Personal communication as a strategy to improve the quality of household organic waste - Does it work? results from a quasi-experimental study in Northern Hesse, Germany.

Household organic waste has great potential for closing nutrient cycles in agriculture. This requires proper waste separation by households. Personal communication at the doorstep potentially improves household waste separation behaviour but it is expensive and findings from existing research are mixed. Based on results of previous studies and from a quasi-experiment with non-equivalent groups design in two German municipalities, this paper argues that efficiency of personal communication depends on its context. It can positively influence behaviour when recycling is voluntary and participation rates are low. However, it has no significant effects if recycling is mandatory. One explanation could be different perceptions of recycling in mandatory and voluntary schemes. In voluntary schemes door stepping can activate the intrinsic motivation of households. In mandatory schemes, all households need to participate irrespective of intrinsic motivation. This research shows that this creates a situation in which a small share of households is responsible for almost all contamination. This can be overcome by considering extrinsic factors that affect recycling behaviour. The paper recommends further research to understand which combination of incentives, sanctions and information is efficient in affecting behaviour change in mandatory recycling schemes.

Organic Fluorine Compounds and Their Uses as Molecular MR-Based Temperature Sensors.

The interest in fluorinated substances has increased significantly in recent decades due to their diverse properties and possible uses. An important analytical method in this context is NMR spectroscopy, which provides information on the structure as well as on intermolecular interactions or generally on changes in the environment of the nucleus under consideration. A physical quantity that is of great importance in most studies is temperature. However, this is not always easy, e. g. in shielded systems or within an organism. However, the application potential in chemical reactors or in medical diagnosis and therapy is very high and for this reason 13 fluorinated organic compound were chosen for a first 19 F NMR signal temperature sensitivity examination for determination of local temperatures in solution. Polyfluorinated molecules with separate 19 F MR signals are particularly suitable for temperature determination. Those can be serve as internal error-correcting thermometers without the need of a reference substance. Under these conditions, a 19 F MR signal shift of up to 0.03 ppm/K was detectable. Fluorine position and chemical environment were very important for the temperature sensitivity.

Evidence of considerable C and N transfer from peas to cereals via direct root contact but not via mycorrhiza.

Intercropping of legumes and cereals is an important management method for improving yield stability, especially in organic farming systems. However, knowledge is restricted on the relevance of different nutrient transfer pathways. The objective of the study was to quantify nitrogen (N) and carbon (C) transfer from peas to triticale by (1) direct root contact (= R), (2) arbuscular mycorrhizal fungi (AMF; = A), and (3) diffusion (= D). Pea (Pisum sativum cv. Frisson and P2) and triticale (Triticum × Secale cv. Benetto) plants as intercrop were grown for 105 days. Treatment ADR enabled all transfer paths between the two crops. Treatment AD with root exclusion enabled AMF and diffusion transfer between peas and triticale. Treatment A with a diffusion gap barrier only allowed AMF transfer. Pea plants were labelled every 14 days with a 13C glucose and 15N urea solution, using the cotton wick technique. Direct root contact resulted in the highest pea rhizodeposition and thus the largest absolute amounts of N and C transfer to triticale. Root exclusion generally changed composition of rhizodeposits from fine root residues towards root exudates. Pea plant-N consisted of 17% N derived from rhizodeposition (NdfR) in treatment ADR but only 8% in the treatments AD and A, independently of pea variety, whereas pea plant-C consisted of 13% C derived from rhizodeposition (CdfR), without pea variety and transfer path treatment effects. Averaging all transfer path treatments, 6.7% of NdfR and 2.7% of CdfR was transferred from Frisson and P2 to triticale plants. Approximately 90% of this NdfR was transferred by direct root contact from Frisson to triticale and only 10% by AMF, whereas only 55% of CdfR was transferred to triticale by direct root contact, 40% by AMF and 5% by diffusion. Similar percentages were transferred from mutant P2 to triticale. Root exclusion generally changed RD composition from fine root residues towards root exudates.

IT support in emergency remote teaching in response to COVID-19.

Background: The COVID-19 pandemic hit the German education system unexpectedly and forced its universities to shift to Emergency Remote Teaching (ERT). The Data Integration Center (DIC) of the University Hospital Magdeburg and the Institute of Biometry and Medical Informatics (IBMI) has developed a concept based on existing structures that can be quickly implemented and used by the Medical Faculty at Otto von Guericke University. This manuscript focuses on the IT support for lecturers, which allows them to concentrate on teaching their lessons, although the authors are aware that this is only a small part of the entire subject. Additionally, there is a great awareness that ERT can never replace well-structured in-person classes. Concept: The key feature of the concept uses the well-working management system for all physical rooms of the university by designing a virtual video conference room for every physical room. This allows high interactivity for lectures and seminars while applying proven teaching methods. Additionally, a collaboration software system to document all lessons learned and a technical support team have been available for the teaching staff. Courses with a hands-on approach require more personal interaction than lectures. Therefore, the issues of practical trainings have not been solved with this concept, but been tackled by using questionnaires and minimizing contacts during attestations. Applied IT tools: The concept's requirements were met by Zoom Meetings, Confluence, HIS/LSF and Moodle. Discussion and Conclusion: The concept helped the lecturers to provide high-quality teaching for students at universities. Additionally, it allows for a dynamic response to new needs and problems. The concept will be reviewed as part of a higher Universal Design for Learning concept and may support lecturers in the following semesters in hybrid meetings with real and virtual attendees.

Low-cost LED-based Photo-CIDNP Enables Biocompatible Hyperpolarization of 19 F for NMR and MRI at 7†T and 4.7†T.

Substrates containing 19 F can serve as background-free reporter molecules for NMR and MRI. However, in vivo applications are still limited due to the lower signal-to-noise ratio (SNR) when compared with 1 H NMR. Although hyperpolarization can increase the SNR, to date, only photo-chemically induced dynamic nuclear polarization (photo-CIDNP) allows for hyperpolarization without harmful metal catalysts. Photo-CIDNP was shown to significantly enhance 19 F NMR signals of 3-fluoro-DL-tyrosine in aqueous solution using flavins as photosensitizers. However, lasers were used for photoexcitation, which is expensive and requires appropriate protection procedures in a medical or lab environment. Herein, we report 19 F MR hyperpolarization at 4.7 T and 7 T with a biocompatible system using a low-cost and easy-to-handle LED-based set-up. First hyperpolarized 19 F MR images could be acquired, because photo-CIDNP enabled repetitive hyperpolarization without adding new substrates.

Characterization of the in vitro and in vivo properties of CFZ533, a blocking and non-depleting anti-CD40 monoclonal antibody.

The CD40-CD154 costimulatory pathway is essential for T cell-dependent immune responses, development of humoral memory, and antigen presenting cell function. These immune functions have been implicated in the pathology of multiple autoimmune diseases as well as allograft rejection. We have generated CFZ533, a fully human, pathway blocking anti-CD40 monoclonal antibody that has been modified with a N297A mutation to render it unable to mediate Fcγ-dependent effector functions. CFZ533 inhibited CD154-induced activation of human leukocytes in vitro, but failed to induce human leukocyte activation. Additionally, CFZ533 was unable to mediate depletion of human CD40 expressing B cells. In vivo, CFZ533 blocked primary and recall T cell-dependent antibody responses in nonhuman primates and abrogated germinal formation without depleting peripheral blood B cells. We also established a relationship between plasma concentrations of CFZ533 and CD40 pathway-relevant pharmacodynamic effects in tissue. Collectively these data support the scientific rationale and posology for clinical utility of this antibody in select autoimmune diseases and solid organ transplantation.

Metamaterial-based transmit and receive system for whole-body magnetic resonance imaging at ultra-high magnetic fields.

Magnetic resonance imaging (MRI) at ultra-high fields (UHF), such as 7 T, provides an enhanced signal-to-noise ratio and has led to unprecedented high-resolution anatomic images and brain activation maps. Although a variety of radio frequency (RF) coil architectures have been developed for imaging at UHF conditions, they usually are specialized for small volumes of interests (VoI). So far, whole-body coil resonators are not available for commercial UHF human whole-body MRI systems. The goal of the present study was the development and validation of a transmit and receive system for large VoIs that operates at a 7 T human whole-body MRI system. A Metamaterial Ring Antenna System (MRAS) consisting of several ring antennas was developed, since it allows for the imaging of extended VoIs. Furthermore, the MRAS not only requires lower intensities of the irradiated RF energy, but also provides a more confined and focused injection of excitation energy on selected body parts. The MRAS consisted of several antennas with 50 cm inner diameter, 10 cm width and 0.5 cm depth. The position of the rings was freely adjustable. Conformal resonant right-/left-handed metamaterial was used for each ring antenna with two quadrature feeding ports for RF power. The system was successfully implemented and demonstrated with both a silicone oil and a water-NaCl-isopropanol phantom as well as in vivo by acquiring whole-body images of a crab-eating macaque. The potential for future neuroimaging applications was demonstrated by the acquired high-resolution anatomic images of the macaque's head. Phantom and in vivo measurements of crab-eating macaques provided high-resolution images with large VoIs up to 40 cm in xy-direction and 45 cm in z-direction. The results of this work demonstrate the feasibility of the MRAS system for UHF MRI as proof of principle. The MRAS shows a substantial potential for MR imaging of larger volumes at 7 T UHF. This new technique may provide new diagnostic potential in spatially extended pathologies such as searching for spread-out tumor metastases or monitoring systemic inflammatory processes.

Dynamics of scroll waves in a cylinder jacket geometry.

The dynamics of scroll waves in a narrow cylinder jacket-shaped reactor is investigated experimentally by optical tomography. The fate of the scroll waves of excitation in the Belousov-Zhabotinsky reaction depends on the thickness of the cylinder jacket. While at sufficiently wide cylinder jackets vertically oriented scroll waves remain stable, the probability that the filament of a scroll hits a lateral wall increases as the cylinder jacket narrows. This may lead to the rupture of the initial filament and pinning of the filament ends at the lateral walls. Filaments that pin to opposite lateral walls shrink and reorient to a horizontal orientation; such a reorientation corresponds to a transition from an intramural to a transmural scroll wave. The kinetics of the reorientation and shrinkage of the scrolls were studied. Furthermore, we find that no new filaments were generated upon collision of excitation waves at the side of the cylinder jacket opposite to the scroll wave. Thus, under the studied conditions, we do not observe any new generation of filaments due to a phenomenon like reentry.

Pathophysiological Consequences of a Break in S1P1-Dependent Homeostasis of Vascular Permeability Revealed by S1P1 Competitive Antagonism.

RATIONAL: Homeostasis of vascular barriers depends upon sphingosine 1-phosphate (S1P) signaling via the S1P1 receptor. Accordingly, S1P1 competitive antagonism is known to reduce vascular barrier integrity with still unclear pathophysiological consequences. This was explored in the present study using NIBR-0213, a potent and selective S1P1 competitive antagonist. RESULTS: NIBR-0213 was tolerated at the efficacious oral dose of 30 mg/kg BID in the rat adjuvant-induced arthritis (AiA) model, with no sign of labored breathing. However, it induced dose-dependent acute vascular pulmonary leakage and pleural effusion that fully resolved within 3-4 days, as evidenced by MRI monitoring. At the supra-maximal oral dose of 300 mg/kg QD, NIBR-0213 impaired lung function (with increased breathing rate and reduced tidal volume) within the first 24 hrs. Two weeks of NIBR-0213 oral dosing at 30, 100 and 300 mg/kg QD induced moderate pulmonary changes, characterized by alveolar wall thickening, macrophage accumulation, fibrosis, micro-hemorrhage, edema and necrosis. In addition to this picture of chronic inflammation, perivascular edema and myofiber degeneration observed in the heart were also indicative of vascular leakage and its consequences. CONCLUSIONS: Overall, these observations suggest that, in the rat, the lung is the main target organ for the S1P1 competitive antagonism-induced acute vascular leakage, which appears first as transient and asymptomatic but could lead, upon chronic dosing, to lung remodeling with functional impairments. Hence, this not only raises the question of organ specificity in the homeostasis of vascular barriers, but also provides insight into the pre-clinical evaluation of a potential safety window for S1P1 competitive antagonists as drug candidates.

SOM230: a new therapeutic modality for Cushing's disease.

A rational drug design approach involving transposition of functional groups from SRIF into a reduced size cyclohexapeptide template has led to the discovery of SOM230, a novel, stable cyclohexapeptide somatostatin mimic which exhibits unique high affinity binding to human somatostatin receptors (sst1-5). This unique receptor subtype binding profile, in particular the exceptional high affinity binding to sst5, led to SOM230 being approved by EMEA and FDA in 2012 as the first effective pituitary directed therapeutic modality for Cushing's disease.

Effects of different compost amendments on the abundance and composition of alkB harboring bacterial communities in a soil under industrial use contaminated with hydrocarbons.

Alkane degrading microorganisms play an important role for the bioremediation of petrogenic contaminated environments. In this study, we investigated the effects of compost addition on the abundance and diversity of bacteria harboring the alkane monooxygenase gene (alkB) in an oil-contaminated soil originated from an industrial zone in Celje, Slovenia (Technosol). Soil without any amendments (control soil) and soil amended with two composts differing in their maturation stage and nutrient availability, were incubated under controlled conditions in a microcosm experiment and sampled after 0, 6, 12, and 36 weeks of incubation. As expected the addition of compost stimulated the degradation of alkanes in the investigated soil shortly after the addition. By using quantitative real-time PCR higher number of alkB genes were detected in soil samples amended with compost compared to the control soils. To get an insight into the composition of alkB harboring microbial communities, we performed next generation sequencing of amplicons of alkB gene fragment. Richness and diversity of alkB gene harboring prokaryotes was higher in soil mixed with compost compared to control soils with stronger effects of the less maturated, nutrient poor compost. The phylogenetic analysis of communities suggested that the addition of compost stimulated the abundance of alkB harboring Actinobacteria during the experiment independent from the maturation stage of the compost. AlkB harboring γ-proteobacteria like Shewanella or Hydrocarboniphaga as well as α-proteobacteria of the genus Agrobacterium responded also positively to the addition of compost to soil. The amendment of the less maturated, nutrient poor compost resulted in addition in a large increase of alkB harboring bacteria of the Cytophaga group (Microscilla) mainly at the early sampling time points. Our data indicates that compost amendments significantly change abundance and diversity pattern of alkB harboring microbes in Technosol and might be a useful agent to stimulate bioremediation of hydrocarbons in contaminated soils.

Partial deficiency of sphingosine-1-phosphate lyase confers protection in experimental autoimmune encephalomyelitis.

BACKGROUND: Sphingosine-1-phosphate (S1P) regulates the egress of T cells from lymphoid organs; levels of S1P in the tissues are controlled by S1P lyase (Sgpl1). Hence, Sgpl1 offers a target to block T cell-dependent inflammatory processes. However, the involvement of Sgpl1 in models of disease has not been fully elucidated yet, since Sgpl1 KO mice have a short life-span. METHODOLOGY: We generated inducible Sgpl1 KO mice featuring partial reduction of Sgpl1 activity and analyzed them with respect to sphingolipid levels, T-cell distribution, and response in models of inflammation. PRINCIPAL FINDINGS: The partially Sgpl1 deficient mice are viable but feature profound reduction of peripheral T cells, similar to the constitutive KO mice. While thymic T cell development in these mice appears normal, mature T cells are retained in thymus and lymph nodes, leading to reduced T cell numbers in spleen and blood, with a skewing towards increased proportions of memory T cells and T regulatory cells. The therapeutic relevance of Sgpl1 is demonstrated by the fact that the inducible KO mice are protected in experimental autoimmune encephalomyelitis (EAE). T cell immigration into the CNS was found to be profoundly reduced. Since S1P levels in the brain of the animals are unchanged, we conclude that protection in EAE is due to the peripheral effect on T cells, leading to reduced CNS immigration, rather than on local effects in the CNS. SIGNIFICANCE: The data suggest Sgpl1 as a novel therapeutic target for the treatment of multiple sclerosis.

Cellular assay for the characterization of sphingosine-1-phosphate lyase inhibitors.

Sphingosine-1-phosphate (S1P) lyase represents a target for therapeutic intervention in immune regulation. Inhibitors of the lyase can be identified by established biochemical assays, but a cellular test system for such inhibitors has not been described so far. We found that silencing or inhibition of S1P lyase with short interfering RNA (siRNA) or active site-directed inhibitors in cultured mammalian cells does not cause a relevant increase of S1P in the cells as measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). However, the addition of sphingosine to cultures of cell lines or primary cells provides a source of intracellular S1P that is susceptible to degradation by the lyase and, hence, increases on inhibition or silencing of the enzyme. The assay was optimized with respect to sphingosine concentration, incubation time, and cell density and was established for routine use with HEK293 cells. The assay was found to be suitable for the testing of novel active site-directed S1P lyase inhibitors, providing important information on their relative potency in intact cells.

Discovery of BAF312 (Siponimod), a Potent and Selective S1P Receptor Modulator.

A novel series of alkoxyimino derivatives as S1P1 agonists were discovered through de novo design using FTY720 as the chemical starting point. Extensive structure-activity relationship studies led to the discovery of (E)-1-(4-(1-(((4-cyclohexyl-3-(trifluoromethyl)benzyl)oxy)imino)ethyl)-2-ethylbenzyl)azetidine-3-carboxylic acid (32, BAF312, Siponimod), which has recently completed phase 2 clinical trials in patients with relapsing-remitting multiple sclerosis.

An oral sphingosine 1-phosphate receptor 1 (S1P(1)) antagonist prodrug with efficacy in vivo: discovery, synthesis, and evaluation.

A prodrug approach to optimize the oral exposure of a series of sphingosine 1-phosphate receptor 1 (S1P(1)) antagonists for chronic efficacy studies led to the discovery of (S)-2-{[3'-(4-chloro-2,5-dimethylphenylsulfonylamino)-3,5-dimethylbiphenyl-4-carbonyl]methylamino}-4-dimethylaminobutyric acid methyl ester 14. Methyl ester prodrug 14 is hydrolyzed in vivo to the corresponding carboxylic acid 15, a potent and selective S1P(1) antagonist. Oral administration of the prodrug 14 induces sustained peripheral blood lymphocyte reduction in rats. In a rat cardiac transplantation model coadministration of a nonefficacious dose of prodrug 14 with a nonefficacious dose of sotrastaurin (19), a protein kinase C inhibitor, or everolimus (20), an mTOR inhibitor, effectively prolonged the survival time of rat cardiac allografts. This demonstrates that clinically useful immunomodulation mediated by the S1P(1) receptor can be achieved with an S1P(1) antagonist generated in vivo after oral administration of its prodrug.

A potent and selective S1P(1) antagonist with efficacy in experimental autoimmune encephalomyelitis.

Lymphocyte trafficking is critically regulated by the Sphingosine 1-phosphate receptor-1 (S1P(1)), a G protein-coupled receptor that has been highlighted as a promising therapeutic target in autoimmunity. Fingolimod (FTY720, Gilenya) is a S1P(1) receptor agonist that has recently been approved for the treatment of multiple sclerosis (MS). Here, we report the discovery of NIBR-0213, a potent and selective S1P(1) antagonist that induces long-lasting reduction of peripheral blood lymphocyte counts after oral dosing. NIBR-0213 showed comparable therapeutic efficacy to fingolimod in experimental autoimmune encephalomyelitis (EAE), a model of human MS. These data provide convincing evidence that S1P(1) antagonists are effective in EAE. In addition, the profile of NIBR-0213 makes it an attractive candidate to further study the consequences of S1P(1) receptor antagonism and to differentiate the effects from those of S1P(1) agonists.

Pyrazole derived from (+)-3-carene; a novel potent, selective scaffold for sphingosine-1-phosphate (S1P(1)) receptor agonists.

High throughput screening and hit to lead optimization led to the identification of 'carene' as a promising scaffold showing selective S1P(1) receptor agonism. In parallel to this work we have established a pharmacophore model for the S1P(1) receptor highlighting the minimal structural requirement necessary for potent receptor agonism.

Effects of the novel protein kinase C inhibitor AEB071 (Sotrastaurin) on rat cardiac allograft survival using single agent treatment or combination therapy with cyclosporine, everolimus or FTY720.

NVP-AEB071 (AEB, sotrastaurin), an oral inhibitor of protein kinase C (PKC), effectively blocks T-cell activation. The immunosuppressive effects of oral AEB were demonstrated in a rat local graft versus host (GvH) reaction and rat cardiac transplantation models. T-cell activation was suppressed by 95% in blood from AEB-treated rats, with a positive correlation between T-cell inhibition and AEB blood concentration. In GvH studies, AEB inhibited lymph node swelling dose-dependently (3-30 mg/kg). BN and DA cardiac allografts were acutely rejected within 6-10 days post-transplantation in untreated LEW rats. AEB at 10 and 30 mg/kg b.i.d. prolonged BN graft survival to a mean survival time of 15 and >28 days, and DA grafts to 6.5 and 17.5 days, respectively. In the DA to LEW model, combining a nonefficacious dose of AEB (10 mg/kg b.i.d.) with a nonefficacious dose of cyclosporine, everolimus or FTY720 led to prolonged median survival times (26 days, >68 days and >68 days, respectively). Pharmacokinetic monitoring excluded drug-drug interactions, suggesting synergy. In conclusion, these studies are the first to demonstrate that AEB prolongs rat heart allograft survival safely as monotherapy and in combination with nonefficacious doses of cyclosporine, everolimus or FTY720. Thus, AEB may have the potential to offer an alternative to calcineurin inhibitor-based therapies.

Energy or compost from green waste? - A CO(2) - based assessment.

Green waste is increasingly extracted from the material recycling chain and, as a result of the financial subsidy arising from the German renewable energy law for the generation of energy from renewable raw materials; it is fed into the energy recovery process in biomass power stations. A reduction in climate relevant gases is also linked to the material recovery of green waste - in particular when using composts gained from the process as a new raw material in different types of potting compost and plant culture media as a replacement for peat. Unlike energy recovery, material valorisation is not currently subsidised. Through the analysis of material and energy valorisation methods for green waste, with particular emphasis on primary resource consumption and CO(2)-balance, it could be determined that the use of green waste for energy generation and its recovery for material and peat replacement purposes can be considered to be on a par. Based on energy recovery or material oriented scenarios, it can be further deduced that no method on its own will achieve the desired outcome and that a combination of recycling processes is more likely to lead to a significant decrease of greenhouse gas emissions.

Reduced cardiac side-effect potential by introduction of polar groups: discovery of NIBR-1282, an orally bioavailable CCR5 antagonist which is active in vivo.

Introduction of polar groups in a series of potent CCR5 antagonists which are very likely to adversely affect the conduction system in the heart led to the identification of NIBR-1282 which did not show adverse effects when tested in an isolated rabbit heart ex vivo model. Administration of NIBR-1282 in combination with a non-efficacious dose of CsA led to significant prolongation of kidney allograft survival in cynomolgus monkeys.