•Assessment of agricultural run-off (ARO) and global warming in aquatic microcosms•Direct ARO effects were higher phytoplankton biomass and lower grazer growth•Biotic interactions reversed the direct ...effect of ARO on phytoplankton•ARO effects were enhanced with multiple pulses compared to a single addition•Warming had no major effect on primary producers, consumers or their interactions
Aquatic ecosystems are exposed to multiple stressors such as agricultural run-off (ARO) and climate-change related increase of temperature. We aimed to determine how ARO and the frequency of its input can affect shallow lake ecosystems through direct and indirect effects on primary producers and primary consumers, and whether warming can mitigate or reinforce the impact of ARO. We performed a set of microcosm experiments simulating ARO using a cocktail of three organic pesticides (terbuthylazine, tebuconazole, pirimicarb), copper and nitrate. Two experiments were performed to determine the direct effect of ARO on primary producers (submerged macrophytes, periphyton and phytoplankton) and on the grazing snail Lymnaea stagnalis, respectively. Three different ARO concentrations added as single doses or as multiple pulses at two different temperatures (22°C and 26°C) were applied. In a third experiment, primary producers and consumers were exposed together to allow trophic interactions. When functional groups were exposed alone, ARO had a direct positive effect on phytoplankton and a strong negative effect on L. stagnalis. When exposed together, primary producer responses were contrasting, as the negative effect of ARO on grazers led to an indirect positive effect on periphyton. Periphyton in turn exerted a strong control on phytoplankton, leading to an indirect negative effect of ARO on phytoplankton. Macrophytes showed little response to the stressors. Multiple pulse exposure increased the effect of ARO on L. stagnalis and periphyton when compared with the same quantity of ARO added as a single dose. The increase in temperature had only limited effects. Our results highlight the importance of indirect effects of stressors, here mediated by grazers and periphyton, and the frequency of the ARO input in aquatic ecosystems.
Display omitted
Aging is associated with an increased risk of cardiovascular disease and death. Here we show that oral supplementation of the natural polyamine spermidine extends the lifespan of mice and exerts ...cardioprotective effects, reducing cardiac hypertrophy and preserving diastolic function in old mice. Spermidine feeding enhanced cardiac autophagy, mitophagy and mitochondrial respiration, and it also improved the mechano-elastical properties of cardiomyocytes in vivo, coinciding with increased titin phosphorylation and suppressed subclinical inflammation. Spermidine feeding failed to provide cardioprotection in mice that lack the autophagy-related protein Atg5 in cardiomyocytes. In Dahl salt-sensitive rats that were fed a high-salt diet, a model for hypertension-induced congestive heart failure, spermidine feeding reduced systemic blood pressure, increased titin phosphorylation and prevented cardiac hypertrophy and a decline in diastolic function, thus delaying the progression to heart failure. In humans, high levels of dietary spermidine, as assessed from food questionnaires, correlated with reduced blood pressure and a lower incidence of cardiovascular disease. Our results suggest a new and feasible strategy for protection against cardiovascular disease.
MicroRNAs comprise a broad class of small non-coding RNAs that control expression of complementary target messenger RNAs. Dysregulation of microRNAs by several mechanisms has been described in ...various disease states including cardiac disease. Whereas previous studies of cardiac disease have focused on microRNAs that are primarily expressed in cardiomyocytes, the role of microRNAs expressed in other cell types of the heart is unclear. Here we show that microRNA-21 (miR-21, also known as Mirn21) regulates the ERK-MAP kinase signalling pathway in cardiac fibroblasts, which has impacts on global cardiac structure and function. miR-21 levels are increased selectively in fibroblasts of the failing heart, augmenting ERK-MAP kinase activity through inhibition of sprouty homologue 1 (Spry1). This mechanism regulates fibroblast survival and growth factor secretion, apparently controlling the extent of interstitial fibrosis and cardiac hypertrophy. In vivo silencing of miR-21 by a specific antagomir in a mouse pressure-overload-induced disease model reduces cardiac ERK-MAP kinase activity, inhibits interstitial fibrosis and attenuates cardiac dysfunction. These findings reveal that microRNAs can contribute to myocardial disease by an effect in cardiac fibroblasts. Our results validate miR-21 as a disease target in heart failure and establish the therapeutic efficacy of microRNA therapeutic intervention in a cardiovascular disease setting.
A total of 156 patients (age range 1.3-18.0 years, median 13.2 years; 91 (58.3%) male) with newly diagnosed CML (N = 146 chronic phase (CML-CP), N = 3 accelerated phase (CML-AP), N = 7 blastic phase ...(CML-BP)) received imatinib up-front (300, 400, 500 mg/m
, respectively) within a prospective phase III trial. Therapy response, progression-free survival, causes of treatment failure, and side effects were analyzed in 148 children and adolescents with complete data. Event-free survival rate by 18 months for patients in CML-CP (median follow-up time 25 months, range: 1-120) was 97% (95% CI, 94.2-99.9%). According to the 2006 ELN-criteria complete hematologic response by month 3, complete cytogenetic response (CCyR) by month 12, and major molecular response (MMR) by month 18 were achieved in 98, 63, and 59% of the patients, respectively. By month 36, 86% of the patients achieved CCyR and 74% achieved MMR. Thirty-eight patients (27%) experienced imatinib failure because of unsatisfactory response or intolerance (N = 9). In all, 28/148 patients (19%) underwent stem cell transplantation (SCT). In the SCT sub-cohort 2/23 patients diagnosed in CML-CP, 0/1 in CML-AP, and 2/4 in CML-BP, respectively, died of relapse (N = 3) or SCT-related complications (N = 2). This large pediatric trial extends and confirms data from smaller series that first-line imatinib in children is highly effective.
Maturation of the glomerular basement membrane (GBM) is essential for maintaining the integrity of the renal filtration barrier. Impaired maturation causes proteinuria and renal fibrosis in the type ...IV collagen disease Alport syndrome. This study evaluates the role of collagen receptors in maturation of the GBM, matrix accumulation and renal fibrosis by using mice deficient for discoidin domain receptor 1 (DDR1), integrin subunit α2 (ITGA2), and type IV collagen α3 (COL4A3). Loss of both collagen receptors DDR1 and integrin α2β1 delays maturation of the GBM: due to a porous GBM filtration barrier high molecular weight proteinuria that more than doubles between day 60 and day 100. Thereafter, maturation of the GBM causes proteinuria to drop down to one tenth until day 200. Proteinuria and the porous GBM cause accumulation of glomerular and tubulointerstitial matrix, which both decrease significantly after GBM-maturation until day 250. In parallel, in a disease with impaired GBM-maturation such as Alport syndrome, loss of integrin α2β1 positively delays renal fibrosis: COL4A3−/−/ITGA2−/− double knockouts exhibited reduced proteinuria and urea nitrogen compared to COL4A3−/−/ITGA2+/− and COL4A3−/−/ITGA2+/+ mice. The double knockouts lived 20% longer and showed less glomerular and tubulointerstitial extracellular matrix deposition than the COL4A3−/− Alport mice with normal integrin α2β1 expression. Electron microscopy illustrated improvements in the glomerular basement membrane structure. MMP2, MMP9, MMP12 and TIMP1 were expressed at significantly higher levels (compared to wild-type mice) in COL4A3−/−/ITGA2+/+ Alport mice, but not in COL4A3+/+/ITGA2−/− mice. In conclusion, the collagen receptors DDR1 and integrin α2β1 contribute to regulate GBM-maturation and to control matrix accumulation. As demonstrated in the type IV collagen disease Alport syndrome, glomerular cell–matrix interactions via collagen receptors play an important role in the progression of renal fibrosis.
•Loss of both collagen receptors DDR1 and integrin α2β1 delays maturation of the glomerular basement membrane.•Loss of integrin α2β1 in COL4A3-/- mice with the type IV collagen disease Alport syndrome delays renal fibrosis.•COL4A3-/-/ITGA2-/- mice live longer and show less matrix deposition than Alport mice with normal ITGA2+/+-expression.•Glomerular cell-matrix interactions via collagen receptors play an important role in the progression of renal fibrosis.•The blockage of collagen receptors may be a promising new strategy to treat chronic progressive fibrotic kidney diseases.
The dynamics of colloidal particles at interfaces between two fluids plays a central role in microrheology, encapsulation, emulsification, biofilm formation, water remediation and the ...interface-driven assembly of materials. Common intuition corroborated by hydrodynamic theories suggests that such dynamics is governed by a viscous force lower than that observed in the more viscous fluid. Here, we show experimentally that a particle straddling an air/water interface feels a large viscous drag that is unexpectedly larger than that measured in the bulk. We suggest that such a result arises from thermally activated fluctuations of the interface at the solid/air/liquid triple line and their coupling to the particle drag through the fluctuation-dissipation theorem. Our findings should inform approaches for improved control of the kinetically driven assembly of anisotropic particles with a large triple-line-length/particle-size ratio, and help to understand the formation and structure of such arrested materials.
Transcatheter aortic valve replacement (TAVR) has rapidly become a viable alternative to the conventional isolated surgical aortic valve replacement (iSAVR) for treating severe symptomatic aortic ...stenosis. However, data on younger patients is scarce and a gap exists between data-based recommendations and the clinical use of TAVR. In our study, we utilized a machine learning (ML) driven approach to model the complex decision-making process of Heart Teams when treating young patients with severe symptomatic aortic stenosis with either TAVR or iSAVR and to identify the relevant considerations. Out of the considered factors, the variables most prominently featured in our ML model were congestive heart failure, established risk assessment scores, previous cardiac surgeries, a reduced left ventricular ejection fraction and peripheral vascular disease. Our study demonstrates a viable application of ML-based approaches for studying and understanding complex clinical decision-making processes.
Do voters want their party to be office- or policy-seekers in coalition negotiations? This question has been left unstudied in political science research so far. While existing research shows that ...policies matter for voters when forming their preferences for coalitions, in this study it is argued that voters find it at the same time important that their preferred party gains offices. Specifically, voters' office-seeking considerations are expected to increase the more indifferent they are to the policy content of a coalition agreement. To test this assumption, an original conjoint experiment among Green Party voters in the context of the German federal election in 2021 has been conducted. The findings demonstrate that voters' office-seeking considerations become more important the more similar coalition agreements are with regard to their policy content. These findings have important implications for the understanding of voters' preferences regarding coalitions.
► In this study, we develop and evaluate a structure–function–diversity model of grassland ecosystems. ► The model is parameterized from plant functional traits of 13 perennial grass species. ► The ...model is evaluated on species performance in monoculture and mixture across disturbance and fertility gradients. ► We demonstrate the model ability to simulate species performance and plant community structure.
A structure–function–diversity model of grassland ecosystems (Gemini) has been developed. For a potentially unlimited number of clonal plant populations, it explicitly simulates competition for two key resources (light and nitrogen) along vertical canopy and soil profiles. Population turnover, shoot and root morphogenesis, photosynthesis, respiration, transpiration, N acquisition by uptake, allocation of assimilates between structural compartments, and reserve storage and remobilization, are simulated for each plant population. The object-oriented structure of the modeling framework allows to couple, or not, the simulated plant populations to other sub-models describing climate variables, soil functioning, grazing behavior and grassland management. Partitioning of growth between shoot structures, leaf photosynthetic proteins and roots is based on two assumptions: (i) functional balance between root and shoot activity, (ii) coordination of leaf photosynthesis. The model was parameterized from plant functional trait measurements of 13 native perennial pasture grass species grown in monocultures at high N availability and low cutting frequency in a field trial. Predicted and measured annual dry-matter yields were highly correlated without bias across species, N supply and cutting frequency treatments in monocultures and in mixtures of six species. Results show the ability of this mechanistic model to simulate without bias nitrogen and disturbance responses of net primary productivity and of plant community structure.
PDF
