The significance of bioelectricity on all levels of organization of an organism. Part 1: From the subcellular level to cells

Bioelectricity plays an essential role in the structural and functional organization of biological organisms. In this first part of our multi-part series of articles, we summarise the importance of bioelectricity for the basic structural level of biological organization, i.e. from the subcellular level (charges, ion channels, molecules and cell organelles) to cells

A future very-high-energy view of our Galaxy

The survey of the inner Galaxy with H.E.S.S. was remarkably successful in detecting a wide range of new very-high-energy gamma-ray sources. New TeV gamma-ray emitting source classes were established, although several of the sources remain unidentified, and progress has been made in understanding particle acceleration in astrophysical sources. In this work, we constructed a model of a population of such very-high-energy gamma-ray emitters and normalised the flux and size distribution of this population model to the H.E.S.S.-discovered sources. Extrapolating that population of objects to lower flux levels we investigate what a future array of imaging atmospheric telescopes (IACTs) such as AGIS or CTA might detect in a survey of the Inner Galaxy with an order of magnitude improvement in sensitivity. The sheer number of sources detected together with the improved resolving power will likely result in a huge improvement in our understanding of the populations of galactic gamma-ray sources. A deep survey of the inner Milky Way would also support studies of the interstellar diffuse gamma-ray emission in regions of high cosmic-ray density. In the final section of this paper we investigate the science potential for the Galactic Centre region for studying energy-dependent diffusion with such a future array.Comment: Proceeding of "Heidelberg International Symposium on High Energy Gamma-Ray Astronomy", held in Heidelberg, 7-11 July 2008, submitted to AIP Conference Proceedings. 4 pages, 4 figure

Dysregulated Immunity in Pulmonary Hypertension: From Companion to Composer

Pulmonary hypertension (PH) represents a grave condition associated with high morbidity and mortality, emphasizing a desperate need for innovative and targeted therapeutic strategies. Cumulative evidence suggests that inflammation and dysregulated immunity interdependently affect maladaptive organ perfusion and congestion as hemodynamic hallmarks of the pathophysiology of PH. The role of altered cellular and humoral immunity in PH gains increasing attention, especially in pulmonary arterial hypertension (PAH), revealing novel mechanistic insights into the underlying immunopathology. Whether these immunophysiological aspects display a universal character and also hold true for other types of PH (e.g., PH associated with left heart disease, PH-LHD), or whether there are unique immunological signatures depending on the underlying cause of disease are points of consideration and discussion. Inflammatory mediators and cellular immune circuits connect the local inflammatory landscape in the lung and heart through inter-organ communication, involving, e.g., the complement system, sphingosine-1-phosphate (S1P), cytokines and subsets of, e.g., monocytes, macrophages, natural killer (NK) cells, dendritic cells (DCs), and T- and B-lymphocytes with distinct and organ-specific pro- and anti-inflammatory functions in homeostasis and disease. Perivascular macrophage expansion and monocyte recruitment have been proposed as key pathogenic drivers of vascular remodeling, the principal pathological mechanism in PAH, pinpointing toward future directions of anti-inflammatory therapeutic strategies. Moreover, different B- and T-effector cells as well as DCs may play an important role in the pathophysiology of PH as an imbalance of T-helper-17-cells (T(H)17) activated by monocyte-derived DCs, a potentially protective role of regulatory T-cells (T-reg) and autoantibody-producing plasma cells occur in diverse PH animal models and human PH. This article highlights novel aspects of the innate and adaptive immunity and their interaction as disease mediators of PH and its specific subtypes, noticeable inflammatory mediators and summarizes therapeutic targets and strategies arising thereby

Probing subcellular iron availability with genetically encoded nitric oxide biosensors

Cellular iron supply is required for various biochemical processes. Measuring bioavailable iron in cells aids in obtaining a better understanding of its biochemical activities but is technically challenging. Existing techniques have several constraints that make precise localization difficult, and the lack of a functional readout makes it unclear whether the tested labile iron is available for metalloproteins. Here, we use geNOps; a ferrous iron-dependent genetically encoded fluorescent nitric oxide (NO) biosensor, to measure available iron in cellular locales. We exploited the nitrosylation-dependent fluorescence quenching of geNOps as a direct readout for cellular iron absorption, distribution, and availability. Our findings show that, in addition to ferrous iron salts, the complex of iron (III) with N,N’-bis (2-hydroxybenzyl)ethylenediamine-N,N’-diacetic acid (HBED) can activate the iron (II)-dependent NO probe within intact cells. Cell treatment for only 20 min with iron sucrose was also sufficient to activate the biosensor in the cytosol and mitochondria significantly; however, ferric carboxymaltose failed to functionalize the probe, even after 2 h of cell treatment. Our findings show that the geNOps approach detects available iron (II) in cultured cells and can be applied to assay functional iron (II) at the (sub)cellular level.Vifor Pharm

Kupffer Cells and Blood Monocytes Orchestrate the Clearance of Iron-Carbohydrate Nanoparticles from Serum.

Intravenous (IV) iron nanoparticle preparations are widely used to treat iron deficiency. The mechanism of mononuclear phagocyte system-mediated clearance of IV iron nanoparticles is unknown. The early uptake and homeostasis of iron after injection of ferric carboxymaltose (FCM) in mice was studied. An increase in serum iron was observed at 2.5 h followed by a return to baseline by 24 h. An increase in circulating monocytes was observed, particularly Ly6Chi and Ly6Clow. FCM was also associated with a time-dependent decrease in liver Kupffer cells (KCs) and increase in liver monocytes. The increase in liver monocytes suggests an influx of iron-rich blood monocytes, while some KCs underwent apoptosis. Adoptive transfer experiments demonstrated that following liver infiltration, blood monocytes differentiated to KCs. KCs were also critical for IV iron uptake and biodegradation. Indeed, anti-Colony Stimulating Factor 1 Receptor (CSF1R)-mediated depletion of KCs resulted in elevated serum iron levels and impaired iron uptake by the liver. Gene expression profiling indicated that C-C chemokine receptor type 5 (CCR5) might be involved in monocyte recruitment to the liver, confirmed by pharmaceutical inhibition of CCR5. Liver KCs play a pivotal role in the clearance and storage of IV iron and KCs appear to be supported by the expanded blood monocyte population

Techno-economic analysis of battery storage systems and hydrogen-based storage systems as an alternative to grid expansion in the medium voltage grid in Germany

The decentralization of the energy system in Germany is leading to enormous investments in grid expansion, as the current regulation creates an obligation to expand the power grid to eliminate bottlenecks. Meanwhile, opportunities to leverage grid-friendly control of storage systems are neglected to alleviate the need for investment. For this reason, it is necessary to investigate intelligent alternatives to grid expansion, such as storage systems, to efficiently integrate distributed technologies into the power system and reduce the need for grid expansion. In this work, two representative configurations of a medium voltage grid in Germany are developed for the years 2022 and 2050, and different storage systems are compared economically with the grid expansion in a model-based simulation. Hydrogen storage and battery storage were chosen as storage systems. The results show that grid expansion is the least expensive option if only the grid expansion costs are included in the analysis. However, if additional uses for the storage systems are considered, the battery storage systems are more economical. While in the scenario for 2050 the grid expansion causes costs of approx. 56,000 EUR per year, revenues of at least 58,000 EUR per year can be achieved via the revenue opportunities of the battery storage, representing a 3.5% margin. Heat extraction, arbitrage trading, and avoidance of grid expansion in superimposed grid levels were integrated as additional revenue streams/sources. A robust data basis and cost degressions were assumed for the simulations to generate meaningful results. Overall, hydrogen storage systems are economically inferior to battery storage systems and grid expansion for this use case. The results demonstrate the complexity of analyzing the trade-offs in terms of storage as an alternative to grid expansion as well as the opportunities presented using battery storage instead

A Guide for Publishing, Using, and Licensing Research Software in Germany

Research software has become a central asset in academic research. In Germany, the German Research Foundation (DFG, Deutsche Forschungsgemeinschaft) recently updated the Guidelines for Safeguarding Good Research Practice. Research software is now valued similarly to classic publications and data with implications for research software sustainability and legal aspects. In this document, we present four decision trees and corresponding legal documentation tables to aid researchers. The decision trees should ease to identify i) the software policy of your institution, ii) restrictions imposed by contributors and the environment, iii) licensing collisions if 3rd party software is included, and iv) problems in licensing (existing) research software

Mechanism‐Based Design of the First GlnA4‐Specific Inhibitors

γ‐Glutamylamine synthetases are an important class of enzymes that play a key role in glutamate‐based metabolism. Methionine sulfoximine (MSO) is a well‐established inhibitor for the archetypal glutamine synthetase (GS) but inhibitors for most GS‐like enzymes are unknown. Assuming a conserved catalytic mechanism for GS and GS‐like enzymes, we explored if subtype‐selective inhibitors can be obtained by merging MSO with the cognate substrates of the respective GS‐like enzymes. Using GlnA4Sc from Streptomyces coelicolor, an enzyme recently shown to produce γ‐glutamylethanolamine, we demonstrate that MSO can be reengineered in a straightforward fashion into potent and selective GlnA4Sc inhibitors. Linkage chemistry as well as linker length between the MSO moiety and the terminal hydroxyl group derived from ethanolamine were in agreement with the postulated phosphorylated catalytic intermediate. The best GlnA4 inhibitor 7 b potently blocked S. coelicolor growth in the presence of ethanolamine as the sole nitrogen source. Our results provide the first GlnA4Sc‐specific inhibitors and suggest a general strategy to develop mechanism‐based inhibitors for GS‐like enzymes

An IRT Analysis of Motive Questionnaires: The Unified Motive Scales

Multiple inventories claiming to assess the same explicit motive (achievement, power, or affiliation) show only mediocre convergent validity. In three studies (N = 1685) the structure, nomological net, and content coverage of multiple existing motive scales was investigated with exploratory factor analyses. The analyses revealed four approach factors (achievement, power, affiliation, and intimacy) and a general avoidance factor with a facet structure. New scales (the Unified Motive Scales; UMS) were developed using IRT, reflecting these underlying dimensions. In comparison to existing questionnaires, the UMS have the highest measurement precision and provide short (6-item) and ultra-short (3-item) scales. In a fourth study (N = 96), the UMS demonstrated incremental validity over existing motive scales with respect to several outcome criteria