Mitophagy-Related Cell Death Mediated by Vacquinol-1 and TRPM7 Blockade in Glioblastoma IV

Glioblastoma IV (GBM) is one of the deadliest malignant diseases in adults and is characterized by a high mutation rate and multiple traits to suppress inborn and acquired immunity. We here approached autophagy-related cell death in newly established GBM cell lines derived from individual tumor isolates. Treatment with a small molecule, termed Vacquinol-1 (Vac) exhibited 100% GBM cell death, which was related to mitochondrial dysfunction, calcium-induced endoplasmic reticulum (ER)-stress, and autophagy. The toxicity of Vac was significantly increased by the inhibition of transient receptor potential cation channel, subfamily M, member 7 (TRPM7). TRPM7 is overexpressed in GBM as well as in many other tumors and thus may be a potential target by the natural compound carvacrol. Of note, at higher concentrations, Vac also induced growth inhibition and cell death in non-transformed cell types. However, in the presence of the TRPM7 inhibitor carvacrol, the tumor-selective effect of Vac was very much increased. Results given in the present study are based on long-term video microscopy using IncuCyteZOOM®, calcium measurements, and 3D ultrastructural analysis using the cryofixed material

Postoperative pain management in children: Guidance from the pain committee of the European Society for Paediatric Anaesthesiology (ESPA Pain Management Ladder Initiative)

The main remit of the European Society for Paediatric Anaesthesiology (ESPA) Pain Committee is to improve the quality of pain management in children. The ESPA Pain Management Ladder is a clinical practice advisory based upon expert consensus to help to ensure a basic standard of perioperative pain management for all children. Further steps are suggested to improve pain management once a basic standard has been achieved. The guidance is grouped by the type of surgical procedure and layered to suggest basic, intermediate, and advanced pain management methods. The committee members are aware that there are marked differences in financial and personal resources in different institutions and countries and also considerable variations in the availability of analgesic drugs across Europe. We recommend that the guidance should be used as a framework to guide best practice

Seismogenic zone structure of the southern Middle America Trench, Costa Rica

The shallow seismogenic portion of subduction zones generates damaging large and great earthquakes. This study provides structural constraints on the seismogenic zone of the Middle America Trench offshore central Costa Rica and insights into the physical and mechanical characteristics controlling seismogenesis. We have located ~300 events that occurred following the MW 6.9, 20 August 1999, Quepos, Costa Rica, underthrusting earthquake using a three-dimensional velocity model and arrival time data recorded by a temporary local network of land and ocean bottom seismometers. We use aftershock locations to define the geometry and characteristics of the seismogenic zone in this region. These events define a plane dipping at 19° that marks the interface between the Cocos Plate and the Panama Block. The majority of aftershocks occur below 10 km and above 30 km depth below sea level, corresponding to 30–35 km and 95 km from the trench axis, respectively. Relative event relocation produces a seismicity pattern similar to that obtained using absolute locations, increasing confidence in the geometry of the seismogenic zone. The aftershock locations spatially correlate with the downdip extension of the oceanic Quepos Plateau and reflect the structure of the main shock rupture asperity. This strengthens an earlier argument that the 1999 Quepos earthquake ruptured specific bathymetric highs on the downgoing plate. We believe that subduction of this highly disrupted seafloor has established a set of conditions which presently limit the seismogenic zone to be between 10 and 35 km below sea level

The importance of benthic-pelagic coupling for marine ecosystem functioning in a changing world

Benthic-pelagic coupling is manifested as the exchange of energy, mass, or nutrients between benthic and pelagic habitats. It plays a prominent role in aquatic ecosystems, and it is crucial to functions from nutrient cycling to energy transfer in food webs. Coastal and estuarine ecosystem structure and function are strongly affected by anthropogenic pressures; however, there are large gaps in our understanding of the responses of inorganic nutrient and organic matter fluxes between benthic habitats and the water column. We illustrate the varied nature of physical and biological benthic-pelagic coupling processes and their potential sensitivity to three anthropogenic pressures - climate change, nutrient loading, and fishing - using the Baltic Sea as a case study and summarize current knowledge on the exchange of inorganic nutrients and organic material between habitats. Traditionally measured benthic-pelagic coupling processes (e.g., nutrient exchange and sedimentation of organic material) are to some extent quantifiable, but the magnitude and variability of biological processes are rarely assessed, preventing quantitative comparisons. Changing oxygen conditions will continue to have widespread effects on the processes that govern inorganic and organic matter exchange among habitats while climate change and nutrient load reductions may have large effects on organic matter sedimentation. Many biological processes (predation, bioturbation) are expected to be sensitive to anthropogenic drivers, but the outcomes for ecosystem function are largely unknown. We emphasize how improved empirical and experimental understanding of benthic-pelagic coupling processes and their variability are necessary to inform models that can quantify the feedbacks among processes and ecosystem responses to a changing world.Peer reviewe

Fast rates of subduction erosion along the Costa Rica Pacific margin: implications for non-steady rates of crustal recycling at subduction zones

At least since the middle Miocene (∼16 Ma), subduction erosion has been the dominant process controlling the tectonic evolution of the Pacific margin of Costa Rica. Ocean Drilling Program Site 1042 recovered 16.5 Ma nearshore sediment at ∼3.9 km depth, ∼7 km landward of the trench axis. The overlying Miocene to Quaternary sediment contains benthic foraminifera documenting margin subsidence from upper bathyal (∼200 m) to abyssal (∼2000 m) depth. The rate of subsidence was low during the early to middle Miocene but increased sharply in the late Miocene-early Pliocene (5–6.5 Ma) and at the Pliocene-Pleistocene boundary (2.4 Ma). Foraminifera data, bedding dip, and the geometry of slope sediment indicate that tilting of the forearc occurred coincident with the onset of rapid late Miocene subsidence. Seismic images show that normal faulting is widespread across the continental slope; however, extension by faulting only accounts for a minor amount of the post-6.5 Ma subsidence. Basal tectonic erosion is invoked to explain the subsidence. The short-term rate of removal of rock from the forearc is about 107–123 km3 Myr−1 km−1. Mass removal is a nonsteady state process affecting the chemical balance of the arc: the ocean sediment input, with the short-term erosion rate, is a factor of 10 smaller than the eroded mass input. The low 10Be concentration in the volcanic arc of Costa Rica could be explained by dilution with eroded material. The late Miocene onset of rapid subsidence is coeval with the arrival of the Cocos Ridge at the subduction zone. The underthrusting of thick and thermally younger ocean crust decreased the subduction angle of the slab along a large segment of the margin and changed the dynamic equilibrium of the margin taper. This process may have induced the increase in the rate of subduction erosion and thus the recycling of crustal material to the mantle

Three-dimensional P-wave velocity structure on the shallow part of the Central Costa Rican Pacific margin from Local Earthquake Tomography using off- and onshore networks

The Central Costa Rican Pacific margin is characterized by a high-seismicity rate, coincident with the subduction of rough-relief ocean floor and has generated earthquakes with magnitude up to seven in the past. We inverted selected P-wave traveltimes from earthquakes recorded by a combined on- and offshore seismological array deployed during 6 months in the area, simultaneously determining hypocentres and the 3-D tomographic velocity structure on the shallow part of the subduction zone (<70 km). The results reflect the complexity associated to subduction of ocean-floor morphology and the transition from normal to thickened subducting oceanic crust. The subducting slab is imaged as a high-velocity perturbation with a band of low velocities (LVB) on top encompassing the intraslab seismicity deeper than ∼30 km. The LVB is locally thickened by the presence of at least two subducted seamounts beneath the margin wedge. There is a general eastward widening of the LVB over a relatively short distance, closely coinciding with the onset of an inverted forearc basin onshore and the appearance of an aseismic low-velocity anomaly beneath the inner forearc. The latter coincides spatially with an area of the subaerial forearc where differential uplift of blocks has been described, suggesting tectonic underplating of eroded material against the base of the upper plate crust. Alternatively, the low velocities could be induced by an accumulation of upward migrating fluids. Other observed velocity perturbations are attributed to several processes taking place at different depths, such as slab hydration through outer rise faulting, tectonic erosion and slab dehydration

Thermal regime of the Costa Rican convergent margin: 2. Thermal models of the shallow Middle America subduction zone offshore Costa Rica

At the Costa Rica margin along the Middle America Trench along‐strike variations in heat flow are well mapped. These variations can be understood in terms of either ventilated fluid flow, where exposed basement allows fluids to freely advect heat between the crustal aquifer and ocean, or insulated fluid flow where continuous sediment cover restricts heat advection to within the crustal aquifer. We model fluid flow within the subducting aquifer using Nusselt number approximations coupled with finite element models of subduction and explore its effect on temperatures along the subduction thrust. The sensitivity of these models to the initial thermal state of the plate and styles of fluid flow, either ventilated or insulated, is explored. Heat flow measurements on cool crust accreted at the East Pacific Rise are consistent with ventilated hydrothermal cooling that continues with subduction. These models yield much cooler temperatures than predicted from simulations initialized with conductive predictions and without hydrothermal circulation. Heat flow transects on warm crust accreted at the Cocos‐Nazca spreading center are consistent with models of insulated hydrothermal circulation that advects heat updip within the subducting crustal aquifer. Near the trench these models are warmer than conductive predictions and cooler than conductive predictions downdip of the trench. Comparisons between microseismicity and modeled isotherms suggest that the updip limit of microseismicity occurs at temperatures warmer than 100°C and that the downdip extent of microseismicity is bounded by the intersection of the subduction thrust with the base of the overriding crust

The SIB Swiss Institute of Bioinformatics' resources: focus on curated databases

The SIB Swiss Institute of Bioinformatics (www.isb-sib.ch) provides world-class bioinformatics databases, software tools, services and training to the international life science community in academia and industry. These solutions allow life scientists to turn the exponentially growing amount of data into knowledge. Here, we provide an overview of SIB's resources and competence areas, with a strong focus on curated databases and SIB's most popular and widely used resources. In particular, SIB's Bioinformatics resource portal ExPASy features over 150 resources, including UniProtKB/Swiss-Prot, ENZYME, PROSITE, neXtProt, STRING, UniCarbKB, SugarBindDB, SwissRegulon, EPD, arrayMap, Bgee, SWISS-MODEL Repository, OMA, OrthoDB and other databases, which are briefly described in this article

Zwei Steuerbefreiungs-Urkunden.

Donated by Klaus KreiserReprinted from in : Documenta Islamica Inedita, Berlin, 195