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N6-methyladenosine (m6A) is an abundant internal RNA modification1,2 that is catalysed predominantly by the METTL3–METTL14 methyltransferase complex3,4. The m6A methyltransferase METTL3 has been linked to the initiation and maintenance of acute myeloid leukaemia (AML), but the potential of therapeutic applications targeting this enzyme remains unknown5–7. Here we present the identification and characterization of STM2457, a highly potent and selective first-in-class catalytic inhibitor of METTL3, and a crystal structure of STM2457 in complex with METTL3–METTL14. Treatment of tumours with STM2457 leads to reduced AML growth and an increase in differentiation and apoptosis. These cellular effects are accompanied by selective reduction of m6A levels on known leukaemogenic mRNAs and a decrease in their expression consistent with a translational defect. We demonstrate that pharmacological inhibition of METTL3 in vivo leads to impaired engraftment and prolonged survival in various mouse models of AML, specifically targeting key stem cell subpopulations of AML. Collectively, these results reveal the inhibition of METTL3 as a potential therapeutic strategy against AML, and provide proof of concept that the targeting of RNA-modifying enzymes represents a promising avenue for anticancer therapy. Treatment with a specific inhibitor of the N6-methyladenosine methyltransferase METTL3 leads to reduced growth of cancer cells, indicating the potential of approaches targeting RNA-modifying enzymes for anticancer therapy.

5-Methylcytosine (5mC) is an epigenetic mark known to contribute to the regulation of gene expression in a wide range of biological systems. Ten Eleven Translocation (TET) dioxygenases oxidize 5mC to 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine in metazoans and fungi. Moreover, two recent reports imply the existence of other species of modified cytosine in unicellular alga Chlamydomonas reinhardtii and malaria parasite Plasmodium falciparum. Here we provide an overview of the spectrum of cytosine modifications and their roles in demethylation of DNA and regulation of gene expression in different eukaryotic organisms.

5-Methylcytosine (5mC) is an epigenetic mark known to contribute to the regulation of gene expression in a wide range of biological systems. Ten Eleven Translocation (TET) dioxygenases oxidize 5mC to 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine in metazoans and fungi. Moreover, two recent reports imply the existence of other species of modified cytosine in unicellular alga Chlamydomonas reinhardtii and malaria parasite Plasmodium falciparum. Here we provide an overview of the spectrum of cytosine modifications and their roles in demethylation of DNA and regulation of gene expression in different eukaryotic organisms.

Earthquakes are natural or man-made events that can occur everywhere in the Earth. Many regions in our planet have the disadvantage to experience more earthquakes compared to other regions, for example in the areas near the boundaries of the tectonic plates. Therefore it is very important to have a course in the schools where pupils learn about earthquakes but also learn what have to be avoided in the construction of the buildings. For this reason pupils construct an earthquake simulator (platform) using simple materials in the course of geography-geology. The simple materials are cardboards, tape, balloons, or small balls and other cheap materials. Pupils construct small structures with one or two floors from different materials in order to observe how these different structures will behave in a possible earthquake. Pupils vibrate the platform randomly or with more concrete way for example they vibrate the platform in a longitudinal or in a transversal way. Additionally pupils fasten a mobile phone in the platform and observe the acceleration of the platform through a suitable application.

Background Extracranial carotid artery aneurysms (ECCAs) are rare; however, they are associated with a high risk of stroke and mortality if untreated. In the present review, we compared the major outcomes between open and endovascular repair of ECCAs. Methods We systematically searched PubMed, Embase, Scopus, and the Cochrane Library for clinical studies reported online up to September 2020 that had evaluated major outcomes after both open and endovascular repair of ECCAs. Eligible studies were required to have evaluated at least the 30-day mortality or stroke and/or transient ischemic attack rates. The quality of the studies was also evaluated. Results Overall, seven studies (three high quality, two medium quality, and two low quality) with 374 patients and 383 ECCAs were eligible. All the studies had been reported from 2004 to 2020. In total, 220 open repairs were compared with 81 endovascular repairs. The open and endovascular treatments showed similar 30-day mortality rates (4% vs 0%; pooled odds ratio [OR], 2.67; 95% confidence interval [CI], 0.291-24.451) and stroke and transient ischemic attack rates (5.5% vs 1.2%; pooled OR, 1.42; 95% CI, 0.412-4.886). Open repair was associated in six studies with a greater incidence of cranial nerve injury compared with endovascular repair (14.5% vs 0%; OR, 3.98; 95% CI, 1.178-13.471). The hematoma or bleeding rate was also similar between the two methods in six studies (5.2% vs 0%; OR, 1.92; 95% CI, 0.518-7.094). Conclusions Open and endovascular repair of ECCAs is associated with similarly low early mortality and cerebrovascular event rates, although open repair showed a greater risk of cranial nerve injuries. An endovascular approach could be more appropriate when the aneurysm is located distally or requires extensive dissection. More studies are needed with standardized follow-up durations to evaluate late outcomes.

We construct four large data sets of bilateral real exchange rates based on traded good prices (food and clothing, respectively) and broader price indices (consumer price index, CPI, and wholesale price index, WPI). On these data sets, we run non†parametric regressions to examine how the real exchange rate, the price differential, and the nominal exchange rate react to an overvalued real exchange rate over time. In line with the theory we develop, our regressions show the following: First, real exchange rates are mean†reverting. Second, prices converge. Third, price convergence implies purchasing power divergence and thus does not contribute to real exchange rate convergence. Indeed, when price adjustment is fast (as for our traded good price data sets), we even observe diverging nominal exchange rates. Our findings suggest that movements both away from and towards PPP may be less related to traded good price movements than is commonly thought.

This study explores monetary policy conduct by the German Central Bank just after switching to floating exchange rates and before adopting the European single currency. With the world economy going through the ‘great inflation’ first, and the ‘great moderation’ then, the focus is on the DM/US dollar exchange rate, as a proxy of external constraints. A Taylor-type interest rate rule with a sufficiently high inflation coefficient emerges as an equilibrium relation in a Vector Error Correction model, and operates as a reaction function. The exchange rate enters significantly and the dynamics generated are consistent with the derived rule and the macroeconomic theory. Hence, I argue that the Bundesbank kept an eye on the exchange rate and remained devoted to the long-standing policy of price stability.

R-loops are nucleic acid structures formed by an RNA:DNA hybrid and unpaired single-stranded DNA that represent a source of genomic instability in mammalian cells1,2,3,4. Here we show that N6-methyladenosine (m6A) modification, contributing to different aspects of messenger RNA metabolism5,6, is detectable on the majority of RNA:DNA hybrids in human pluripotent stem cells. We demonstrate that m6A-containing R-loops accumulate during G2/M and are depleted at G0/G1 phases of the cell cycle, and that the m6A reader promoting mRNA degradation, YTHDF2 (ref. 7), interacts with R-loop-enriched loci in dividing cells. Consequently, YTHDF2 knockout leads to increased R-loop levels, cell growth retardation and accumulation of γH2AX, a marker for DNA double-strand breaks, in mammalian cells. Our results suggest that m6A regulates accumulation of R-loops, implying a role for this modification in safeguarding genomic stability.

In the present study Aprepitant (APT) ternary solid dispersions (SDs) were developed and evaluated for the first time. Specifically, ternary SDs of APT with Poloxamer 188 and Soluplus&reg, (SOL) were prepared via melt mixing and compared to binary APT/Poloxamer 188 and APT/SOL SDs. Initially, combined thermo-gravimetric and hot-stage polarized light microscopy studies indicated that all tested compounds were thermally stable up to 280 &deg, C, while Poloxamer 188 acted as a plasticizer to SOL by significantly reducing the temperature required to fully solubilize the API during SD preparation. Differential scanning calorimetry combined with wide angle X-ray diffraction studies showed that crystalline API was dispersed in both binary and ternary SDs, while Fourier transformation-infrared spectroscopy studies revealed no molecular interactions among the components. Scanning electron microscopy combined with EDAX element analysis showed that the API was dispersed in nano-scale within the polymer matrices, while increasing APT content led to increasing API nano-crystals within the SDs. Finally, dissolution studies showed that the prepared formulations enhanced dissolution of Aprepitant and its mechanism analysis was further studied. A mathematical model was also investigated to evaluate the drug release mechanism.

R-loops are nucleic acid structures formed by an RNA:DNA hybrid and unpaired single-stranded DNA that represent a source of genomic instability in mammalian cells

This is a post-peer-review, pre-copyedit version of an article published in Open Economic Reviews. The final authenticated version is available online at: http://dx.doi.org/10.1007/s11079-017-9473-9, Traded good prices affect the real exchange rate first through their effect on the overall price level and second through their effect on the nominal exchange rate. Whereas the price level effect, which is positive in sign, is universally recognized, the nominal exchange rate effect, which is negative in sign, is routinely ignored. We calculate to which extent real exchange rate changes are accounted for by traded good prices and other components of the real exchange rate. We find that the nominal exchange rate effect neutralizes the price level effect entirely, suggesting that, contrary to popular belief, good market arbitrage is not conducive to purchasing power parity (the purchasing power parity fallacy). Rather than traded or non-traded good prices, the main driving force behind the real exchange rate is currency market pressure, a variable that, as we argue, is largely determined by the cumulative trade and capital flows of a country

Advances in chromatin state mapping, high-throughput DNA sequencing, and bioinformatics have revolutionized the study and interpretability of epigenomic variation. The increasing feasibility of obtaining and analyzing detailed information on epigenetic mechanisms across many individuals and populations has enabled the study of epigenomic variation at the population level and its contributions to phenotypic variation, acclimation, ecological adaptation, and disease traits. Over the past decade, researchers from disparate life sciences ranging from epidemiology to marine conservation have begun approaching their subjects through the lens of population epigenomics. Epigenetic mechanisms involve molecular alterations in chromatin through DNA methylation and histone modifications, as well as complex non-coding RNAs and enzyme machinery, all leading to altered transcription and post-transcriptional RNA processing resulting in changes in gene expression. Genetic and environmental variation and stochastic epimutations give rise to epigenomic variation. Notably, some forms of epigenomic variation are quite stable and in some instances may be transmitted through one or more rounds of meiosis. Epigenomic variation can contribute significantly to phenotypic plasticity, stress responses, disease conditions, and acclimation and adaptation to habitat conditions across a wide variety of organisms during their lifetime but also across multiple generations. The purpose of this chapter is to provide an overview of population epigenomics concepts, approaches, challenges, and applications. We discuss the molecular basis of epigenetic mechanisms and their variation and heritability across diverse tissues and taxa. We then discuss the sources of epigenomic variation, within – and among – population epigenomic variation in plants and animals, and the evolutionary context of epigenomic variation before reviewing current molecular and bioinformatics methods for screening epigenomic variation. We then explore the contribution and association of epigenomic variation with phenotypic and ecological adaptation traits in plants and common disease conditions in humans and pharmacoepigenomics, as well as the main challenges and future research directions in population epigenomics.

For several decades, 5-methylcytosine (5mC) has been thought to be the only DNA modification with a functional significance in metazoans. The discovery of enzymatic oxidation of 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) as well as detection of N6-methyladenine (6mA) in the DNA of multicellular organisms provided additional degrees of complexity to the epigenetic research. According to a growing body of experimental evidence, these novel DNA modifications may play specific roles in different cellular and developmental processes. Importantly, as some of these marks (e. g. 5hmC, 5fC and 5caC) exhibit tissue- and developmental stage-specific occurrence in vertebrates, immunochemistry represents an important tool allowing assessment of spatial distribution of DNA modifications in different biological contexts. Here the methods for computational analysis of DNA modifications visualized by immunostaining followed by confocal microscopy are described. Specifically, the generation of 2.5 dimension (2.5D) signal intensity plots, signal intensity profiles, quantification of staining intensity in multiple cells and determination of signal colocalization coefficients are shown. Collectively, these techniques may be operational in evaluating the levels and localization of these DNA modifications in the nucleus, contributing to elucidating their biological roles in metazoans.

In the present study Aprepitant (APT) ternary solid dispersions (SDs) were developed and evaluated for the first time. Specifically, ternary SDs of APT with Poloxamer 188 and Soluplus&reg, (SOL) were prepared via melt mixing and compared to binary APT/Poloxamer 188 and APT/SOL SDs. Initially, combined thermo-gravimetric and hot-stage polarized light microscopy studies indicated that all tested compounds were thermally stable up to 280 &deg, C, while Poloxamer 188 acted as a plasticizer to SOL by significantly reducing the temperature required to fully solubilize the API during SD preparation. Differential scanning calorimetry combined with wide angle X-ray diffraction studies showed that crystalline API was dispersed in both binary and ternary SDs, while Fourier transformation-infrared spectroscopy studies revealed no molecular interactions among the components. Scanning electron microscopy combined with EDAX element analysis showed that the API was dispersed in nano-scale within the polymer matrices, while increasing APT content led to increasing API nano-crystals within the SDs. Finally, dissolution studies showed that the prepared formulations enhanced dissolution of Aprepitant and its mechanism analysis was further studied. A mathematical model was also investigated to evaluate the drug release mechanism

Η παρούσα έρευνα μελετά τη σχέση που έχει η γνωστική ανάπτυξη στην επίλυση προβλημάτων σε δυάδες ή ατομικά, σε μαθητές έκτης δημοτικού με τη χρήση του αριθμητικού γρίφου Sudoku. Στόχος της μικτής αυτής έρευνας ήταν να διαφανεί αν οι μαθητές έχουν καλύτερα αποτελέσματα κατά την επίλυση του γρίφου Sudoku, όταν τοποθετηθούν σε ομοιογενείς ή ανομοιογενείς ομάδες. Συγκεκριμένα, τα ερωτήματα της έρευνας ήταν: πρώτο, ποιος τύπος δυάδας (ομοιογενής ή ανομοιογενής) είναι αποτελεσματικότερος, δεύτερο, όταν τα άτομα εργάζονται ατομικά ποιος τύπος γνωστικής ανάπτυξης επιφέρει τα καλύτερα δυνατά αποτελέσματα στην επίλυση του Sudoku και τρίτο, ποιος ήταν ο βαθμός συνεργασίας των δυάδων. Τα δύο πρώτα ερωτήματα απαντήθηκαν ποσοτικά, ενώ το τρίτο απαντήθηκε ποιοτικά. Στην έρευνα συμμετείχαν 220 μαθητές από 13 διαφορετικές τάξεις της έκτης δημοτικού συμπλήρωσαν το εργαλείο γνωστικής ανάπτυξης Group Assessment of Logical Thinking (GALT), που κατασκευάστηκε από τους Roadrangka, Yeany και Padilla (1983). Στη συνέχεια, 60 μαθητές επέλυσαν τον γρίφο Sudoku ατομικά και άλλοι 160 μαθητές τον έλυσαν σε δυάδες. Ένα από τα κύρια ευρήματα της έρευνας ήταν η μη ανάπτυξη συνεργασίας ανάμεσα στις δυάδες, με αποτέλεσμα οι επιδόσεις στην ατομική ικανότητα επίλυσης προβλήματος να μη διαφέρουν μεταξύ των ατόμων που εργάστηκαν ατομικά και των ατόμων που εργάστηκαν μέσα σε δυάδα στα αντίστοιχα επίπεδα γνωστικής ανάπτυξης., Collaborative learning is a subject that has occupied many researchers throughout the world. Many researchers have maintained that when students of all school stages, from kindergarten to higher education work in teams, this leads to high performance (Johnson, Skon, & Johnson, 1980), but also has a positive impact emotionally and psychologically (Schmitz & Winskel, 2008). However, there have been studies claiming that teamwork does not actually result in any substantive improvement in students’ efficiency (Samuelsson, 2010), or that only some students gain from this method of learning (Sears & Reagin, 2013). The present study explores how cognitive development relates to problem solving in pairs or individually, in students of the sixth grade in school using the numerical puzzle Sudoku. More specifically, the study explored four different types of pairs of two, according to the level of cognitive development (high – high, high – low, average – average and low – low) and three different types of units (high, average, low), all taken from sixth graders of a public elementary school. Additionally, the research studied whether solving Sudoku was more effective in pairs rather than individually. The sample of this research included thirteen sixth grade classes from a public elementary school in a city in Cyprus. The city was intentionally selected to facilitate the research. Two hundred twenty students completed the tool of cognitive development Group Assessment of Logical Thinking (GALT). Then, 60 students individually solved the Sudoku puzzle, while 160 students solved the puzzle in pairs. The results of the qualitative study showed that there were differences between the four types of pairs in terms of how they collaborated. Although students showed interest or even enthusiasm in solving the Sudoku puzzle, the majority of them did not work together so as to improve their performance. The results of the quantitative study confirmed that students failed to cooperate. The performance of the Individual Problem Solving Ability was not different among the four types of pairs. The majority of high-level cognitive development pairs started to solve the puzzle competitively. However, in the process they worked together to solve the puzzle correctly. They also behaved in an intensely self-centred way. In non-homogeneous pairs, low-performing students had a passive role in the group. Additionally, it seemed that the level of cooperation was related to high performance. The research demonstrated that students had difficulty in developing combinational thinking. This was the reason they could not solve the puzzle. Pairs did not cooperate, despite the fact that they had clear guidelines to do that. This finding should be a concern for teachers and the educational system of Cyprus, in general. The role of the teacher should be supportive in helping students overcome their difficulties, considering the theory of Vygotsky (2012) on systematic facilitating, development, and the Zone of Proximal Development.

The paper attempts to identify an empirical relationship that characterizes the way the Bundesbank adjusted its short-term rate with respect to various objectives. By building on a careful exploration of the properties of the variables involved, it is established that interest rate rules -often remarkably similar to the Taylor rule-remain valid and relevant in a Vector Error Correction framework, and thereby proposing a distinctive interpretation of German monetary policy during the period 1975-1998. (C) 2009 Elsevier B.V. All rights reserved. 0.588 JCR (2009) Q3, 154/247 Economics UEM

The existence and stability of dissipative breathers in rf SQUID (Superconducting Quantum Interference Device) arrays is investigated numerically. In such arrays, the nonlinearity which is intrinsic to each SQUID, along with the weak magnetic coupling of each SQUID to its nearest neighbors, result in the formation of discrete breathers. We analyze several discrete breather excitations in rf SQUID arrays driven by alternating flux sources in the presence of losses. The delicate balance between internal power losses and input power, results in the formation of dissipative discrete breather (DDB) structures up to relatively large coupling parameters. It is shown that DDBs may locally alter the magnetic response of an rf SQUID array from paramagnetic to diamagnetic or vice versa., Comment: 5 pages, 4 figures

We have performed molecular dynamics simulations for a total duration of more than 10 µs (with most molecular trajectories being 1 µs in duration) to study, the effect of a single mutation on hen lysozyme protein stability and denaturing, using an IBM Blue Gene/L™ supercomputer. One goal of this study was to assess the use of certain force fields to reproduce experimental results of protein unfolding using thermal denaturing techniques. A second and more important goal was to gain microscopic insights into the mechanism of protein misfolding using both thermal and chemical denaturing techniques. We found that the thermal denaturing results were robust and reproducible with various force fields. The chemical denaturing results explained why the single amino-acid mutation on residue Trp62 causes the disruption of long-range interactions in the tertiary structure. Simulation results revealed that the Trp62 residue was the key to a cooperative long-range interaction within the wild-type protein. Specifically, Trp62 acts as a bridge between two neighboring basic residues through a π-type H-bond or π-cation interaction to form an Arg-Trp-Arg "sandwich-like" structure. Our findings support the general conclusions of the experiment and provide an interesting molecular depiction of the disruption of the long-range interactions.

Recent NMR experiments have revealed that a single residue mutation W62G on protein hen's-egg white lysozyme can cause a dramatic loss of long-range interactions and protein stability; however, the molecular mechanism for this surprising phenomenon is not completely clear. In this mini-review, we have summarized some of our recent work on the molecular mechanism with large-scale molecular modelling, and also utilized a new wavelet method to analyse the local structural clusters present in both the wild-type and mutant folding trajectories. These extensive MD (Molecular Dynamics) simulations (10+ μs) were performed in 8 M urea, mimicking the experimental condition. Detailed analyses revealed that the Trp62 residue is the key to a co-operative long-range interaction within the wild-type protein: it acts as a bridge between neighbouring basic residues, mainly arginine residues, through π-type hydrogen bonds or π-cation interactions to form an Arg-Trp-Arg ‘sandwich-like’ local structure. The local cluster near Trp62 further extends its interaction to other clusters, such as the one near Trp111, through Arg112, which is involved in such an Arg-Trp-Arg bridging structure, thus achieving the long-range interactions for the wild-type. On the other hand, the mutant does not have this bridging effect and forms much less local clusters or contacts, and therefore results in a much less stable structure. Overall, these findings not only support the general conclusions of the experiment, but also provide a detailed but somewhat different molecular picture of the disruption of the long-range interactions.

Background DNA methylation (5-methylcytosine (5mC)) patterns are often altered in cancers. Ten-eleven translocation (Tet) proteins oxidise 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). In addition to their presumptive specific biological roles, these oxidised forms of 5mC may serve as intermediates in demethylation process. According to several reports, 5hmC levels are strongly decreased in cancers; however, the distribution of 5fC and 5caC in malignant tissue has not been studied. Findings Here, we examine the levels of 5hmC and 5caC in 28 samples of normal breast tissue, 59 samples of invasive human breast cancer and 74 samples of gliomas using immunochemistry. In agreement with previous reports, we show that 71 % of normal breast samples exhibit strong 5hmC signal, compared with only 18 % of breast cancer samples with equivalent levels of 5hmC staining. Unexpectedly, although 5caC is not detectable in normal breast tissue, 27 % of breast cancer samples exhibit significant staining for this modification (p

Biomolecular simulations enabled by massively parallel supercomputers such as BlueGene/L promise to bridge the gap between the currently accessible simulation time scale and the experimental time scale for many important protein folding processes. In this study, molecular dynamics simulations were carried out for both the wild-type and the mutant hen lysozyme (TRP62GLY) to study the single mutation effect on lysozyme stability and misfolding. Our thermal denaturing simulations at 400-500 K with both the OPLSAA and the CHARMM force fields show that the mutant structure is indeed much less stable than the wild-type, which is consistent with the recent urea denaturing experiment (Dobson et al. Science 2002, 295, 1719-1722; Nature 2003, 424, 783-788). Detailed results also reveal that the single mutation TRP62GLY first induces the loss of native contacts in the beta-domain region of the lysozyme protein at high temperatures, and then the unfolding process spreads into the alpha-domain region through Helix C. Even though the OPLSAA force field in general shows a more stable protein structure than does the CHARMM force field at high temperatures, the two force fields examined here display qualitatively similar results for the misfolding process, indicating that the thermal denaturing of the single mutation is robust and reproducible with various modern force fields.

This paper presents results on a communications-intensive kernel, the three-dimensional fast Fourier transform (3D FFT), running on the 2,048-node Blue Gene®/L (BG/L) prototype. Two implementations of the volumetric FFT algorithm were characterized, one built on the Message Passing Interface library and another built on an active packet Application Program Interface supported by the hardware bring-up environment, the BG/L advanced diagnostics environment. Preliminary performance experiments on the BG/L prototype indicate that both of our implementations scale well up to 1,024 nodes for 3D FFTs of size 128 × 128 × 128. The performance of the volumetric FFT is also compared with that of the Fastest Fourier Transform in the West (FFTW) library. In general, the volumetric FFT outperforms a port of the FFTW Version 2.1.5 library on large-node-count partitions.