Two major branches of anti-cadmium defense in the mouse: MTF-1/metallothioneins and glutathione

Metal-responsive transcription factor 1 (MTF-1) regulates expression of its target genes in response to various stress conditions, notably heavy metal load, via binding to metal response elements (MREs) in the respective enhancer/promoter regions. Furthermore, it serves a vital function in embryonic liver development. However, targeted deletion of Mtf1 in the liver after birth is no longer lethal. For this study, Mtf1 conditional knockout mice and control littermates were both mock- or cadmium-treated and liver-specific transcription was analyzed. Besides the well-characterized metallothionein genes, several new MTF-1 target genes with MRE motifs in the promoter region emerged. MTF-1 is required for the basal expression of selenoprotein W, muscle 1 gene (Sepw1) that encodes a glutathione-binding and putative antioxidant protein, supporting a role of MTF-1 in the oxidative stress response. Furthermore, MTF-1 mediates the cadmium-induced expression of N-myc downstream regulated gene 1 (Ndrg1), which is induced by several stress conditions and is overexpressed in many cancers. MTF-1 is also involved in the cadmium response of cysteine- and glycine-rich protein 1 gene (Csrp1), which is implicated in cytoskeletal organization. In contrast, MTF-1 represses the basal expression of Slc39a10, a putative zinc transporter. In a pathway independent of MTF-1, cadmium also induced the transcription of genes involved in the synthesis and regeneration of glutathione, a cadmium-binding antioxidant. These data provide strong evidence for two major branches of cellular anti-cadmium defense, one via MTF-1 and its target genes, notably metallothioneins, the other via glutathione, with an apparent overlap in selenoprotein

Detailed Inspection of Metal Implants

Detailed visual inspection of metal hips is the first step in retrieval analysis. In this study a systematic visual inspection protocol was developed to quantify bearing surface changes and their associations with material loss was investigated. Simple and multiple linear regression models found that moderate surface scratching, discolouration, haziness and the size of visible wear scars were all significantly associated with material loss (R2 = 5% - 73%, p<0.05). Visual inspection is not a substitute for measurement of material loss but an understanding of bearing surface changes may offer unique clues as to the mechanisms of failure of retrieved hips

An extracellular steric seeding mechanism for Eph-ephrin signaling platform assembly

Erythropoetin-producing hepatoma (Eph) receptors are cell-surface protein tyrosine kinases mediating cell-cell communication. Upon activation, they form signaling clusters. We report crystal structures of the full ectodomain of human EphA2 (eEphA2) both alone and in complex with the receptor-binding domain of the ligand ephrinA5 (ephrinA5 RBD). Unliganded eEphA2 forms linear arrays of staggered parallel receptors involving two patches of residues conserved across A-class Ephs. eEphA2-ephrinA5 RBD forms a more elaborate assembly, whose interfaces include the same conserved regions on eEphA2, but rearranged to accommodate ephrinA5 RBD. Cell-surface expression of mutant EphA2s showed that these interfaces are critical for localization at cell-cell contacts and activation-dependent degradation. Our results suggest a 'nucleation' mechanism whereby a limited number of ligand-receptor interactions 'seed' an arrangement of receptors which can propagate into extended signaling arrays

Detail-oriented cognitive style and social communicative deficits, within and beyond the autism spectrum: independent traits that grow into developmental interdependence

At the heart of debates over underlying causes of autism is the "Kanner hypothesis" that autistic deficits in social reciprocity, and a cognitive/perceptual 'style' favouring detail-oriented cognition, co-vary in autistic individuals. A separate line of work indicates these two domains are normally distributed throughout the population, with autism representing an extremity. This realisation brings the Kanner debate into the realm of normative co-variation, providing more ways to test the hypothesis, and insights into typical development; for instance, in the context of normative functioning, the Kanner hypothesis implies social costs to spatial/numerical prowess

Biological Contamination Prevention for Outer Solar System Moons of Astrobiological Interest: What Do We Need to Know?

To ensure that scientific investments in space exploration are not compromised by terrestrial contamination of celestial bodies, special care needs to be taken to preserve planetary conditions for future astrobiological exploration. Significant effort has been made and is being taken to address planetary protection in the context of inner Solar System exploration. In particular for missions to Mars, detailed internationally accepted guidelines have been established. For missions to the icy moons in the outer Solar System, Europa and Enceladus, the planetary protection requirements are so far based on a probabilistic approach and a conservative estimate of poorly known parameters. One objective of the European Commission-funded project, Planetary Protection of Outer Solar System, was to assess the existing planetary protection approach, to identify inherent knowledge gaps, and to recommend scientific investigations necessary to update the requirements for missions to the icy moons

Party competition over decentralisation: the influence of ideology and electoral incentives on issue emphasis

Under what conditions is decentralisation a salient issue for state-wide political parties? It is argued in this article that the extent to which state-wide parties emphasise decentralisation depends on their strategic considerations: on their overall ideology, on the electoral incentives created by the context in which they compete, and on the interaction between the two. The results of the analysis of party manifestos in 31 countries since 1945 are as follows. First, parties that pay greater attention to cultural matters relative to economic matters tend to talk more about decentralisation. Second, the systemic salience of decentralisation also encourages parties to talk more about decentralisation. Third, the larger the regionally based ethnic groups within a country, the more salience all state-wide political parties will attach to decentralisation. Finally, only parties that put greater relative emphasis on cultural matters tend to respond to the electoral threat of regionalist parties. The influence of territorial diversity on the salience of decentralisation thus works through two channels and is partly conditioned by political parties’ ideological profile

Pleurotomy with subxyphoid pleural drain affords similar effects to pleural integrity in pulmonary function after off-pump coronary artery bypass graft

Background: Exacerbation of pulmonary dysfunction has been reported in patients receiving a pleural drain inserted through the intercostal space in comparison to patients with an intact pleura undergoing coronary artery bypass grafting (CABG). Evidence suggests that shifting the site of pleural drain insertion to the subxyphoid position minimizes chest wall trauma and preserves respiratory function in the early postoperative period. the aim of this study was to compare the pulmonary function parameters, clinical outcomes, and pain score between patients undergoing pleurotomy with pleural drain placed in the subxyphoid position and patients with intact pleural cavity after off-pump CABG (OPCAB) using left internal thoracic artery (LITA).Methods: Seventy-one patients were allocated into two groups: I (n = 38 open left pleural cavity and pleural drain inserted in the subxyphoid position); II (n = 33 intact pleural cavity). Pulmonary function tests and clinical parameters were recorded preoperatively and on postoperative days (POD) 1, 3 and 5. Arterial blood gas analysis and shunt fraction were evaluated preoperatively and in POD1. Pain score was assessed on POD1. To monitor pleural effusion and atelectasis chest radiography was performed routinely 1 day before operation and until POD5.Results: in both groups a significant impairment was found in lung function parameters until on POD5. However, no significant difference in forced vital capacity and forced expiratory volume in 1 second were seen between groups. A significant decrease in partial pressure of arterial oxygen and an increase in shunt fraction values were observed on POD1 in both groups, but no statistical difference was found when the groups were compared. Pleural effusion and atelectasis until on POD5 were similar in both groups. There were no statistical differences in pain score, duration of mechanical ventilation and postoperative hospital stay between groups.Conclusion: Subxyphoid insertion of pleural drain provides similar effects to preserved pleural integrity in pulmonary function, clinical outcomes, and thoracic pain after OPCAB. Therefore, our results support the hypothesis that once pleural cavities are incidentally or purposely opened during LITA dissection, subxyphoid placement of the pleural drain is recommended.Universidade Federal de São Paulo, Escola Paulista Med, Pirajussara Hosp, Dept Med,Cardiol Discipline, BR-04024002 São Paulo, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, São Paulo Hosp, Dept Med,Cardiol Discipline, BR-04024002 São Paulo, BrazilUniversidade Federal de São Paulo, Physiotherapy Sch, Dept Human Movement Sci, BR-11060001 Santos, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, São Paulo Hosp, Dept Med,Pneumol Discipline, BR-04039002 São Paulo, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Pirajussara Hosp, Dept Med,Cardiovasc Surg Discipline, BR-04024002 São Paulo, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, São Paulo Hosp, Dept Med,Cardiovasc Surg Discipline, BR-04024002 São Paulo, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Pirajussara Hosp, Dept Med,Cardiol Discipline, BR-04024002 São Paulo, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, São Paulo Hosp, Dept Med,Cardiol Discipline, BR-04024002 São Paulo, BrazilUniversidade Federal de São Paulo, Physiotherapy Sch, Dept Human Movement Sci, BR-11060001 Santos, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, São Paulo Hosp, Dept Med,Pneumol Discipline, BR-04039002 São Paulo, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Pirajussara Hosp, Dept Med,Cardiovasc Surg Discipline, BR-04024002 São Paulo, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, São Paulo Hosp, Dept Med,Cardiovasc Surg Discipline, BR-04024002 São Paulo, BrazilWeb of Scienc

Transcriptome response to heavy metal stress in Drosophila reveals a new zinc transporter that confers resistance to zinc

All organisms are confronted with external variations in trace element abundance. To elucidate the mechanisms that maintain metal homeostasis and protect against heavy metal stress, we have determined the transcriptome responses in Drosophila to sublethal doses of cadmium, zinc, copper, as well as to copper depletion. Furthermore, we analyzed the transcriptome of a metal-responsive transcription factor (MTF-1) null mutant. The gene family encoding metallothioneins, and the ABC transporter CG10505 that encodes a homolog of ‘yeast cadmium factor’ were induced by all three metals. Zinc and cadmium responses have similar features: genes upregulated by both metals include those for glutathione S-transferases GstD2 and GstD5, and for zinc transporter-like proteins designated ZnT35C and ZnT63C. Several of the metal-induced genes that emerged in our study are regulated by the transcription factor MTF-1. mRNA studies in MTF-1 overexpressing or null mutant flies and in silico search for metal response elements (binding sites for MTF-1) confirmed novel MTF-1 regulated genes such as ferritins, the ABC transporter CG10505 and the zinc transporter ZnT35C. The latter was analyzed in most detail; biochemical and genetic approaches, including targeted mutation, indicate that ZnT35C is involved in cellular and organismal zinc efflux and plays a major role in zinc detoxification