Scale-up of cell culture processes using Digital Twins

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Antimicrobial Activity of Rhenium Di- and Tricarbonyl Diimine Complexes: Insights on Membrane-Bound S. aureus Protein Binding

Antimicrobial resistance is one of the major human health threats, with significant impacts on the global economy. Antibiotics are becoming increasingly ineffective as drug-resistance spreads, imposing an urgent need for new and innovative antimicrobial agents. Metal complexes are an untapped source of antimicrobial potential. Rhenium complexes, amongst others, are particularly attractive due to their low in vivo toxicity and high antimicrobial activity, but little is known about their targets and mechanism of action. In this study, a series of rhenium di- and tricarbonyl diimine complexes were prepared and evaluated for their antimicrobial potential against eight different microorganisms comprising Gram-negative and -positive bacteria. Our data showed that none of the Re dicarbonyl or neutral tricarbonyl species have either bactericidal or bacteriostatic potential. In order to identify possible targets of the molecules, and thus possibly understand the observed differences in the antimicrobial efficacy of the molecules, we computationally evaluated the binding affinity of active and inactive complexes against structurally characterized membrane-bound S. aureus proteins. The computational analysis indicates two possible major targets for this class of compounds, namely lipoteichoic acids flippase (LtaA) and lipoprotein signal peptidase II (LspA). Our results, consistent with the published in vitro studies, will be useful for the future design of rhenium tricarbonyl diimine-based antibiotics

Interrogating China’s Global Urban Presence

This paper examines the socio-economic and geopolitical outcomes associated with infrastructure development across multiple scales. Starting from the premise that planetary socio-technical transformations in this vein have distinctly national drivers, we focus on the urban agency of Chinese-led investment. The paper explores how different forms of infrastructural development generated by the Belt and Road Initiative (BRI) affects transformations in the political and material fabric of cities and their host regions. We approach BRI-related infrastructural practice through three interconnected optics – discourse, instruments, and politics – so as to interrogate the articulation of projects linked to the BRI within the material site of the urban. Based on theorisations of infrastructure from an urban perspective and a critical review of literature on the BRI itself, we develop three illustrative case studies at different spatial scales and within different geographic contexts – in Pakistan, Central Europe and the UK. To examine the cases as well as their embeddedness in broader debates on the topic, we use a systematic review methodology relying on a wide variety of sources. We offer comparative and relational perspectives on the manner in which these relatively diverse cases demonstrate China’s role as a global urban actor

Medium Cut-Off (MCO) Membranes Reduce Inflammation in Chronic Dialysis Patients—A Randomized Controlled Clinical Trial

Background To increase the removal of middle-sized uremic toxins a new membrane with enhanced permeability and selectivity, called Medium Cut-Off membrane (MCO-Ci) has been developed that at the same time ensures the retention of albumin. Because many middle-sized substances may contribute to micro-inflammation we hypothesized that the use of MCO-Ci influences the inflammatory state in hemodialysis patients. Methods The randomized crossover trial in 48 patients compared MCO-Ci dialysis to High-flux dialysis of 4 weeks duration each plus 8 weeks extension phase. Primary endpoint was the gene expression of TNF-α and IL-6 in peripheral blood mononuclear cells (PBMCs), secondary endpoints were plasma levels of specified inflammatory mediators and cytokines. Results After four weeks of MCO-Ci the expression of TNF-α mRNA (Relative quantification (RQ) from 0.92 ± 0.34 to 0.75 ± 0.31, -18.5%, p<0.001)-α and IL-6 mRNA (RQ from 0.78 ± 0.80 to 0.60 ± 0.43, -23.1%, p<0.01) was reduced to a significantly greater extent than with High-flux dialyzers (TNF mRNA-RQ: -14.3%; IL-6 mRNA-RQ: -3.5%). After retransformation of logarithmically transformed data, measurements after MCO were reduced to 82% of those after HF (95% CI 74%–91%). 4 weeks use of MCO-Ci resulted in long- lasting change in plasma levels of several cytokines and other substances with a significant decrease for sTNFR1, kappa and lambda free light chains, urea and an increase for Lp-PLA2 (PLA2G7) compared to High-flux. Albumin levels dropped significantly after 4 weeks of MCO dialysis but increased after additional 8 weeks of MCO dialysis. Twelve weeks treatment with MCO-Ci was well tolerated regarding the number of (S)AEs. In the extension period levels of CRP, TNF-α-mRNA and IL-6 mRNA remained stable in High-flux as well as in MCO-Ci. Conclusions MCO-Ci dialyzers modulate inflammation in chronic HD patients to a greater extent compared to High-flux dialyzers. Transcription of pro-inflammatory cytokines in peripheral leukocytes is markedly reduced and removal of soluble mediators is enhanced with MCO dialysis. Serum albumin concentrations stabilize after an initial drop. These results encourage further trials with longer treatment periods and clinical endpoints

Development of Mine Soils in a Chronosequence of Forestry-Reclaimed Sites in Eastern Kentucky

Surface mining for coal has contributed to widespread deforestation and soil loss in coal mining regions around the world, and particularly in Appalachia, USA. Mined land reforestation is of interest in this and other regions where forests are the dominant pre-mining land use. This study evaluated mine soil development on surface-mined sites reforested according to the Forestry Reclamation Approach, representing a chronosequence of time ranging from 0 to 19 years after reclamation. Soils were sampled in depth increments to 50 cm and analyzed for a suite of soil physical and chemical characteristics. Overall, soil fines (silt + clay) tended to increase over time since reclamation (17% silt at year 0 increasing to 35% at year 11; 3.2% clay at year 0 increasing to 5.7% at year 14) while concentrations of metals (e.g., Al, Mg, Mn, Na) demonstrated varied relationships with time since reclamation. Concentrations of organic carbon (OC) tended to increase with time (0.9% OC at year 0 increasing to 2.3% at year 14), and were most enriched in near-surface soils. Some soil characteristics (e.g., Na, OC, Ca) demonstrated patterns of increasing similarity to the forest control, while others were distinct from the forest control throughout the chronosequence (e.g., Al, clay, Mn, gravel). Future surveys of these soils over time will elucidate longer-term patterns in soil development, and better characterize the time scales over which these soils might be expected to approximate forest soil conditions

Efficient Direct Nitrosylation of alpha-Diimine Rhenium Tricarbonyl Complexes to Structurally Nearly Identical Higher Charge Congeners Activable towards Photo-CO Release

The reaction of rhenium alpha-diimine (N-N) tricarbonyl complexes with nitrosonium tetrafluoroborate yields the corresponding dicarbonyl-nitrosyl [Re(CO)(2)(NO)(N-N)X](+) species (where X = halide). The complexes, accessible in a single step in good yield, are structurally nearly identical higher charge congeners of the tricarbonyl molecules. Substitution chemistry aimed at the realization of equivalent dicationic species (intended for applications as potential antimicrobial agents), revealed that the reactivity of metal ion in [Re(CO)(2)(NO)(N-N)X](+) is that of a hard Re acid, probably due to the stronger pi-acceptor properties of NO+ as compared to those of CO. The metal ion thus shows great affinity for pi-basic ligands, which are consequently difficult to replace by, e.g., sigma-donor or weak pi-acids like pyridine. Attempts of direct nitrosylation of alpha-diimine fac-[Re(CO)(3)](+) complexes bearing pi-basic OR-type ligands gave the [Re(CO)(2)(NO)(N-N)(BF4)][BF4] salt as the only product in good yield, featuring a stable Re-FBF3 bond. The solid state crystal structure of nearly all molecules presented could be elucidated. A fundamental consequence of the chemistry of [Re(CO)(2)(NO)(N-N)X](+) complexes, it that the same can be photo-activated towards CO release and represent an entirely new class of photoCORMs

Expanded Hemodialysis Therapy Ameliorates Uremia-Induced Systemic Microinflammation and Endothelial Dysfunction by Modulating VEGF, TNF-α and AP-1 Signaling

Systemic chronic microinflammation and altered cytokine signaling, with adjunct cardiovascular disease (CVD), endothelial maladaptation and dysfunction is common in dialysis patients suffering from end-stage renal disease and associated with increased morbidity and mortality. New hemodialysis filters might offer improvements. We here studied the impact of novel improved molecular cut-off hemodialysis filters on systemic microinflammation, uremia and endothelial dysfunction. Human endothelial cells (ECs) were incubated with uremic serum obtained from patients treated with two different hemodialysis regimens in the Permeability Enhancement to Reduce Chronic Inflammation (PERCI-II) crossover clinical trial, comparing High-Flux (HF) and Medium Cut-Off (MCO) membranes, and then assessed for their vascular endothelial growth factor (VEGF) production and angiogenesis. Compared to HF membranes, dialysis with MCO membranes lead to a reduction in proinflammatory mediators and reduced endothelial VEGF production and angiogenesis. Cytokine multiplex screening identified tumor necrosis factor (TNF) superfamily members as promising targets. The influence of TNF-alpha and its soluble receptors (sTNF-R1 and sTNF-R2) on endothelial VEGF promoter activation, protein release, and the involved signaling pathways was analyzed, revealing that this detrimental signaling was indeed induced by TNF-alpha and mediated by AP-1/c-FOS signaling. In conclusion, uremic toxins, in particular TNF-signaling, promote endothelial maladaptation, VEGF expression and aberrant angiogenesis, which can be positively modulated by dialysis with novel MCO membranes

The State of the Art in Language Workbenches. Conclusions from the Language Workbench Challenge

Language workbenches are tools that provide high-level mechanisms for the implementation of (domain-specific) languages. Language workbenches are an active area of research that also receives many contributions from industry. To compare and discuss existing language workbenches, the annual Language Workbench Challenge was launched in 2011. Each year, participants are challenged to realize a given domain-specific language with their workbenches as a basis for discussion and comparison. In this paper, we describe the state of the art of language workbenches as observed in the previous editions of the Language Workbench Challenge. In particular, we capture the design space of language workbenches in a feature model and show where in this design space the participants of the 2013 Language Workbench Challenge reside. We compare these workbenches based on a DSL for questionnaires that was realized in all workbenches