for Tight Junction Function and Maintenance of the Skin Barrier
Článek Encodes the Catalytic Subunit of N Alpha-Acetyltransferase that Regulates Development, Metabolism and Adult Lifespan
Článek Disruption of SUMO-Specific Protease 2 Induces Mitochondria Mediated Neurodegeneration
Článek Caudal Regulates the Spatiotemporal Dynamics of Pair-Rule Waves in
Článek It's All in Your Mind: Determining Germ Cell Fate by Neuronal IRE-1 in
Článek A Conserved Role for Homologs in Protecting Dopaminergic Neurons from Oxidative Stress
Článek The Master Activator of IncA/C Conjugative Plasmids Stimulates Genomic Islands and Multidrug Resistance Dissemination
Článek An AGEF-1/Arf GTPase/AP-1 Ensemble Antagonizes LET-23 EGFR Basolateral Localization and Signaling during Vulva Induction
Článek The Proteomic Landscape of the Suprachiasmatic Nucleus Clock Reveals Large-Scale Coordination of Key Biological Processes
Článek RNA-Processing Protein TDP-43 Regulates FOXO-Dependent Protein Quality Control in Stress Response
Článek A Complex Genetic Switch Involving Overlapping Divergent Promoters and DNA Looping Regulates Expression of Conjugation Genes of a Gram-positive Plasmid
Článek ZTF-8 Interacts with the 9-1-1 Complex and Is Required for DNA Damage Response and Double-Strand Break Repair in the Germline
Článek Integrating Functional Data to Prioritize Causal Variants in Statistical Fine-Mapping Studies
Článek Tpz1-Ccq1 and Tpz1-Poz1 Interactions within Fission Yeast Shelterin Modulate Ccq1 Thr93 Phosphorylation and Telomerase Recruitment
Článek Salt-Induced Stabilization of EIN3/EIL1 Confers Salinity Tolerance by Deterring ROS Accumulation in
Článek Telomeric (s) in spp. Encode Mediator Subunits That Regulate Distinct Virulence Traits
Článek Ethylene-Induced Inhibition of Root Growth Requires Abscisic Acid Function in Rice ( L.) Seedlings
Článek Ancient Expansion of the Hox Cluster in Lepidoptera Generated Four Homeobox Genes Implicated in Extra-Embryonic Tissue Formation
Článek Mechanism of Suppression of Chromosomal Instability by DNA Polymerase POLQ
Článek A Mutation in the Mouse Gene Leads to Impaired Hedgehog Signaling
Článek Keeping mtDNA in Shape between Generations
Článek Targeted Exon Capture and Sequencing in Sporadic Amyotrophic Lateral Sclerosis
Článek TIF-IA-Dependent Regulation of Ribosome Synthesis in Muscle Is Required to Maintain Systemic Insulin Signaling and Larval Growth
Článek At Short Telomeres Tel1 Directs Early Replication and Phosphorylates Rif1
Článek Evidence of a Bacterial Receptor for Lysozyme: Binding of Lysozyme to the Anti-σ Factor RsiV Controls Activation of the ECF σ Factor σ
Článek Hsp40s Specify Functions of Hsp104 and Hsp90 Protein Chaperone Machines
Článek Feeding State, Insulin and NPR-1 Modulate Chemoreceptor Gene Expression via Integration of Sensory and Circuit Inputs
Článek Functional Interaction between Ribosomal Protein L6 and RbgA during Ribosome Assembly
Článek Multiple Regulatory Systems Coordinate DNA Replication with Cell Growth in
Článek Fast Evolution from Precast Bricks: Genomics of Young Freshwater Populations of Threespine Stickleback
Článek Mmp1 Processing of the PDF Neuropeptide Regulates Circadian Structural Plasticity of Pacemaker Neurons
Článek The Nuclear Immune Receptor Is Required for -Dependent Constitutive Defense Activation in
Článek Genetic Modifiers of Neurofibromatosis Type 1-Associated Café-au-Lait Macule Count Identified Using Multi-platform Analysis
Článek Juvenile Hormone-Receptor Complex Acts on and to Promote Polyploidy and Vitellogenesis in the Migratory Locust
Článek Uncovering Enhancer Functions Using the α-Globin Locus
Článek The Analysis of Mutant Alleles of Different Strength Reveals Multiple Functions of Topoisomerase 2 in Regulation of Chromosome Structure
Článek Metabolic Respiration Induces AMPK- and Ire1p-Dependent Activation of the p38-Type HOG MAPK Pathway
Článek The Specification and Global Reprogramming of Histone Epigenetic Marks during Gamete Formation and Early Embryo Development in
Článek The DAF-16 FOXO Transcription Factor Regulates to Modulate Stress Resistance in , Linking Insulin/IGF-1 Signaling to Protein N-Terminal Acetylation
Článek Genetic Influences on Translation in Yeast
Článek Analysis of Mutants Defective in the Cdk8 Module of Mediator Reveal Links between Metabolism and Biofilm Formation
Článek Ribosomal Readthrough at a Short UGA Stop Codon Context Triggers Dual Localization of Metabolic Enzymes in Fungi and Animals
Článek Gene Duplication Restores the Viability of Δ and Δ Mutants
Článek Selection on a Variant Associated with Improved Viral Clearance Drives Local, Adaptive Pseudogenization of Interferon Lambda 4 ()
Článek Break-Induced Replication Requires DNA Damage-Induced Phosphorylation of Pif1 and Leads to Telomere Lengthening
Článek Dynamic Partnership between TFIIH, PGC-1α and SIRT1 Is Impaired in Trichothiodystrophy
Článek Signature Gene Expression Reveals Novel Clues to the Molecular Mechanisms of Dimorphic Transition in
Článek Mutations in Moderate or Severe Intellectual Disability
Článek Multifaceted Genome Control by Set1 Dependent and Independent of H3K4 Methylation and the Set1C/COMPASS Complex
Článek A Role for Taiman in Insect Metamorphosis
Článek The Small RNA Rli27 Regulates a Cell Wall Protein inside Eukaryotic Cells by Targeting a Long 5′-UTR Variant
Článek MMS Exposure Promotes Increased MtDNA Mutagenesis in the Presence of Replication-Defective Disease-Associated DNA Polymerase γ Variants
Článek Coexistence and Within-Host Evolution of Diversified Lineages of Hypermutable in Long-term Cystic Fibrosis Infections
Článek Comprehensive Mapping of the Flagellar Regulatory Network
Článek Topoisomerase II Is Required for the Proper Separation of Heterochromatic Regions during Female Meiosis
Článek A Splice Mutation in the Gene Causes High Glycogen Content and Low Meat Quality in Pig Skeletal Muscle
Článek KDM5 Interacts with Foxo to Modulate Cellular Levels of Oxidative Stress
Článek H2B Mono-ubiquitylation Facilitates Fork Stalling and Recovery during Replication Stress by Coordinating Rad53 Activation and Chromatin Assembly
Článek Copy Number Variation in the Horse Genome
Článek Unifying Genetic Canalization, Genetic Constraint, and Genotype-by-Environment Interaction: QTL by Genomic Background by Environment Interaction of Flowering Time in
Článek Spinster Homolog 2 () Deficiency Causes Early Onset Progressive Hearing Loss
Článek Genome-Wide Discovery of Drug-Dependent Human Liver Regulatory Elements
Článek Developmentally-Regulated Excision of the SPβ Prophage Reconstitutes a Gene Required for Spore Envelope Maturation in
Článek Protein Phosphatase 4 Promotes Chromosome Pairing and Synapsis, and Contributes to Maintaining Crossover Competence with Increasing Age
Článek The bHLH-PAS Transcription Factor Dysfusion Regulates Tarsal Joint Formation in Response to Notch Activity during Leg Development
Článek A Mouse Model Uncovers LKB1 as an UVB-Induced DNA Damage Sensor Mediating CDKN1A (p21) Degradation
Článek Notch3 Interactome Analysis Identified WWP2 as a Negative Regulator of Notch3 Signaling in Ovarian Cancer
Článek An Integrated Cell Purification and Genomics Strategy Reveals Multiple Regulators of Pancreas Development
Článek Dominant Sequences of Human Major Histocompatibility Complex Conserved Extended Haplotypes from to
Článek The Vesicle Protein SAM-4 Regulates the Processivity of Synaptic Vesicle Transport
Článek A Gain-of-Function Mutation in Impeded Bone Development through Increasing Expression in DA2B Mice
Článek Nephronophthisis-Associated Regulates Cell Cycle Progression, Apoptosis and Epithelial-to-Mesenchymal Transition
Článek Beclin 1 Is Required for Neuron Viability and Regulates Endosome Pathways via the UVRAG-VPS34 Complex
Článek The Not5 Subunit of the Ccr4-Not Complex Connects Transcription and Translation
Článek Abnormal Dosage of Ultraconserved Elements Is Highly Disfavored in Healthy Cells but Not Cancer Cells
Článek Genome-Wide Distribution of RNA-DNA Hybrids Identifies RNase H Targets in tRNA Genes, Retrotransposons and Mitochondria
Článek The Chromosomal Association of the Smc5/6 Complex Depends on Cohesion and Predicts the Level of Sister Chromatid Entanglement
Článek Cell-Autonomous Progeroid Changes in Conditional Mouse Models for Repair Endonuclease XPG Deficiency
Článok vyšiel v časopise

PLOS Genetics

2014 Číslo 10
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Aktuální možnosti diagnostiky a léčby litiáz
nový kurz
Autori: MUDr. Tomáš Ürge, PhD.
Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#