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Tumor-associated macrophages (TAMs) promote tumor growth and metastasis by suppressing tumor immune surveillance. Herein, we provide evidence that the immunosuppressive phenotype of TAMs is controlled by long-chain fatty acid metabolism, specifically unsaturated fatty acids, here exemplified by oleate. Consequently, en-route enriched lipid droplets were identified as essential organelles, which represent effective targets for chemical inhibitors to block in vitro polarization of TAMs and tumor growth in vivo. In line, analysis of human tumors revealed that myeloid cells infiltrating colon cancer but not gastric cancer tissue indeed accumulate lipid droplets. Mechanistically, our data indicate that oleate-induced polarization of myeloid cells depends on the mammalian target of the rapamycin pathway. Thus, our findings reveal an alternative therapeutic strategy by targeting the pro-tumoral myeloid cells on a metabolic level.
Background. In horses and ponies numerous medical conditions are known to be linked with inflammation in different tissues, especially in the liver. Besides affecting other metabolic pathways such as the expression of certain interleukins (IL), inflammation is associated with stress of the endoplasmic reticulum (ER). In particular, ER stress leads to adaptive stress response and can be measured by several markers of inflammatory and stress signalling pathways, like nuclear factor kappa B (NF-kB). Objectives. To investigate lipopolysaccharide (LPS)-induced inflammatory reactions and their modulation in horses and ponies by feeding a polyphenol-rich supplement consisting of green tea and curcuma. Methods. In a cross-over study, 11 animals were allocated to either a placebo or a supplement group and supplemented with 10 g of a blend of green tea and curcuma extract (GCE) or a placebo (calcium carbonate) once daily. After 21 days of supplementation, all animals underwent a LPS challenge to induce moderate systemic inflammation. Blood samples and liver biopsies were taken at standardized time points: 24 hours before and 12 hours after LPS challenge. Inflammatory blood parameters such as serum amyloid A (SAA), haptoglobin and retinol binding protein 4 (RBP4) were measured in serum. Hepatic mRNA levels of selected markers of inflammation such as haptoglobin, tumor necrosis factor alpha (TNF-alpha), IL-1 beta, IL-6, cluster of differentiation 68 (CD68), fibroblast growth factor 21 (FGF-21), NF-kappa B, activating transcription factor 4 (ATF4) were quantified by RT-qPCR. In addition, liver biopsies were examined histologically for inflammatory alterations. Results. Blood markers of acute inflammatory response increased after LPS challenge. In the liver, the proinflammatory cytokine IL-1 beta showed significantly lower mRNA levels after LPS challenge in the supplemented group (P = 0.04) compared to the placebo group. Levels of the hepatic CD68 mRNA increased significantly in the placebo group (P = 0.04). There were no significant differences between supplemented and placebo groups concerning other markers of inflammation and markers of ER stress within the liver. The number of hepatic macrophages were not different after LPS challenge in both feeding groups. Conclusion. LPS was able to induce inflammation but seemed less suitable to induce ER stress in the horses and ponies. The polyphenol-rich supplement showed some potential to reduce inflammatory responses. Nevertheless, the supplementation did not exert an overall anti-inflammatory effect in horses and ponies.
BackgroundPachycladon cheesemanii is a close relative of Arabidopsis thaliana and is an allotetraploid perennial herb which is widespread in the South Island of New Zealand. It grows at altitudes of up to 1000m where it is subject to relatively high levels of ultraviolet (UV)-B radiation. To gain first insights into how Pachycladon copes with UV-B stress, we sequenced its genome and compared the UV-B tolerance of two Pachycladon accessions with those of two A. thaliana accessions from different altitudes.ResultsA high-quality draft genome of P. cheesemanii was assembled with a high percentage of conserved single-copy plant orthologs. Synteny analysis with genomes from other species of the Brassicaceae family found a close phylogenetic relationship of P. cheesemanii with Boechera stricta from Brassicaceae lineage I. While UV-B radiation caused a greater growth reduction in the A. thaliana accessions than in the P. cheesemanii accessions, growth was not reduced in one P. cheesemanii accession. The homologues of A. thaliana UV-B radiation response genes were duplicated in P. cheesemanii, and an expression analysis of those genes indicated that the tolerance mechanism in P. cheesemanii appears to differ from that in A. thaliana.ConclusionAlthough the P. cheesemanii genome shows close similarity with that of A. thaliana, it appears to have evolved novel strategies allowing the plant to tolerate relatively high UV-B radiation.
Both climate-change damages and climate-change mitigation will incur economic costs. While the risk of severe damages increases with the level of global warming (Dell et al., 2014; IPCC, 2014b, 2018; Lenton et al., 2008), mitigating costs increase steeply with more stringent warming limits (IPCC, 2014a; Luderer et al., 2013; Rogelj et al., 2015). Here, we show that the global warming limit that minimizes this century's total economic costs of climate change lies between 1.9 and 2 ∘C, if temperature changes continue to impact national economic growth rates as observed in the past and if instantaneous growth effects are neither compensated nor amplified by additional growth effects in the following years. The result is robust across a wide range of normative assumptions on the valuation of future welfare and inequality aversion. We combine estimates of climate-change impacts on economic growth for 186 countries (applying an empirical damage function from Burke et al., 2015) with mitigation costs derived from a state-of-the-art energy–economy–climate model with a wide range of highly resolved mitigation options (Kriegler et al., 2017; Luderer et al., 2013, 2015). Our purely economic assessment, even though it omits non-market damages, provides support for the international Paris Agreement on climate change. The political goal of limiting global warming to “well below 2 degrees” is thus also an economically optimal goal given above assumptions on adaptation and damage persistence.
Movement ecology aims to provide common terminology and an integrative framework of movement research across all groups of organisms. Yet such work has focused on unitary organisms so far, and thus the important group of filamentous fungi has not been considered in this context. With the exception of spore dispersal, movement in filamentous fungi has not been integrated into the movement ecology field. At the same time, the field of fungal ecology has been advancing research on topics like informed growth, mycelial translocations, or fungal highways using its own terminology and frameworks, overlooking the theoretical developments within movement ecology. We provide a conceptual and terminological framework for interdisciplinary collaboration between these two disciplines, and show how both can benefit from closer links: We show how placing the knowledge from fungal biology and ecology into the framework of movement ecology can inspire both theoretical and empirical developments, eventually leading towards a better understanding of fungal ecology and community assembly. Conversely, by a greater focus on movement specificities of filamentous fungi, movement ecology stands to benefit from the challenge to evolve its concepts and terminology towards even greater universality. We show how our concept can be applied for other modular organisms (such as clonal plants and slime molds), and how this can lead towards comparative studies with the relationship between organismal movement and ecosystems in the focus.
The Alpine orogen formed as a result of the collision between the Adriatic and European plates. Significant crustal heterogeneity exists within the region due to the long history of interplay between these plates, other continental and oceanic blocks in the region, and inherited crustal features from earlier orogenies. Deformation relating to the collision continues to the present day. Here, a seismically constrained, 3-D structural and density model of the lithosphere of the Alps and their respective forelands, derived from integrating numerous geoscientific datasets, was adjusted to match the observed gravity field. It is shown that the distribution of seismicity and deformation within the region correlates well to thickness and density changes within the crust, and that the present-day Adriatic crust is both thinner and denser (22.5 km, 2800 kg m(-3) ) than the European crust (27.5 km, 2750 kg m(-3)). Alpine crust derived from each respective plate is found to show the same trend, with zones of Adriatic provenance (Austro-Alpine unit and Southern Alps) found to be denser and those of European provenance (Helvetic zone and Tauern Window) to be less dense. This suggests that the respective plates and related terranes had similar crustal properties to the present-day ones prior to orogenesis. The model generated here is available for open-access use to further discussions about the crust in the region.
Climate change is affecting the rate of carbon cycling, particularly in the Arctic. Permafrost degradation through deeper thaw and physical disturbances results in the release of carbon dioxide and methane to the atmosphere and to an increase in lateral dissolved organic matter (DOM) fluxes. Whereas riverine DOM fluxes of the large Arctic rivers are well assessed, knowledge is limited with regard to small catchments that cover more than 40% of the Arctic drainage basin. Here, we use absorption measurements to characterize changes in DOM quantity and quality in a low Arctic (Herschel Island, Yukon, Canada) and a high Arctic (Cape Bounty, Melville Island, Nunavut, Canada) setting with regard to geographical differences, impacts of permafrost degradation, and rainfall events. We find that DOM quantity and quality is controlled by differences in vegetation cover and soil organic carbon content (SOCC). The low Arctic site has higher SOCC and greater abundance of plant material resulting in higher chromophoric dissolved organic matter (cDOM) and dissolved organic carbon (DOC) than in the high Arctic. DOC concentration and cDOM in surface waters at both sites show strong linear relationships similar to the one for the great Arctic rivers. We used the optical characteristics of DOM such as cDOM absorption, specific ultraviolet absorbance (SUVA), ultraviolet (UV) spectral slopes (S275-295), and slope ratio (SR) for assessing quality changes downstream, at base flow and storm flow conditions, and in relation to permafrost disturbance. DOM in streams at both sites demonstrated optical signatures indicative of photodegradation downstream processes, even over short distances of 2000 m. Flow pathways and the connected hydrological residence time control DOM quality. Deeper flow pathways allow the export of permafrost-derived DOM (i.e. from deeper in the active layer), whereas shallow pathways with shorter residence times lead to the export of fresh surface- and near-surface-derived DOM. Compared to the large Arctic rivers, DOM quality exported from the small catchments studied here is much fresher and therefore prone to degradation. Assessing optical properties of DOM and linking them to catchment properties will be a useful tool for understanding changing DOM fluxes and quality at a pan-Arctic scale.
Swimming performance can be improved not only by in-water sport-specific training but also by means of dry land-training (e.g., plyometric jump training [PJT]). This study examined the effects of an 8-week PJT on proxies of muscle power and swimming performance in prepubertal male swimmers. Participants were randomly allocated to a PJT group (PJT; n = 14; age: 10.3 +/- 0.4 years, maturity-offset = -3 +/- 0.3) or a control group (CG; n = 12; age: 10.5 +/- 0.4 years, maturity-offset = -2.8 +/- 0.3). Swimmers in PJT and CG performed 6 training sessions per week. Each training session lasted between 80 and 90 minutes. Over the 8 weeks in-season training period, PJT performed two PJT sessions per week, each lasting between 25 to 30 minutes (similar to 1 hour per week) in replacement of sport-specific swimming drills. During that time, CG followed their regular sport-specific swimming training (e.g., coordination, breathing, improving swimming strokes). Overall training volume was similar between groups. Pre- and post-training, tests were conducted to assess proxies of muscle power (countermovement-jump [CMJ]), standing-long-jump [SLJ]) and sport-specific swimming performances (15-, 25-, and 50-m front-crawl, 25-m kick without push [25-m kick WP], and 25-m front-crawl WP). No training or test-related injuries were detected over the course of the study. Between-group analyses derived from magnitude-based inferences showed trivial-to-large effects in favour of PJT for all tests (ES = 0.28 to 1.43). Within-group analyses for the PJT showed small performance improvements for CMJ (effect-size [ES] = 0.53), 25-m kick WP (ES = 0.25), and 50-m front crawl (ES = 0.56) tests. Moderate performance improvements were observed for the SLJ, 25-m front-crawl WP, 15-m and 25-m front-crawl tests (ES = 0.95, 0.60, 0.99, and 0.85, respectively). For CG, the within-group results showed trivial performance declines for the CMJ (ES=-0.13) and the 50-m front-crawl test (ES = -0.04). In addition, trivial-to-small performance improvements were observed for the SLJ (ES = 0.09), 25-m kick WP (ES = 0.02), 25-m front-crawl WP (ES = 0.19), 25-m front-crawl (ES = 0.2), (SLJ [ES = 0.09, and 15-m front crawl (ES = 0.36). Short-term in-season PJT, integrated into the regular swimming training, was more effective than regular swimming training alone in improving jump and sport-specific swimming performances in prepubertal male swimmers.
Dielectric Relaxation Spectroscopy (DRS) and Thermally Stimulated Depolarization Current (TSDC) measurements were employed to study dielectric-relaxation processes, structural transitions and electric-polarization phenomena in poly(vinylidenefluoride-trifluoroethylene-chlorofluoroethylene) (P(VDF-TrFE-CFE)) terpolymer films. Results from DRS confirm the existence of two separate dispersion regions related to a para-to-ferroelectric phase transition and to the glass transition. The dipolar TSDC peak correlates with the loss peak of the ? relaxation that represents the glass transition. The electric polarization calculated from the dipolar TSDC peak (glass transition) shows a non-linear electric-field dependence and saturates at high electric poling fields. As the observed behaviour is essentially the same as that of the electric polarization obtained from direct polarization-versus-electric-field hysteresis measurements, TSDC experiments are also suitable for studying the polarization in relaxor-ferroelectric polymers. A saturation polarization of 44 mC m(?2) was found for an electric field of 190 MV m(?1).
The synthesis of chiral nanoporous carbons based on chiral ionic liquids (CILs) of amino acids as precursors is described. Such unique precursors for the carbonization of CILs yield chiral carbonaceous materials with high surface area (approximate to 620 m(2) g(-1)). The enantioselectivities of the porous carbons are examined by advanced techniques such as selective adsorption of enantiomers using cyclic voltammetry, isothermal titration calorimetry, and mass spectrometry. These techniques demonstrate the chiral nature and high enantioselectivity of the chiral carbon materials. Overall, we believe that the novel approach presented here can contribute significantly to the development of new chiral carbon materials that will find important applications in chiral chemistry, such as in chiral catalysis and separation and in chiral sensors. From a scientific point of view, the approach and results reported here can significantly deepen our understanding of chirality at the nanoscale and of the structure and nature of chiral nonporous materials and surfaces.
Deformation associated with plate convergence at subduction zones is accommodated by a complex system involving fault slip and viscoelastic flow. These processes have proven difficult to disentangle. The 2010 M-w 8.8 Maule earthquake occurred close to the Chilean coast within a dense network of continuously recording Global Positioning System stations, which provide a comprehensive history of surface strain. We use these data to assemble a detailed picture of a structurally controlled megathrust fault frictional patchwork and the three-dimensional rheological and time-dependent viscosity structure of the lower crust and upper mantle, all of which control the relative importance of afterslip and viscoelastic relaxation during postseismic deformation. These results enhance our understanding of subduction dynamics including the interplay of localized and distributed deformation during the subduction zone earthquake cycle.
In this report, we illustrate the considerable impact of researcher degrees of freedom with respect to exclusion of participants in paradigms with a learning element. We illustrate this empirically through case examples from human fear conditioning research, in which the exclusion of ‘non-learners’ and ‘non-responders’ is common – despite a lack of consensus on how to define these groups. We illustrate the substantial heterogeneity in exclusion criteria identified in a systematic literature search and highlight the potential problems and pitfalls of different definitions through case examples based on re-analyses of existing data sets. On the basis of these studies, we propose a consensus on evidence-based rather than idiosyncratic criteria, including clear guidelines on reporting details. Taken together, we illustrate how flexibility in data collection and analysis can be avoided, which will benefit the robustness and replicability of research findings and can be expected to be applicable to other fields of research that involve a learning element.
Farber disease is a rare lysosomal storage disorder resulting from acid ceramidase deficiency and subsequent ceramide accumulation. No treatments for Farber disease are clinically available, and affected patients have a severely shortened lifespan. We have recently reported a novel acid ceramidase deficiency model that mirrors the human disease closely. Acid sphingomyelinase is the enzyme that generates ceramide upstream of acid ceramidase in the lysosomes. Using our acid ceramidase deficiency model, we tested if acid sphingomyelinase could be a potential novel therapeutic target for the treatment of Farber disease. A number of functional acid sphingomyelinase inhibitors are clinically available and have been used for decades to treat major depression. Using these as a therapeutic for Farber disease, thus, has the potential to improve central nervous symptoms of the disease as well, something all other treatment options for Farber disease can’t achieve so far. As a proof-of-concept study, we first cross-bred acid ceramidase deficient mice with acid sphingomyelinase deficient mice in order to prevent ceramide accumulation. Double-deficient mice had reduced ceramide accumulation, fewer disease manifestations, and prolonged survival. We next targeted acid sphingomyelinase pharmacologically, to test if these findings would translate to a setting with clinical applicability. Surprisingly, the treatment of acid ceramidase deficient mice with the acid sphingomyelinase inhibitor amitriptyline was toxic to acid ceramidase deficient mice and killed them within a few days of treatment. In conclusion, our study provides the first proof-of-concept that acid sphingomyelinase could be a potential new therapeutic target for Farber disease to reduce disease manifestations and prolong survival. However, we also identified previously unknown toxicity of the functional acid sphingomyelinase inhibitor amitriptyline in the context of Farber disease, strongly cautioning against the use of this substance class for Farber disease patients.
Nature-based solutions (NBS) have recently received attention due to their potential ability to sustainably reduce hydro-meteorological risks, providing co-benefits for both ecosystems and affected people. Therefore, pioneering research has dedicated efforts to optimize the design of NBS, to evaluate their wider co-benefits and to understand promoting and/or hampering governance conditions for the uptake of NBS. In this article, we aim to complement this research by conducting a comprehensive literature review of factors shaping people’s perceptions of NBS as a means to reduce hydro-meteorological risks. Based on 102 studies, we identified six topics shaping the current discussion in this field of research: (1) valuation of the co-benefits (including those related to ecosystems and society); (2) evaluation of risk reduction efficacy; (3) stakeholder participation; (4) socio-economic and location-specific conditions; (5) environmental attitude, and (6) uncertainty. Our analysis reveals that concerned empirical insights are diverse and even contradictory, they vary in the depth of the insights generated and are often not comparable for a lack of a sound theoretical-methodological grounding. We, therefore, propose a conceptual model outlining avenues for future research by indicating potential inter-linkages between constructs underlying perceptions of NBS to hydro-meteorological risks.
The movement of microswimmers is often described by active Brownian particle models. Here we introduce a variant of these models with several internal states of the swimmer to describe stochastic strategies for directional swimming such as run and tumble or run and reverse that are used by microorganisms for chemotaxis. The model includes a mechanism to generate a directional bias for chemotaxis and interactions with external fields (e.g., gravity, magnetic field, fluid flow) that impose forces or torques on the swimmer. We show how this modified model can be applied to various scenarios: First, the run and tumble motion of E. coli is used to establish a paradigm for chemotaxis and investigate how it is affected by external forces. Then, we study magneto-aerotaxis in magnetotactic bacteria, which is biased not only by an oxygen gradient towards a preferred concentration, but also by magnetic fields, which exert a torque on an intracellular chain of magnets. We study the competition of magnetic alignment with active reorientation and show that the magnetic orientation can improve chemotaxis and thereby provide an advantage to the bacteria, even at rather large inclination angles of the magnetic field relative to the oxygen gradient, a case reminiscent of what is expected for the bacteria at or close to the equator. The highest gain in chemotactic velocity is obtained for run and tumble with a magnetic field parallel to the gradient, but in general a mechanism for reverse motion is necessary to swim against the magnetic field and a run and reverse strategy is more advantageous in the presence of a magnetic torque. This finding is consistent with observations that the dominant mode of directional changes in magnetotactic bacteria is reversal rather than tumbles. Moreover, it provides guidance for the design of future magnetic biohybrid swimmers. Author summary In this paper, we propose a modified Active Brownian particle model to describe bacterial swimming behavior under the influence of external forces and torques, in particular of a magnetic torque. This type of interaction is particularly important for magnetic biohybrids (i.e. motile bacteria coupled to a synthetic magnetic component) and for magnetotactic bacteria (i.e. bacteria with a natural intracellular magnetic chain), which perform chemotaxis to swim along chemical gradients, but are also directed by an external magnetic field. The model allows us to investigate the benefits and disadvantages of such coupling between two different directionality mechanisms. In particular we show that the magnetic torque can speed chemotaxis up in some conditions, while it can hinder it in other cases. In addition to an understanding of the swimming strategies of naturally magnetotactic organisms, the results may guide the design of future biomedical devices.
Intolerance to lactose or fructose is frequently diagnosed in children with chronic abdominal pain (CAP). However, the causal relationship remains a matter of discussion. A cohort of 253 patients, aged 7-12 years, presenting with unexplained CAP received standardized diagnostics. Additional diagnostic tests were performed based on their medical history and physical and laboratory investigations. Fructose and lactose hydrogen breath tests (H2BT) as well as empiric diagnostic elimination diets were performed in 135 patients reporting abdominal pain related to the consumption of lactose or fructose to evaluate carbohydrate intolerance as a potential cause of CAP. Carbohydrate malabsorption by H2BT was found in 55 (41%) out of 135 patients. An abnormal increase in H2BT was revealed in 30% (35/118) of patients after fructose consumption and in 18% (20/114) of patients after lactose administration. Forty-six percent (25/54) reported pain relief during a diagnostic elimination diet. In total, 17 patients had lactose malabsorption, 29 fructose malabsorption, and nine combined carbohydrate malabsorption. Carbohydrate intolerance as a cause of CAP was diagnosed at follow-up in only 18% (10/55) of patients with malabsorption after the elimination of the respective carbohydrate. Thus, carbohydrate malabsorption appears to be an incidental finding in children with functional abdominal pain disorders, rather than its cause. Therefore, testing of carbohydrate intolerance should only be considered in children with a strong clinical suspicion and with the goal to prevent long-term unnecessary dietary restrictions in children suffering from CAP.
Molecularly imprinted polymers (MIPs) mimic the binding sites of antibodies by substituting the amino acid-scaffold of proteins by synthetic polymers. In this work, the first MIP for the recognition of the diagnostically relevant enzyme butyrylcholinesterase (BuChE) is presented. The MIP was prepared using electropolymerization of the functional monomer o-phenylenediamine and was deposited as a thin film on a glassy carbon electrode by oxidative potentiodynamic polymerization. Rebinding and removal of the template were detected by cyclic voltammetry using ferricyanide as a redox marker. Furthermore, the enzymatic activity of BuChE rebound to the MIP was measured via the anodic oxidation of thiocholine, the reaction product of butyrylthiocholine. The response was linear between 50 pM and 2 nM concentrations of BuChE with a detection limit of 14.7 pM. In addition to the high sensitivity for BuChE, the sensor responded towards pseudo-irreversible inhibitors in the lower mM range.
Anti-Consumption
(2019)
Transcending the conventional debate around efficiency in sustainable consumption, anti-consumption patterns leading to decreased levels of material consumption have been gaining importance. Change agents are crucial for the promotion of such patterns, so there may be lessons for governance interventions that can be learnt from the every-day experiences of those who actively implement and promote sustainability in the field of anti-consumption. Eighteen social innovation pioneers, who engage in and diffuse practices of voluntary simplicity and collaborative consumption as sustainable options of anti-consumption share their knowledge and personal insights in expert interviews for this research. Our qualitative content analysis reveals drivers, barriers, and governance strategies to strengthen anti-consumption patterns, which are negotiated between the market, the state, and civil society. Recommendations derived from the interviews concern entrepreneurship, municipal infrastructures in support of local grassroots projects, regulative policy measures, more positive communication to strengthen the visibility of initiatives and emphasize individual benefits, establishing a sense of community, anti-consumer activism, and education. We argue for complementary action between top-down strategies, bottom-up initiatives, corporate activities, and consumer behavior. The results are valuable to researchers, activists, marketers, and policymakers who seek to enhance their understanding of materially reduced consumption patterns based on the real-life experiences of active pioneers in the field.
Melancholia
(2019)
Recent discovery of oxic methane production in sea and lake waters, as well as wetlands, demands re-thinking of the global methane cycle and re-assessment of the contribution of oxic waters to atmospheric methane emission. Here we analysed system-wide sources and sinks of surface-water methane in a temperate lake. Using a mass balance analysis, we show that internal methane production in well-oxygenated surface water is an important source for surface-water methane during the stratified period. Combining our results and literature reports, oxic methane contribution to emission follows a predictive function of littoral sediment area and surface mixed layer volume. The contribution of oxic methane source(s) is predicted to increase with lake size, accounting for the majority (>50%) of surface methane emission for lakes with surface areas >1 km(2).