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Abstract
Background
The CRISPR/Cas9 system has opened new perspectives to study the molecular basis of cerebral cavernous malformations (CCMs) in personalized disease models. However, precise genome editing in endothelial and other hard‐to‐transfect cells remains challenging.
Methods
In a proof‐of‐principle study, we first isolated blood outgrowth endothelial cells (BOECs) from a CCM1 mutation carrier with multiple CCMs. In a CRISPR/Cas9 gene correction approach, a high‐fidelity Cas9 variant was then transfected into patient‐derived BOECs using a ribonucleoprotein complex and a single‐strand DNA oligonucleotide. In addition, patient‐specific CCM1 knockout clones were expanded after CRISPR/Cas9 gene inactivation.
Results
Deep sequencing demonstrated correction of the mutant allele in nearly 33% of all cells whereas no CRISPR/Cas9‐induced mutations in predicted off‐target loci were identified. Corrected BOECs could be cultured in cell mixtures but demonstrated impaired clonal survival. In contrast, CCM1‐deficient BOECs displayed increased resistance to stress‐induced apoptotic cell death and could be clonally expanded to high passages. When cultured together, CCM1‐deficient BOECs largely replaced corrected as well as heterozygous BOECs.
Conclusion
We here demonstrate that a non‐viral CRISPR/Cas9 approach can not only be used for gene knockout but also for precise gene correction in hard‐to‐transfect endothelial cells (ECs). Comparing patient‐derived isogenic CCM1+/+, CCM1+/−, and CCM1−/− ECs, we show that the inactivation of the second allele results in clonal evolution of ECs lacking CCM1 which likely reflects the initiation phase of CCM genesis.
Abstract
Metabolomics studies now approach large sample sizes and the health characterization of the study population often include complete blood count (CBC) results. Upon careful interpretation the CBC aids diagnosis and provides insight into the health status of the patient within a clinical setting. Uncovering metabolic signatures associated with parameters of the CBC in apparently healthy individuals may facilitate interpretation of metabolomics studies in general and related to diseases. For this purpose 879 subjects from the population‐based Study of Health in Pomerania (SHIP)‐TREND were included. Using metabolomics data resulting from mass‐spectrometry based measurements in plasma samples associations of specific CBC parameters with metabolites were determined by linear regression models. In total, 118 metabolites significantly associated with at least one of the CBC parameters. Strongest associations were observed with metabolites of heme degradation and energy production/consumption. Inverse association seen with mean corpuscular volume and mean corpuscular haemoglobin comprised metabolites potentially related to kidney function. The presently identified metabolic signatures are likely derived from the general function and formation/elimination of blood cells. The wealth of associated metabolites strongly argues to consider CBC in the interpretation of metabolomics studies, in particular if mutual effects on those parameters by the disease of interest are known.
Summary
The susceptibility of Candida albicans biofilms to a non‐thermal plasma treatment has been investigated in terms of growth, survival and cell viability by a series of in vitro experiments. For different time periods, the C. albicans strain SC5314 was treated with a microwave‐induced plasma torch (MiniMIP). The MiniMIP treatment had a strong effect (reduction factor (RF) = 2.97 after 50 s treatment) at a distance of 3 cm between the nozzle and the superior regions of the biofilms. In addition, a viability reduction of 77% after a 20 s plasma treatment and a metabolism reduction of 90% after a 40 s plasma treatment time were observed for C. albicans. After such a treatment, the biofilms revealed an altered morphology of their cells by atomic force microscopy (AFM). Additionally, fluorescence microscopy and confocal laser scanning microscopy (CLSM) analyses of plasma‐treated biofilms showed that an inactivation of cells mainly appeared on the bottom side of the biofilms. Thus, the plasma inactivation of the overgrown surface reveals a new possibility to combat biofilms.
Abstract
Erucic (22:1, cisΔ13) and gondoic acids (20:1, cisΔ11) are building blocks obtained from renewable sources for the oleochemical industry. Different biocatalytic strategies for the enrichment of these compounds with high recovery yields were developed in our group. Geotrichum candidum lipases (GCL) strongly discriminate against fatty acids longer than 18 carbon atoms. Thus, GCL‐I and ‐II were investigated using hydrolysis or ethanolysis reactions with Crambe and Camelina oils. Hydrolysis was also studied using fatty acid ethyl esters (FAEE) derived from the corresponding oil. Both isoforms were highly selective; however, interesting differences were observed. Although it has been reported that GCL‐I displays a higher preference toward 18 cisΔ9, which is present in the studied oils at high levels, GCL‐II showed higher enrichment values during hydrolysis independent of the substrate used. Hence, enrichments of 87% (Crambe oil) and 82% (Crambe FAEE) for erucic acid and 50% (Camelina oil) and 45% (Camelina FAEE) for gondoic acid, with recovery values between 89% and 99%, were achieved. On the contrary, the best enzyme for ethanolysis was GCL‐I (82% and 41% for erucic and gondoic acid, respectively). In this case, although GCL‐II also displayed good enrichment and recovery levels (77% and 28%, respectively), they were lower compared to the former reactions. In both ethanolysis reactions, the FAEE fraction contained between 92% and 97% of 18 unsaturated fatty acids.
Abstract
The efficient multifunctionalization by one‐pot or cascade catalytic systems has developed as an important research field, but is often challenging due to incompatibilities or cross‐reactivities of the catalysts leading to side product formation. Herein we report the stereoselective preparation of cis‐ and trans‐4‐aminocyclohexanol from the potentially bio‐based precursor 1,4‐cyclohexanedione. We identified regio‐ and stereoselective enzymes catalyzing reduction and transamination of the diketone, which can be performed in a one‐pot sequential or cascade mode. For this, we identified regioselective keto reductases for the selective mono reduction of the diketone to give 4‐hydroxycyclohexanone. The system is modular and by choosing stereocomplementary amine transaminases, both cis‐ and trans‐4‐aminocyclohexanol were synthesized with good to excellent diastereomeric ratios. Furthermore, we identified an amine transaminase that produces cis‐1,4‐cyclohexanediamine with diastereomeric ratios >98 : 2. These examples highlight that the high selectivity of enzymes enable short and stereoselective cascade multifunctionalizations to generate high‐value building blocks from renewable starting materials.
Introduction
Abstract
Background
Early mobilization improves physical independency of critically ill patients at hospital discharge in a general intensive care unit (ICU)‐cohort. We aimed to investigate clinical and molecular benefits or detriments of early mobilization and muscle activating measures in a high‐risk ICU‐acquired weakness cohort.
Methods
Fifty patients with a SOFA score ≥9 within 72 h after ICU admission were randomized to muscle activating measures such as neuromuscular electrical stimulation or whole‐body vibration in addition to early protocol‐based physiotherapy (intervention) or early protocol‐based physiotherapy alone (control). Muscle strength and function were assessed by Medical Research Council (MRC) score, handgrip strength and Functional Independence Measure at first awakening, ICU discharge, and 12 month follow‐up. Patients underwent open surgical muscle biopsy on day 15. We investigated the impact of muscle activating measures in addition to early protocol‐based physiotherapy on muscle strength and function as well as on muscle wasting, morphology, and homeostasis in patients with sepsis and ICU‐acquired weakness. We compared the data with patients treated with common physiotherapeutic practice (CPP) earlier.
Results
ICU‐acquired weakness occurs within the entire cohort, and muscle activating measures did not improve muscle strength or function at first awakening (MRC median [IQR]: CPP 3.3 [3.0–4.3]; control 3.0 [2.7–3.4]; intervention 3.0 [2.1–3.8]; P > 0.05 for all), ICU discharge (MRC median [IQR]: CPP 3.8 [3.4–4.4]; control 3.9 [3.3–4.0]; intervention 3.6 [2.8–4.0]; P > 0.05 for all), and 12 month follow‐up (MRC median [IQR]: control 5.0 [4.3–5.0]; intervention 4.8 [4.3–5.0]; P = 0.342 for all). No signs of necrosis or inflammatory infiltration were present in the histological analysis. Myocyte cross‐sectional area in the intervention group was significantly larger in comparison with the control group (type I +10%; type IIa +13%; type IIb +3%; P < 0.001 for all) and CPP (type I +36%; type IIa +49%; type IIb +65%; P < 0.001 for all). This increase was accompanied by an up‐regulated gene expression for myosin heavy chains (fold change median [IQR]: MYH1 2.3 [1.1–2.7]; MYH2 0.7 [0.2–1.8]; MYH4 5.1 [2.2–15.3]) and an unaffected gene expression for TRIM63, TRIM62, and FBXO32.
Conclusions
In our patients with sepsis syndrome at high risk for ICU‐acquired weakness muscle activating measures in addition to early protocol‐based physiotherapy did not improve muscle strength or function at first awakening, ICU discharge, or 12 month follow‐up. Yet it prevented muscle atrophy.
Abstract
Background
Duchenne muscular dystrophy (DMD) is a progressive muscle‐wasting disease caused by mutations in the dystrophin gene, which leads to structural instability of the dystrophin–glycoprotein‐complex with subsequent muscle degeneration. In addition, muscle inflammation has been implicated in disease progression and therapeutically addressed with glucocorticosteroids. These have numerous adverse effects. Treatment with human immunoglobulin G (IgG) improved clinical and para‐clinical parameters in the early disease phase in the well‐established mdx mouse model. The aim of the present study was to confirm the efficacy of IgG in a long‐term pre‐clinical study in mdx mice.
Methods
IgG (2 g/kg body weight) or NaCl solution as control was administered monthly over 18 months by intraperitoneal injection in mdx mice beginning at 3 weeks of age. Several clinical outcome measures including endurance, muscle strength, and echocardiography were assessed. After 18 months, the animals were sacrificed, blood was collected for analysis, and muscle samples were obtained for ex vivo muscle contraction tests, quantitative PCR, and histology.
Results
IgG significantly improved the daily voluntary running performance (1.9 m more total daily running distance, P < 0.0001) and slowed the decrease in grip strength by 0.1 mN, (P = 0.018). IgG reduced fatigability of the diaphragm (improved ratio to maximum force by 0.09 ± 0.04, P = 0.044), but specific tetanic force remained unchanged in the ex vivo muscle contraction test. Cardiac function was significantly better after IgG, especially fractional area shortening (P = 0.012). These results were accompanied by a reduction in cardiac fibrosis and the infiltration of T cells (P = 0.0002) and macrophages (P = 0.0027). In addition, treatment with IgG resulted in a significant reduction of the infiltration of T cells (P ≤ 0.036) in the diaphragm, gastrocnemius, quadriceps, and a similar trend in tibialis anterior and macrophages (P ≤ 0.045) in gastrocnemius, quadriceps, tibialis anterior, and a similar trend in the diaphragm, as well as a decrease in myopathic changes as reflected by a reduced central nuclear index in the diaphragm, tibialis anterior, and quadriceps (P ≤ 0.002 in all).
Conclusions
The present study underscores the importance of an inflammatory contribution to the disease progression of DMD. The data demonstrate the long‐term efficacy of IgG in the mdx mouse. IgG is well tolerated by humans and could preferentially complement gene therapy in DMD. The data call for a clinical trial with IgG in DMD.
Abstract
Because isoenzymes of the experimentally and therapeutically extremely relevant sirtuin family show high similarity, addressing the unique selectivity pocket of sirtuin 2 is a promising strategy towards selective inhibitors. An unrelated approach towards selective inhibition of isoenzymes with varied tissue distribution is targeted drug delivery or spatiotemporal activation by photochemical activation. Azologization of two nicotinamide‐mimicking lead structures was undertaken to combine both approaches and yielded a set of 33 azobenzenes and azopyridines that have been evaluated for their photochemical behaviour and bioactivity. For some compounds, inhibitory activity reached the sub‐micromolar range in their thermodynamically favoured E form and could be decreased by photoisomerization to the metastable Z form. Besides, derivatization with long‐chain fatty acids yielded potent sirtuin 2 inhibitors, featuring another intriguing aspect of azo‐based photoswitches. In these compounds, switching to the Z isomer increased aqueous solubility and thereby enhanced biological activity by up to a factor of 21. The biological activity of two compounds was confirmed by hyperacetylation of sirtuin specific histone proteins in a cell‐based activity assay.
Summary
Background
Epidemiology and management practices of invasive fungal diseases (IFD) after allogeneic haematopoietic stem cell transplantation (HSCT) are a subject of constant change. We investigated the contemporary incidence, diagnostics, antifungal management and outcome at a major paediatric transplant centre in Germany.
Methods
The single‐centre retrospective observational study included all paediatric allogeneic HSCT patients (pts) transplanted between 2005 and 2015. Patient‐related data were assessed up to 365 days post‐transplant. The primary endpoint was the incidence of possible, probable and proven IFDs. Secondary endpoints included diagnostics and antifungal treatment; analysis of risk factors; and overall survival with the last follow‐up in January 2017.
Results
A total of 221 first (196), second (21) or third (4) procedures were performed in 200 pts (median age: 9 years, range, 0.5‐22) for leukaemia/lymphoma (149) and non‐malignant disorders (72). Prophylaxis was administered in 208 HSCT procedures (94%; fluconazole, 116, mould‐active agents, 92). At least one computed tomography scan of the chest was performed in 146, and at least one galactomannan antigen assay in 60 procedures. There were 15 cases of proven (candidemia, 4; aspergillosis, 4) or probable (aspergillosis, 7) IFDs, accounting for an incidence rate of 6.8%. Overall mortality at last follow‐up was 30%; the occurrence of proven/probable IFDs was associated with a reduced survival probability (P < .001).
Conclusion
Morbidity and mortality from IFDs at our institution were consistent with data reported from other centres. Utilisation of healthcare resources for prevention, diagnosis and management of IFDs was considerable.
Abstract
This article takes a novel look at the relationship between government activity, partisan preferences and varieties of capitalism. Evidence from panel regressions for 25 EU countries from 1990 to 2014 suggests that there are major divides among European countries in terms of the drivers of government activity, that is, government spending and government regulation. The European divide appears to be even more pronounced between liberal and coordinated economic systems than between the classical geographical divide of east and west, which is typically used in most contributions. While both divides apply to the determinants of government activity in general, a reversal of the classical partisan effect for the east is to be found only in specific cases and, is most likely in government spending in liberal eastern countries.
Abstract
Aim
Species–area relationships (SARs) are fundamental scaling laws in ecology although their shape is still disputed. At larger areas, power laws best represent SARs. Yet, it remains unclear whether SARs follow other shapes at finer spatial grains in continuous vegetation. We asked which function describes SARs best at small grains and explored how sampling methodology or the environment influence SAR shape.
Location
Palaearctic grasslands and other non‐forested habitats.
Taxa
Vascular plants, bryophytes and lichens.
Methods
We used the GrassPlot database, containing standardized vegetation‐plot data from vascular plants, bryophytes and lichens spanning a wide range of grassland types throughout the Palaearctic and including 2,057 nested‐plot series with at least seven grain sizes ranging from 1 cm2 to 1,024 m2. Using nonlinear regression, we assessed the appropriateness of different SAR functions (power, power quadratic, power breakpoint, logarithmic, Michaelis–Menten). Based on AICc, we tested whether the ranking of functions differed among taxonomic groups, methodological settings, biomes or vegetation types.
Results
The power function was the most suitable function across the studied taxonomic groups. The superiority of this function increased from lichens to bryophytes to vascular plants to all three taxonomic groups together. The sampling method was highly influential as rooted presence sampling decreased the performance of the power function. By contrast, biome and vegetation type had practically no influence on the superiority of the power law.
Main conclusions
We conclude that SARs of sessile organisms at smaller spatial grains are best approximated by a power function. This coincides with several other comprehensive studies of SARs at different grain sizes and for different taxa, thus supporting the general appropriateness of the power function for modelling species diversity over a wide range of grain sizes. The poor performance of the Michaelis–Menten function demonstrates that richness within plant communities generally does not approach any saturation, thus calling into question the concept of minimal area.
Abstract
Spiders of the genus Micaria are ground‐living mimics of ants. Species delineation in these spiders is challenging, mainly because of exceptional high levels of intraspecific variation masking species boundaries. As implied by preliminary DNA barcode data from Central Europe, the Holarctic and very widely distributed glossy ant‐spider M. pulicaria shows cryptic diversity. Here, we disentangle the hidden diversity by means of an integrative taxonomy approach, using mitochondrial DNA, morphometrics, traditional genitalic characters and ecology. Our data suggest the clear delineation of two distinct species, which supports the conception of 19th century taxonomists. These early naturalists distinguished M. pulicaria and a second closely related species based on morphology and natural history, which were synonymized in subsequent taxonomic studies. Therefore, we re‐circumscribe M. pulicaria and revalidate the long forgotten M. micans. These two Micaria species co‐occur sympatrically in vast areas of the western Palearctic, while the Nearctic region is populated by M. pulicaria alone. Male genitalic traits are more dissimilar in the area of sympatry than in allopatry, suggesting a decisive role of reproductive character displacement in species diversification. Our study emphasizes the value of the early taxonomic literature in integrative taxonomic studies, as it may contain crucial information on natural history that are not regularly recorded by modern taxonomists.
Abstract
Caveolae position CaV3.2 (T‐type Ca2+ channel encoded by the α‐3.2 subunit) sufficiently close to RyR (ryanodine receptors) for extracellular Ca2+ influx to trigger Ca2+ sparks and large‐conductance Ca2+‐activated K+ channel feedback in vascular smooth muscle. We hypothesize that this mechanism of Ca2+ spark generation is affected by age. Using smooth muscle cells (VSMCs) from mouse mesenteric arteries, we found that both Cav3.2 channel inhibition by Ni2+ (50 µM) and caveolae disruption by methyl‐ß‐cyclodextrin or genetic abolition of Eps15 homology domain‐containing protein (EHD2) inhibited Ca2+ sparks in cells from young (4 months) but not old (12 months) mice. In accordance, expression of Cav3.2 channel was higher in mesenteric arteries from young than old mice. Similar effects were observed for caveolae density. Using SMAKO Cav1.2−/− mice, caffeine (RyR activator) and thapsigargin (Ca2+ transport ATPase inhibitor), we found that sufficient SR Ca2+ load is a prerequisite for the CaV3.2‐RyR axis to generate Ca2+ sparks. We identified a fraction of Ca2+ sparks in aged VSMCs, which is sensitive to the TRP channel blocker Gd3+ (100 µM), but insensitive to CaV1.2 and CaV3.2 channel blockade. Our data demonstrate that the VSMC CaV3.2‐RyR axis is down‐regulated by aging. This defective CaV3.2‐RyR coupling is counterbalanced by a Gd3+ sensitive Ca2+ pathway providing compensatory Ca2+ influx for triggering Ca2+ sparks in aged VSMCs.
Abstract
Higher biodiversity can stabilize the productivity and functioning of grassland communities when subjected to extreme climatic events. The positive biodiversity–stability relationship emerges via increased resistance and/or recovery to these events. However, invader presence might disrupt this diversity–stability relationship by altering biotic interactions. Investigating such disruptions is important given that invasion by non‐native species and extreme climatic events are expected to increase in the future due to anthropogenic pressure. Here we present one of the first multisite invader × biodiversity × drought manipulation experiment to examine combined effects of biodiversity and invasion on drought resistance and recovery at three semi‐natural grassland sites across Europe. The stability of biomass production to an extreme drought manipulation (100% rainfall reduction; BE: 88 days, BG: 85 days, DE: 76 days) was quantified in field mesocosms with a richness gradient of 1, 3, and 6 species and three invasion treatments (no invader, Lupinus polyphyllus, Senecio inaequidens). Our results suggest that biodiversity stabilized community productivity by increasing the ability of native species to recover from extreme drought events. However, invader presence turned the positive and stabilizing effects of diversity on native species recovery into a neutral relationship. This effect was independent of the two invader's own capacity to recover from an extreme drought event. In summary, we found that invader presence may disrupt how native community interactions lead to stability of ecosystems in response to extreme climatic events. Consequently, the interaction of three global change drivers, climate extremes, diversity decline, and invasive species, may exacerbate their effects on ecosystem functioning.
Abstract
This paper focuses on the expectation formation process of professional forecasters by relying on survey data on forecasts regarding gross domestic product growth, consumer price index inflation and 3‐month interest rates for a broad set of countries. We examine the interrelation between macroeconomic forecasts and also the impact of uncertainty on forecasts by allowing for cross‐country interdependencies and time variation in the coefficients. We find that professional forecasts are often in line with the Taylor rule and identify significant expectation spillovers from monetary policy in the USA.
Sphagnum growth under N saturation: interactive effects of water level and P or K fertilization
(2020)
Abstract
Sphagnum biomass is a promising material that could be used as a substitute for peat in growing media and can be sustainably produced by converting existing drainage‐based peatland agriculture into wet, climate‐friendly agriculture (paludiculture). Our study focuses on yield maximization of Sphagnum as a crop.
We tested the effects of three water level regimes and of phosphorus or potassium fertilization on the growth of four Sphagnum species (S. papillosum, S. palustre, S. fimbriatum, S. fallax). To simulate field conditions in Central and Western Europe we carried out a glasshouse experiment under nitrogen‐saturated conditions.
A constant high water table (remaining at 2 cm below capitulum during growth) led to highest productivity for all tested species. Water table fluctuations between 2 and 9 cm below capitulum during growth and a water level 2 cm below capitulum at the start but falling relatively during plant growth led to significantly lower productivity. Fertilization had no effect on Sphagnum growth under conditions with high atmospheric deposition such as in NW Germany (38 kg N, 0.3 kg P, 7.6 kg K·ha−1·year−1).
Large‐scale maximization of Sphagnum yields requires precise water management, with water tables just below the capitula and rising with Sphagnum growth. The nutrient load in large areas of Central and Western Europe from atmospheric deposition and irrigation water is high but, with an optimal water supply, does not hamper Sphagnum growth, at least not of regional provenances of Sphagnum.
Abstract
Interbedded contourites, turbidites and pelagites are commonplace in many deep‐water slope environments. However, the distinction between these different facies remains a source of controversy. This detailed study of calcareous contourites and associated deep‐marine facies from an Eocene–Miocene sedimentary succession on Cyprus clearly documents the diagnostic value of microfacies in this debate. In particular, the variability of archetypical bi‐gradational contourite sequences and their internal subdivision (bedding, layering and lamination) are explored. Contourites can be distinguished from turbidites, pelagites and hemipelagites by means of carbonate microfacies in combination with bed‐scale characteristics. Particle composition provides valuable information on sediment provenance. Depositional texture, determined by the ratio between carbonate mud and bioclasts, is crucial for identifying bi‐gradational sequences in both muddy and sandy contourites, and normally‐graded sequences in turbidite beds. Equally important are the type and preservation of traction structures, as well as the temporality and impact of bioturbation. Shell fragmentation under conditions of increased hydrodynamic agitation (textural inversion) is recognized as a carbonate‐specific feature of bioclastic sandy contourites.
Summary
Sphagnum farming can substitute peat with renewable biomass and thus help mitigate climate change. Large volumes of the required founder material can only be supplied sustainably by axenic cultivation in bioreactors.
We established axenic in vitro cultures from sporophytes of 19 Sphagnum species collected in Austria, Germany, Latvia, the Netherlands, Russia, and Sweden: S. angustifolium, S. balticum, S. capillifolium, S. centrale, S. compactum, S. cuspidatum, S. fallax, S. fimbriatum, S. fuscum, S. lindbergii, S. medium/divinum, S. palustre, S. papillosum, S. rubellum, S. russowii, S. squarrosum, S. subnitens, S. subfulvum and S. warnstorfii. These species cover five of the six European Sphagnum subgenera; namely, Acutifolia, Cuspidata, Rigida, Sphagnum and Squarrosa.
Their growth was measured in suspension cultures, whereas their ploidy was determined by flow cytometry and compared with the genome size of Physcomitrella patens. We identified haploid and diploid Sphagnum species, found that their cells are predominantly arrested in the G1 phase of the cell cycle, and did not find a correlation between plant productivity and ploidy. DNA barcoding was achieved by sequencing introns of the BRK1 genes.
With this collection, high‐quality founder material for diverse large‐scale applications, but also for basic Sphagnum research, is available from the International Moss Stock Center.
S2k guidelines for the therapy of pathological scars (hypertrophic scars and keloids) – Update 2020
(2020)
Abstract
Understanding how organisms adapt to complex environments is a central goal of evolutionary biology and ecology. This issue is of special interest in the current era of rapidly changing climatic conditions. Here, we investigate clinal variation and plastic responses in life history, morphology and physiology in the butterfly Pieris napi along a pan‐European gradient by exposing butterflies raised in captivity to different temperatures. We found clinal variation in body size, growth rates and concomitant development time, wing aspect ratio, wing melanization and heat tolerance. Individuals from warmer environments were more heat‐tolerant and had less melanised wings and a shorter development, but still they were larger than individuals from cooler environments. These findings suggest selection for rapid growth in the warmth and for wing melanization in the cold, and thus fine‐tuned genetic adaptation to local climates. Irrespective of the origin of butterflies, the effects of higher developmental temperature were largely as expected, speeding up development; reducing body size, potential metabolic activity and wing melanization; while increasing heat tolerance. At least in part, these patterns likely reflect adaptive phenotypic plasticity. In summary, our study revealed pronounced plastic and genetic responses, which may indicate high adaptive capacities in our study organism. Whether this may help such species, though, to deal with current climate change needs further investigation, as clinal patterns have typically evolved over long periods.
Abstract
Peatlands are lands with a peat layer at the surface, containing a large proportion of organic carbon. Such lands cover ≈1 000 000 km2 in Europe, which is almost 10% of the total surface area. In many countries, peatlands have been artificially drained over centuries, leading to not only enormous emissions of CO2 but also soil subsidence, mobilization of nutrients, higher flood risks, and loss of biodiversity. These problems can largely be solved by stopping drainage and rewetting the land. Wet peatlands do not release CO2, can potentially sequester carbon, help to improve water quality, provide habitat for rare and threatened biodiversity, and can still be used for production of biomass (“paludiculture”). Wisely adjusted land use on peatlands can substantially contribute to low‐emission goals and further benefits for farmers, the economy, society, and the environment.
Abstract
Improving our sparse knowledge of the mating and reproductive behaviour of white rhinoceros (Ceratotherium simum Burchell, 1817) is essential for the effective conservation of this iconic species. By combining morphological, physiological and habitat data with paternity assignments of 104 known mother–offspring pairs collected over a period of 13 years, we provide the most comprehensive analysis of the mating system in this species. We show that while the overall mating system was promiscuous, and both males and females produced more offspring when mating with several partners, half of all females with multiple offspring were monogamous. Additionally, we find that mating and reproductive success varied significantly among territorial males in two independent sets of males. In females, however, variation in the mating and the reproductive success was not larger than expected by random demographic fluctuations. Horn size, testosterone metabolite concentration, territory size, habitat openness and the volume of preferred food within the territory did not seem to influence male mating or reproductive success. Moreover, there was no sign of inbreeding avoidance: females tended to mate more frequently with closely related males, and one daughter produced a progeny with her father. The lack of inbreeding avoidance, in combination with the skew in male reproductive success, the partial monogamy in females and the territorial‐based mating system, jeopardizes the already low genetic variation in the species. Considering that the majority of populations are restricted to fenced reserves and private farms, we recommend taking preventive measures that aim to reduce inbreeding in white rhinoceros. A video abstract can be viewed here.
Abstract
Aims
Pinus uncinata is the major treeline‐forming species in the Pyrenees. Yet, the role of its reproduction and dispersal as drivers of treeline dynamics remains unknown. Here we quantify seed production, dispersal and germination changes along the elevation gradient to assess whether they may constrain the foreseen treeline advance in the Pyrenees.
Location
Central Pyrenees, Catalonia, NE Spain.
Methods
We established four plots along an elevation gradient from the closed subalpine forest to the krummholz zone at five study sites. In each plot, we collected cones from five to six trees, measured their length, and triggered their opening in the laboratory to count the number of empty seeds and the number and weight of full seeds. We used the collected seeds in a germination experiment under controlled conditions in growth chambers. Additionally, we installed seed traps along the forest–alpine grassland transition to measure seed rain for three consecutive years in three of the study sites.
Results
The number of full seeds per cone decreased along the elevation gradient and was correlated with cone length. However, the proportion of full seeds per cone and their weight did not differ between elevation positions. Seed rain decreased drastically with elevation and no seeds arrived into the alpine grassland traps consistently across study years. Although germination success did not significantly differ between elevation provenances (i.e., elevation position of origin), we found significant differences in germination dynamics between study sites and between elevation provenances within sites.
Conclusions
Our results indicate that whereas the viability of Pinus uncinata seeds is not limited by elevation, seed production and dispersal are constraining the ongoing rates of treeline advance in the Pyrenees.
Abstract
With the advent of molecular genetic methods, an increasing number of morphologically cryptic taxa has been discovered. The majority of them, however, remains formally undescribed and without a proper name although their importance in ecology and evolution is increasingly being acknowledged. Despite suggestions to complement traditional descriptions with genetic characters, the taxonomic community appears to be reluctant to adopt this proposition. As an incentive, we introduce QUIDDICH, a tool for the QUick IDentification of DIgnostic CHaracters, which automatically scans a DNA or amino acid alignment for those columns that allow to distinguish taxa and classifies them into four different types of diagnostic characters. QUIDDICH is a system‐independent, fast and user‐friendly tool that requires few manual steps and provides a comprehensive output, which can be included in formal taxonomic descriptions. Thus, cryptic taxa do not have to remain in taxonomic crypsis and, bearing a proper name, can readily be included in biodiversity assessments and ecological and evolutionary analyses. QUIDDICH can be obtained from the comprehensive R archive network (CRAN, https://cran.r-project.org/package=quiddich).
Abstract
Non‐native invasive species are threatening ecosystems and biodiversity worldwide. High genetic variation is thought to be a critical factor for invasion success. Accordingly, the global invasion of a few clonal lineages of the gastropod Potamopyrgus antipodarum is thus both puzzling and has the potential to help illuminate why some invasions succeed while others fail. Here, we used SNP markers and a geographically broad sampling scheme (N = 1617) including native New Zealand populations and invasive North American and European populations to provide the first widescale population genetic assessment of the relationships between and among native and invasive P. antipodarum. We used a combination of traditional and Bayesian molecular analyses to demonstrate that New Zealand populations harbour very high diversity relative to the invasive populations and are the source of the two main European genetic lineages. One of these two European lineages was in turn the source of at least one of the two main North American genetic clusters of invasive P. antipodarum, located in Lake Ontario. The other widespread North American group had a more complex origin that included the other European lineage and two New Zealand clusters. Altogether, our analyses suggest that just a small handful of clonal lineages of P. antipodarum were responsible for invasion across continents. Our findings provide critical information for prevention of additional invasions and control of existing invasive populations and are of broader relevance towards understanding the establishment and evolution of asexual populations and the forces driving biological invasion.
Direct monitoring of drug‐induced mechanical response of individual cells by atomic force microscopy
(2020)
Abstract
Mechanical characteristics of individual cells play a vital role in many biological processes and are considered as indicators of the cells’ states. Disturbances including methyl‐β‐cyclodextrin (MβCD) and cytochalasin D (cytoD) are known to significantly affect the state of cells, but little is known about the real‐time response of single cells to these drugs in their physiological condition. Here, nanoindentation‐based atomic force microscopy (AFM) was used to measure the elasticity of human embryonic kidney cells in the presence and absence of these pharmaceuticals. The results showed that depletion of cholesterol in the plasma membrane with MβCD resulted in cell stiffening whereas depolymerization of the actin cytoskeleton by cytoD resulted in cell softening. Using AFM for real‐time measurements, we observed that cells mechanically responded right after these drugs were added. In more detail, the cell´s elasticity suddenly increased with increasing instability upon cholesterol extraction while it is rapidly decreased without changing cellular stability upon depolymerizing actin cytoskeleton. These results demonstrated that actin cytoskeleton and cholesterol contributed differently to the cell mechanical characteristics.
Abstract
Background and aims: Intestinal adaptation in short bowel syndrome (SBS) includes morphologic processes and functional mechanisms. This study investigated whether digestive enzyme expression in the duodenum and colon is upregulated in SBS patients. Method: Sucrase‐isomaltase (SI), lactase‐phlorizin hydrolase (LPH), and neutral Aminopeptidase N (ApN) were analyzed in duodenal and colonic biopsies from nine SBS patients in a late stage of adaptation as well as healthy and disease controls by immunoelectron microscopy (IEM), Western blots, and enzyme activities. Furthermore, proliferation rates and intestinal microbiota were analyzed in the mucosal specimen. Results: We found significantly increased amounts of SI, LPH, and ApN in colonocytes in most SBS patients with large variation and strongest effect for SI and ApN. Digestive enzyme expression was only partially elevated in duodenal enterocytes due to a low proliferation level measured by Ki‐67 staining. Microbiome analysis revealed high amounts of Lactobacillus resp. low amounts of Proteobacteria in SBS patients with preservation of colon and ileocecal valve. Colonic expression was associated with a better clinical course in single cases. Conclusion: In SBS patients disaccharidases and peptidases can be upregulated in the colon. Stimulation of this colonic intestinalization process by drugs, nutrients, and pre‐ or probiotics might offer better therapeutic approaches.
Abstract
While chemical communication has been investigated intensively in vertebrates and insects, relatively little is known about the sensory world of spiders despite the fact that chemical cues play a key role in natural and sexual selection in this group. In insects, olfaction is performed with wall–pore and gustation with tip‐pore sensilla. Since spiders possess tip‐pore sensilla only, it is unclear how they accomplish olfaction. We scrutinized the ultrastructure of the trichoid tip‐pore sensilla of the orb weaving spider Argiope bruennichi—a common Palearctic species the males of which are known to be attracted by female sex pheromone. We also investigated the congener Argiope blanda. We examined whether the tip‐pore sensilla differ in ultrastructure depending on sex and their position on the tarsi of walking legs of which only the distal parts are in contact with the substrate. We hypothesized as yet undetected differences in ultrastructure that suggest gustatory versus olfactory functions. All tarsal tip‐pore sensilla of both species exhibit characters typical of contact‐chemoreceptors, such as (a) the presence of a pore at the tip of the sensillum shaft, (b) 2–22 uniciliated chemoreceptive cells with elongated and unbranched dendrites reaching up to the tip‐pore, (c) two integrated mechanoreceptive cells with short dendrites and large tubular bodies attached to the sensillum shaft's base, and (d) a socket structure with suspension fibres that render the sensillum shaft flexible. The newly found third mechanoreceptive cell attached to the proximal end of the peridendritic shaft cylinder by a small tubular body was likely overlooked in previous studies. The organization of tarsal tip‐pore sensilla did not differ depending on the position on the tarsus nor between the sexes. As no wall‐pore sensilla were detected, we discuss the probability that a single type of sensillum performs both gustation and olfaction in spiders.
Changes in food characteristics reveal indirect effects of lake browning on zooplankton performance
(2020)
Abstract
Browning caused by colored dissolved organic matter is predicted to have large effects on aquatic ecosystems. However, there is limited experimental evidence about direct and indirect effects of browning on zooplankton in complex field settings. We used a combination of an ecosystem‐scale enclosure experiment and laboratory incubations to test how prolonged browning affects physiological and life‐history traits of the water flea Daphnia longispina, a key species in lake food webs, and whether any such effects are reversible. Daphnids and water were collected from enclosures in a deep clear‐water lake, where the natural plankton community had been exposed for 10 weeks to browning or to control conditions in clear water. Daphnid abundance was much lower in the brown than in the clear enclosure. Surprisingly, however, daphnids continuously kept in brown enclosure water in the laboratory showed increased metabolic performance and survival, and also produced more offspring than daphnids kept in clear enclosure water. This outcome was related to more and higher‐quality seston in brown compared to clear water. Moreover, daphnids transferred from clear to brown water or vice versa adjusted their nucleic acid and protein contents, as indicators of physiological state, to similar levels as individuals previously exposed to the respective recipient environment, indicating immediate and reversible browning effects on metabolic performance. These results demonstrate the importance of conducting experiments in settings that capture both indirect effects (i.e., emerging from species interactions in communities) and direct effects on individuals for assessing impacts of browning and other environmental changes on lakes.
Summary
This study aimed to establish a robust and reliable metaproteomics protocol for an in‐depth characterization of marine particle‐associated (PA) bacteria. To this end, we compared six well‐established protein extraction protocols together with different MS‐sample preparation techniques using particles sampled during a North Sea spring algae bloom in 2009. In the final optimized workflow, proteins are extracted using a combination of SDS‐containing lysis buffer and cell disruption by bead‐beating, separated by SDS‐PAGE, in‐gel digested and analysed by LC–MS/MS, before MASCOT search against a metagenome‐based database and data processing/visualization with the in‐house‐developed bioinformatics tools Prophane and Paver. As an application example, free‐living (FL) and particulate communities sampled in April 2009 were analysed, resulting in an as yet unprecedented number of 9354 and 5034 identified protein groups for FL and PA bacteria, respectively. Our data suggest that FL and PA communities appeared similar in their taxonomic distribution, with notable exceptions: eukaryotic proteins and proteins assigned to Flavobacteriia, Cyanobacteria, and some proteobacterial genera were found more abundant on particles, whilst overall proteins belonging to Proteobacteria were more dominant in the FL fraction. Furthermore, our data points to functional differences including proteins involved in polysaccharide degradation, sugar‐ and phosphorus uptake, adhesion, motility, and stress response.
Abstract
The RADPAC trial evaluated paclitaxel with everolimus in patients with advanced gastroesophageal cancer (GEC) who have progressed after therapy with a fluoropyrimidine/platinum‐containing regimen. Patients were randomly assigned to receive paclitaxel (80 mg/m2) on day 1, 8 and 15 plus everolimus (10 mg daily, arm B) d1‐d28 or placebo (arm A), repeated every 28 days. Primary end point was overall survival (OS). Efficacy was assessed in the intention‐to‐treat population and safety in all patients who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov, number NCT01248403. Between October 2011 and September 2015, 300 patients (median age: 62 years; median lines prior therapy: 2; 47.7% of patients had prior taxane therapy) were randomly assigned (arm A, 150, arm B, 150). In the intention to treat population, there was no significant difference in progression‐free survival (PFS; everolimus, 2.2 vs placebo, 2.07 months, HR 0.88, P = .3) or OS (everolimus, 6.1 vs placebo, 5.0 months, HR 0.93, P = .54). For patients with prior taxane use, everolimus improved PFS (everolimus, 2.7 vs placebo 1.8 months, HR 0.69, P = .03) and OS (everolimus, 5.8 vs placebo 3.9 months, HR 0.73, P = .07). Combination of paclitaxel and everolimus was associated with significantly more grade 3‐5 mucositis (13.3% vs 0.7%; P < .001). The addition of everolimus to paclitaxel did not improve outcomes in pretreated metastatic gastric/gastroesophageal junction (GEJ) cancer. Activity was seen in the taxane pretreated group. Additional biomarker studies are planned to look for subgroups that may have a benefit.
Abstract
Purpose
This study aims to assess the implementation of published research, contraindications, and warnings on the prescription of dual renin‐angiotensin‐hormone system (RAS) blockade in ambulatory care in Germany.
Methods
Cohort study based on health claims data of 6.7 million subjects from 2008 to 2015. Yearly prevalence and incidence for dual RAS blockade with (a) angiotensin‐converting enzyme inhibitors and angiotensin‐receptor blockers (ACEI + ARB) and (b) aliskiren and ACEI or ARB (aliskiren + ACEI/ARB) were calculated. We assessed prescriber specialty and associations between discontinuing dual RAS blockade with specialist (internal medicine, cardiology, nephrology) visits and hospital discharge in the previous year.
Results
A total of 2 984 517 patients were included (age 51.4 ± SD 18.4 y, 48.5% male). Prescription rates for ACEI + ARB decreased from 0.6% (n = 17 907) to 0.4% (n = 12 237) and for aliskiren + ACEI/ARB from 0.23% (n = 6634) to 0.03% (n = 818). Incident prescriptions decreased from 0.23% (n = 6705) to 0.19% (n = 5055) (ACE + ARB) and from 0.1% (n = 2796) to 0.005% (n = 142) (aliskiren + ACE/ARB); 59% of ACEI + ARB and 48% of aliskiren + ACE/ARB combinations were prescribed only by one physician. Of those, 73% (ACEI + ARB) and 58% (aliskiren + ACE/ARB) were primary care providers (PCPs). Discontinuing dual RAS blockade was associated with specialist care and hospital discharge in the previous year (specialist care: RR 1.4, 95% CI, 1.3‐1.6; hospital visit: RR 1.5, 95% CI, 1.3‐1.6).
Conclusions
Our results suggest a delayed uptake of treatment recommendation for ACEI + ARB and a higher impact of Dear Doctor letters addressing PCPs directly compared with published research, contraindications, and warnings. Targeted continuous medical education, practice software alerts, and stronger involvement of pharmacists might improve the implementation of medication safety recommendations in ambulatory care.
Abstract
Background
Identifying predictors for general cognitive training (GCT) success in healthy older adults has many potential uses, including aiding intervention and improving individual dementia risk prediction, which are of high importance in health care. However, the factors that predict training improvements and the temporal course of predictors (eg, do the same prognostic factors predict training success after a short training period, such as 6 weeks, as well as after a longer training period, such as 6 months?) are largely unknown.
Methods
Data (N = 4,184 healthy older individuals) from two arms (GCT vs. control) of a three‐arm randomized controlled trial were reanalyzed to investigate predictors of GCT success in five cognitive tasks (grammatical reasoning, spatial working memory, digit vigilance, paired association learning, and verbal learning) at three time points (after 6 weeks, 3 months, and 6 months of training). Possible investigated predictors were sociodemographic variables, depressive symptoms, number of training sessions, cognitive baseline values, and all interaction terms (group*predictor).
Results
Being female was predictive for improvement in grammatical reasoning at 6 weeks in the GCT group, and lower cognitive baseline scores were predictive for improvement in spatial working memory and verbal learning at 6 months.
Conclusion
Our data indicate that predictors seem to change over time; remarkably, lower baseline performance at study entry is only a significant predictor at 6 months training. Possible reasons for these results are discussed in relation to the compensation hypothesis. J Am Geriatr Soc 68:‐, 2020.
Molecular dynamics simulations to the bidirectional adhesion signaling pathway of integrin αVβ3
(2020)
Abstract
The bidirectional force transmission process of integrin through the cell membrane is still not well understood. Several possible mechanisms have been discussed in literature on the basis of experimental data, and in this study, we investigate these mechanisms by free and steered molecular dynamics simulations. For the first time, constant velocity pulling on the complete integrin molecule inside a dipalmitoyl‐phosphatidylcholine membrane is conducted. From the results, the most likely mechanism for inside‐out and outside‐in signaling is the switchblade model with further separation of the transmembrane helices.
To suit a wide variety of space mission profiles, different designs of ion thrusters were developed, such as the High‐Efficiency‐Multistage‐Plasma thrusters (HEMP‐T). In the past, the optimization of ion thrusters was a difficult and time‐consuming process and evolved experimentally. Because the construction of new designs is expensive, cheaper methods for optimization were sought‐after. Computer‐based simulations are a cheap and useful method towards predictive modelling. The physics in HEMP‐T requires a kinetic model. The Particle‐in‐Cell (PIC) method delivers self‐consistent solutions for the plasmas of ion thrusters, but it is limited by the high amount of computing time required to study a specific system. Therefore, it is not suited to explore a wide operational and design space. An approach to decrease computing time is self‐similarity scaling schemes, which can be derived from the kinetic equations. One specific self‐similarity scheme is investigated quantitatively in this work for selected HEMP‐Ts, using PIC simulations. The possible application of the scaling is explained and the limits of this approach are derived.
Abstract
Objectives
Visual shade selection is the most commonly used method in dentistry and a challenge for every dentist. However, differences to natural tooth color and the differences of each shade guide are well known. The aim of this paper is to investigate the suitability of two different color scales for determining the color of no‐match templates.
Materials and methods
Volunteers (N = 76) selected a shade color of a no‐match template with two shade guides (VITA Classical shade guide (VC) and VITA Linearguide 3D‐Master (V3D LG), both Vita Zahnfabrik). The neutral grey background was laterally illuminated with a color differentiation lamp (Dialite, Eickhorst GmbH). For the volunteers’ accuracy, the triangle's area was used which are emerge by the color coordinates of a template (LTaTbT) and the color coordinates of the two decisions (L1a1b1 and L2a2b2). Statistical software was used to evaluate the differences in ΔE00 with α = .01.
Results
A deviation in the median of ΔE00 of 7.6 (V3D LG, first choice) to 6.6 (VC, second choice) was detected, while U test showed no significant differences in the median for both color scales. But the triangle's area generated by both shade decisions and tooth color with V3D LG was significant smaller (14.2) then VC (19.2) (P ≤ .001).
Conclusions
When comparing both results no significant difference in the subject's shade selection and the shade guides was detected. The new evaluation strategy using the size of the triangle's areas proves the superiority of the V3D LG due to a better distribution of the tooth color shades within the color space.
Abstract
Two decades after the discovery of adult‐born neurons in the brains of decapod crustaceans, the deutocerebral proliferative system (DPS) producing these neural lineages has become a model of adult neurogenesis in invertebrates. Studies on crayfish have provided substantial insights into the anatomy, cellular dynamics, and regulation of the DPS. Contrary to traditional thinking, recent evidence suggests that the neurogenic niche in the crayfish DPS lacks self‐renewing stem cells, its cell pool being instead sustained via integration of hemocytes generated by the innate immune system. Here, we investigated the origin, division and migration patterns of the adult‐born neural progenitor (NP) lineages in detail. We show that the niche cell pool is not only replenished by hemocyte integration but also by limited numbers of symmetric cell divisions with some characteristics reminiscent of interkinetic nuclear migration. Once specified in the niche, first generation NPs act as transit‐amplifying intermediate NPs that eventually exit and produce multicellular clones as they move along migratory streams toward target brain areas. Different clones may migrate simultaneously in the streams but occupy separate tracks and show spatio‐temporally flexible division patterns. Based on this, we propose an extended DPS model that emphasizes structural similarities to pseudostratified neuroepithelia in other arthropods and vertebrates. This model includes hemocyte integration and intrinsic cell proliferation to synergistically counteract niche cell pool depletion during the animal's lifespan. Further, we discuss parallels to recent findings on mammalian adult neurogenesis, as both systems seem to exhibit a similar decoupling of proliferative replenishment divisions and consuming neurogenic divisions.
Abstract
Methylation of free hydroxyl groups is an important modification for flavonoids. It not only greatly increases absorption and oral bioavailability of flavonoids, but also brings new biological activities. Flavonoid methylation is usually achieved by a specific group of plant O‐methyltransferases (OMTs) which typically exhibit high substrate specificity. Here we investigated the effect of several residues in the binding pocket of the Clarkia breweri isoeugenol OMT on the substrate scope and regioselectivity against flavonoids. The mutation T133M, identified as reported in our previous publication, increased the activity of the enzyme against several flavonoids, namely eriodictyol, naringenin, luteolin, quercetin and even the isoflavonoid genistein, while a reduced set of amino acids at positions 322 and 326 affected both, the activity and the regioselectivity of the methyltranferase. On the basis of this work, methylated flavonoids that are rare in nature were produced in high purity.
Abstract
Biocatalysis has found numerous applications in various fields as an alternative to chemical catalysis. The use of enzymes in organic synthesis, especially to make chiral compounds for pharmaceuticals as well for the flavors and fragrance industry, are the most prominent examples. In addition, biocatalysts are used on a large scale to make specialty and even bulk chemicals. This review intends to give illustrative examples in this field with a special focus on scalable chemical production using enzymes. It also discusses the opportunities and limitations of enzymatic syntheses using distinct examples and provides an outlook on emerging enzyme classes.
Long-chain aliphatic amines such as (S,Z)-hepta- dec-9-en-7-amine and 9-aminoheptadecane were synthesized from ricinoleic acid and oleic acid, respectively, by whole-cell cascade reactions using the combination of an alcohol dehydrogenase (ADH) from Micrococcus luteus, an engi- neered amine transaminase from Vibrio fluvialis (Vf-ATA), and a photoactivated decarboxylase from Chlorella variabilis NC64A (Cv-FAP) in a one-pot process. In addition, long chain aliphatic esters such as 10-(heptanoyloxy)dec-8-ene and octyl- nonanoate were prepared from ricinoleic acid and oleic acid, respectively, by using the combination of the ADH, a Baeyer– Villiger monooxygenase variant from Pseudomonas putida KT2440, and the Cv-FAP. The target compounds were produced at rates of up to 37 U g1 dry cells with conversions up to 90 %. Therefore, this study contributes to the preparation of industrially relevant long-chain aliphatic chiral amines and esters from renewable fatty acid resources.
Abstract
Aims
Treating patients with acute decompensated heart failure (ADHF) presenting with volume overload is a common task. However, optimal guidance of decongesting therapy and treatment targets are not well defined. The inferior vena cava (IVC) diameter and its collapsibility can be used to estimate right atrial pressure, which is a measure of right‐sided haemodynamic congestion. The CAVA‐ADHF‐DZHK10 trial is designed to test the hypothesis that ultrasound assessment of the IVC in addition to clinical assessment improves decongestion as compared with clinical assessment alone.
Methods and results
CAVA‐ADHF‐DZHK10 is a randomized, controlled, patient‐blinded, multicentre, parallel‐group trial randomly assigning 388 patients with ADHF to either decongesting therapy guided by ultrasound assessment of the IVC in addition to clinical assessment or clinical assessment alone. IVC ultrasound will be performed daily between baseline and hospital discharge in all patients. However, ultrasound results will only be reported to treating physicians in the intervention group. Treatment target is relief of congestion‐related signs and symptoms in both groups with the additional goal to reduce the IVC diameter ≤21 mm and increase IVC collapsibility >50% in the intervention group. The primary endpoint is change in N‐terminal pro‐brain natriuretic peptide from baseline to hospital discharge. Secondary endpoints evaluate feasibility, efficacy of decongestion on other scales, and the impact of the intervention on clinical endpoints.
Conclusions
CAVA‐ADHF‐DZHK10 will investigate whether IVC ultrasound supplementing clinical assessment improves decongestion in patients admitted for ADHF.
Abstract
A device for the transaminase‐catalysed synthesis combined with continuous recovery of chiral amines was designed. The system enabled the separation of the reaction components in three liquid phases: a reaction phase, an organic solvent phase (where the poorly water soluble ketone substrate was supplied), and an aqueous extraction phase for continuous product recovery. The transaminase‐mediated asymmetric synthesis of (S)‐1‐methyl‐3‐phenylpropylamine was employed as model reaction. Factors influencing the performance of the system, such as reactor geometry, working volumes and operating parameters, were investigated. Specifically, reaction yield and product recovery were enhanced by i) reducing the thickness of the reaction phase, while continuously stirring and ii) reducing the volume of the extraction phase. Under the optimal condition tested, 85 % of the product formed was extracted and a product concentration value of 9 g/L was reached. However, co‐extraction of the unreacted amine donor (17 %) was observed. Advantages and drawbacks of this process compared to existing technologies, as well as possible optimization strategies are discussed.
Abstract
Head motion during magnetic resonance imaging (MRI) induces image artifacts that affect virtually every brain measure. In parallel, cross‐sectional observations indicate a correlation of head motion with age, psychiatric disease status and obesity, raising the possibility of a systematic artifact‐induced bias in neuroimaging outcomes in these conditions, due to the differences in head motion. Yet, a causal link between obesity and head motion has not been tested in an experimental design. Here, we show that a change in body mass index (BMI) (i.e., weight loss after bariatric surgery) systematically decreases head motion during MRI. In this setting, reduced imaging artifacts due to lower head motion might result in biased estimates of neural differences induced by changes in BMI. Overall, our finding urges the need to rigorously control for head motion during MRI to enable valid results of neuroimaging outcomes in populations that differ in head motion due to obesity or other conditions.
Abstract
This work presents a stepwise reversible two‐electron transfer induced hydrogen shift leading to the conversion of a bis‐pyrrolinium cation to an E‐diaminoalkene and vice versa. Remarkably, the forward and the reverse reaction, which are both reversible, follow two completely different reaction pathways. Establishing such unprecedented property in this type of processes was possible by developing a novel synthetic route towards the starting dication. All intermediates involved in both the forward and the backward reactions were comprehensively characterized by a combination of spectroscopic, crystallographic, electrochemical, spectroelectrochemical, and theoretical methods. The presented synthetic route opens up new possibilities for the generation of multi‐pyrrolinium cation scaffold‐based organic redox systems, which constitute decidedly sought‐after molecules in contemporary chemistry.
Abstract
A DNA G‐quadruplex adopting a (3+1) hybrid structure was modified in two adjacent syn positions of the antiparallel strand with anti‐favoring 2′‐deoxy‐2′‐fluoro‐riboguanosine (FrG) analogues. The two substitutions promoted a structural rearrangement to a topology with the 5′‐terminal G residue located in the central tetrad and the two modified residues linked by a V‐shaped zero‐nucleotide loop. Strikingly, whereas a sugar pucker in the preferred north domain is found for both modified nucleotides, the FrG analogue preceding the V‐loop is forced to adopt the unfavored syn conformation in the new quadruplex fold. Apparently, a preferred C3′‐endo sugar pucker within the V‐loop architecture outweighs the propensity of the FrG analogue to adopt an anti glycosidic conformation. Refolding into a V‐loop topology is likewise observed for a sequence modified at corresponding positions with two riboguanosine substitutions. In contrast, 2′‐F‐arabinoguanosine analogues with their favored south‐east sugar conformation do not support formation of the V‐loop topology. Examination of known G‐quadruplexes with a V‐shaped loop highlights the critical role of the sugar conformation for this distinct structural motif.
Abstract
Over the last years, there has been an enormous increase in the knowledge on koi herpesvirus (KHV), koi herpesvirus disease (KHVD), pathogenesis and virus variants. Different KHV lineages have clearly been identified, possible genomic changes during replication in different cell cultures at different temperatures but also in several hosts have been identified, a persistent stage of infection has been specified and it has been shown that infection with KHV is not host specific at all, but KHVD is. Additionally, it has been shown that it is possible to combat KHVD by immunization with inactivated and attenuated live vaccines using different delivery systems but also to benefit from alternative treatments with e.g. exopolysaccharids obtained from Arthrospira platensis.