Regulation of gene and protein expression in cardiac myocyte hypertrophy and apoptosis

Considerable efforts have been expended in elucidating the inter-cellular and intra-cellular signaling pathways which elicit cardiac myocyte hypertrophy or apoptosis, and in identifying the changes which are associated with the end-stage of the response. The challenge now is to link the two. Although some of the signaling effects will be the acute modulation of existing protein function, long-term effects which bring about and maintain the hypertrophic state or which culminate in cell death are mediated at the level of gene and protein expression. With the advances in micro-array technology and genome sequencing, it is now possible to obtain a picture of the global gene expression profile in myocytes or in whole heart which dictates the proteins which could be made. This is not the final picture since additional regulation at the level of translation modulates the relative proportions of each protein that can be made from the transcriptome. Even here, further regulation of protein stability and turnover means that ultimately it is still necessary to examine the proteome to determine what may cause the functional changes in a cell. Thus, in order to gain a full picture of events which regulate the response and gain some insight into possible points of intervention for therapy, it is necessary to examine gene expression, mRNA translation and protein expression in concert.

Using U0126 to dissect the role of the extracellular signal-regulated kinase 1/2 (ERK1/2) cascade in the regulation of gene expression by endothelin-1 in cardiac myocytes

The hypertrophic agonist endothelin-1 rapidly but transiently activates the extracellular signal-regulated kinase 1/2 (ERK1/2) cascade (and other signalling pathways) in cardiac myocytes, but the events linking this to hypertrophy are not understood. Using Affymetrix rat U34A microarrays, we identified the short-term (2-4 h) changes in gene expression induced in neonatal myocytes by endothelin-1 alone or in combination with the ERK1/2 cascade inhibitor, U0126. Expression of 15 genes was significantly changed by U0126 alone, and expression of an additional 78 genes was significantly changed by endothelin-1. Of the genes upregulated by U0126, four are classically induced through the aryl hydrocarbon receptor (AhR) by dioxins suggesting that U0126 activates the xenobiotic response element in cardiac myocytes potentially independently of effects on ERK1/2 signalling. The 78 genes showing altered expression with endothelin-1 formed five clusters: (i) three clusters showing upregulation by endothelin-1 according to time course (4 h > 2 h; 2 h > 4 h; 2 h approximately 4 h) with at least partial inhibition by U0126; (ii) a cluster of 11 genes upregulated by endothelin-1 but unaffected by U0126 suggesting regulation through signalling pathways other than ERK1/2; (iii) a cluster of six genes downregulated by endothelin-1 with attenuation by U0126. Thus, U0126 apparently activates the AhR in cardiac myocytes (which must be taken into account in protracted studies), but careful analysis allows identification of genes potentially regulated acutely via the ERK1/2 cascade. Our data suggest that the majority of changes in gene expression induced by endothelin-1 are mediated by the ERK1/2 cascade.

Large snowfall events in the south-eastern Alps

Anthropogenic snowfall events in the UK: examples of urban weather modification?

Snow in the UK is generally associated with synoptic or mesoscale weather systems, thus snowfall during quiescent anticyclonic conditions is surprising and might not even be forecast. Consequently it could present a hazard. Snowfall during anticyclonic freezing fog conditions at Didcot and Hereford in December 2006 is investigated here. These two snowfalls seem to present circumstances in which anthropogenically-produced aerosols could have provided ice nuclei within the freezing fog, and therefore might provide characteristic examples of Anthropogenic Snowfall Events (ASEs).

Understanding the processes governing climate variability and change, climate predictability and the probability of extreme events

The purpose of Research Theme 4 (RT4) was to advance understanding of the basic science issues at the heart of the ENSEMBLES project, focusing on the key processes that govern climate variability and change, and that determine the predictability of climate. Particular attention was given to understanding linear and non-linear feedbacks that may lead to climate surprises,and to understanding the factors that govern the probability of extreme events. Improved understanding of these issues will contribute significantly to the quantification and reduction of uncertainty in seasonal to decadal predictions and projections of climate change. RT4 exploited the ENSEMBLES integrations (stream 1) performed in RT2A as well as undertaking its own experimentation to explore key processes within the climate system. It was working at the cutting edge of problems related to climate feedbacks, the interaction between climate variability and climate change � especially how climate change pertains to extreme events, and the predictability of the climate system on a range of time-scales. The statisticalmethodologies developed for extreme event analysis are new and state-of-the-art. The RT4-coordinated experiments, which have been conducted with six different atmospheric GCMs forced by common timeinvariant sea surface temperature (SST) and sea-ice fields (removing some sources of inter-model variability), are designed to help to understand model uncertainty (rather than scenario or initial condition uncertainty) in predictions of the response to greenhouse-gas-induced warming. RT4 links strongly with RT5 on the evaluation of the ENSEMBLES prediction system and feeds back its results to RT1 to guide improvements in the Earth system models and, through its research on predictability, to steer the development of methods for initialising the ensembles

Over expression of Plk1 does not induce cell division in rat cardiac myocytes in vitro

BACKGROUND: Mammalian cardiac myocytes withdraw from the cell cycle during post-natal development, resulting in a non-proliferating, fully differentiated adult phenotype that is unable to repair damage to the myocardium, such as occurs following a myocardial infarction. We and others previously have shown that forced expression of certain cell cycle molecules in adult cardiac myocytes can promote cell cycle progression and division in these cells. The mitotic serine/threonine kinase, Polo-like kinase-1 (Plk1), is known to phosphorylate and activate a number of mitotic targets, including Cdc2/Cyclin B1, and to promote cell division. PRINCIPAL FINDINGS: The mammalian Plk family are all differentially regulated during the development of rat cardiac myocytes, with Plk1 showing the most dramatic decrease in both mRNA, protein and activity in the adult. We determined the potential of Plk1 to induce cell cycle progression and division in cultured rat cardiac myocytes. A persistent and progressive loss of Plk1 expression was observed during myocyte development that correlated with the withdrawal of adult rat cardiac myocytes from the cell cycle. Interestingly, when Plk1 was over-expressed in cardiac myocytes by adenovirus infection, it was not able to promote cell cycle progression, as determined by cell number and percent binucleation. CONCLUSIONS: We conclude that, in contrast to Cdc2/Cyclin B1 over-expression, the forced expression of Plk1 in adult cardiac myocytes is not sufficient to induce cell division and myocardial repair.

Hydrochemical variations and contaminant load in the Rio Tinto (Spain) during flood events

The aim of this work is to study the hydrochemical variations during flood events in the Rio Tinto, SW Spain. Three separate rainfall/flood events were monitored in October 2004 following the dry season. In general, concentrations markedly increased following the first event (Fe from 99 to 1130 mg/L; Q(max) = 0.78 m(3)/s) while dissolved loads peaked in the second event (Fe = 7.5 kg/s, Cu = 0.83 kg/s, Zn = 0.82 kg/s; Q(max) = 77 m(3)/s) and discharge in the third event (Q(max) = 127 m(3)/s). This pattern reflects a progressive depletion of metals and sulphate stored in the dry summer as soluble evaporitic salt minerals and concentrated pore fluids, with dilution by freshwater becoming increasingly dominant as the month progressed. Variations in relative concentrations were attributed to oxyhydroxysulphate Fe precipitation, to relative changes in the sources of acid mine drainage (e.g. salt minerals, mine tunnels, spoil heaps etc.) and to differences in the rainfall distributions along the catchment. The contaminant load carried by the river during October 2004 was enormous, totalling some 770 t of Fe, 420 t of Al, 100 t of Cu, 100 t of Zn and 71 t of Mn. This represents the largest recorded example of this flush-out process in an acid mine drainage setting. Approximately 1000 times more water and 1408 200 times more dissolved elements were carried by the river during October 2004 than during the dry, low-flow conditions of September 2004, highlighting the key role of flood Events in the annual pollutant transport budget of semi-arid and and systems and the need to monitor these events in detail in order to accurately quantify pollutant transport. (c) 2007 Elsevier B.V. All rights reserved.

Correlating Bayesian date estimates with climatic events and domestication using a bovine case study

The tribe Bovini contains a number of commercially and culturally important species, such as cattle. Understanding their evolutionary time scale is important for distinguishing between post-glacial and domestication-associated population expansions, but estimates of bovine divergence times have been hindered by a lack of reliable calibration points. We present a Bayesian phylogenetic analysis of 481 mitochondrial D-loop sequences, including 228 radiocarbon-dated ancient DNA sequences, using a multi-demographic coalescent model. By employing the radiocarbon dates as internal calibrations, we co-estimate the bovine phylogeny and divergence times in a relaxed-clock framework. The analysis yields evidence for significant population expansions in both taurine and zebu cattle, European aurochs and yak clades. The divergence age estimates support domestication-associated expansion times (less than 12 kyr) for the major haplogroups of cattle. We compare the molecular and palaeontological estimates for the Bison-Bos divergence.

Late pleistocene ice export events into the Arctic Ocean from the M'Clure Strait Ice Stream, Canadian Arctic Archipelago

Rapidly-flowing sectors of an ice sheet (ice streams) can play ail important role in abrupt climate change through tile delivery of icebergs and meltwater and tile Subsequent disruption of ocean thermohaline circulation (e.g., the North Atlantic's Heinrich events). Recently, several cores have been raised from the Arctic Ocean which document the existence of massive ice export events during tile Late Pleistocene and whose provenance has been linked to Source regions in the Canadian Arctic Archipelago. In this paper, satellite imagery is used to map glacial geomorphology in the vicinity of Victoria Island, Banks Island and Prince of Wales Island (Canadian Arctic) in order to reconstruct ice flow patterns in the highly complex glacial landscape. A total of 88 discrete flow-sets are mapped and of these, 13 exhibit the characteristic geomorphology of palaeo-ice streams (i.e., parallel patterns of large, highly elongated mega-scale glacial lineations forming a convergent flow pattern with abrupt lateral margins). Previous studies by other workers and cross-cutting relationships indicate that the majority of these ice streams are relatively young and operated during or immediately prior to deglaciation. Our new mapping, however, documents a large (> 700 km long; 110 km wide) and relatively old ice stream imprint centred in M'Clintock Channel and converging into Viscount Melville Sound. A trough mouth fan located on the continental shelf Suggests that it extended along M'Clure Strait and was grounded at tile shelf edge. The location of the M'Clure Strait Ice Stream exactly matches the Source area of 4 (possibly 5) major ice export events recorded in core PS 1230 raised from Fram Strait, the major ice exit for the Arctic Ocean. These ice export events occur at similar to 12.9, similar to 15.6, similar to 22 and 29.8 ka (C-14 yr BP) and we argue that they record vigorous episodes of activity of the M'Clure Strait Ice Stream. The timing of these events is remarkably similar to the North Atlantic's Heinrich events and we take this as evidence that the M'Clure Strait Ice Stream was also activated around the same time. This may hold important implications for tile cause of the North Atlantic's Heinrich events and hints at tile possibility of a pall-ice sheet response. (c) 2005 Elsevier B.V. All rights reserved.

Psychophysiological responses to appraisal dimensions in a computer game

A computer game was used to study psychophysiological reactions to emotion-relevant events. Two dimensions proposed by Scherer (1984a, 1984b) in his appraisal theory, the intrinsic pleasantness and goal conduciveness of game events, were studied in a factorial design. The relative level at which a player performed at the moment of an event was also taken into account. A total of 33 participants played the game while cardiac activity, skin conductance, skin temperature, and muscle activity as well as emotion self-reports were assessed. The self-reports indicate that game events altered levels of pride, joy, anger, and surprise. Goal conduciveness had little effect on muscle activity but was associated with significant autonomic effects, including changes to interbeat interval, pulse transit time, skin conductance, and finger temperature. The manipulation of intrinsic pleasantness had little impact on physiological responses. The results show the utility of attempting to manipulate emotion-constituent appraisals and measure their peripheral physiological signatures.

Influence of the seasonal cycle on the termination of El Nino events in a coupled general circulation model

In this study, the mechanisms leading to the El Nino peak and demise are explored through a coupled general circulation model ensemble approach evaluated against observations. The results here suggest that the timing of the peak and demise for intense El Nino events is highly predictable as the evolution of the coupled system is strongly driven by a southward shift of the intense equatorial Pacific westerly anomalies during boreal winter. In fact, this systematic late-year shift drives an intense eastern Pacific thermocline shallowing, constraining a rapid El Nino demise in the following months. This wind shift results from a southward displacement in winter of the central Pacific warmest SSTs in response to the seasonal evolution of solar insolation. In contrast, the intensity of this seasonal feedback mechanism and its impact on the coupled system are significantly weaker in moderate El Nino events, resulting in a less pronounced thermocline shallowing. This shallowing transfers the coupled system into an unstable state in spring but is not sufficient to systematically constrain the equatorial Pacific evolution toward a rapid El Nino termination. However, for some moderate events, the occurrence of intense easterly wind anomalies in the eastern Pacific during that period initiate a rapid surge of cold SSTs leading to La Nina conditions. In other cases, weaker trade winds combined with a slightly deeper thermocline allow the coupled system to maintain a broad warm phase evolving through the entire spring and summer and a delayed El Nino demise, an evolution that is similar to the prolonged 1986/87 El Nino event. La Nina events also show a similar tendency to peak in boreal winter, with characteristics and mechanisms mainly symmetric to those described for moderate El Nino cases.