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Dermal Delivery of the High-Molecular-Weight Drug Tacrolimus by Means of Polyglycerol-Based Nanogels
(2019)
Polyglycerol-based thermoresponsive nanogels (tNGs) have been shown to have excellent skin hydration properties and to be valuable delivery systems for sustained release of drugs into skin. In this study, we compared the skin penetration of tacrolimus formulated in tNGs with a commercial 0.1% tacrolimus ointment. The penetration of the drug was investigated in ex vivo abdominal and breast skin, while different methods for skin barrier disruption were investigated to improve skin permeability or simulate inflammatory conditions with compromised skin barrier. The amount of penetrated tacrolimus was measured in skin extracts by liquid chromatography tandem-mass spectrometry (LC-MS/MS), whereas the inflammatory markers IL-6 and IL-8 were detected by enzyme-linked immunosorbent assay (ELISA). Higher amounts of tacrolimus penetrated in breast as compared to abdominal skin or in barrier-disrupted as compared to intact skin, confirming that the stratum corneum is the main barrier for tacrolimus skin penetration. The anti-proliferative effect of the penetrated drug was measured in skin tissue/Jurkat cells co-cultures. Interestingly, tNGs exhibited similar anti-proliferative effects as the 0.1% tacrolimus ointment. We conclude that polyglycerol-based nanogels represent an interesting alternative to paraffin-based formulations for the treatment of inflammatory skin conditions.
We extend the scope of European palaeogenomics by sequencing the genomes of Late Upper Palaeolithic (13,300 years old, 1.4-fold coverage) and Mesolithic (9,700 years old, 15.4-fold) males from western Georgia in the Caucasus and a Late Upper Palaeolithic (13,700 years old, 9.5-fold) male from Switzerland. While we detect Late Palaeolithic-Mesolithic genomic continuity in both regions, we find that Caucasus hunter-gatherers (CHG) belong to a distinct ancient clade that split from western hunter-gatherers similar to 45 kya, shortly after the expansion of anatomically modern humans into Europe and from the ancestors of Neolithic farmers similar to 25 kya, around the Last Glacial Maximum. CHG genomes significantly contributed to the Yamnaya steppe herders who migrated into Europe similar to 3,000 BC, supporting a formative Caucasus influence on this important Early Bronze age culture. CHG left their imprint on modern populations from the Caucasus and also central and south Asia possibly marking the arrival of Indo-Aryan languages.
Understanding heat transport in sedimentary basins requires an assessment of the regional 3D heat distribution and of the main physical mechanisms responsible for the transport of heat. We review results from different 3D numerical simulations of heat transport based on 3D basin models of the Central European Basin System (CEBS). Therefore we compare differently detailed 3D structural models of the area, previously published individually, to assess the influence of (1) different configurations of the deeper lithosphere, (2) the mechanism of heat transport considered and (3) large faults dissecting the sedimentary succession on the resulting thermal field and groundwater flow. Based on this comparison we propose a modelling strategy linking the regional and lithosphere-scale to the sub-basin and basin-fill scale and appropriately considering the effective heat transport processes. We find that conduction as the dominant mechanism of heat transport in sedimentary basins is controlled by the distribution of thermal conductivities, compositional and thickness variations of both the conductive and radiogenic crystalline crust as well as the insulating sediments and by variations in the depth to the thermal lithosphere-asthenosphere boundary. Variations of these factors cause thermal anomalies of specific wavelength and must be accounted for in regional thermal studies. In addition advective heat transport also exerts control on the thermal field on the regional scale. In contrast, convective heat transport and heat transport along faults is only locally important and needs to be considered for exploration on the reservoir scale. The general applicability of the proposed workflow makes it of interest for a broad range of application in geosciences including oil and gas exploration, geothermal utilization or carbon capture and sequestration issues. (C) 2014 Elsevier Ltd. All rights reserved.
The weather in Eurasia, Australia, and North and South America is largely controlled by the strength and position of extratropical storm tracks. Future climate change will likely affect these storm tracks and the associated transport of energy, momentum, and water vapour. Many recent studies have analyzed how storm tracks will change under climate change, and how these changes are related to atmospheric dynamics. However, there are still discrepancies between different studies on how storm tracks will change under future climate scenarios. Here, we show that under global warming the CMIP5 ensemble of coupled climate models projects only little relative changes in vertically averaged mid-latitude mean storm track activity during the northern winter, but agree in projecting a substantial decrease during summer. Seasonal changes in the Southern Hemisphere show the opposite behaviour, with an intensification in winter and no change during summer. These distinct seasonal changes in northern summer and southern winter storm tracks lead to an amplified seasonal cycle in a future climate. Similar changes are seen in the mid-latitude mean Eady growth rate maximum, a measure that combines changes in vertical shear and static stability based on baroclinic instability theory. Regression analysis between changes in the storm tracks and changes in the maximum Eady growth rate reveal that most models agree in a positive association between the two quantities over mid-latitude regions.
The Great Hungarian Plain was a crossroads of cultural transformations that have shaped European prehistory. Here we analyse a 5,000-year transect of human genomes, sampled from petrous bones giving consistently excellent endogenous DNA yields, from 13 Hungarian Neolithic, Copper, Bronze and Iron Age burials including two to high (similar to 22x) and seven to similar to 1x coverage, to investigate the impact of these on Europe's genetic landscape. These data suggest genomic shifts with the advent of the Neolithic, Bronze and Iron Ages, with interleaved periods of genome stability. The earliest Neolithic context genome shows a European hunter-gatherer genetic signature and a restricted ancestral population size, suggesting direct contact between cultures after the arrival of the first farmers into Europe. The latest, Iron Age, sample reveals an eastern genomic influence concordant with introduced Steppe burial rites. We observe transition towards lighter pigmentation and surprisingly, no Neolithic presence of lactase persistence.
1,4-Di(homo)allyl-2,5-diketopiperazines are synthesized and polymerized via ADMET using the Hoveyda-Grubbs 2nd generation catalyst. The but-3-enylated diketopiperazine can be converted into unsaturated tertiary polyamide with molar mass of <3000 g mol(-1), whereas the allylated diketopiperazine cannot. Double-bond isomerization occurs regardless of whether or not benzoquinone is present. A polyesteramide with a higher molar mass of ca. 4800 g mol(-1) is obtained by the alternating copolymerization (ALTMET) of 1,4-di(but-3-enyl)-2,5-di ketopiperazine and ethylene glycol diacrylate. A post-polymerization modification of the poly(ester)amides via radical thiol-ene chemistry, however, fails.
The mid- to late Holocene interval is characterised by a highly variable climate in response to a gradual change in orbital insolation. The seasonal impact of these changes on the Eifel Maar region is not yet well documented largely due to uncertainties about the completeness of this archive ("missing varves" in the well known Lake Holzmaar) and a limited understanding of the factors (e.g. temperature, precipitation) influencing the seasonality archived within the lamination/varves. In this study we approach these challenges from a different perspective. Using detailed microfacies investigations we: (1) demonstrate that the ambiguity about the "missing varves" is related to the climate induced complex biotic and abiotic laminations that led to mis-identification of varves; (2) use a combination of detailed microfacies investigations (varve structure, seasonality of biotic and abiotic signals), lamination quality, varve counts on multiple cores, published and new radiocarbon dates to develop a continuous master chronology based on the Bayesian modelling approach. The dates of major climate, volcanic, and archaeological event(s) determined using our model are in good agreement with the independently determined ages of the same events from other archives, confirming the accuracy of our age model; (3) test the sensitivity of the seasonal proxies to the available data on mid-Holocene changes in temperature and precipitation; (4) demonstrate that the changes in lake eutrophicity are correlative with temperature changes in NW Europe and probably triggered by solar variability; and (5) show that the early Iron Age onset of eutrophication in Lake Holzmaar was climate induced and began several decades before the impact of anthropogenic activity was seen in the form of intensified detrital erosion in the catchment area. Our work has implications for understanding the impact of climate change and anthropogenic activities on limnological systems. (C) 2014 Elsevier B.V. All rights reserved.
Two dimensional gas chromatography coupled to time-of-flight mass spectrometry (GCxGC-TOF-MS) is a promising technique to overcome limits of complex metabolome analysis using one dimensional GC-TOF-MS. Especially at the stage of data export and data mining, however, convenient procedures to cope with the complexity of GCxGC-TOF-MS data are still in development. Here, we present a high sample throughput protocol exploiting first and second retention index for spectral library search and subsequent construction of a high dimensional data matrix useful for statistical analysis. The method was applied to the analysis of 13 C-labelling experiments in the unicellular green alga Chlamydomonas reinhardtii. We developed a rapid sampling and extraction procedure for Chlamydomonas reinhardtii laboratory strain (CC503), a cell wall deficient mutant. By testing all published quenching protocols we observed dramatic metabolite leakage rates for certain metabolites. To circumvent metabolite leakage, samples were directly quenched and analyzed without separation of the medium. The growth medium was adapted to this rapid sampling protocol to avoid interference with GCxGC-TOF-MS analysis. To analyse batches of samples a new software tool, MetMax, was implemented which extracts the isotopomer matrix from stable isotope labelling experiments together with the first and second retention index (RI1 and RI2). To exploit RI1 and RI2 for metabolite identification we used the Golm metabolome database (GMD [1] with RI1/ RI2-reference spectra and new search algorithms. Using those techniques we analysed the dynamics of (CO2)-C-13 and C-13- acetate uptake in Chlamydomonas reinhardtii cells in two different steady states namely photoautotrophic and mixotrophic growth conditions.
The challenge is providing teachers with the resources they need to strengthen their instructions and better prepare students for the jobs of the 21st Century. Technology can help meet the challenge. Teachers’ Tryscience is a noncommercial offer, developed by the New York Hall of Science, TeachEngineering, the National Board for Professional Teaching Standards and IBM Citizenship to provide teachers with such resources. The workshop provides deeper insight into this tool and discussion of how to support teaching of informatics in schools.
.NET Gadgeteer Workshop
(2013)
Problem solving is one of the central activities performed by computer scientists as well as by computer science learners. Whereas the teaching of algorithms and programming languages is usually well structured within a curriculum, the development of learners’ problem-solving skills is largely implicit and less structured. Students at all levels often face difficulties in problem analysis and solution construction. The basic assumption of the workshop is that without some formal instruction on effective strategies, even the most inventive learner may resort to unproductive trial-and-error problemsolving processes. Hence, it is important to teach problem-solving strategies and to guide teachers on how to teach their pupils this cognitive tool. Computer science educators should be aware of the difficulties and acquire appropriate pedagogical tools to help their learners gain and experience problem-solving skills.
A method is presented of acquiring the principles of three sorting algorithms through developing interactive applications in Excel.
We present a concept of better integration of practical teaching in student teacher education in Computer Science. As an introduction to the workshop different possible scenarios are discussed on the basis of examples. Afterwards workshop participants will have the opportunity to discuss the application of the aconcepts in other settings.
In this paper we report on our experiments in teaching computer science concepts with a mix of tangible and abstract object manipulations. The goal we set ourselves was to let pupils discover the challenges one has to meet to automatically manipulate formatted text. We worked with a group of 25 secondary school pupils (9-10th grade), and they were actually able to “invent” the concept of mark-up language. From this experiment we distilled a set of activities which will be replicated in other classes (6th grade) under the guidance of maths teachers.
Informatics as a school subject has been virtually absent from bilingual education programs in German secondary schools. Most bilingual programs in German secondary education started out by focusing on subjects from the field of social sciences. Teachers and bilingual curriculum experts alike have been regarding those as the most suitable subjects for bilingual instruction – largely due to the intercultural perspective that a bilingual approach provides. And though one cannot deny the gain that ensues from an intercultural perspective on subjects such as history or geography, this benefit is certainly not limited to social science subjects. In consequence, bilingual curriculum designers have already begun to include other subjects such as physics or chemistry in bilingual school programs. It only seems a small step to extend this to informatics. This paper will start out by addressing potential benefits of adding informatics to the range of subjects taught as part of English-language bilingual programs in German secondary education. In a second step it will sketch out a methodological (= didactical) model for teaching informatics to German learners through English. It will then provide two items of hands-on and tested teaching material in accordance with this model. The discussion will conclude with a brief outlook on the chances and prerequisites of firmly establishing informatics as part of bilingual school curricula in Germany.
We shall examine the Pedagogical Content Knowledge (PCK) of Computer Science (CS) teachers concerning students’ Computational Thinking (CT) problem solving skills within the context of a CS course in Dutch secondary education and thus obtain an operational definition of CT and ascertain appropriate teaching methodology. Next we shall develop an instrument to assess students’ CT and design a curriculum intervention geared toward teaching and improving students’ CT problem solving skills and competences. As a result, this research will yield an operational definition of CT, knowledge about CT PCK, a CT assessment instrument and teaching materials and accompanying teacher instructions. It shall contribute to CS teacher education, development of CT education and to education in other (STEM) subjects where CT plays a supporting role, both nationally and internationally.
We launched an original large-scale experiment concerning informatics learning in French high schools. We are using the France-IOI platform to federate resources and share observation for research. The first step is the implementation of an adaptive hypermedia based on very fine grain epistemic modules for Python programming learning. We define the necessary traces to be built in order to study the trajectories of navigation the pupils will draw across this hypermedia. It may be browsed by pupils either as a course support, or an extra help to solve the list of exercises (mainly for algorithmics discovery). By leaving the locus of control to the learner, we want to observe the different trajectories they finally draw through our system. These trajectories may be abstracted and interpreted as strategies and then compared for their relative efficiency. Our hypothesis is that learners have different profiles and may use the appropriate strategy accordingly. This paper presents the research questions, the method and the expected results.
The traditional purpose of algorithm in education is to prepare students for programming. In our effort to introduce the practically missing computing science into Czech general secondary education, we have revisited this purpose.We propose an approach, which is in better accordance with the goals of general secondary education in Czechia. The importance of programming is diminishing, while recognition of algorithmic procedures and precise (yet concise) communication of algorithms is gaining importance. This includes expressing algorithms in natural language, which is more useful for most of the students than programming. We propose criteria to evaluate such descriptions. Finally, an idea about the limitations is required (inefficient algorithms, unsolvable problems, Turing’s test). We describe these adjusted educational goals and an outline of the resulting course. Our experience with carrying out the proposed intentions is satisfactory, although we did not accomplish all the defined goals.
Japan launched the new Course of Study in April 2012, which has been carried out in elementary schools and junior high schools. It will also be implemented in senior high schools from April 2013. This article presents an overview of the information studies education in the new Course of Study for K-12. Besides, the authors point out what role experts of informatics and information studies education should play in the general education centered around information studies that is meant to help people of the nation to lead an active, powerful, and flexible life until the satisfying end.
This article is a summary of the work carried out by the Ministry of Education in Turkey, in terms of the development of a new ICT Curriculum, together with the e-Training of teachers who will play an important role in the forthcoming pilot study. Based on recent literature on the topic, the article starts by introducing the “F@tih Project”, a national project that aims to effectively integrate technology into schools. After assessing teachers’ and students’ ICT competencies, as defined internationally, the review continues with the proposed model for the e-training of teachers. Summarizing the process of development of the new ICT curriculum, researchers underline key points of the curriculum such as dimensions, levels and competencies. Then teachers’ e-training approaches, together with selected tools, are explained in line with the importance and stages of action research that will be used throughout the pilot implementation of the curriculum and e-training process.