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A functional polymorphism C-509T in TGFβ-1 promoter contributes to susceptibility and prognosis of lone atrial fibrillation in Chinese population.

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A Functional Polymorphism C-509T in TGFb-1 Promoter Contributes to Susceptibility and Prognosis of Lone Atrial Fibrillation in Chinese Population Hailong Cao1., Qing Zhou1., Rongfang Lan2., Oluf Dimitri Røe3,4, Xin Chen2, Yijiang Chen3, Dongjin Wang1* 1 Department of Thoracic and Cardiovascular Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China, 2 Department of Cardiology, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China, 3 Department of Thoracic and Cardiovascular Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China, 4 Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway Abstract Transforming growth factor-b1 (TGF-b1) is an important mediator of atrial fibrosis and atrial fibrillation (AF). But the involved genetic mechanism is unknown. Herein, the TGF-b1 C-509T polymorphism (rs1800469) was genotyped in a case-control study of 840 patients and 845 controls in Chinese population to explore the association between the polymorphism and susceptibility and prognosis of lone AF. As a result, the CT and/or TT genotypes had an increased lone AF risk [adjusted odds ratio (OR) = 1.50 for CT, OR = 3.72 for TT, and OR = 2.15 for CT/TT], compared with the TGF-b1CC genotype. Moreover, patients carrying CT/TT genotypes showed a higher possibility of AF recurrence after catheter ablation, compared with patients carrying CC genotype. In a genotype-phenotype correlation analysis using 24 normal left atrial appendage samples, increasing gradients of atrial TGF-b1 expression levels positively correlated with atrial collagen volume fraction were identified in samples with CC, CT and TT genotypes. The in vitro luciferase assays also showed a higher luciferase activity of the -509T allele than that of the -509C allele. In conclusion, the TGF-b1 C-509T polymorphism is involved in the etiology of lone AF and thus may be a marker for genetic susceptibility to lone AF and predicting prognosis after catheter ablation in Chinese populations. Therefore, we provide new information about treatment strategies and our understanding of TGF-b1 in AF. Citation: Cao H, Zhou Q, Lan R, Røe OD, Chen X, et al. (2014) A Functional Polymorphism C-509T in TGFb-1 Promoter Contributes to Susceptibility and Prognosis of Lone Atrial Fibrillation in Chinese Population. PLoS ONE 9(11): e112912. doi:10.1371/journal.pone.0112912 Editor: Kandiah Jeyaseelan, National University of Singapore, Singapore Received July 1, 2014; Accepted October 16, 2014; Published November 17, 2014 Copyright: ß 2014 Cao et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files. Funding: This work was supported in part by the National Natural Science Foundation of China [81200133], Jiangsu Top Expert Program in Six Professions [WSN032], Medical science project supported by Jiangsu health department [Z201411], Key Project supported by Medical Science and technology development Foundation, Nanjing Department of Health [YKK12056], the Fundamental Research Funds for the Central Universities [021414330063]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * Email: gldjw@163.com . These authors contributed equally to this work. Introduction Atrial fibrillation (AF), the most common cardiac arrhythmia, is associated with increased morbidity, mortality and cost [1]. To date, the precise mechanism of AF remains largely unknown. It is particularly true for patients with lone AF (LAF), which is AF in the absence of heart disease or comorbidities predisposing to the arrhythmia. However, increasing evidence showed that the atrial fibrosis is essential for the development and progression of AF [2– 3]. It is accepted that transforming growth factor-b1 (TGF-b1) is the most powerful profibrotic factor, stimulating the secretion of collagen into the extracellular matrix by fibroblasts [4]. Overexpression of TGF-b1 selectively induced atrial fibrosis, leading to increased conduction heterogeneity and AF vulnerability without affecting the cellular electrophysiology [5]. Inhibition of TGF-b1 expression by Tranilast significantly reduced the atrial fibrosis, as a result, reduced conduction abnormalities and AF vulnerability were observed [6]. These studies suggest that TGF-b1 plays an essential role in inducing AF. In the human TGF-b1 gene, three polymorphisms in the promoter are presently known [7]. It was proposed in a previous in vitro study that the differences in the induced expression and production of TGF-b1 were a consequence of genetic sequence polymorphisms in the regulatory promoter region [8]. Nevertheless, in Chinese and other Asians, the genetic polymorphism in the promoter was detected only in -509 [9–10]. Therefore, we hypothesized that the TGF-b1 C-509T polymorphism was associated with LAF risk and AF recurrence after catheter ablation in Chinese population. Furthermore, we also designed to explore whether this polymorphism had an effect on TGF-b1 expression in vitro and left atrial appendage (LAA) tissue. PLOS ONE | www.plosone.org 1 November 2014 | Volume 9 | Issue 11 | e112912 A Polymorphism in TGFb-1 and Atrial Fibrillation Materials and Methods 2.1. Ethics statement This hospital-based case-control study was approved by the Review Boards of the Affiliated Drum Tower Hospital of Nanjing University Medical School and the First Affiliated Hospital of Nanjing Medical University (2007-NJEA-10). All subjects provided written informed consent to be included in the study. The study was conducted according to the Helsinki Declaration and approved by the ethics committees of the respective institutions (2007-NJEA-10). We have complied with the World Medical Association Declaration of Helsinki regarding ethical conduct of research involving human subjects. 2.2. Study Subjects We consecutively recruited 2786 non-valvular AF patients between October 2007 and June 2013. Each patient donated 5 ml venous blood upon admission to the hospital and was interviewed to collect demographic data and clinical information. Among them, a total of 860 patients were diagnosed as lone AF, which was based on the following criteria [11]: age at first diagnosis of AF , 60 years, no past cardiovascular history, no evidence suggesting ischemic heart disease, no cardiomyopathy, no heart failure, no valvular heart disease, no diabetes, no hypertension within two years of the onset of AF, no hyperthyroidism. Sex- and agematched 860 AF-free control subjects with written informed consent were genetically unrelated to the cases. They were recruited from healthy subjects without individual history of AF and other chronic diseases. All subjects were genetically unrelated ethnic Han Chinese. Among all the subjects, genotyping was failed in 20 cases (2.59%) and 15 controls (1.88%) due to DNA quality or quantity. Therefore, 840 lone AF cases and 845 healthy controls were finally included in the susceptibility analyses. Among the 840 cases, 725 received first-time catheter ablation and were successfully cardioverted to stable SR. During the follow-up, 112 patients were lost and 3 cases died because trauma or cerebrovascular accident. Therefore, a total of 610 patients had complete followups and clinical information. 2.3. Follow-Up AF-free time was calculated from the date of ablation to the date of recurrence or last follow-up. Atrial arrhythmias that occurred during the first 2 months after ablation, which is considered a blanking period [12], were not counted as recurrences. Antiarrhythmic medications, including amiodarone, metoprolol or propafenone, were generally continued to the end of third month after ablation unless recurrent arrhythmia indicated the need for continued treatment. All patients with documented arrhythmia and those maintained on antiarrhythmics for control of AF beyond the blanking period were counted as recurrences. Patients had scheduled clinical visits, 12-lead ECG, and 24-hour Holter monitoring at 3, 6, and 12 months after ablation and then yearly after the first year. Moreover, patients would receive ECG monitoring in local clinics at anytime if they had AF-related symptoms. AF recurrence was identified by symptoms with ECG documentation of an atrial tachyarrhythmia lasting $30 seconds on a 12-lead ECG or Holter monitor recording. AF recurrence during the follow-up was considered censored. 2.4. Genotyping Genomic DNA was isolated from leukocytes of venous blood by proteinase K digestion and phenol/chloroform extraction. The Table 1. Baseline characteristics of subjects with LAF and controls. Variables Patient number (n) Sex, M/F (n) Age at enrollment (yrs) Age at first diagnosis of AF (yrs) Paroxysmal/Persistent AF (n) Body mass index (kg/m2) Cigarette smoking (n) Alcohol intake . = 1 drink per day (n) Hypercholesterolaemia (n) Left atrial dimension (mm) Medications before enrollment (n) Digitalis Propafenone Amiodarone Beta-blocker ACE-I/ARB Calcium-channel blocker Warfarin Statins Values are presented as mean6SD or number of patients. ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker. doi:10.1371/journal.pone.0112912.t001 LAF group 840 561/279 52.8610.9 45.6611.3 592/248 23.862.9 138 98 46 39.166.7 90 135 155 258 171 50 311 20 Control group 845 562/283 52.8614.9 N/A N/A 23.963.0 168 96 65 31.163.6 N/A N/A N/A N/A N/A N/A N/A N/A p-value 0.904 0.938 0.501 0.066 0.844 0.067 ,0.001 - PLOS ONE | www.plosone.org 2 November 2014 | Volume 9 | Issue 11 | e112912 Table 2. Genotype and allele frequencies of the TGF-b1 C-509T polymorphism between the cases and controls and their associations with risk of LAF. Genotypes LAF (n = 840) n% Controls (n = 845) n% CC 152 18.1 273 32.3 CT 338 40.2 404 47.8 TT 350 41.7 168 19.9 pa 0.001 ,0.001 ,0.001 ,0.001 ,0.001 Adjusted OR (95% CI)b (95% CI)b 1.00 (reference) 1.50 (1.17–1.92) 3.72 (2.83–4.88) 2.15 (1.71–2.70) PLOS ONE | www.plosone.org CT/TT 688 81.9 572 67.7 C allele 642 38.2 950 56.2 T allele 1038 61.8 740 43.8 p trend aTwo-sided x2 test for either genotype distributions or allele frequencies between the cases and controls. bAdjusted for age, sex, body mass index, smoking status, drinking status, and hypercholesteremia in logistic regression model. doi:10.1371/journal.pone.0112912.t002 A Polymorphism in TGFb-1 and Atrial Fibrillation TGF-b1 C-509T polymorphism was determined using the PCR– restriction fragment length polymorphism method. The PCR primers for the TGF-b1 C-509T polymorphism were 59GCTAAGGCATGGCACCGCTT-39 (forward) and 59-GAAGGAGGGTCTGTCAACATGGG-39 (reverse). PCR was performed in a total volume of 20 mL containing 50 ng genomic DNA, 106Taq buffer, 0.02 mmol?L21 of MgCl2, 0.05 mmol?L21 of dNTP mix, 10 pmol?mL21 of each primer and 1 U Taq DNA polymerase. After initial denaturation at 95uC for 5 minutes, the reaction was carried out at 95uC denaturation for 30 seconds, annealing for 40 seconds at 62uC and extension for 45 seconds at 72uC for a total of 34 cycles, and a final elongation at 72uC for 10 minutes. The 270-bp PCR products were digested by the restriction enzyme (Eco81I, SauI) (MBI Fermentas, Vilnius, Lithuania) at 37uC overnight. The digested products were then analyzed by electrophoresis in 3% agarose gel stained with 0.5% ethidium bromide and photographed under UV illumination. The C allele was cut into 198-bp and 72-bp fragments, whereas the T allele was not digested. The polymorphism analysis was carried out by two persons independently in a blinded manner. More than 15% of the samples were randomly selected for confirmation, and the results were 100% concordant. 2.5. LAA samples In order to determine the expression of TGF-b1 and interstitial fibrosis, we collected 24 LAA tissues from healthy heart donors for transplantation. They were trauma victims and were free of cardiovascular pathology and documented AF. LAA specimens were obtained before perfusion. A part of each LAA was fixed in paraformaldehyde for histology, and the others were immediately snap-frozen in liquid nitrogen for laboratory analysis. 2.6. Real-time quantitative RT-PCR The primers of TGF-b1 (Forward primer [F]: 59- CTAATGGTGGAAACCCACAACG-39, Reverse primer [R]: 59-TATCGCCAGGAATTGTTGCTG-39, NM_000660) and glyceraldehydes 3-phosphate dehydrogenase (GAPDH) (Forward primer [F]: 59-ATGGGGAAGGTGAAGGTCG-39, Reverse primer [R]: 59-GGGGTCATTGATGGCAACAATA-39, NM_002046) were synthesized by Invitrogen Co., Hong Kong, China. Total RNA was isolated from frozen RAAs by acid-phenol extraction in the presence of chaotropic salts (TRIzol, Invitrogen) and subsequent isopropanol ethanol precipitation. The synthesis of cDNA was according to the manufacturer’s instructions with the reverse transcriptase kit (Promega Co., US). The real-time PCR was performed using the LightCycler 480 system (Roche Diagnostics, Switzerland) with a total volume of 20 ml containing 10 ml 26Master Mix SYBR Green I (Takara, Japan), 0.25 mM forward primers, 0.25 mM reverse primers, 2 ml cDNA template, and H2O to a final volume of 20 ml. The protocol of real-time PCR consisted of 40 cycles, and cycling parameters were as follows: denaturation at 94uC for 10 seconds, annealing at 61uC for 15 seconds and extension at 72uC for 20 seconds. The results were analyzed using Roche LightCycler 480 software. Data of transcripts were calculated relative to GAPDH using the 22DDCt method. The measurements of each sample were performed in triplicate. 2.7. Western blot Frozen LAAs were used for protein isolation as described previously [13]. Proteins (40 mg/lane) were separated by sodium dodecyl sulfate polyacrylamide gel electropheresis and transferred onto Polylinylidene Fluoride membranes using a Bio-Rad semidry transfer system (Bio-Rad). The membranes were blocked with 5% 3 November 2014 | Volume 9 | Issue 11 | e112912 A Polymorphism in TGFb-1 and Atrial Fibrillation Table 3. Results of Cox multivariate regression analysis on cumulative AF recurrence after catheter ablation. Final variables Hypertension at enrollment Persistent AF Postoperative Statins Left atrial dimension C-509T (CT/TT vs. CC) b, regression coefficient; HR, hazard ratio. doi:10.1371/journal.pone.0112912.t003 b 0.289 1.456 –0.211 1.651 1.416 SEM 0.159 0.147 0.145 0.143 0.236 HR 1.335 4.289 0.810 5.212 4.121 95% CI 0.977–1.824 3.217–5.718 0.610–1.076 3.937–6.900 2.597–6.539 p-value 0.070 ,0.001 0.146 ,0.001 ,0.001 Figure 1. Kaplan-Meier survival curves showing freedom from AF recurrence after catheter ablation according to TGF-b1 C-509T polymorphism. (A) Survival free from AF recurrence in CC (n = 120), CT (n = 231) and TT (n = 259) groups. (B) Survival free from AF recurrence in CC (n = 120) and CT/TT (n = 490) groups. doi:10.1371/journal.pone.0112912.g001 PLOS ONE | www.plosone.org 4 November 2014 | Volume 9 | Issue 11 | e112912 A Polymorphism in TGFb-1 and Atrial Fibrillation Figure 2. Effect of the C-509 T polymorphism in the TGF-b1 promoter activity. (A) Schematic representation of reporter plasmids containing the -509C or -509 T allele, which was inserted upstream of the luciferase reporter gene in the pGL3 basic plasmid. (B) Two constructs were transiently transfected into the mouse cardiac fibroblasts. The luciferase activity of each construct was normalized against the internal control of Renilla luciferase (blank). Values are mean6SD. doi:10.1371/journal.pone.0112912.g002 non-fat dry milk and then probed with mouse monoclonal TGFb1 (ab27969, Abcam, USA) and horseradish peroxidase (HRP)conjugated mouse monoclonal anti-GAPDH (KC-5G5, KangChen Biotech, China). The working dilutions were 1:2000 (TGFb1) and 1:5000 (GAPDH). The resulting reaction was visualized using HRP-conjugated anti-mouse secondary antibody (SantaCruz Biotechnology, the Netherlands), followed by incubation with ECL Western Blot Detection Kit (Amersham, the Netherlands) for 1 minute. The blots were exposed to Kodak film for 5 minutes and immunoreactive bands developed for quantification using The Discovery Series image analysis software (Bio-Rad) normalized by the corresponding value of GAPDH. Experiments were repeated three times and the mean was scored. 2.8. Masson’s trichrome staining After fixation with 4% paraformaldehyde in phosphate-buffered saline (PH: 7.4) for 24 h, the tissues were subjected to alcoholic dehydration and embedded in paraffin. 4 mm serial sections were sliced and subjected to Masson’s trichrome staining to highlight collagen fibers. Collagen volume fraction (CVF) was determined by the HPISA 100 chromatic color pathological analysis system (Olympus, Japan) using five random images from each slide and five slides per sample, and the mean values of CVF were obtained by one investigator blinded to the groups. 2.9. Promoter functional assay The isolation and culture of mouse atrial fibroblasts were previously described [14]. The TGF-b1 promoter-luciferase reporter plasmids containing either -509C or -509T sequences were prepared by amplifying the 270-bp TGF-b1 promoter region by using primers with restriction sites. The primers were 59- Figure 3. Atrial expression of TGF-b1 among different genotypes in healthy heart donors. (A) equilibrium value of MeCpG steps (,+14 deg.) [31,44]. In comparison, methylation has a significantly lower stability cost when happening at major groove positions, such as 211 and 21 base pair from dyad (mutations 9 and 12), where the roll of the nucleosome bound conformation (+10 deg.) is more compatible with the equilibrium geometry of MeCpG steps. The nucleosome destabilizing effect of cytosine methylation increases with the number of methylated cytosines, following the same position dependence as the single methylations. The multiple-methylation case reveals that each major groove meth- PLOS Computational Biology | www.ploscompbiol.org 3 November 2013 | Volume 9 | Issue 11 | e1003354 DNA Methylation and Nucleosome Positioning ylation destabilizes the nucleosome by around 1 kJ/mol (close to the average estimate of 2 kJ/mol obtained for from individual methylation studies), while each minor groove methylation destabilizes it by up to 5 kJ/mol (average free energy as single mutation is around 6 kJ/mol). This energetic position-dependence is the reverse of what was observed in a recent FRET/SAXS study [30]. The differences can be attributed to the use of different ionic conditions and different sequences: a modified Widom-601 sequence of 157 bp, which already contains multiple CpG steps in mixed orientations, and which could assume different positioning due to the introduction of new CpG steps and by effect of the methylation. The analysis of our trajectories reveals a larger root mean square deviation (RMSD) and fluctuation (RMSF; see Figures S2– S3 in Text S1) for the methylated nucleosomes, but failed to detect any systematic change in DNA geometry or in intermolecular DNA-histone energy related to methylation (Fig. S1B, S1C, S4–S6 in Text S1). The hydrophobic effect should favor orientation of the methyl group out from the solvent but this effect alone is not likely to justify the positional dependent stability changes in Figure 2, as the differential solvation of the methyl groups in the bound and unbound states is only in the order of a fraction of a water molecule (Figure S5 in Text S1). We find however, a reasonable correlation between methylation-induced changes in hydrogen bond and stacking interactions of the bases and the change in nucleosome stability (see Figure S6 in Text S1). This finding suggests that methylation-induced nucleosome destabilization is related to the poorer ability of methylated DNA to fit into the required conformation for DNA in a nucleosome. Changes in the elastic deformation energy between methylated and un-methylated DNA correlate with nucleosomal differential binding free energies To further analyze the idea that methylation-induced nucleosome destabilization is connected to a worse fit of methylated DNA into the required nucleosome-bound conformation, we computed the elastic energy of the nucleosomal DNA using a harmonic deformation method [36,37,44]. This method provides a rough estimate of the energy required to deform a DNA fiber to adopt the super helical conformation in the nucleosome (full details in Suppl. Information Text S1). As shown in Figure 2, there is an evident correlation between the increase that methylation produces in the elastic deformation energy (DDE def.) and the free energy variation (DDG bind.) computed from MD/TI calculations. Clearly, methylation increases the stiffness of the CpG step [31], raising the energy cost required to wrap DNA around the histone octamers. This extra energy cost will be smaller in regions of high positive roll (naked DNA MeCpG steps have a higher roll than CpG steps [31]) than in regions of high negative roll. Thus, simple elastic considerations explain why methylation is better tolerated when the DNA faces the histones through the major groove (where positive roll is required) that when it faces histones through the minor groove (where negative roll is required). Nucleosome methylation can give rise to nucleosome repositioning We have established that methylation affects the wrapping of DNA in nucleosomes, but how does this translate into chromatin structure? As noted above, accumulation of minor groove methylations strongly destabilizes the nucleosome, and could trigger nucleosome unfolding, or notable changes in positioning or phasing of DNA around the histone core. While accumulation of methylations might be well tolerated if placed in favorable positions, accumulation in unfavorable positions would destabilize the nucleosome, which might trigger changes in chromatin structure. Chromatin could in fact react in two different ways in response to significant levels of methylation in unfavorable positions: i) the DNA could either detach from the histone core, leading to nucleosome eviction or nucleosome repositioning, or ii) the DNA could rotate around the histone core, changing its phase to place MeCpG steps in favorable positions. Both effects are anticipated to alter DNA accessibility and impact gene expression regulation. The sub-microsecond time scale of our MD trajectories of methylated DNAs bound to nucleosomes is not large enough to capture these effects, but clear trends are visible in cases of multiple mutations occurring in unfavorable positions, where unmethylated and methylated DNA sequences are out of phase by around 28 degrees (Figure S7 in Text S1). Due to this repositioning, large or small, DNA could move and the nucleosome structure could assume a more compact and distorted conformation, as detected by Lee and Lee [29], or a slightly open conformation as found in Jimenez-Useche et al. [30]. Using the harmonic deformation method, we additionally predicted the change in stability induced by cytosine methylation for millions of different nucleosomal DNA sequences. Consistently with our calculations, we used two extreme scenarios to prepare our DNA sequences (see Fig. 3): i) all positions where the minor grooves contact the histone core are occupied by CpG steps, and ii) all positions where the major grooves contact the histone core are occupied by CpG steps. We then computed the elastic energy required to wrap the DNA around the histone proteins in unmethylated and methylated states, and, as expected, observed that methylation disfavors DNA wrapping (Figure 3A). We have rescaled the elastic energy differences with a factor of 0.23 to match the DDG prediction in figure 2B. In agreement with the rest of our results, our analysis confirms that the effect of methylation is position-dependent. In fact, the overall difference between the two extreme methylation scenarios (all-in-minor vs all-in-major) is larger than 60 kJ/mol, the average difference being around 15 kJ/ mol. We have also computed the elastic energy differences for a million sequences with CpG/MeCpG steps positioned at all possible intermediate locations with respect to the position (figure 3B). The large differences between the extreme cases can induce rotations of DNA around the histone core, shifting its phase to allow the placement of the methylated CpG steps facing the histones through the major groove. It is illustrative to compare the magnitude of CpG methylation penalty with sequence dependent differences. Since there are roughly 1.5e88 possible 147 base pairs long sequence combinations (i.e., (4n+4(n/2))/2, n = 147), it is unfeasible to calculate all the possible sequence effects. However, using our elastic model we can provide a range of values based on a reasonably large number of samples. If we consider all possible nucleosomal sequences in the yeast genome (around 12 Mbp), the energy difference between the best and the worst sequence that could form a nucleosome is 0.7 kj/mol per base (a minimum of 1 kJ/mol and maximum of around 1.7 kJ/mol per base, the first best and the last worst sequences are displayed in Table S3 in Text S1). We repeated the same calculation for one million random sequences and we obtained equivalent results. Placing one CpG step every helical turn gives an average energetic difference between minor groove and major groove methylation of 15 kJ/ mol, which translates into ,0.5 kJ/mol per methyl group, 2 kJ/ mol per base for the largest effects. Considering that not all nucleosome base pair steps are likely to be CpG steps, we can conclude that the balance between the destabilization due to CpG methylation and sequence repositioning will depend on the PLOS Computational Biology | www.ploscompbiol.org 4 November 2013 | Volume 9 | Issue 11 | e1003354 DNA Methylation and Nucleosome Positioning Figure 3. Methylated and non-methylated DNA elastic deformation energies. (A) Distribution of deformation energies for 147 bplong random DNA sequences with CpG steps positioned every 10 base steps (one helical turn) in minor (red and dark red) and major (light and dark blue) grooves respectively. The energy values were rescaled by the slope of a best-fit straight line of figure 2, which is 0.23, to por la lectura a través de la lectura de la prensa. La educación en los medios las fuerzas dispersas en función de los soportes mediáticos y orientarse más hacia la educación en medios que al dominio adquiere pleno derecho y entidad en la sección sexta titulada «competencias sociales y cívi- técnico de los aparatos. cas» que indica que «los alum- nos deberán ser capaces de juz- gar y tendrán espíritu crítico, lo que supone ser educados en los las programaciones oficiales, ya que, a lo largo de un medios y tener conciencia de su lugar y de su influencia estudio de los textos, los documentalistas del CLEMI en la sociedad». han podido señalar más de una centena de referencias a la educación de los medios en el seno de disciplinas 4. Un entorno positivo como el francés, la historia, la geografía, las lenguas, Si nos atenemos a las cifras, el panorama de la las artes plásticas : trabajos sobre las portadas de educación en medios es muy positivo. Una gran ope- prensa, reflexiones sobre temas mediáticos, análisis de ración de visibilidad como la «Semana de la prensa y publicidad, análisis de imágenes desde todos los ángu- de los medios en la escuela», coordinada por el CLE- los, reflexión sobre las noticias en los países europeos, MI, confirma año tras año, después de 17 convocato- información y opinión rias, el atractivo que ejerce sobre los profesores y los Esta presencia se constata desde la escuela mater- alumnos. Concebida como una gran operación de nal (2 a 6 años) donde, por ejemplo, se le pregunta a complementariedad entre la escuela y los profesiona- los niños más pequeños si saben diferenciar entre un les de los medios, alrededor del aprendizaje ciudada- periódico, un libro, un catálogo, a través de activida- no de la comunicación mediática, este evento moviliza des sensoriales, si saben para qué sirve un cartel, un durante toda una semana un porcentaje elevado de periódico, un cuaderno, un ordenador si son capa- centros escolares que representan un potencial de 4,3 ces de reconocer y distinguir imágenes de origen y de millones de alumnos (cifras de 2006). Basada en el naturaleza distintas. Podríamos continuar con más voluntariado, la semana permite desarrollar activida- ejemplos en todos los niveles de enseñanza y práctica- des más o menos ambiciosas centradas en la introduc- Páginas 43-48 ción de los medios en la vida de la escuela a través de la instalación de kioscos, organización de debates con profesionales y la confección por parte de los alumnos de documentos difundidos en los medios profesionales. Es la ocasión de dar un empujón a la educación en medios y de disfrutarlos. Los medios –un millar en 2006– se asocian de maneras diversas ofreciendo ejemplares de periódicos, acceso a noticias o a imágenes, proponiendo encuentros, permitiendo intervenir a los jóvenes en sus ondas o en sus columnas Esta operación da luz al trabajo de la educación en medios y moviliza a los diferentes participantes en el proyecto. 5. La formación de los docentes La formación es uno de los pilares principales de la educación en los medios. Su función es indispensable ya que no se trata de una disciplina, sino de una enseñanza que se hace sobre la base del voluntariado y del compromiso personal. Se trata de convencer, de mostrar, de interactuar. En primer lugar es necesario incluirla en la formación continua de los docentes, cuyo volumen se ha incrementado desde 1981 con la aparición de una verdadera política de formación continua de personal. Es difícil dar una imagen completa del volumen y del público, pero si nos atenemos a las cifras del CLEMI, hay más de 24.000 profesores que han asistido y se han involucrado durante 2004-05. 5.1. La formación continua En la mayoría de los casos, los profesores reciben su formación en contextos cercanos a su centro de trabajo, o incluso en este mismo. Después de una política centrada en la oferta que hacían los formadores, se valora más positivamente la demanda por parte del profesorado, ya que sólo así será verdaderamente fructífera. Los cursos de formación se repartieron en varias categorías: desde los formatos más tradicionales (cursos, debates, animaciones), hasta actividades de asesoramiento y de acompañamiento, y por supuesto los coloquios que permiten un trabajo en profundidad ya que van acompañados de expertos investigadores y profesionales. Citemos, por ejemplo en 2005, los coloquios del CLEMI-Toulouse sobre el cine documental o el del CLEMI-Dijon sobre «Políticos y medios: ¿connivencia?». Estos coloquios, que forman parte de un trabajo pedagógico regular, reagrupan a los diferentes participantes regionales y nacionales alrededor de grandes temas de la educación en medios y permiten generar nuevos conocimientos de aproximación y una profundización. Páginas 43-48 Hay otro tipo de formación original que se viene desarrollando desde hace menos tiempo, a través de cursos profesionales, como por ejemplo, en el Festival Internacional de Foto-periodismo «Visa para la imagen», en Perpignan. La formación se consolida en el curso, da acceso a las exposiciones, a las conferencias de profesionales y a los grandes debates, pero añade además propuestas pedagógicas y reflexiones didácticas destinadas a los docentes. Estas nuevas modalidades de formación son también consecuencia del agotamiento de la formación tradicional en las regiones. Los contenidos más frecuentes en formación continua conciernen tanto a los temas más clásicos como a los cambios que se están llevando a cabo en las prácticas mediáticas. Así encontramos distintas tendencias para 2004-05: La imagen desde el ángulo de la producción de imágenes animadas, el análisis de la imagen de la información o las imágenes del J.T. La prensa escrita y el periódico escolar. Internet y la información en línea. Medios y educación de los medios. 5.2 La formación inicial La formación inicial está aun en un grado muy ini- cial. El hecho de que la educación en medios no sea una disciplina impide su presencia en los IUFM (Institutos Universitarios de Formación de Maestros) que dan una prioridad absoluta a la didáctica de las disciplinas. En 2003, alrededor de 1.400 cursillistas sobre un total de 30.000 participaron en un momento u otro de un módulo de educación en medios. Estos módulos se ofrecen en función del interés que ese formador encuentra puntualmente y forman parte a menudo de varias disciplinas: documentación, letras, historia-geografía Estamos aún lejos de una política concertada en este dominio. La optativa «Cine-audiovisual» ha entrado desde hace muy poco tiempo en algunos IUFM destinada a obtener un certificado de enseñanza de la opción audiovisual y cine. Internet tiene cabida también en los cursos de formación inicial, recientemente con la aparición de un certificado informático y de Internet para los docentes, dirigido más a constatar competencias personales que a valorar una aptitud para enseñarlos. 6. ¿Y el futuro? El problema del futuro se plantea una vez más por la irrupción de nuevas técnicas y nuevos soportes. La difusión acelerada de lo digital replantea hoy muchas cuestiones relativas a prácticas mediáticas. Muchos Comunicar, 28, 2007 47 Comunicar, 28, 2007 Enrique Martínez-Salanova '2007 para Comunicar 48 trabajos que llevan el rótulo de la educación en medios solicitan una revisión ya que los conceptos cambian. La metodología elaborada en el marco de la educación en medios parece incluso permitir la inclinación de la sociedad de la información hacia una sociedad del conocimiento, como defiende la UNESCO. En Francia, se necesitaría unir las fuerzas dispersas en función de los soportes mediáticos y orientarse más hacia la educación en medios que al dominio técnico de los aparatos. Los avances recientes en el reconocimiento de estos contenidos y las competencias que supondrían podrían permitirlo. Referencias CLEMI/ACADEMIE DE BORDEAUX (Ed.) (2003): Parcours médias au collège: approches disciplinaires et transdisciplinaires. Aquitaine, Sceren-CRDP. GONNET, J. (2001): Education aux médias. Les controverses fécondes. Paris, Hachette Education/CNDP. SAVINO, J.; MARMIESSE, C. et BENSA, F. (2005): L’éducation aux médias de la maternelle au lycée. Direction de l’Enseignement Scolaire. Paris, Ministère de l’Education Nationale, Sceren/CNDP, Témoigner. BEVORT, E. et FREMONT, P. (2001): Médias, violence et education. Paris, CNDP, Actes et rapports pour l’éducation. – www.clemi.org: fiches pédagogiques, rapports et liens avec les pages régionales/académiques. – www.ac-nancy-metz.fr/cinemav/quai.html: Le site «Quai des images» est dédié à l’enseignement du cinéma et de l’audiovisuel. – www.france5.fr/education: la rubrique «Côté profs» a une entrée «education aux médias». – www.educaunet.org: Programme européen d’éducation aux risques liés à Internet. dResedfeleexliobnuetsacón Páginas 43-48
A functional polymorphism C-509T in TGFβ-1 promoter contributes to susceptibility and prognosis of lone atrial fibrillation in Chinese population.
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A functional polymorphism C-509T in TGFβ-1 promoter contributes to susceptibility and prognosis of lone atrial fibrillation in Chinese population.

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