Nonviraler Gentransfer der felinen Zytokin-Gene IL-2, IFNγ und GM-CSF als adjuvante Immuntherapie beim Fibrosarkom der Katze

Das feline Fibrosarkom hat mit einer Rezidivneigung von bis zu 70 % nach alleiniger chirurgischer Entfernung eine ungünstige Heilungsprognose. Auch adjuvante Chemo- oder Strahlentherapien führen nur in 42 % der Patienten zu einer rezidivfreien Zeit von über einem Jahr. In der vorliegenden Arbeit soll ein nonvirales Gentransfersystem etabliert werden, bei dem erstmalig eine Kombination aus drei felinen Zytokin-Genen zur adjuvanten Immunstimulation nach Tumorexstirpation beim Fibrosarkom der Katze eingesetzt wird. Ziel dieser Studie ist die Festlegung einer maximal tolerierten Dosis. Mit Hilfe eines Nebenwirkungskataloges, der auf der Common-Toxicity-Criteria-Tabelle des National Cancer Instiute basiert, werden klinische wie auch labordiagnostische Parameter objektiv erfasst und in Relation zur Therapie gestellt. Nach definierten Aufnahmekriterien werden Katzen mit Fibrosarkomen von prak-tischen Tierärzten an die Medizinische Kleintierklinik überwiesen. Es werden nur Tiere in die Studie aufgenommen, deren Tumoren (Primärtumor oder Rezidiv) am Rumpf lokalisiert sind. Die Tumorexstirpation muss in einer Sitzung möglich sein und darf dabei weder zu einer Gliedmaßenamputation noch zur Eröffnung einer Körperhöhle führen. Katzen, bei denen Hinweise auf Metastasen oder eine andere schwere Krankheit vorliegen, sowie Tiere, die bereits zuvor mit einer Chemo-, Strahlen- oder Gentherapie behandelt wurden, können nicht in die Studie aufge-nommen werden. Nach Tumorexstirpation wird den Tieren ein Kollagenschwamm in das Tumorbett implantiert. Dieser Kollagenschwamm trägt Plasmide, die jeweils für feIL-2, feIFNγ und feGM-CSF kodieren. Die Plasmid-DNA ist zusätzlich an Polyethylenimin (PEI) assoziiert und mit einem Hüllpolymer (P6YE5C) ummantelt. Insgesamt werden 15 Tiere in vier verschiedenen Dosisgruppen therapiert. Gruppe I (n=3) mit 75 μg je Plasmid, Gruppe II (n=3) mit 150 μg je Plasmid, Gruppe III (n=6) mit 300 μg je Plasmid und in Dosisgruppe IV (n=3) mit 600 μg je Plasmid. Als Ver-gleichsgruppe gelten vier Katzen, die unter gleichen Bedingungen nur mit einer en bloc Resektion behandelt werden. In die Studie werden 15 Katzen (mk=9, wk=6) im Alter zwischen drei und 15 Jahren aufgenommen. Die Fibrosarkome sind häufiger im Interscapularbereich lokalisiert. Bei keinem Patienten kommt es zu therapiebedingten Beeinträchtigungen des Allgemeinbefindens. Drei Katzen entwickeln postoperativ ein Serom, das ohne thera-peutisches Eingreifen resorbiert wird. Systemische Veränderungen, die auf die Therapie zurückgeführt werden, manifestieren sich erst in Dosisgruppe IV mit einem Abfall der Lymphozytenpopulation. Dabei fallen in einem Zeitraum bis 45 Tage nach Implantation des Kollagenschwammes die Lymphozyten bis zu 70 % des Ausgangs-wertes ab. Bei dieser Phase I-Studie handelt es sich um eine Dosisfindungsstudie. Diese wird durch das Auftreten erster Nebenwirkungen, die auf das Transgen oder auf dessen Expressionsprodukt zurückgeführt werden können, beendet. Die maximal tolerierte Dosis wird somit in vorliegender Studie auf 600 μg je Zytokin-Plasmid festgesetzt

Barriers along the Digital Social Innovation Process: A Structured Literature Review

Digital social innovation (DSI) is an emerging phenomenon drawing knowledge from digital innovation (DI) and social innovation (SI), offering opportunities to contribute to societal change by leveraging the potential of digital technologies. Although DSI has evoked increasing interest, research and practice are far from realising its full potential as many barriers arise along the DSI process. Thus, holistic insights into DSI process and its barriers are essential. Therefore, we identify barriers along the DSI process through a structured literature review considering DI, SI, and DSI literature. As a result, we identified 28 barriers and classified them into the DSI barrier framework. The DSI barrier framework builds on the DI framework of Kohli and Melville (2019) and extends it by including the societal environment. We thus shed light on the DSI process and provide holistic insights into the barriers along the DSI process

Characterization of novel SSR markers in diverse sainfoin (Onobrychis viciifolia) germplasm

Background: Sainfoin is a perennial forage legume with beneficial properties for animal husbandry due to the presence of secondary metabolites. However, worldwide cultivation of sainfoin is marginal due to the lack of varieties with good agronomic performance, adapted to a broad range of environmental conditions. Little is known about the genetics of sainfoin and only few genetic markers are available to assist breeding and genetic investigations. The objective of this study was to develop a set of SSR markers useful for genetic studies in sainfoin and their characterization in diverse germplasm.Results: A set of 400 SSR primer combinations were tested for amplification and their ability to detect polymorphisms in a set of 32 sainfoin individuals, representing distinct varieties or landraces. Alleles were scored for presence or absence and polymorphism information content of each SSR locus was calculated with an adapted formula taking into account the tetraploid character of sainfoin. Relationships among individuals were visualized using cluster and principle components analysis. Of the 400 primer combinations tested, 101 reliably detected polymorphisms among the 32 sainfoin individuals. Among the 1154 alleles amplified 250 private alleles were observed. The number of alleles per locus ranged from 2 to 24 with an average of 11.4 alleles. The average polymorphism information content reached values of 0.14 to 0.36. The clustering of the 32 individuals suggested a separation into two groups depending on the origin of the accessions.Conclusions: The SSR markers characterized and tested in this study provide a valuable tool to detect polymorphisms in sainfoin for future genetic studies and breeding programs. As a proof of concept, we showed that these markers can be used to separate sainfoin individuals based on their origin

Breeding Alfalfa (Medicago sativa L.) in Mixture with Grasses

Cultivation of forage mixtures offers several advantages over monocultures, but forage legumes like alfalfa (Medicago sativa L.) are mostly bred in pure stands. Our goal was to assess the extent of accession-by-cultivation system interaction when alfalfa plants are grown in pure stands or in an easily adaptable nursery system together with their companion grasses, thereby determining the system most suitable for selection in mixture. Spaced plants of 50 alfalfa accessions were grown on bare soil as control treatment (CONV), in a sown sward of short growing lawn cultivars of tall fescue (Festuca arundinacea Schreb.) and red fescue (F. rubra L.) (LAWN), and in a sown sward of taller forage cultivars of the same species (FORA). Accession-by-cultivation system interaction variances were large for growth habit but small for vigor. Phenotypic correlation coefficients (rp) among the cultivation systems were high for vigor, whereby LAWN was somewhat more predictive for FORA (rp, FORA−LAWN = 0.83) than CONV (rp, FORA−CONV = 0.77). Observed accession-by-genotype interactions can be used pro or contra necessity for selection in mixture. However, the LAWN cultivation system might be a good compromise for practical breeding, allowing to account for given competition effects among species and to easily assess traits in the nursery

Sedimentary evidence of the Late Holocene tsunami in the Shetland Islands (UK) at Loch Flugarth, northern Mainland

Tsunami deposits around the North Sea basin are needed to assess the long-term hazard of tsunamis. Here, we present sedimentary evidence of the youngest tsunami on the Shetland Islands from Loch Flugarth, a coastal lake on northern Mainland. Three gravity cores show organic-rich background sedimentation with many sub-centimetre-scale sand layers, reflecting recurring storm overwash and a sediment source limited to the active beach and uppermost subtidal zone. A basal 13-cm-thick sand layer, dated to 426–787 cal. a CE based on 14C, 137Cs and Bayesian age–depth modelling, was found in all cores. High-resolution grain-size analysis identified four normally graded or massive sublayers with inversely graded traction carpets at the base of two sublayers. A thin organic-rich ‘mud’ drape and a ‘mud’ cap cover the two uppermost sublayers, which also contain small rip-up clasts. Grain-size distributions show a difference between the basal sand layer and the coarser and better sorted storm layers above. Multivariate statistical analysis of X-ray fluorescence core scanning data also distinguishes both sand units: Zr, Fe and Ti dominate the thick basal sand, while the thin storm layers are high in K and Si. Enriched Zr and Ti in the basal sand layer, in combination with increased magnetic susceptibility, may be related to higher heavy mineral content reflecting an additional marine sediment source below the storm-wave base that is activated by a tsunami. Based on reinterpretation of chronological data from two different published sites and the chronostratigraphy of the present study, the tsunami seems to date to c. 1400 cal. a BP. Although the source of the tsunami remains unclear, the lack of evidence for this event outside of the Shetland Islands suggests that it had a local source and was smaller than the older Storegga tsunami (8.15 cal. ka BP), which affected most of the North Sea basin.</p

A 1500‐year record of North Atlantic storm flooding from lacustrine sediments, Shetland Islands (UK)

Severe storm flooding poses a major hazard to the coasts of north‐western Europe. However, the long‐term recurrence patterns of extreme coastal flooding and their governing factors are poorly understood. Therefore, high‐resolution sedimentary records of past North Atlantic storm flooding are required. This multi‐proxy study reconstructs storm‐induced overwash processes from coastal lake sediments on the Shetland Islands using grain‐size and geochemical data, and the re‐analysis of historical data. The chronostratigraphy is based on Bayesian age–depth modelling using accelerator mass spectrometry 14 C and 137 Cs data. A high XRF‐based Si/Ti ratio and the unimodal grain‐size distribution link the sand layers to the beach and thus storm‐induced overwash events. Periods with more frequent storm flooding occurred 980–1050, 1150–1300, 1450–1550, 1820–1900 and 1950–2000 ce, which is largely consistent with a positive North Atlantic Oscillation mode. The Little Ice Age (1400–1850 ce ) shows a gap of major sand layers suggesting a southward shift of storm tracks and a seasonal variance with more storm floods in spring and autumn. Warmer phases shifted winter storm tracks towards the north‐east Atlantic, indicating a possible trend for future storm‐track changes and increased storm flooding in the northern North Sea region

Miocene high elevation and high relief in the Central Alps

Reconstructing Oligocene–Miocene paleoelevation contributes to our understanding of the evolutionary history of the European Alps and sheds light on geodynamic and Earth surface processes involved in the development of Alpine topography. Despite being one of the most intensively explored mountain ranges worldwide, constraints on the elevation history of the European Alps remain scarce. Here we present stable and clumped isotope measurements to provide a new paleoelevation estimate for the mid-Miocene (∼14.5 Ma) European Central Alps. We apply stable isotope δ–δ paleoaltimetry to near-sea-level pedogenic carbonate oxygen isotope (δ18O) records from the Northern Alpine Foreland Basin (Swiss Molasse Basin) and high-Alpine phyllosilicate hydrogen isotope (δD) records from the Simplon Fault Zone (Swiss Alps). We further explore Miocene paleoclimate and paleoenvironmental conditions in the Swiss Molasse Basin through carbonate stable (δ18O, δ13C) and clumped (Δ47) isotope data from three foreland basin sections in different alluvial megafan settings (proximal, mid-fan, and distal). Combined pedogenic carbonate δ18O values and Δ47 temperatures (30±5 ∘C) yield a near-sea-level precipitation δ18Ow value of -5.8±1.2‰ and, in conjunction with the high-Alpine phyllosilicate δD value of  -14.6±0.3‰, suggest that the region surrounding the Simplon Fault Zone attained surface elevations of &gt;4000 m no later than the mid-Miocene. Our near-sea-level δ18Ow estimate is supported by paleoclimate (iGCM ECHAM5-wiso) modeled δ18O values, which vary between −4.2 ‰ and −7.6 ‰ for the Northern Alpine Foreland Basin

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Benefits of condensed tannins in forage legumes fed to ruminants:Importance of structure, concentration, and diet composition

Condensed tannins (CTs) account for up to 20% of the dry matter in forage legumes used as ruminant feeds. Beneficial animal responses to CTs have included improved growth, milk and wool production, fertility, and reduced methane emissions and ammonia volatilization from dung or urine. Most important is the ability of such forages to combat the effects of gastrointestinal parasitic nematodes. Inconsistent animal responses to CTs were initially attributed to concentration in the diet, but recent research has highlighted the importance of their molecular structures, as well as concentration, and also the composition of the diet containing the CTs. The importance of CT structural traits cannot be underestimated. Interdisciplinary research is the key to unraveling the relationships between CT traits and bioactivities and will enable future on-farm exploitation of these natural plant compounds. Research is also needed to provide plant breeders with guidelines and screening tools to optimize CT traits, in both the forage and the whole diet. In addition, improvements are needed in the competitiveness and agronomic traits of CT-containing legumes and our understanding of options for their inclusion in ruminant diets. Farmers need varieties that are competitive in mixed swards and have predictable bioactivities. This review covers recent results from multidisciplinary research on sainfoin (Onobrychis Mill. spp.) and provides an overview of current developments with several other tanniniferous forages. Tannin chemistry is now being linked with agronomy, plant breeding, animal nutrition, and parasitology. The past decade has yielded considerable progress but also generated more questions — an enviable consequence of new knowledge

Regulation of GDF-15, a distant TGF-β superfamily member, in a mouse model of cerebral ischemia

GDF-15 is a novel distant member of the TGF-β superfamily and is widely distributed in the brain and peripheral nervous system. We have previously reported that GDF-15 is a potent neurotrophic factor for lesioned dopaminergic neurons in the substantia nigra, and that GDF-15-deficient mice show progressive postnatal losses of motor and sensory neurons. We have now investigated the regulation of GDF-15 mRNA and immunoreactivity in the murine hippocampal formation and selected cortical areas following an ischemic lesion by occlusion of the middle cerebral artery (MCAO). MCAO prominently upregulates GDF-15 mRNA in the hippocampus and parietal cortex at 3 h and 24 h after lesion. GDF-15 immunoreactivity, which is hardly detectable in the unlesioned brain, is drastically upregulated in neurons identified by double-staining with NeuN. NeuN staining reveals that most, if not all, neurons in the granular layer of the dentate gyrus and pyramidal layers of the cornu ammonis become GDF-15-immunoreactive. Moderate induction of GDF-15 immunoreactivity has been observed in a small number of microglial cells identified by labeling with tomato lectin, whereas astroglial cells remain GDF-15-negative after MCAO. Comparative analysis of the size of the infarcted area after MCAO in GDF-15 wild-type and knockout mice has failed to reveal significant differences. Together, our data substantiate the notion that GDF-15 is prominently upregulated in the lesioned brain and might be involved in orchestrating post-lesional responses other than the trophic support of neurons