Gold Open-Access
Refine
Year of publication
- 2017 (52) (remove)
Document Type
- Article (45)
- Other (2)
- Postprint (2)
- Review (2)
- Master's Thesis (1)
Keywords
- Bergbau (2)
- EDTA (2)
- Myodes glareolus (2)
- NTA (2)
- Puumala virus seroprevalence (2)
- Reisetagebücher (2)
- Sklaverei (2)
- biomimetic mineralization (2)
- biomineralization (2)
- brushite (2)
Institute
- Institut für Biochemie und Biologie (16)
- Institut für Romanistik (10)
- Institut für Geowissenschaften (7)
- Institut für Ernährungswissenschaft (3)
- Institut für Physik und Astronomie (3)
- Institut für Umweltwissenschaften und Geographie (3)
- Department Sport- und Gesundheitswissenschaften (2)
- Department Erziehungswissenschaft (1)
- Institut für Chemie (1)
- Institut für Mathematik (1)
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.
Molecules often fragment after photoionization in the gas phase. Usually, this process can only be investigated spectroscopically as long as there exists electron correlation between the photofragments. Important parameters, like their kinetic energy after separation, cannot be investigated. We are reporting on a femtosecond time-resolved Auger electron spectroscopy study concerning the photofragmentation dynamics of thymine. We observe the appearance of clearly distinguishable signatures from thymines neutral photofragment isocyanic acid. Furthermore, we observe a time-dependent shift of its spectrum, which we can attribute to the influence of the charged fragment on the Auger electron. This allows us to map our time-dependent dataset onto the fragmentation coordinate. The time dependence of the shift supports efficient transformation of the excess energy gained from photoionization into kinetic energy of the fragments. Our method is broadly applicable to the investigation of photofragmentation processes.
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.
Broad-spectrum antibiotic combination therapy is frequently applied due to increasing resistance development of infective pathogens. The objective of the present study was to evaluate two common empiric broad-spectrum combination therapies consisting of either linezolid (LZD) or vancomycin (VAN) combined with meropenem (MER) against Staphylococcus aureus (S. aureus) as the most frequent causative pathogen of severe infections. A semimechanistic pharmacokinetic-pharmacodynamic (PK-PD) model mimicking a simplified bacterial life-cycle of S. aureus was developed upon time-kill curve data to describe the effects of LZD, VAN, and MER alone and in dual combinations. The PK-PD model was successfully (i) evaluated with external data from two clinical S. aureus isolates and further drug combinations and (ii) challenged to predict common clinical PK-PD indices and breakpoints. Finally, clinical trial simulations were performed that revealed that the combination of VAN-MER might be favorable over LZD-MER due to an unfavorable antagonistic interaction between LZD and MER.
ecoAO
(2017)
Although aldehyde oxidase (AO) is an important hepatic drug-metabolizing enzyme, it remains understudied and is consequently often overlooked in preclinical studies, an oversight that has resulted in the failure of multiple clinical trials. AO’s preclusion to investigation stems from the following: (1) difficulties synthesizing metabolic standards due to the chemospecificity and regiospecificity of the enzyme and (2) significant inherent variability across existing in vitro systems including liver cytosol, S9 fractions, and primary hepatocytes, which lack specificity and generate discordant expression and activity profiles. Here, we describe a practical bacterial biotransformation system, ecoAO, addressing both issues simultaneously. ecoAO is a cell paste of MoCo-producing Escherichia coli strain TP1017 expressing human AO. It exhibits specific activity toward known substrates, zoniporide, 4-trans-(N,N-dimethylamino)cinnamaldehyde, O6-benzylguanine, and zaleplon; it also has utility as a biocatalyst, yielding milligram quantities of synthetically challenging metabolite standards such as 2-oxo-zoniporide. Moreover, ecoAO enables routine determination of kcat and V/K, which are essential parameters for accurate in vivo clearance predictions. Furthermore, ecoAO has potential as a preclinical in vitro screening tool for AO activity, as demonstrated by its metabolism of 3-aminoquinoline, a previously uncharacterized substrate. ecoAO promises to provide easy access to metabolites with the potential to improve pharmacokinetic clearance predictions and guide drug development.
Objectives: Postural control in elderly people is impaired by degradations of sensory, motor, and higher-level adaptive mechanisms. Here, we characterize the effects of a progressive balance training programon these postural control impairments using a brain network model based on system identification techniques. Methods and Material: We analyzed postural control of 35 healthy elderly subjects and compared findings to data from 35 healthy young volunteers. Eighteen elderly subjects performed a 10 week balance training conducted twice per week. Balance training was carried out in static and dynamic movement states, on support surfaces with different elastic compliances, under different visual conditions and motor tasks. Postural control was characterized by spontaneous sway and postural reactions to pseudorandom anterior-posterior tilts of the support surface. Data were interpreted using a parameter identification procedure based on a brain network model. Conclusion: Balance training reduced overactive proprioceptive feedback and restored vestibular orientation in elderly. Based on the assumption of a linear deterioration of postural control across the life span, the training effect can be extrapolated as a juvenescence of 10 years. This study points to a considerable benefit of a continuous balance training in elderly, even without any sensorimotor deficits.
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.
The invasion success of the cyanobacterium Cylindrospermopsis raciborskii in experimental mesocosms
(2017)
The potentially toxic, invasive cyanobacterium Cylindrospermopsis raciborskii, originating from sub-tropical regions, has spread into temperate climate zones in almost all continents. Potential factors in its success are temperature, light and nutrient levels. Grazing losses through zooplankton have been measured in the laboratory but are typically not regarded as a factor in (failed) invasion success. In some potentially suitable lakes, C. raciborskii has never been found, although it is present in water bodies close by. Therefore, we tested the invasive potential of three different isolates introduced into natural plankton communities using laboratory mesocosm experiments under three grazing levels: ambient zooplankton densities, removal of large species using 100 mu m mesh and a ca. doubling of large species. Three C. raciborskii isolates originating from the same geographic region (North-East Germany) were added separately to the four replicates of each treatment and kept in semi-continuous cultures for 21 days. Two isolates disappeared from the mesocosms and were also not viable in filtered lake water indicating that the lake water itself or the switch from culture medium to lake water led to the decay of the inoculated C. raciborskii. Only one out of the three isolates persisted in the plankton communities at a rather low level and only in the treatment without larger zooplankton. This result demonstrates that under potentially suitable environmental conditions, top-down control from zooplankton might hamper the establishment of C. raciborskii. Non-metric multidimensional scaling showed distinct variation in resident phytoplankton communities between the different grazing levels, thus differential grazing impact shaped the resident community in different ways allowing C. raciborskii only to invade under competitive (= low grazing pressure) conditions. Furthermore, even after invasion failure, the temporary presence of C. raciborskii influenced the phytoplankton community.
Background. Metal recycling factories (MRFs) have developed rapidly in Nigeria as recycling policies have been increasingly embraced. These MRFs are point sources for introducing potentially toxic elements (PTEs) into environmental media. Objectives. The aim of this study was to determine the constituents (elemental and mineralogy) of the wastes (slag and particulate matter, (PM)) and soils around the MRFs and to determine the level of pollution within the area. Methods. Sixty samples (30 slag samples, 15 soil samples and 15 PM samples) were collected for this study. The soils, slag and PM samples were analyzed for elemental constituents using inductively coupled plasma optical emission spectrometry. Mineralogy of the PM was determined using scanning electron microscope-energy dispersive spectroscopy (SEM-EDS), and soil mineralogy was determined by an X-ray diffractometer (XRD). Results. The results of the soil analyses revealed the following concentrations for the selected metals in mg/kg include lead (Pb) (21.0-2399.0), zinc (Zn) (56.0-4188.0), copper (Cu) (10.0-1470.0), nickel (Ni) (6.0-215.0), chromium (Cr) (921.0-1737.0) and cadmium (Cd) (below detectable limit (Bdl)-18.1). For the slags the results were Pb (68.0-.333.0), Zn (1364.0-3062), Cu (119.0-1470.0), Ni (12.0-675.0), Cr (297-1737) and Cd (Bdl-15.8). The results in mu g/g for the metal analysis in PM were Pb (4.6-160.0), Zn (18.0-471.0), Cu (2.5-11.0), Ni (0.8-4.2), and Cr (2.5-11.0), while Cd was undetected. The slags are currently utilized for filling the foundations of buildings and roads, providing additional pathways for the introduction of PTEs into the environment from the suspended materials generated from mechanical breakdown of the slags. Conclusions. The MRFs were found to have impacted the quality of environmental media through the introduction of PTEs, impairing soil quality, in addition to PM, which can have detrimental health consequences. Further studies on the health implications of these pollutants and their impacts on human health are needed. Competing Interests. The authors declare no competing financial interests
DPP4 inhibition prevents AKI
(2017)
Lutein is an essential dietary carotenoid with health benefits and is inter alia responsible for the colouration of egg yolk. The relationship between lutein accumulation and egg yolk colouration was therefore studied in more detail. After feeding a low-luteine diet for 21 days, 14 birds (Lohmann brown hens aged 20 weeks) were fed a diet containing marigold (80 mg lutein/kg feed) and 14 other birds were fed a diet containing oleoresin (45 mg lutein/kg feed) for 21 days; for both groups of birds, this feeding period was followed by withdrawal for 21 days. The Roche Yolk Colour Fan (RYCF) score (0 to 15, where higher values denote greater colour intensity; R-2=0.87; P<0.01) and redness (R-2=0.89; P<0.01) increased with increasing lutein content of egg yolk. Total carotenoid content had a poor relationship with lightness (R-2=0.13; P>0.05) and yellowness (R-2=0.12; P>0.05) of the yolk. It may be concluded that increased lutein is potentially responsible for an increased RYCF score and redness (a*), but decreased yellowness (b*) and lightness (L*), of egg yolk.
Improving society's ability to prepare for, respond to and recover from flooding requires integrated, anticipatory flood risk management (FRM). However, most countries still focus their efforts on responding to flooding events if and when they occur rather than addressing their current and future vulnerability to flooding. Flood insurance is one mechanism that could promote a more ex ante approach to risk by supporting risk reduction activities. This paper uses an adapted version of Easton's System Theory to investigate the role of insurance for FRM in Germany and England. We introduce an anticipatory FRM framework, which allows flood insurance to be considered as part of a broader policy field. We analyze if and how flood insurance can catalyze a change toward a more anticipatory approach to FRM. In particular we consider insurance's role in influencing five key components of anticipatory FRM: risk knowledge, prevention through better planning, property‐level protection measures, structural protection and preparedness (for response). We find that in both countries FRM is still a reactive, event‐driven process, while anticipatory FRM remains underdeveloped. Collaboration between insurers and FRM decision‐makers has already been successful, for example in improving risk knowledge and awareness, while in other areas insurance acts as a disincentive for more risk reduction action. In both countries there is evidence that insurance can play a significant role in encouraging anticipatory FRM, but this remains underutilized. Effective collaboration between insurers and government should not be seen as a cost, but as an investment to secure future insurability through flood resilience.
Adaptation to flood risk
(2017)
As flood impacts are increasing in large parts of the world, understanding the primary drivers of changes in risk is essential for effective adaptation. To gain more knowledge on the basis of empirical case studies, we analyze eight paired floods, that is, consecutive flood events that occurred in the same region, with the second flood causing significantly lower damage. These success stories of risk reduction were selected across different socioeconomic and hydro-climatic contexts. The potential of societies to adapt is uncovered by describing triggered societal changes, as well as formal measures and spontaneous processes that reduced flood risk. This novel approach has the potential to build the basis for an international data collection and analysis effort to better understand and attribute changes in risk due to hydrological extremes in the framework of the IAHSs Panta Rhei initiative. Across all case studies, we find that lower damage caused by the second event was mainly due to significant reductions in vulnerability, for example, via raised risk awareness, preparedness, and improvements of organizational emergency management. Thus, vulnerability reduction plays an essential role for successful adaptation. Our work shows that there is a high potential to adapt, but there remains the challenge to stimulate measures that reduce vulnerability and risk in periods in which extreme events do not occur.
Bacteria swim in sequences of straight runs that are interrupted by turning events. They drive their swimming locomotion with the help of rotating helical flagella. Depending on the number of flagella and their arrangement across the cell body, different run-and-turn patterns can be observed. Here, we present fluorescence microscopy recordings showing that cells of the soil bacterium Pseudomonas putida that are decorated with a polar tuft of helical flagella, can alternate between two distinct swimming patterns. On the one hand, they can undergo a classical push-pull-push cycle that is well known from monopolarly flagellated bacteria but has not been reported for species with a polar bundle of multiple flagella. Alternatively, upon leaving the pulling mode, they can enter a third slow swimming phase, where they propel themselves with their helical bundle wrapped around the cell body. A theoretical estimate based on a random-walk model shows that the spreading of a population of swimmers is strongly enhanced when cycling through a sequence of pushing, pulling, and wrapped flagellar configurations as compared to the simple push-pull-push pattern.
A substantial amount of research has revealed that cyberbully-victims have more emotional and behavioral problems than either cyberbullying victims or perpetrators. However, until now, little research has been conducted into the factors that contribute to the interplay between cyberbullying victimization and perpetration. The purpose of this study was to examine the relationship between cyberbullying victimization, perpetration, and two emotional components of alexithymia, namely difficulties in identifying and describing one's own feelings. Self-report questions were administered to 1549 adolescents between 12 and 18 years old (M = 14.51; SD = 1.68; 42.1% (n = 652) male) from Germany and Thailand. Results showed that cyberbullying victimization and alexithymia are associated with cyberbullying perpetration. Moreover, alexithymia mediated the associations between cyberbullying victimization and adolescents' cyberbullying perpetration. Consequently, we suggest that the ability to describe and identify one's own feelings might be important for understanding the link between cyberbullying, victimization, and perpetration. The results may help develop prevention and intervention programs focused on reducing cyberbullying.
Ecosystem boundaries, such as the Arctic-Boreal treeline, are strongly coupled with climate and were spatially highly dynamic during past glacial-interglacial cycles. Only a few studies cover vegetation changes since the last interglacial, as most of the former landscapes are inundated and difficult to access. Using pollen analysis and sedimentary ancient DNA (sedaDNA) metabarcoding, we reveal vegetation changes on Bol’shoy Lyakhovsky Island since the last interglacial from permafrost sediments. Last interglacial samples depict high levels of floral diversity with the presence of trees (Larix, Picea, Populus) and shrubs (Alnus, Betula, Ribes, Cornus, Saliceae) on the currently treeless island. After the Last Glacial Maximum, Larix re-colonised the island but disappeared along with most shrub taxa. This was probably caused by Holocene sea-level rise, which led to increased oceanic conditions on the island. Additionally, we applied two newly developed larch-specific chloroplast markers to evaluate their potential for tracking past population dynamics from environmental samples. The novel markers were successfully re-sequenced and exhibited two variants of each marker in last interglacial samples. SedaDNA can track vegetation changes as well as genetic changes across geographic space through time and can improve our understanding of past processes that shape modern patterns.
The SusKat-ABC (Sustainable Atmosphere for the Kathmandu Valley-Atmospheric Brown Clouds) international air pollution measurement campaign was carried out from December 2012 to June 2013 in the Kathmandu Valley and surrounding regions in Nepal. The Kathmandu Valley is a bowl-shaped basin with a severe air pollution problem. This paper reports measurements of two major greenhouse gases (GHGs), methane (CH4) and carbon dioxide (CO2), along with the pollutant CO, that began during the campaign and were extended for 1 year at the SusKat-ABC supersite in Bode, a semi-urban location in the Kathmandu Valley. Simultaneous measurements were also made during 2015 in Bode and a nearby rural site (Chanban) similar to 25 km (aerial distance) to the southwest of Bode on the other side of a tall ridge. The ambient mixing ratios of methane (CH4), carbon dioxide (CO2), water vapor, and carbon monoxide (CO) were measured with a cavity ring-down spectrometer (G2401; Picarro, USA) along with meteorological parameters for 1 year (March 2013-March 2014). These measurements are the first of their kind in the central Himalayan foothills. At Bode, the annual average mixing ratios of CO2 and CH4 were 419.3 (+/- 6.0) ppm and 2.192 (+/- 0.066) ppm, respectively. These values are higher than the levels observed at background sites such as Mauna Loa, USA (CO2: 396.8 +/- 2.0 ppm, CH4: 1.831 +/- 0.110 ppm) and Waliguan, China (CO2: 397.7 +/- 3.6 ppm, CH4: 1.879 +/- 0.009 ppm) during the same period and at other urban and semi-urban sites in the region, such as Ahmedabad and Shadnagar (India). They varied slightly across the seasons at Bode, with seasonal average CH4 mixing ratios of 2.157 (+/- 0.230) ppm in the pre-monsoon season, 2.199 (+/- 0.241) ppm in the monsoon, 2.210 (+/- 0.200) ppm in the post-monsoon, and 2.214 (+/- 0.209) ppm in the winter season. The average CO2 mixing ratios were 426.2 (+/- 25.5) ppm in the pre-monsoon, 413.5 (+/- 24.2) ppm in the monsoon, 417.3 (+/- 23.1) ppm in the postmonsoon, and 421.9 (+/- 20.3) ppm in the winter season. The maximum seasonal mean mixing ratio of CH4 in winter was only 0.057 ppm or 2.6% higher than the seasonal minimum during the pre-monsoon period, while CO2 was 12.8 ppm or 3.1% higher during the pre-monsoon period (seasonal maximum) than during the monsoon (seasonal minimum). On the other hand, the CO mixing ratio at Bode was 191% higher during the winter than during the monsoon season. The enhancement in CO2 mixing ratios during the pre-monsoon season is associated with additional CO2 emissions from forest fires and agro-residue burning in northern South Asia in addition to local emissions in the Kathmandu Valley. Published CO = CO2 ratios of different emission sources in Nepal and India were compared with the observed CO = CO2 ratios in this study. This comparison suggested that the major sources in the Kathmandu Valley were residential cooking and vehicle exhaust in all seasons except winter. In winter, brick kiln emissions were a major source. Simultaneous measurements in Bode and Chanban (15 July-3 October 2015) revealed that the mixing ratios of CO2, CH4, and CO were 3.8, 12, and 64% higher in Bode than Chanban. The Kathmandu Valley thus has significant emissions from local sources, which can also be attributed to its bowl-shaped geography that is conducive to pollution build-up. At Bode, all three gas species (CO2, CH4, and CO) showed strong diurnal patterns in their mixing ratios with a pronounced morning peak (ca. 08:00), a dip in the afternoon, and a gradual increase again through the night until the next morning. CH4 and CO at Chanban, however, did not show any noticeable diurnal variations. These measurements provide the first insights into the diurnal and seasonal variation in key greenhouse gases and air pollutants and their local and regional sources, which is important information for atmospheric research in the region.
Feigning Democracy
(2017)
Reducing Emissions from Deforestation and forest Degradation plus the sustainable management of forest and enhancement of carbon stocks (REDD+) is a global climate change mitigation initiative. The United Nations REDD Programme (UN-REDD) is training governments in developing countries, including Nigeria, to implement REDD+. To protect local people, UN-REDD has developed social safeguards including a commitment to strengthen local democracy to prevent an elite capture of REDD+ benefits. This study examines local participation and representation in the UN-REDD international policy board and in the national-level design process for the Nigeria-REDD proposal, to see if practices are congruent with the UN-REDD commitment to local democracy. It is based on research in Nigeria in 2012 and 2013, and finds that local representation in the UN-REDD policy board and in Nigeria-REDD is not substantive. Participation is merely symbolic. For example, elected local government authorities, who ostensibly represent rural people, are neither present in the UN-REDD board nor were they invited to the participatory forums that vetted the Nigeria-REDD. They were excluded because they were politically weak. However, UN-REDD approved the Nigeria-REDD proposal without a strategy to include or strengthen elected local governments. The study concludes with recommendations to help the UN-REDD strengthen elected local government authority in Nigeria in support of democratic local representation.
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.
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.