Remodelling of human atrial K+ currents but not ion channel expression by chronic β-blockade

Chronic β-adrenoceptor antagonist (β-blocker) treatment in patients is associated with a potentially anti-arrhythmic prolongation of the atrial action potential duration (APD), which may involve remodelling of repolarising K+ currents. The aim of this study was to investigate the effects of chronic β-blockade on transient outward, sustained and inward rectifier K+ currents (ITO, IKSUS and IK1) in human atrial myocytes and on the expression of underlying ion channel subunits. Ion currents were recorded from human right atrial isolated myocytes using the whole-cell-patch clamp technique. Tissue mRNA and protein levels were measured using real time RT-PCR and Western blotting. Chronic β-blockade was associated with a 41% reduction in ITO density: 9.3 ± 0.8 (30 myocytes, 15 patients) vs 15.7 ± 1.1 pA/pF (32, 14), p < 0.05; without affecting its voltage-, time- or rate dependence. IK1 was reduced by 34% at −120 mV (p < 0.05). Neither IKSUS, nor its increase by acute β-stimulation with isoprenaline, was affected by chronic β-blockade. Mathematical modelling suggested that the combination of ITO- and IK1-decrease could result in a 28% increase in APD90. Chronic β-blockade did not alter mRNA or protein expression of the ITO pore-forming subunit, Kv4.3, or mRNA expression of the accessory subunits KChIP2, KChAP, Kvβ1, Kvβ2 or frequenin. There was no reduction in mRNA expression of Kir2.1 or TWIK to account for the reduction in IK1. A reduction in atrial ITO and IK1 associated with chronic β-blocker treatment in patients may contribute to the associated action potential prolongation, and this cannot be explained by a reduction in expression of associated ion channel subunits

Systems biological and mechanistic modelling of radiation-induced cancer

This paper summarises the five presentations at the First International Workshop on Systems Radiation Biology that were concerned with mechanistic models for carcinogenesis. The mathematical description of various hypotheses about the carcinogenic process, and its comparison with available data is an example of systems biology. It promises better understanding of effects at the whole body level based on properties of cells and signalling mechanisms between them. Of these five presentations, three dealt with multistage carcinogenesis within the framework of stochastic multistage clonal expansion models, another presented a deterministic multistage model incorporating chromosomal aberrations and neoplastic transformation, and the last presented a model of DNA double-strand break repair pathways for second breast cancers following radiation therapy

Physiological Stress Mediates the Honesty of Social Signals

Peer reviewedPublisher PD

Compassion as a practical and evolved ethic for conservation

© The Author(s) 2015. Published by Oxford University Press on behalf of the American Institute of Biological Sciences. The ethical position underpinning decisionmaking is an important concern for conservation biologists when setting priorities for interventions. The recent debate on how best to protect nature has centered on contrasting intrinsic and aesthetic values against utilitarian and economic values, driven by an inevitable global rise in conservation conflicts. These discussions have primarily been targeted at species and ecosystems for success, without explicitly expressing concern for the intrinsic value and welfare of individual animals. In part, this is because animal welfare has historically been thought of as an impediment to conservation. However, practical implementations of conservation that provide good welfare outcomes for individuals are no longer conceptually challenging; they have become reality. This reality, included under the auspices of "compassionate conservation," reflects an evolved ethic for sharing space with nature and is a major step forward for conservation

Th2 Cell-Intrinsic Hypo-Responsiveness Determines Susceptibility to Helminth Infection

The suppression of protective Type 2 immunity is a principal factor driving the chronicity of helminth infections, and has been attributed to a range of Th2 cell-extrinsic immune-regulators. However, the intrinsic fate of parasite-specific Th2 cells within a chronic immune down-regulatory environment, and the resultant impact such fate changes may have on host resistance is unknown. We used IL-4gfp reporter mice to demonstrate that during chronic helminth infection with the filarial nematode Litomosoides sigmodontis, CD4(+) Th2 cells are conditioned towards an intrinsically hypo-responsive phenotype, characterised by a loss of functional ability to proliferate and produce the cytokines IL-4, IL-5 and IL-2. Th2 cell hypo-responsiveness was a key element determining susceptibility to L. sigmodontis infection, and could be reversed in vivo by blockade of PD-1 resulting in long-term recovery of Th2 cell functional quality and enhanced resistance. Contrasting with T cell dysfunction in Type 1 settings, the control of Th2 cell hypo-responsiveness by PD-1 was mediated through PD-L2, and not PD-L1. Thus, intrinsic changes in Th2 cell quality leading to a functionally hypo-responsive phenotype play a key role in determining susceptibility to filarial infection, and the therapeutic manipulation of Th2 cell-intrinsic quality provides a potential avenue for promoting resistance to helminths

Laying the Foundations for a Human-Predator Conflict Solution: Assessing the Impact of Bonelli's Eagle on Rabbits and Partridges

BACKGROUND: Predation may potentially lead to negative effects on both prey (directly via predators) and predators (indirectly via human persecution). Predation pressure studies are, therefore, of major interest in the fields of theoretical knowledge and conservation of prey or predator species, with wide ramifications and profound implications in human-wildlife conflicts. However, detailed works on this issue in highly valuable--in conservation terms--Mediterranean ecosystems are virtually absent. This paper explores the predator-hunting conflict by examining a paradigmatic, Mediterranean-wide (endangered) predator-two prey (small game) system. METHODOLOGY/PRINCIPAL FINDINGS: We estimated the predation impact ('kill rate' and 'predation rate', i.e., number of prey and proportion of the prey population eaten, respectively) of Bonelli's eagle Aquila fasciata on rabbit Oryctolagus cuniculus and red-legged partridge Alectoris rufa populations in two seasons (the eagle's breeding and non-breeding periods, 100 days each) in SE Spain. The mean estimated kill rate by the seven eagle reproductive units in the study area was c. 304 rabbits and c. 262 partridges in the breeding season, and c. 237 rabbits and c. 121 partridges in the non-breeding period. This resulted in very low predation rates (range: 0.3-2.5%) for both prey and seasons. CONCLUSIONS/SIGNIFICANCE: The potential role of Bonelli's eagles as a limiting factor for rabbits and partridges at the population scale was very poor. The conflict between game profitability and conservation interest of either prey or predators is apparently very localised, and eagles, quarry species and game interests seem compatible in most of the study area. Currently, both the persecution and negative perception of Bonelli's eagle (the 'partridge-eating eagle' in Spanish) have a null theoretical basis in most of this area

Priming food intake with weight control cues: systematic review with a meta-analysis

Background A growing number of studies suggest that exposure to cues which are associated with weight control can prime or prompt controlled food intake in tempting food environments. However, findings are mixed and understanding which types of cues and for whom such cues may be most effective is needed to inform subsequent research and societal applications. A systematic review and meta-analysis were conducted to evaluate the effects of exposure to weight control cues compared with control cues on food intake. Methods PsycINFO, Medline, Embase and Web of Science were searched using key terms. Hedge’s g was used to calculate effect sizes based on mean food intake, standard deviations and sample sizes extracted from relevant publications and, a random effects model was used for the meta-analysis. Results Twenty-five articles consisting of 26 studies were eligible. Data from 25 studies (31 effect sizes) were available for the meta-analysis. Overall, weight control cues reduced food intake, albeit to a trivial effect (ES: -0.149, 95% CI: -0.271 to − 0.027). Subgroup analyses when studies which induced negative affect were removed showed that for individuals with strong weight control goals the effect was small-to-moderate (ES: -0.440, 95% CI: -0.718 to − 0.163), whereas for individuals with weak weight control goals this effect was trivial and non-significant (ES: 0.014, 95% CI: -0.249 to 0.278). Cue type and level of engagement did not significantly moderate the effect; however, specific cues (low-calorie foods and thin models) and attended engagement yielded significant effects. Caution is needed interpreting these findings as most studies were rated with high risk of bias and a number of studies could not be included in the subgroup analyses. Conclusions Based on the data available, weight control cues reduce food intake in individuals with strong weight control goals. Further research is needed to explore longer term effects of cue exposure and confirm underlying mechanisms. PROSPERO registry#CRD42016052396

Possible mechanisms and rankings for agents screened in the Human Cell Melanoma Prevention Assay.

Alterations to the tissue microenvironment appear to play a critical role in the initial stages of melanocyte to melanoma transition, the development of invasive potential, and the resistance to therapy (Postovit et al., Cancer Res, 66:7833, 2006). Given the importance of the E-cadherin/N-cadherin homeostatic tissue control of melanocyte growth and differentiation and the E-cadherin to N-cadherin switch that is found in the conversion from normal to metastatic melanoma, the interplay of the two endpoints may be relevant for identifying possible melanoma prevention activity. We have developed a melanoma chemoprevention assay based on this cadherin switch using human radial growth melanoma cells. The four endpoints examined were: induction of annexin V (apoptosis), induction of HLA-ABC, cell surface expression of E-cadherin, and N-cadherin. Only limited responses were observed with the annexin V and HLA-ABC endpoints; however, the cadherin endpoints appear to be informative. We screened eleven potential melanoma preventive agents that represent a broad range of mechanistic classes using this assay. E-Cadherin expression was enhanced for nine of eleven agents. The induced E-cadherin expression levels exceeded those found in the no UV/no drug control cells for four of the nine positive agents. Atorvastatin showed the greatest efficacy for this endpoint. An inhibition of N-Cadherin was produced by four of eleven agents: atorvastatin, Lovastatin, rosiglitazone maleate, and Verapamil. With the exception of Verapamil, these agents inhibited cell surface N-cadherin expression at six or more concentrations. The potential melanoma prevention efficacies for the more potent agents were ranked as follows: rosiglitazone maleate > atorvastatin > Lovastatin > Rapamycin, gemfibrozil. Each of these agents was active at concentrations that are clinically achievable. Supported by NCI contract #N01-CN-43300

Possible mechanisms and rankings for agents screened in the Human Cell Melanoma Prevention Assay.

Alterations to the tissue microenvironment appear to play a critical role in the initial stages of melanocyte to melanoma transition, the development of invasive potential, and the resistance to therapy (Postovit et al., Cancer Res, 66:7833, 2006). Given the importance of the E-cadherin/N-cadherin homeostatic tissue control of melanocyte growth and differentiation and the E-cadherin to N-cadherin switch that is found in the conversion from normal to metastatic melanoma, the interplay of the two endpoints may be relevant for identifying possible melanoma prevention activity. We have developed a melanoma chemoprevention assay based on this cadherin switch using human radial growth melanoma cells. The four endpoints examined were: induction of annexin V (apoptosis), induction of HLA-ABC, cell surface expression of E-cadherin, and N-cadherin. Only limited responses were observed with the annexin V and HLA-ABC endpoints; however, the cadherin endpoints appear to be informative. We screened eleven potential melanoma preventive agents that represent a broad range of mechanistic classes using this assay. E-Cadherin expression was enhanced for nine of eleven agents. The induced E-cadherin expression levels exceeded those found in the no UV/no drug control cells for four of the nine positive agents. Atorvastatin showed the greatest efficacy for this endpoint. An inhibition of N-Cadherin was produced by four of eleven agents: atorvastatin, Lovastatin, rosiglitazone maleate, and Verapamil. With the exception of Verapamil, these agents inhibited cell surface N-cadherin expression at six or more concentrations. The potential melanoma prevention efficacies for the more potent agents were ranked as follows: rosiglitazone maleate > atorvastatin > Lovastatin > Rapamycin, gemfibrozil. Each of these agents was active at concentrations that are clinically achievable. Supported by NCI contract #N01-CN-43300