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Strong experimental evidence in animal and cellular models supports a pivotal role of sphingosine kinase-1 (SK1) in oncogenesis. In many human cancers, SK1 levels are upregulated and these increases are linked to poor prognosis in patients. Here, by employing untargeted NMR- based metabolomic profiling combined with functional validations, we report the crucial role of SK1 in the metabolic shift known as the Warburg effect in A2780 ovarian cancer cells. Indeed, expression of SK1 induced a high glycolytic rate, characterized by increased levels of lactate along with increased expression of the proton/monocarboxylate symporter MCT1, and decreased oxidative metabolism, associated with the accumulation of intermediates of the tricarboxylic acid cycle and reduction in CO2 production. Additionally, SK1-expressing cells displayed a significant increase in glucose uptake paralleled by GLUT3 transporter upregulation. The role of SK1 is not limited to the induction of aerobic glycolysis, affecting metabolic pathways that appear to support the biosynthesis of macromolecules. These findings highlight the role of SK1 signaling axis in cancer metabolic reprogramming, pointing out innovative strategies for cancer therapies.
Epigenetic maintenance of gene repression is essential for development. Polycomb complexes are central to this memory, but many aspects of the underlying mechanism remain unclear. LIKE HETEROCHROMATIN PROTEIN 1 (LHP1) binds Polycomb-deposited H3K27me3 and is required for repression of many Polycomb target genes in Arabidopsis. Here we show that LHP1 binds RNA in vitro through the intrinsically disordered hinge region. By independently perturbing the RNA-binding hinge region and H3K27me3 (trimethylation of histone H3 at Lys27) recognition, we found that both facilitate LHP1 localization and H3K27me3 maintenance. Disruption of the RNAbinding hinge region also prevented formation of subnuclear foci, structures potentially important for epigenetic repression.
Plant functional traits reflect individual and community ecological strategies. They allow the detection of directional changes in community dynamics and ecosystemic processes, being an additional tool to assess biodiversity than species richness. Analysis of functional patterns in plant communities provides mechanistic insight into biodiversity alterations due to anthropogenic activity. Although studies have consi-dered of either anthropogenic management or nutrient availability on functional traits in temperate grasslands, studies combining effects of both drivers are scarce. Here, we assessed the impacts of management intensity (fertilization, mowing, grazing), nutrient stoichiometry (C, N, P, K), and vegetation composition on community-weighted means (CWMs) and functional diversity (Rao's Q) from seven plant traits in 150 grasslands in three regions in Germany, using data of 6 years. Land use and nutrient stoichiometry accounted for larger proportions of model variance of CWM and Rao's Q than species richness and productivity. Grazing affected all analyzed trait groups; fertilization and mowing only impacted generative traits. Grazing was clearly associated with nutrient retention strategies, that is, investing in durable structures and production of fewer, less variable seed. Phenological variability was increased. Fertilization and mowing decreased seed number/mass variability, indicating competition-related effects. Impacts of nutrient stoichiometry on trait syndromes varied. Nutrient limitation (large N:P, C:N ratios) promoted species with conservative strategies, that is, investment in durable plant structures rather than fast growth, fewer seed, and delayed flowering onset. In contrast to seed mass, leaf-economics variability was reduced under P shortage. Species diversity was positively associated with the variability of generative traits. Synthesis. Here, land use, nutrient availability, species richness, and plant functional strategies have been shown to interact complexly, driving community composition, and vegetation responses to management intensity. We suggest that deeper understanding of underlying mechanisms shaping community assembly and biodiversity will require analyzing all these parameters.
Alexander von Humboldt war in Polen bereits im ausgehenden 18. Jahrhundert berühmt geworden. Er reiste mehrmals nach Polen und unterhielt Kontakte zu polnischen oder polnischstämmigen Wissenschaftlern. Aus den 30er und 40er Jahren stammen die meisten schriftlichen Belege, die von Beziehungen Humboldts zu solchen Persönlichkeiten wie Ludwik Zejszner, Józef Waraszkiewicz oder Filip Neryusz Walter zeugen. Nicht nachweisbar ist heute dafür Humboldts Kontakt zu Wincenty Pol sowie zu Ignacy Domeyko. Humboldt inspiriert nicht nur polnische Wissenschaftler, sondern auch führende polnische Dichter der Romantik. Viele polnische Exilanten verdanken dem deutschen Gelehrten wertvolle Kontakte, Empfehlungsschreiben und Gesuche bei damaligen Machthabern.
Background: Severe bacterial infections remain a major challenge in intensive care units because of their high prevalence and mortality. Adequate antibiotic exposure has been associated with clinical success in critically ill patients. The objective of this study was to investigate the target attainment of standard meropenem dosing in a heterogeneous critically ill population, to quantify the impact of the full renal function spectrum on meropenem exposure and target attainment, and ultimately to translate the findings into a tool for practical application. Methods: A prospective observational single-centre study was performed with critically ill patients with severe infections receiving standard dosing of meropenem. Serial blood samples were drawn over 4 study days to determine meropenem serum concentrations. Renal function was assessed by creatinine clearance according to the Cockcroft and Gault equation (CLCRCG). Variability in meropenem serum concentrations was quantified at the middle and end of each monitored dosing interval. The attainment of two pharmacokinetic/pharmacodynamic targets (100% T->MIC, 50% T->4xMIC) was evaluated for minimum inhibitory concentration (MIC) values of 2 mg/L and 8 mg/L and standard meropenem dosing (1000 mg, 30-minute infusion, every 8 h). Furthermore, we assessed the impact of CLCRCG on meropenem concentrations and target attainment and developed a tool for risk assessment of target non-attainment. Results: Large inter-and intra-patient variability in meropenem concentrations was observed in the critically ill population (n = 48). Attainment of the target 100% T->MIC was merely 48.4% and 20.6%, given MIC values of 2 mg/L and 8 mg/L, respectively, and similar for the target 50% T->4xMIC. A hyperbolic relationship between CLCRCG (25-255 ml/minute) and meropenem serum concentrations at the end of the dosing interval (C-8h) was derived. For infections with pathogens of MIC 2 mg/L, mild renal impairment up to augmented renal function was identified as a risk factor for target non-attainment (for MIC 8 mg/L, additionally, moderate renal impairment). Conclusions: The investigated standard meropenem dosing regimen appeared to result in insufficient meropenem exposure in a considerable fraction of critically ill patients. An easy-and free-to-use tool (the MeroRisk Calculator) for assessing the risk of target non-attainment for a given renal function and MIC value was developed.
Sequelae of prematurity triggered by oxidative stress and free radical-mediated tissue damage have coined the term “oxygen radical disease of prematurity”. Caffeine, a potent free radical scavenger and adenosine receptor antagonist, reduces rates of brain damage in preterm infants. In the present study, we investigated the effects of caffeine on oxidative stress markers, anti-oxidative response, inflammation, redox-sensitive transcription factors, apoptosis, and extracellular matrix following the induction of hyperoxia in neonatal rats. The brain of a rat pups at postnatal Day 6 (P6) corresponds to that of a human fetal brain at 28–32 weeks gestation and the neonatal rat is an ideal model in which to investigate effects of oxidative stress and neuroprotection of caffeine on the developing brain. Six-day-old Wistar rats were pre-treated with caffeine and exposed to 80% oxygen for 24 and 48 h. Caffeine reduced oxidative stress marker (heme oxygenase-1, lipid peroxidation, hydrogen peroxide, and glutamate-cysteine ligase catalytic subunit (GCLC)), promoted anti-oxidative response (superoxide dismutase, peroxiredoxin 1, and sulfiredoxin 1), down-regulated pro-inflammatory cytokines, modulated redox-sensitive transcription factor expression (Nrf2/Keap1, and NFκB), reduced pro-apoptotic effectors (poly (ADP-ribose) polymerase-1 (PARP-1), apoptosis inducing factor (AIF), and caspase-3), and diminished extracellular matrix degeneration (matrix metalloproteinases (MMP) 2, and inhibitor of metalloproteinase (TIMP) 1/2). Our study affirms that caffeine is a pleiotropic neuroprotective drug in the developing brain due to its anti-oxidant, anti-inflammatory, and anti-apoptotic properties.
Background: In health research, indicators of socioeconomic status (SES) are often used interchangeably and often lack theoretical foundation. This makes it difficult to compare results from different studies and to explore the relationship between SES and health outcomes. To aid researchers in choosing appropriate indicators of SES, this article proposes and tests a theory-based selection of SES indicators using chronic back pain as a health outcome. Results: Chronic back pain intensity was best predicted by the multidimensional index (beta = 0.31, p < 0.05), followed by job position (beta = 0.29, p < 0.05) and education (beta = -0.29, p < 0.05); whereas, income exerted no significant influence. Back pain disability was predicted strongest by education (beta = -0.30, p < 0.05) and job position (beta = 0. 29, p < 0.05). Here, multidimensional index and income had no significant influence. Conclusions: The choice of SES indicators influences predictive power on both back pain dimensions, suggesting SES predictors cannot be used interchangeably. Therefore, researchers should carefully consider prior to each study which SES indicator to use. The introduced framework can be valuable in supporting this decision because it allows for a stable prediction of SES indicator influence and their hierarchy on a specific health outcomes.
Year-to-year variations in crop yields can have major impacts on the livelihoods of subsistence farmers and may trigger significant global price fluctuations, with severe consequences for people in developing countries. Fluctuations can be induced by weather conditions, management decisions, weeds, diseases, and pests. Although an explicit quantification and deeper understanding of weather-induced crop-yield variability is essential for adaptation strategies, so far it has only been addressed by empirical models. Here, we provide conservative estimates of the fraction of reported national yield variabilities that can be attributed to weather by state-of-the-art, process-based crop model simulations. We find that observed weather variations can explain more than 50% of the variability in wheat yields in Australia, Canada, Spain, Hungary, and Romania. For maize, weather sensitivities exceed 50% in seven countries, including the United States. The explained variance exceeds 50% for rice in Japan and South Korea and for soy in Argentina. Avoiding water stress by simulating yields assuming full irrigation shows that water limitation is a major driver of the observed variations in most of these countries. Identifying the mechanisms leading to crop-yield fluctuations is not only fundamental for dampening fluctuations, but is also important in the context of the debate on the attribution of loss and damage to climate change. Since process-based crop models not only account for weather influences on crop yields, but also provide options to represent human-management measures, they could become essential tools for differentiating these drivers, and for exploring options to reduce future yield fluctuations.
The Western honey bee (Apis mellifera) is widely used as commercial pollinator in worldwide agriculture and, therefore, plays an important role in global food security. Among the parasites and pathogens threatening health and survival of honey bees are two species of microsporidia, Nosema apis and Nosema ceranae. Nosema ceranae is considered an emerging pathogen of the Western honey bee. Reports on the spread of N. ceranae suggested that this presumably highly virulent species is replacing its more benign congener N. apis in the global A. mellifera population. We here present a 12 year longitudinal cohort study on the prevalence of N. apis and N. ceranae in Northeast Germany. Between 2005 and 2016, a cohort of about 230 honey bee colonies originating from 23 apiaries was sampled twice a year (spring and autumn) resulting in a total of 5,600 bee samples which were subjected to microscopic and molecular analysis for determining the presence of infections with N. apis or/and N. ceranae. Throughout the entire study period, both N. apis- and N. ceranae-infections could be diagnosed within the cohort. Logistic regression analysis of the prevalence data demonstrated a significant increase of N. ceranae-infections over the last 12 years, both in autumn (reflecting the development during the summer) and in spring (reflecting the development over winter) samples. Cell culture experiments confirmed that N. ceranae has a higher proliferative potential than N. apis at 27. and 33 degrees C potentially explaining the increase in N. ceranae prevalence during summer. In autumn, characterized by generally low infection prevalence, this increase was accompanied by a significant decrease in N. apis- infection prevalence. In contrast, in spring, the season with a higher prevalence of infection, no significant decrease of N. apis infections despite a significant increase in N. ceranae infections could be observed. Therefore, our data do not support a general advantage of N. ceranae over N. apis and an overall replacement of N. apis by N. ceranae in the studied honey bee population.
The final end of imagination
(2017)
One main quandary that emerges in the context of Immanuel Kant’s moral ideal, The Highest Good, is that on the one hand Kant sets it as a moral demand, that is, as a principle that must be comprehended as an attainable end for man in practice while, on the other hand, it is set as a moral ideal, i.e. as something that cannot be concretized and realized within the empirical world. The main goal of this paper is to argue for the realizability of the moral ideal by means of the principle of reflective judgment as a form of judgment that in fact clarifies human limitation. I assert that the very recognition of this limitation constitutes the possibility for hope in that ideal, or for striving towards it, and that this striving is the only way that the moral ideal can be concretized. I examine man’s recognition of self-limitation as a response to the moral demand to realize the moral ideal and the necessity of the power of imagination for this, used reflectively.