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miR-34 and p53: New Insights into a Complex Functional Relationship. - PloS one
miR-34, a tumor suppressor miRNA family transcriptionally activated by p53, is considered a critical mediator of p53 function. However, knockout of the mouse miR-34 family has little or no effect on the p53 response. The relative contribution of different miR-34 family members to p53 function or how much p53 relies on miR-34 in human cells is unclear. Here we show that miR-34a has a complex effect on the p53 response in human cells. In HCT116 cells miR-34a overexpression enhances p53 transcriptional activity, but the closely related family members, miR-34b and miR-34c, even when over-expressed, have little effect. Both TP53 itself and MDM4, a strong p53 transactivation inhibitor, are direct targets of miR-34a. The genes regulated by miR-34a also include four other post-translational inhibitors of p53. miR-34a overexpression leads to variable effects on p53 levels in p53-sufficient human cancer cell lines. In HCT116, miR-34a overexpression increases p53 protein levels and stability. About a quarter of all mRNAs that participate in the human p53 network bind to biotinylated miR-34a, suggesting that many are direct miR-34a targets. However, only about a fifth of the mRNAs that bind to miR-34a also bind to miR-34b or miR-34c. Two human cell lines knocked out for miR-34a have unimpaired p53-mediated responses to genotoxic stress, like mouse cells. The complex positive and negative effects of miR-34 on the p53 network suggest that rather than simply promoting the p53 response, miR-34a might act at a systems level to stabilize the robustness of the p53 response to genotoxic stress.
Expression patterns and immunohistochemical localization of PITX2B transcription factor in the developing mouse heart. - The International journal of developmental biology
The Pitx2 gene is involved in the establishment of vertebrate left-right axis with an important role in subsequent heart organogenesis. Mutations in the Pitx2 gene have been associated with Axenfeld-Rieger syndrome, which is characterized by ocular, craniofacial, and umbilical anomalies, as well as cardiac defects. In addition, recent data have unravelled a molecular link between PITX2 loss of function and atrial fibrillation (AF), supporting an important role of Pitx2 not only in development but also in heart homeostasis.Three PITX2 isoforms have been described in mice: PITX2A, PITX2B, and PITX2C. During heart organogenesis PITX2C seems to play a determinant role in left-right signalling from early somitogenesis onwards. However the participation of PITX2A and/or PITX2B isoforms during cardiogenesis is controversial. Here we report for the first time that Pitx2a and Pitx2b isoforms are jointly expressed with Pitx2c isoform during heart development. Interestingly, in terms of relative quantification of mRNA, Pitx2b and Pitx2c isoforms display similar expression profiles during cardiogenesis, decreasing with further development but maintaining their expression until adult stages. Moreover, a detailed analysis of PITX2B protein during cardiac development shows that PITX2B is dynamically expressed in the developing ventricular septum and asymmetrically expressed in the tricuspid valve primordia suggesting a putative role of PITX2B isoform during ventricular septation as well as in the maturation of the right portion of the atrioventricular canal.
Rpb4/7 facilitates RNA polymerase II CTD dephosphorylation. - Nucleic acids research
The Rpb4 and Rpb7 subunits of eukaryotic RNA polymerase II (RNAPII) participate in a variety of processes from transcription, DNA repair, mRNA export and decay, to translation regulation and stress response. However, their mechanism(s) of action remains unclear. Here, we show that the Rpb4/7 heterodimer in Saccharomyces cerevisiae plays a key role in controlling phosphorylation of the carboxy terminal domain (CTD) of the Rpb1 subunit of RNAPII. Proper phosphorylation of the CTD is critical for the synthesis and processing of RNAPII transcripts. Deletion of RPB4, and mutations that disrupt the integrity of Rpb4/7 or its recruitment to the RNAPII complex, increased phosphorylation of Ser2, Ser5, Ser7 and Thr4 within the CTD. RPB4 interacted genetically with genes encoding CTD phosphatases (SSU72, FCP1), CTD kinases (KIN28, CTK1, SRB10) and a prolyl isomerase that targets the CTD (ESS1). We show that Rpb4 is important for Ssu72 and Fcp1 phosphatases association, recruitment and/or accessibility to the CTD, and that this correlates strongly with Ser5P and Ser2P levels, respectively. Our data also suggest that Fcp1 is the Thr4P phosphatase in yeast. Based on these and other results, we suggest a model in which Rpb4/7 helps recruit and potentially stimulate the activity of CTD-modifying enzymes, a role that is central to RNAPII function.
The yeast prefoldin-like URI-orthologue Bud27 associates with the RSC nucleosome remodeler and modulates transcription. - Nucleic acids research
Bud27, the yeast orthologue of human URI/RMP, is a member of the prefoldin-like family of ATP-independent molecular chaperones. It has recently been shown to mediate the assembly of the three RNA polymerases in an Rpb5-dependent manner. In this work, we present evidence of Bud27 modulating RNA pol II transcription elongation. We show that Bud27 associates with RNA pol II phosphorylated forms (CTD-Ser5P and CTD-Ser2P), and that its absence affects RNA pol II occupancy of transcribed genes. We also reveal that Bud27 associates in vivo with the Sth1 component of the chromatin remodeling complex RSC and mediates its association with RNA pol II. Our data suggest that Bud27, in addition of contributing to Rpb5 folding within the RNA polymerases, also participates in the correct assembly of other chromatin-associated protein complexes, such as RSC, thereby modulating their activity.Â© The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.
Use of elemental and molecular-mass spectrometry to assess the toxicological effects of inorganic mercury in the mouse Mus musculus. - Analytical and bioanalytical chemistry
The biochemical response of mice (Mus musculus) to acute subcutaneous inorganic-mercury exposure was assessed over a 14-day period by analyzing cytosolic extracts of the liver, the kidneys, and blood plasma. Integrated metallomic and metabolomic approaches using elemental and molecular-mass spectrometry were used to obtain comprehensive insight into the toxicological effects of mercury regarding its distribution and possible perturbation of metabolic pathways. The metallomic approach involved the use of size-exclusion chromatography (SEC) coupled with multiaffinity chromatography inductively coupled plasma-mass spectrometry (ICP-MS) and isotopic-dilution analysis. The metabolomic approach involved the direct infusion of polar and lipophilic tissue extracts into a mass spectrometer (DIMS) in the positive and negative acquisition mode (ESI+and ESI-). The use of SEC-ICP-MS enabled us to detect changes in the metalloproteome in the liver and the kidneys during the exposure period, and revealed that interactions between Hg and endogenous Cu and Zn adversely affected the homeostasis of these essential metals. The detection of an Hg-Se detoxification product in mouse plasma substantiated the known interaction between Hg and Se in mammals. Use of DIMS in conjunction with partial-least-squares discriminant analysis (PLS-DA) uncovered time-dependent changes of endogenous metabolites over time, corroborated by histopathology investigation of specific mouse tissues. The perturbations of endogenous metabolic profiles were explained in terms of the adverse effect of mercury on energy metabolism (e.g. glycolysis, Krebs cycle), the degradation of membrane phospholipids (apoptosis), and increased levels of specific lipids in plasma. In summary, use of an SEC-ICP-MS-based metallomics approach in conjunction with molecular-mass-spectrometry-based metabolomics is revealed as a promising strategy to more comprehensively investigate the toxicological effects of harmful environmental pollutants and xenobiotics.
Post-fire salvage logging alters species composition and reduces cover, richness, and diversity in Mediterranean plant communities. - Journal of environmental management
An intense debate exists on the effects of post-fire salvage logging on plant community regeneration, but scant data are available derived from experimental studies. We analyzed the effects of salvage logging on plant community regeneration in terms of species richness, diversity, cover, and composition by experimentally managing a burnt forest on a Mediterranean mountain (Sierra Nevada, S Spain). In each of three plots located at different elevations, three replicates of three treatments were implemented seven months after the fire, differing in the degree of intervention: "Non-Intervention" (all trees left standing), "Partial Cut plus Lopping" (felling 90% of the trees, cutting the main branches, and leaving all the biomass in situ), and "Salvage Logging" (felling and piling the logs, and masticating the woody debris). Plant composition in each treatment was monitored two years after the fire in linear point transects. Post-fire salvage logging was associated with reduced species richness, Shannon diversity, and total plant cover. Moreover, salvaged sites hosted different species assemblages and 25% lower cover of seeder species (but equal cover of resprouters) compared to the other treatments. Cover of trees and shrubs was also lowest in Salvage Logging, which could suggest a potential slow-down of forest regeneration. Most of these results were consistent among the three plots despite plots hosting different plant communities. Concluding, our study suggests that salvage logging may reduce species richness and diversity, as well as the recruitment of woody species, which could delay the natural regeneration of the ecosystem.Copyright Â© 2013 Elsevier Ltd. All rights reserved.
Tocilizumab in patients with active rheumatoid arthritis and inadequate response to disease-modifying antirheumatic drugs or tumor necrosis factor inhibitors: subanalysis of Spanish results of an open-label study close to clinical practice. - ReumatologÃa clinica
To analyze the Spanish experience in an international study which evaluated tocilizumab in patients with rheumatoid arthritis (RA) and an inadequate response to conventional disease-modifying antirheumatic drugs (DMARDs) or tumor necrosis factor inhibitors (TNFis) in a clinical practice setting.Subanalysis of 170 patients with RA from Spain who participated in a phase IIIb, open-label, international clinical trial. Patients presented inadequate response to DMARDs or TNFis. They received 8mg/kg of tocilizumab every 4 weeks in combination with a DMARD or as monotherapy during 20 weeks. Safety and efficacy of tocilizumab were analyzed. Special emphasis was placed on differences between failure to a DMARD or to a TNFi and the need to switch to tocilizumab with or without a washout period in patients who had previously received TNFi.The most common adverse events were infections (25%), increased total cholesterol (38%) and transaminases (15%). Five patients discontinued the study due to an adverse event. After six months of tocilizumab treatment, 71/50/30% of patients had ACR 20/50/70 responses, respectively. A higher proportion of TNFi-naive patients presented an ACR20 response: 76% compared to 64% in the TNFi group with previous washout and 66% in the TNFi group without previous washout.Safety results were consistent with previous results in patients with RA and an inadequate response to DMARDs or TNFis. Tocilizumab is more effective in patients who did not respond to conventional DMARDs than in patients who did not respond to TNFis.Copyright Â© 2013 Elsevier EspaÃ±a, S.L. All rights reserved.
Ventricular septal defect and bidirectional shunting? Things are not what they seem. - World journal for pediatric & congenital heart surgery
This report describes the case of a 19-year-old woman with a diagnosis of muscular ventricular septal defect. Bidirectional shunting was observed during a transthorathic echocardiography evaluation which also suggested normal pulmonary arterial pressure. Moreover, anomalous and hypertrophic right ventricular muscular bands were observed. After having ruled out other possibilities, the plausible explanation is one, which is not described in the literature. The findings may be explained as a sequestrated portion of the cavity of the right ventricle that remains isolated from the rest of the right ventricle (RV) by anomalous and hypertrophic right ventricular muscular bands, with communication only between the left ventricle and the sequestrated part of the RV. This is an unusual variant of two-chambered RV simulating two-chambered left ventricle.
Isometric handgrip does not elicit cardiovascular overload or post-exercise hypotension in hypertensive older women. - Clinical interventions in aging
Arterial hypertension is a serious health problem affecting mainly the elderly population. Recent studies have considered both aerobic and resistance exercises as a non-pharmacological aid for arterial hypertension treatment. However, the cardiovascular responses of the elderly to isometric resistance exercise (eg, isometric handgrip [IHG]) have not yet been documented.The purpose of this study was to investigate cardiovascular responses to different intensities of isometric exercise, as well as the occurrence of post-isometric exercise hypotension in hypertensive elderly people under antihypertensive medication treatment.Twelve women volunteered to participate in the study after a maximal voluntary contraction test (MVC) and standardization of the intervention workload consisting of two sessions of IHG exercise performed in four sets of five contractions of a 10-second duration. Sessions were performed both at 30% of the MVC and 50% of the MVC, using a unilateral IHG protocol. Both intensities were compared with a control session without exercise. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) at rest (R), during peak exercise (PE), and after 5, 10, 15, 30, 45, and 60 minutes of post-exercise recovery were evaluated.No significant changes were observed after isometric exercise corresponding to 30% MVC for either SBP (R: 121 Â± 10; PE: 127 Â± 14; 5 min: 125 Â± 13; 10 min: 123 Â± 12; 15 min: 122 Â± 11; 30 min: 124 Â± 11; 45 min: 124 Â± 10; 60 min: 121 Â± 10 mmHg) or DBP (R: 74 Â± 9; PE: 76 Â± 6; 5 min: 74 Â± 5; 10 min: 72 Â± 8; 15 min: 72 Â± 5; 30 min: 72 Â± 8; 45 min: 73 Â± 6; 60 min: 75 Â± 7 mmHg). Similarly, the 50% MVC did not promote post-isometric exercise hypotension for either SBP (R: 120 Â± 7; PE: 125 Â± 11; 5 min: 120 Â± 9; 10 min: 122 Â± 9; 15 min: 121 Â± 11; 30 min: 121 Â± 9; 45 min: 121 Â± 9; 60 min: 120 Â± 7 mmHg) or DBP (R: 72 Â± 8; PE: 78 Â± 7; 5 min: 72 Â± 7; 10 min: 72 Â± 8; 15 min: 71 Â± 7; 30 min: 72 Â± 8; 45 min: 75 Â± 10; 60 min: 75 Â± 7 mmHg).Our data reveal that cardiovascular overload or post-exercise hypotension did not occur in elderly women with controlled hypertension when they undertook an IHG session. Thus this type of resistance exercise, with mild to moderate intensity, with short time of contraction appears to be safe for this population.
Ice-sheet mass balance and climate change. - Nature
Since the 2007 Intergovernmental Panel on Climate Change Fourth Assessment Report, new observations of ice-sheet mass balance and improved computer simulations of ice-sheet response to continuing climate change have been published. Whereas Greenland is losing ice mass at an increasing pace, current Antarctic ice loss is likely to be less than some recently published estimates. It remains unclear whether East Antarctica has been gaining or losing ice mass over the past 20 years, and uncertainties in ice-mass change for West Antarctica and the Antarctic Peninsula remain large. We discuss the past six years of progress and examine the key problems that remain.
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