Inhibition of NAADP signalling on reperfusion protects the heart by preventing lethal calcium oscillations via two-pore channel 1 and opening of the mitochondrial permeability transition pore

Aims In the heart, a period of ischaemia followed by reperfusion evokes powerful cytosolic Ca2+ oscillations that can cause lethal cell injury. These signals represent attractive cardioprotective targets, but the underlying mechanisms of genesis are ill-defined. Here, we investigated the role of the second messenger nicotinic acid adenine dinucleotide phosphate (NAADP), which is known in several cell types to induce Ca2+ oscillations that initiate from acidic stores such as lysosomes, likely via two-pore channels (TPCs, TPC1 and 2). Methods and results An NAADP antagonist called Ned-K was developed by rational design based on a previously existing scaffold. Ned-K suppressed Ca2+ oscillations and dramatically protected cardiomyocytes from cell death in vitro after ischaemia and reoxygenation, preventing opening of the mitochondrial permeability transition pore. Ned-K profoundly decreased infarct size in mice in vivo. Transgenic mice lacking the endo-lysosomal TPC1 were also protected from injury. Conclusion NAADP signalling plays a major role in reperfusion-induced cell death and represents a potent pathway for protection against reperfusion injury

Pathways of Understanding: the Interactions of Humanity and Global Environmental Change

How humans, interacting within social systems, affect and are affected by global change is explored. Recognizing the impact human activities have on the environment and responding to the need to document the interactions among human activities, the Consortium for International Earth Science Information Network (CIESIN) commissioned a group of 12 scientists to develop a framework illustrating the key human systems that contribute to global change. This framework, called the Social Process Diagram, will help natural and social scientists, educators, resource managers and policy makers envision and analyze how human systems interact among themselves and with the natural system. The Social Process Diagram consists of the following blocks that constitute the Diagram's structural framework: (1) fund of knowledge and experience; (2) preferences and expectations; (3) factors of production and technology; (4) population and social structure; (5) economic systems; (6) political systems and institutions; and (7) global scale environmental processes. To demonstrate potential ways the Diagram can be used, this document includes 3 hypothetical scenarios of global change issues: global warming and sea level rise; the environmental impact of human population migration; and energy and the environment. These scenarios demonstrate the Diagram's usefulness for visualizing specific processes that might be studied to evaluate a particular global change issues. The scenario also shows that interesting and unanticipated questions may emerge as links are explored between categories on the Diagram

NDE for Characterizing Oxidation Damage in Reinforced Carbon-Carbon

In this study, coated reinforced carbon-carbon (RCC) samples of similar structure and composition as that from the NASA space shuttle orbiter s thermal protection system were fabricated with slots in their coating simulating craze cracks. These specimens were used to study oxidation damage detection and characterization using NDE methods. These specimens were heat treated in air at 1143 and 1200 C to create cavities in the carbon substrate underneath the coating as oxygen reacted with the carbon and resulted in its consumption. The cavities varied in diameter from approximately 1 to 3 mm. Single-sided NDE methods were used since they might be practical for on-wing inspection, while x-ray micro-computed tomography (CT) was used to measure cavity sizes in order to validate oxidation models under development for carbon-carbon materials. An RCC sample having a naturally-cracked coating and subsequent oxidation damage was also studied with x-ray micro-CT. This effort is a follow-on study to one that characterized NDE methods for assessing oxidation damage in an RCC sample with drilled holes in the coating. The results of that study are briefly reviewed in this article as well. Additionally, a short discussion on the future role of simulation to aid in these studies is provided

Nondestructive Evaluation (NDE) for Characterizing Oxidation Damage in Cracked Reinforced Carbon-Carbon

In this study, coated reinforced carbon-carbon (RCC) samples of similar structure and composition as that from the NASA space shuttle orbiter's thermal protection system were fabricated with slots in their coating simulating craze cracks. These specimens were used to study oxidation damage detection and characterization using nondestructive evaluation (NDE) methods. These specimens were heat treated in air at 1143 C and 1200 C to create cavities in the carbon substrate underneath the coating as oxygen reacted with the carbon and resulted in its consumption. The cavities varied in diameter from approximately 1 to 3mm. Single-sided NDE methods were used because they might be practical for on-wing inspection, while X-ray micro-computed tomography (CT) was used to measure cavity sizes in order to validate oxidation models under development for carbon-carbon materials. An RCC sample having a naturally cracked coating and subsequent oxidation damage was also studied with X-ray micro-CT. This effort is a follow-on study to one that characterized NDE methods for assessing oxidation damage in an RCC sample with drilled holes in the coating

Tau repeat regions contain conserved histidine residues that modulate microtubule-binding in response to changes in pH.

Tau, a member of the MAP2/tau family of microtubule-associated proteins, stabilizes and organizes axonal microtubules in healthy neurons. In neurodegenerative tauopathies, tau dissociates from microtubules and forms neurotoxic extracellular aggregates. MAP2/tau family proteins are characterized by three to five conserved, intrinsically disordered repeat regions that mediate electrostatic interactions with the microtubule surface. Here, we used molecular dynamics, microtubule-binding experiments, and live-cell microscopy, revealing that highly-conserved histidine residues near the C terminus of each microtubule-binding repeat are pH sensors that can modulate tau-microtubule interaction strength within the physiological intracellular pH range. We observed that at low pH (<7.5), these histidines are positively charged and interact with phenylalanine residues in a hydrophobic cleft between adjacent tubulin dimers. At higher pH (>7.5), tau deprotonation decreased binding to microtubules both in vitro and in cells. Electrostatic and hydrophobic characteristics of histidine were both required for tau-microtubule binding, as substitutions with constitutively and positively charged nonaromatic lysine or uncharged alanine greatly reduced or abolished tau-microtubule binding. Consistent with these findings, tau-microtubule binding was reduced in a cancer cell model with increased intracellular pH but was rapidly restored by decreasing the pH to normal levels. These results add detailed insights into the intracellular regulation of tau activity that may be relevant in both normal and pathological conditions

Climate dynamics preceding summer forest fires in California and the extreme case of 2018

Recent record-breaking wildfire seasons in California prompt an investigation into the climate patterns that typically precede anomalous summer burned forest area. Using burned-area data from the U.S. Forest Service’s Monitoring Trends in Burn Severity (MTBS) product and climate data from the fifth major global reanalysis produced by the European Centre for Medium-Range Weather Forecasts (ERA5) over 1984–2018, relationships between the interannual variability of antecedent climate anomalies and July California burned area are spatially and temporally characterized. Lag correlations show that antecedent high vapor pressure deficit (VPD), high temperatures, frequent extreme high temperature days, low precipitation, high subsidence, high geopotential height, low soil moisture, and low snowpack and snowmelt anomalies all correlate significantly with July California burned area as far back as the January before the fire season. Seasonal regression maps indicate that a global midlatitude atmospheric wave train in late winter is associated with anomalous July California burned area. July 2018, a year with especially high burned area, was to some extent consistent with the general patterns revealed by the regressions: low winter precipitation and high spring VPD preceded the extreme burned area. However, geopotential height anomaly patterns were distinct from those in the regressions. Extreme July heat likely contributed to the extent of the fires ignited that month, even though extreme July temperatures do not historically significantly correlate with July burned area. While the 2018 antecedent climate conditions were typical of a high-burned-area year, they were not extreme, demonstrating the likely limits of statistical prediction of extreme fire seasons and the need for individual case studies of extreme years

Constraints on the Geological History of the Karst System in Southern Missouri, U.S.A. Provided by Radiogenic, Cosmogenic and Physical/Chemical Characteristics of Doline Fill

Območje Ozarkov v južnem Missouriju gradijo predvsem karbonatne, morske, platformne kamnine paleozojske starosti. Teren, ki vsebuje obširen kras, predstavlja kopno že od poznega Paleozojka. Da bi bolje razumeli geološko zgodovino tega kraškega sistema, smo raziskali stratigrafske podatke ohranjene v zapolnitvi velike vrtače pri največjem izviru v okolici. Vzorci zapolnitve iz naravnih izdankov in iz vrtine so bili analizirani s termoluminiscenco (TL) in 10Be kozmogeno metodo. Fizikalno-kemijske značilnosti zapolnitve so bile določene vizualno, z rentgensko metodo in merjenjem velikosti delcev. Podatki vrtine kažejo, da je debelina alohtonega materiala, ki zapolnjuje vrtačo 36,3 m. Ta material prekriva podorne bloke in sedimente debeline vsaj 15,6 m. Glede na teksturo, strukturo in barvo delimo material, ki zapolnjuje vrtačo na 7 con. Analize 10Be koncentracij kažejo, da material za celotni stolpec zapolnitve izvira iz rezidualnega materiala iz srednjega (Illinoian) in zgornjega Pleistocena (Wisconsian). Rentgenske analize glin kažejo, da zapolnitev vrtače vsebuje enake količine kaolinita in illita, kar je skladno z zemeljskim preperevanjem.The Ozark Plateaus region of southern Missouri is underlain by dominantly carbonate marine platform rocks of Paleozoic age. The region has been sub-aerially exposed since the late Paleozoic and is characterized by extensive karst. To better understand the geologic history of this regional karst system, we examined the stratigraphic record preserved in the fill of a large doline near the largest spring in the region. Samples of fill from natural exposures and drill core were analyzed using thermoluminescence (TL) and 10Be cosmogenic techniques, and the physical/chemical characteristics of the fill material were determined by visual inspection, X-ray analyses, and grain-size measurements. Drill-hole data indicate that the allochthonous doline fill is 36.3 m thick and rests on at least 15.6 m of cave breakdown and sediment. The doline fill is divisible into 7 zones. Analysis of 10Be concentrations suggest that the entire doline fill was derived from local residuum during the middle (Illinoian) to late Pleistocene (Wisconsinan). X-ray diffraction analyses of clays throughout the doline fill indicate that they consist of nearly equal amounts of kaolinite and illite, consistent with terrestrial weathering.

Adaptive Event Horizon Tracking and Critical Phenomena in Binary Black Hole Coalescence

This work establishes critical phenomena in the topological transition of black hole coalescence. We describe and validate a computational front tracking event horizon solver, developed for generic studies of the black hole coalescence problem. We then apply this to the Kastor - Traschen axisymmetric analytic solution of the extremal Maxwell - Einstein black hole merger with cosmological constant. The surprising result of this computational analysis is a power law scaling of the minimal throat proportional to time. The minimal throat connecting the two holes obeys this power law during a short time immediately at the beginning of merger. We also confirm the behavior analytically. Thus, at least in one axisymmetric situation a critical phenomenon exists. We give arguments for a broader universality class than the restricted requirements of the Kastor - Traschen solution.Comment: 13 pages, 20 figures Corrected labels on figures 17 through 20. Corrected typos in references. Added some comment