K-ATP channel gene expression is induced by urocortin and mediates its cardioprotective effect

Background-Urocortin is a novel cardioprotective agent that can protect cardiac myocytes from the damaging effects of ischemia/reperfusion both in culture and in the intact heart and is effective when given at reperfusion.Methods and Results-We have analyzed global changes in gone expression in cardiac myocytes after urocortin treatment using gene chip technology. We report that urocortin specifically induces enhanced expression of the Kir 6.1 cardiac potassium channel subunit. On the basis of this finding, we showed that the cardioprotective effect of urocortin both in isolated cardiac cells and in the intact heart is specifically blocked by both generalized and mitochondrial-specific K-ATP channel blockers, whereas the cardioprotective effect of cardiotrophin-1 is unaffected. Conversely, inhibiting the Kir 6.1 channel subunit greatly enhances cardiac cell death after ischemia.Conclusions-This is, to our knowledge, the first report of the altered expression of a K-ATP. channel subunit induced by a cardioprotective agent and demonstrates that K-ATP, channel opening is essential for the effect of this novel cardioprotective agent

TAp73 contributes to the oxidative stress response by regulating protein synthesis.

TAp73 is a transcription factor that plays key roles in brain development, aging, and cancer. At the cellular level, TAp73 is a critical homeostasis-maintaining factor, particularly following oxidative stress. Although major studies focused on TAp73 transcriptional activities have indicated a contribution of TAp73 to cellular metabolism, the mechanisms underlying its role in redox homeostasis have not been completely elucidated. Here we show that TAp73 contributes to the oxidative stress response by participating in the control of protein synthesis. Regulation of mRNA translation occupies a central position in cellular homeostasis during the stress response, often by reducing global rates of protein synthesis and promoting translation of specific mRNAs. TAp73 depletion results in aberrant ribosomal RNA (rRNA) processing and impaired protein synthesis. In particular, polysomal profiles show that TAp73 promotes the integration of mRNAs that encode rRNA-processing factors in polysomes, supporting their translation. Concurrently, TAp73 depletion causes increased sensitivity to oxidative stress that correlates with reduced ATP levels, hyperactivation of AMPK, and translational defects. TAp73 is important for maintaining active translation of mitochondrial transcripts in response to oxidative stress, thus promoting mitochondrial activity. Our results indicate that TAp73 contributes to redox homeostasis by affecting the translational machinery, facilitating the translation of specific mitochondrial transcripts. This study identifies a mechanism by which TAp73 contributes to the oxidative stress response and describes a completely unexpected role for TAp73 in regulating protein synthesis

Spontaneous Stratification in Granular Mixtures

Granular materials size segregate when exposed to external periodic perturbations such as vibrations. Moreover, mixtures of grains of different sizes spontaneously segregate in the absence of external perturbations: when a mixture is simply poured onto a pile, the large grains are more likely to be found near the base, while the small grains are more likely to be near the top. Here, we report a spontaneous phenomenon arising when we pour a mixture between two vertical plates: the mixture spontaneously stratifies into alternating layers of small and large grains whenever the large grains are rougher than the small grains. In contrast, we find only spontaneous segregation when the large grains are more rounded than the small grains. The stratification is related to the occurrence of avalanches; during each avalanche the grains comprising the avalanche spontaneously stratify into a pair of layers through a "kink" mechanism, with the small grains forming a sublayer underneath the layer of large grains.Comment: 4 pages, 6 figures, http://polymer.bu.edu/~hmakse/Home.htm

Moisture transport by Atlantic tropical cyclones onto the North American continent

Tropical Cyclones (TCs) are an important source of freshwater for the North American continent. Many studies have tried to estimate this contribution by identifying TC-induced precipitation events, but few have explicitly diagnosed the moisture fluxes across continental boundaries. We design a set of attribution schemes to isolate the column-integrated moisture fluxes that are directly associated with TCs and to quantify the flux onto the North American Continent due to TCs. Averaged over the 2004–2012 hurricane seasons and integrated over the western, southern and eastern coasts of North America, the seven schemes attribute 7 to 18 % (mean 14 %) of total net onshore flux to Atlantic TCs. A reduced contribution of 10 % (range 9 to 11 %) was found for the 1980–2003 period, though only two schemes could be applied to this earlier period. Over the whole 1980–2012 period, a further 8 % (range 6 to 9 % from two schemes) was attributed to East Pacific TCs, resulting in a total TC contribution of 19 % (range 17 to 22 %) to the ocean-to-land moisture transport onto the North American continent between May and November. Analysis of the attribution uncertainties suggests that incorporating details of individual TC size and shape adds limited value to a fixed radius approach and TC positional errors in the ERA-Interim reanalysis do not affect the results significantly, but biases in peak wind speeds and TC sizes may lead to underestimates of moisture transport. The interannual variability does not appear to be strongly related to the El Nino-Southern Oscillation phenomenon

Emplacement of inflated Pāhoehoe flows in the Naude’s Nek Pass, Lesotho remnant, Karoo continental flood basalt province: use of flow-lobe tumuli in understanding flood basalt emplacement

Physical volcanological features are presented for a 710-m-thick section, of the Naude’s Nek Pass, within the lower part of the Lesotho remnant of the Karoo Large Igneous Province. The section consists of inflated pāhoehoe lava with thin, impersistent sedimentary interbeds towards the base. There are seven discreet packages of compound and hummocky pāhoehoe lobes containing flow-lobe tumuli, making up approximately 50% of the section. Approximately 45% of the sequence consists of 14 sheet lobes, between 10 and 52-m-thick. The majority of the sheet lobes are in two packages indicating prolonged periods of lava supply capable of producing thick sheet lobes. The other sheet lobes are as individual lobes or pairs, within compound flows, suggesting brief increases in lava supply rate. We suggest, contrary to current belief, that there is no evidence that compound flows are proximal to source and sheet lobes (simple flows) are distal to source and we propose that the presence of flow-lobe tumuli in compound flows could be an indicator that a flow is distal to source. We use detailed, previously published, studies of the Thakurvadi Formation (Deccan Traps) as an example. We show that the length of a lobe and therefore the sections that are ‘medial or distal to source’ are specific to each individual lobe and are dependent on the lava supply of each eruptive event, and as such flow lobe tumuli can be used as an indicator of relative distance from source

Synergies for Improving Oil Palm Production and Forest Conservation in Floodplain Landscapes

Lowland tropical forests are increasingly threatened with conversion to oil palm as global demand and high profit drives crop expansion throughout the world’s tropical regions. Yet, landscapes are not homogeneous and regional constraints dictate land suitability for this crop. We conducted a regional study to investigate spatial and economic components of forest conversion to oil palm within a tropical floodplain in the Lower Kinabatangan, Sabah, Malaysian Borneo. The Kinabatangan ecosystem harbours significant biodiversity with globally threatened species but has suffered forest loss and fragmentation. We mapped the oil palm and forested landscapes (using object-based-image analysis, classification and regression tree analysis and on-screen digitising of high-resolution imagery) and undertook economic modelling. Within the study region (520,269 ha), 250,617 ha is cultivated with oil palm with 77% having high Net-Present-Value (NPV) estimates ($413/ha?yr–$637/ha?yr); but 20.5% is under-producing. In fact 6.3% (15,810 ha) of oil palm is commercially redundant (with negative NPV of $-299/ha?yr-$-65/ha?yr) due to palm mortality from flood inundation. These areas would have been important riparian or flooded forest types. Moreover, 30,173 ha of unprotected forest remain and despite its value for connectivity and biodiversity 64% is allocated for future oil palm. However, we estimate that at minimum 54% of these forests are unsuitable for this crop due to inundation events. If conversion to oil palm occurs, we predict a further 16,207 ha will become commercially redundant. This means that over 32,000 ha of forest within the floodplain would have been converted for little or no financial gain yet with significant cost to the ecosystem. Our findings have globally relevant implications for similar floodplain landscapes undergoing forest transformation to agriculture such as oil palm. Understanding landscape level constraints to this crop, and transferring these into policy and practice, may provide conservation and economic opportunities within these seemingly high opportunity cost landscapes

p53 is cleaved by caspases generating fragments localizing to mitochondria

The p53 tumor suppressor protein exerts most of its anti-tumorigenic activity by transcriptionally activating several pro-apoptotic genes. Accumulating evidence also suggests a transcription-independent function of p53 during apoptosis. It has recently been shown that, when activated, a fraction of p53 translocates to mitochondria, causing cytochrome c release. We now demonstrate a caspase-dependent cleavage of p53 resulting in the generation of four fragments, two of which lack a nuclear localization signal and consequently localize to cytosol. Moreover, these two fragments translocate to mitochondria and induce mitochondrial membrane depolarization in the absence of transcriptional activity. This novel feature of p53 supports the model whereby cytosolic p53 exerts major functions in apoptosis and also suggests the presence of a positive feedback loop in which activated caspases cleave p53 to augment mitochondrial membrane depolarization

Does a 'direct' transfer protocol reduce time to coronary angiography for patients with non-ST-elevation acute coronary syndromes? A prospective observational study.

OBJECTIVE: National guidelines recommend 'early' coronary angiography within 96 h of presentation for patients with non-ST elevation acute coronary syndromes (NSTE-ACS). Most patients with NSTE-ACS present to their district general hospital (DGH), and await transfer to the regional cardiac centre for angiography. This care model has inherent time delays, and delivery of timely angiography is problematic. The objective of this study was to assess a novel clinical care pathway for the management of NSTE-ACS, known locally as the Heart Attack Centre-Extension or HAC-X, designed to rapidly identify patients with NSTE-ACS while in DGH emergency departments (ED) and facilitate transfer to the regional interventional centre for 'early' coronary angiography. METHODS: This was an observational study of 702 patients divided into two groups; 391 patients treated before the instigation of the HAC-X pathway (Pre-HAC-X), and 311 patients treated via the novel pathway (Post-HAC-X). Our primary study end point was time from ED admission to coronary angiography. We also assessed the length of hospital stay. RESULTS: Median time from ED admission to coronary angiography was 7.2 (IQR 5.1-10.2) days pre-HAC-X compared to 1.0 (IQR 0.7-2.0) day post-HAC-X (p<0.001). Median length of hospital stay was 3.0 (IQR 2.0-6.0) days post-HAC-X v 9.0 (IQR 6.0-14.0) days pre-HAC-X (p<0.0005). This equates to a reduction of six hospital bed days per NSTE-ACS admission. CONCLUSIONS: The introduction of this novel care pathway was associated with significant reductions in time to angiography and in total hospital bed occupancy for patients with NSTE-ACS

Monotonicity of Fitness Landscapes and Mutation Rate Control

A common view in evolutionary biology is that mutation rates are minimised. However, studies in combinatorial optimisation and search have shown a clear advantage of using variable mutation rates as a control parameter to optimise the performance of evolutionary algorithms. Much biological theory in this area is based on Ronald Fisher's work, who used Euclidean geometry to study the relation between mutation size and expected fitness of the offspring in infinite phenotypic spaces. Here we reconsider this theory based on the alternative geometry of discrete and finite spaces of DNA sequences. First, we consider the geometric case of fitness being isomorphic to distance from an optimum, and show how problems of optimal mutation rate control can be solved exactly or approximately depending on additional constraints of the problem. Then we consider the general case of fitness communicating only partial information about the distance. We define weak monotonicity of fitness landscapes and prove that this property holds in all landscapes that are continuous and open at the optimum. This theoretical result motivates our hypothesis that optimal mutation rate functions in such landscapes will increase when fitness decreases in some neighbourhood of an optimum, resembling the control functions derived in the geometric case. We test this hypothesis experimentally by analysing approximately optimal mutation rate control functions in 115 complete landscapes of binding scores between DNA sequences and transcription factors. Our findings support the hypothesis and find that the increase of mutation rate is more rapid in landscapes that are less monotonic (more rugged). We discuss the relevance of these findings to living organisms