HDAC inhibitors cause site-specific chromatin remodeling at PU.1-bound enhancers in K562 cells

BACKGROUND: Small molecule inhibitors of histone deacetylases (HDACi) hold promise as anticancer agents for particular malignancies. However, clinical use is often confounded by toxicity, perhaps due to indiscriminate hyperacetylation of cellular proteins. Therefore, elucidating the mechanisms by which HDACi trigger differentiation, cell cycle arrest, or apoptosis of cancer cells could inform development of more targeted therapies. We used the myelogenous leukemia line K562 as a model of HDACi-induced differentiation to investigate chromatin accessibility (DNase-seq) and expression (RNA-seq) changes associated with this process. RESULTS: We identified several thousand specific regulatory elements [~10 % of total DNase I-hypersensitive (DHS) sites] that become significantly more or less accessible with sodium butyrate or suberanilohydroxamic acid treatment. Most of the differential DHS sites display hallmarks of enhancers, including being enriched for non-promoter regions, associating with nearby gene expression changes, and increasing luciferase reporter expression in K562 cells. Differential DHS sites were enriched for key hematopoietic lineage transcription factor motifs, including SPI1 (PU.1), a known pioneer factor. We found PU.1 increases binding at opened DHS sites with HDACi treatment by ChIP-seq, but PU.1 knockdown by shRNA fails to block the chromatin accessibility and expression changes. A machine-learning approach indicates H3K27me3 initially marks PU.1-bound sites that open with HDACi treatment, suggesting these sites are epigenetically poised. CONCLUSIONS: We find HDACi treatment of K562 cells results in site-specific chromatin remodeling at epigenetically poised regulatory elements. PU.1 shows evidence of a pioneer role in this process by marking poised enhancers but is not required for transcriptional activation.

Guest Editorial. Special Issue: Temporal logic in engineering

Logic-based models are thriving within artificial intelligence. A great number of new logics have been defined, and their theory investigated. Epistemic logics introduce modal operators for knowledge or belief; deontic logics are about norms, and introduce operators of deontic necessity and possibility (i.e., obligation or prohibition). And then we have a much investigated class—temporal logics—to whose application to engineering this special issue is devoted. This kind of formalism deserves increased widespread recognition and application in engineering, a domain where other kinds of temporal models (e.g., Petri nets) are by now a fairly standard part of the modelling toolbox.

Effect of long-term aging on the rheological characteristics and printing performance of lead-free solder pastes used for flip-chip assembly

Stencil printing of solder pastes is a critical stage in the SMT assembly process as a high proportion of the solder-related defects can be attributed to this stage. As the trend towards product miniaturization continues, there is a greater need for better understanding of the rheological behaviour and printing performance of new paste formulations. This fundamental understanding is crucial for achieving the repeatable solder paste deposits from board-to-board and pad-to-pad required for more reliable solder interconnections. The paper concerns a study on the effect of ageing on the rheological characteristics and printing performance of new lead-free solder pastes formulations used for flip-chip assembly applications. The objective is to correlate the rheological characteristics of aged paste samples to their printing performance. The methodology developed can be used for bench-marking new lead-free paste formulations in terms of shelf life, the potential deterioration in rheological characteristics and their printing performance.

A biological consequence of reducing Arctic ice cover: arrival of the Pacific diatom Neodenticula seminae in the North Atlantic for the first time in 800,000 years

The Continuous Plankton Recorder survey has monitored plankton in the Northwest Atlantic at monthly intervals since 1962, with an interegnum between 1978 and 1990. In May 1999, large numbers of the Pacific diatom Neodenticula seminae were found in Continuous Plankton Recorder (CPR) samples in the Labrador Sea as the first record in the North Atlantic for more than 800 000 years. The event coincided with modifications in Arctic hydrography and circulation, increased flows of Pacific water into the Northwest Atlantic and in the previous year the exceptional occurrence of extensive ice-free water to the North of Canada. These observations indicate that N. seminae was carried in a pulse of Pacific water in 1998/early 1999 via the Canadian Arctic Archipelago and/or Fram Strait. The species occurred previously in the North Atlantic during the Pleistocene from similar to 1.2 to similar to 0.8 Ma as recorded in deep sea sediment cores. The reappearance of N. seminae in the North Atlantic is an indicator of the scale and speed of changes that are taking place in the Arctic and North Atlantic oceans as a consequence of regional climate warming. Because of the unusual nature of the event it appears that a threshold has been passed, marking a change in the circulation between the North Pacific and North Atlantic Oceans via the Arctic. Trans-Arctic migrations from the Pacific into the Atlantic are likely to occur increasingly over the next 100 years as Arctic ice continues to melt affecting Atlantic biodiversity and the biological pump with consequent feedbacks to the carbon cycle.

Is big best? Queen size, usurpation and nest closure in a primitively eusocial sweat bee (Lasioglossum malachurum).

For primitively eusocial insects in which a single foundress establishes a nest at the start of the colony cycle, the solitary provisioning phase before first worker emergence represents a risky period when other, nestless foundresses may attempt to usurp the nest. In the primitively eusocial sweat bee Lasioglossum malachurum (Hymenoptera, Halictidae), spring foundresses compete for nests which are dug into hard soil. Nest-searching foundresses (‘floaters’) frequently inspected nests during this solitary phase and thereby exerted a usurpation pressure on resident queens. Usurpation has been hypothesised to increase across the solitary provisioning phase and favour closure of nests at an aggregation, marking the termination of the solitary provisioning phase by foundresses, before worker emergence. However, our experimental and observational data suggest that usurpation pressure may remain constant or even decrease across the solitary provisioning phase and therefore cannot explain nest closure before first worker emergence. Levels of aggression during encounters between residents and floaters were surprisingly low (9% of encounters across 2 years), and the outcome of confrontations was in favour of residents (resident maintains residency in 94% of encounters across 2 years). Residents were significantly larger than floaters. However, the relationship between queen size and offspring production, though positive, was not statistically significant. Size therefore seems to confer a considerable advantage to a queen during the solitary provisioning phase in terms of nest residency, but its importance in terms of worker production appears marginal. Factors other than intraspecific usurpation need to be invoked to explain the break in provisioning activity of a foundress before first worker emergence.

Adaptation of a questionnaire to assess the epistemological beliefs of mathematics in secondary school teachers

The objective of the study is to determine the psychometric properties of the Epistemological Beliefs Questionnaire on Mathematics. 171 Secondary School Mathematics Teachers of the Central Region of Cuba participated. The results show acceptable internal consistency. The factorial structure of the scale revealed three major factors, consistent with the Model of the Three Constructs: beliefs about knowledge, about learning and teaching. Irregular levels in the development of the epistemological belief system about mathematics of these teachers were shown, with a tendency among naivety and sophistication poles. In conclusion, the questionnaire is useful for evaluating teacher’s beliefs about mathematics.

Placing political economy: organising opposition to free trade before the abolition of the Corn Laws

The unfurling of global capitalism – and its attendant effects – has long been fertile intellectual terrain for geographers. But whilst studies of the processes and mechanisms of globalisation undoubtedly assume a talismanic importance in the discipline, geographers, with few exceptions, have left examinations of early economic liberalism to historians. One such critically important episode in the evolution of the liberal economic project was the repeal of the so-called 'Corn Laws' in 1846. Whilst the precise impact of the Manchester-based Anti-Corn Law League (ACLL) continues to be a matter of conjecture, Eric Sheppard has asserted that their particular take on political economy managed to assume a 'truth-like status' and worldwide universality. But the ACLL's campaign represents only one, albeit decisive, stage in the long intellectual and practical struggle between 'protectionists' and the disciples of free trade. Studies of the non-'Manchester' components have tended to focus squarely upon national politics. This paper examines a pivotal attempt in 1838 by Lord Melbourne's Government to experiment with the effective elimination of import duties on fresh fruit. Unlike most agricultural commodities, table fruit was produced in a tightly defined area, thus allowing the Government's experiment to play out, in theory, without national political fallout. Whilst the Government's clandestine actions left little time for a concerted opposition to develop, Kentish fruit growers soon organised. A formidable lobby was forged that drew wide local support yet also evolved beyond the original 'epistemic community'. Whilst the coalition failed in their efforts to reintroduce protective duties, their actions allow us to see how protectionist ideologies and policies were vivified through practices at many different spatial scales and to better understand the complex spatiality of protectionist takes on political economy. Their campaign also changed – at least in the short term – the course of British mercantile policy.

Paul Karl Feyerabend Las proyecciones de la proliferación teórica en la relación ciencia-metafísica

La doctrina de la Proliferación teórica de Paul Karl Feyerabend ha sido interpretada por sus especialistas como un intento de salvaguardar el ideal del progreso científico. Aunque tales estudios hacen justicia, en parte, a la intencionalidad de nuestro filósofo no explicitan la crítica fundamental que implica para Feyerabend el pluralismo teórico. La proliferación teórica constituye en sí misma una reductio ad absurdum de los distintos intentos del positivismo lógico y del racionalismo crítico por definir la ciencia a expensas de lo metafísico. Este artículo presenta la proliferación teórica como una reivindicación del papel positivo que ocupa la metafísica en el quehacer científico. Se consigna la defensa que hace Feyerabend de la metafísica en cuanto que ésta constituye la posibilidad de superar el conservadurismo conceptual, aumentar de contenido empírico de la ciencia y recuperar el valor descriptivo de las teorías científicas.

A framework for managing uncertain inputs: An axiomization of rewarding

The success postulate in belief revision ensures that new evidence (input) is always trusted. However, admitting uncertain input has been questioned by many researchers. Darwiche and Pearl argued that strengths of evidence should be introduced to determine the outcome of belief change, and provided a preliminary definition towards this thought. In this paper, we start with Darwiche and Pearl’s idea aiming to develop a framework that can capture the influence of the strengths of inputs with some rational assumptions. To achieve this, we first define epistemic states to represent beliefs attached with strength, and then present a set of postulates to describe the change process on epistemic states that is determined by the strengths of input and establish representation theorems to characterize these postulates. As a result, we obtain a unique rewarding operator which is proved to be a merging operator that is in line with many other works. We also investigate existing postulates on belief merging and compare them with our postulates. In addition, we show that from an epistemic state, a corresponding ordinal conditional function by Spohn can be derived and the result of combining two epistemic states is thus reduced to the result of combining two corresponding ordinal conditional functions proposed by Laverny and Lang. Furthermore, when reduced to the belief revision situation, we prove that our results induce all the Darwiche and Pearl’s postulates as well as the Recalcitrance postulate and the Independence postulate.

Evidence for progressive Holocene aridification in southern Africa recorded in Namibian hyrax middens: Implications for African Monsoon dynamics and the

Presented here are stable nitrogen isotope data from a rock hyrax (Procavia capensis) middens from northwestern Namibia that record a series of rapid aridification events beginning at ca. 3800 cal yr BP, and which mark a progressive decrease in regional humidity across the Holocene. Strong correlations exist between this record and other terrestrial and marine archives from southern Africa, indicating that the observed pattern of climate change is regionally coherent. Combined, these data indicate hemispheric synchrony in tropical African climate change during the Holocene, with similar trends characterising the termination of the 'African Humid Period' (AHP) in both the northern and southern tropics. These findings run counter to the widely accepted model of direct low-latitude insolation forcing, which requires an antiphase relationship to exist between the hemispheres. The combined dataset highlights: 1) the importance of forcing mechanisms influencing the high northern latitudes in effecting low-latitude climate change in Africa, and 2) the potential importance of solar forcing and variations in the Earth's geomagnetic shield in determining both long-term and rapid centennial-scale climate changes, identifying a possible mechanism for the variations marking the AHP termination in both the southern and northern tropics. (C) 2010 University of Washington. Published by Elsevier Inc. All rights reserved.

Reflexivity, Scientificity and the Sociology of Religion: Pierre Bourdieu in Debate

This paper explores the relevance of Pierre Bourdieu’s ‘epistemic reflexivity’ for the sociology of religion, in particular by examining his neglected address to the French Association for the Sociology of Religion in 1982. Whilst sociologists of religion have addressed some issues of reflexivity in their practice, less attention has been paid to the crucial scientific requirement, highlighted by Bourdieu, to break from the ‘illusio’ of that field and thus avoid alignments with positions taken by religious actors themselves. As a result, many sociologists inevitably participate in religious contestations and stakes, whether or not they affirm or deny their own religious identification with those they study. Although Bourdieu’s address was a response to a particular national and historical form of the sociology of religion, we argue that it retains much significance today and may lead to fruitful debate within the discipline.

Reducing Uncertainty in Aeroelastic Flutter Boundaries Using Experimental Data

Flutter prediction as currently practiced is usually deterministic, with a single structural model used to represent an aircraft. By using interval analysis to take into account structural variability, recent work has demonstrated that small changes in the structure can lead to very large changes in the altitude at which
utter occurs (Marques, Badcock, et al., J. Aircraft, 2010). In this follow-up work we examine the same phenomenon using probabilistic collocation (PC), an uncertainty quantification technique which can eficiently propagate multivariate stochastic input through a simulation code,
in this case an eigenvalue-based fluid-structure stability code. The resulting analysis predicts the consequences of an uncertain structure on incidence of
utter in probabilistic terms { information that could be useful in planning
flight-tests and assessing the risk of structural failure. The uncertainty in
utter altitude is confirmed to be substantial. Assuming that the structural uncertainty represents a epistemic uncertainty regarding the
structure, it may be reduced with the availability of additional information { for example aeroelastic response data from a flight-test. Such data is used to update the structural uncertainty using Bayes' theorem. The consequent
utter uncertainty is significantly reduced across the entire Mach number range.

'Trusting the numbers': mineral prospecting, raising finance and the governance of knowledge

Mineral prospecting and raising finance for ‘junior’ mining firms has historically been regarded as a speculative activity. For the regulators of securities markets upon which ‘junior’ mining companies seek to raise capital, a perennial problem has been handling not only the indeterminacy of scientific claims, but also the social basis of epistemic practices. This paper examines the production of a system of public warrant and associated knowledge practices intended to enable investors to differentiate between ‘destructive’ and ‘productive’ varieties of financial speculation. It traces the use of the notion of ‘disclosure’ in constructing and legitimizing the ‘juniors’ market in Canada. It argues that though the work of ‘economics’ may be necessary in the construction of markets, it is by no means sufficient. Attention must also be given to the ways in which legal models of ‘the free-market’ can be translated and constantly re-worked across the sites and spaces of regulatory practice, animating the geographies of markets.

Habitat effects on the spatial ecology of the European badger (Meles meles)

This study investigates how habitat variation affects sett density, the number of animals per social group and group territory size in the badger (Meles meles). Identical methods were applied in three habitat types: lowland parkland with mixed woodland, pastoral farmland and upland rough pasture with moorland, representing areas of presumed good, medium and poor badger habitat, respectively. Contiguous main setts were identified and bait-marking was used to estimate territory size. Group size was estimated by direct enumeration. Variation in sett density, group size and territory size supported the hypothesis that badger group and territory size are influenced by habitat type. This was further supported by analyses of data from other studies in the British Isles. The implications for badger spatial ecology, badger survey techniques and the badger's role in the epidemiology of TB are discussed.

THE ORGANIZATION OF THE NERVOUS-SYSTEM IN PLATHELMINTHES - THE NEUROPEPTIDE F-IMMUNOREACTIVE PATTERN IN CATENULIDA, MACROSTOMIDA, PROSERIATA

The organization of the nervous system of Archilopsis unipunctata Promonotus schultzei and Paramonotus hamatus (Monocelididae, Proseriata) and Stenostomum leucops (Catenulida) and Microstomum lineare (Macrostomida) was studied by immunocytochemistry, using antibodies to the authentic flatworm neuropeptide F (NPF) (Moniezia expansa). The organization of the nervous system of the Monocelididae was compared to that of the nervous system of Bothriomolus balticus (Otoplanidae), a previously studied species of another family of the Proseriata. The results show that the main nerve cords (MCs), independent of lateral or ventral position in the Monocelididae and the Otoplanidae, correspond to each other. The study also confirms the status of the lateral cords as main cords (MCs) in S. leucops and M. lineare. Common for MCs in the members of the investigated taxa are the following features: MCs consist of many fibres, originate from the brain and are adjoined to 5-HT-positive neurons. In Monocelididae and Otoplanidae, the MCs additionally have the same type of contact to the pharyngeal nervous system. Also common for both proseriate families is the organization of the two lateral nerve cords, with weaker connections to the brain, and the pair of dorsal cords running above the brain. The organization of the minor cords differs. The Monocelididae have a pair of thin ventral cords forming a mirror image of the dorsal pair. Furthermore, an unpaired ventral medial cord connecting medial commissural cells was observed in P. schultzei. Marginal nerve cords, observed in Otoplanidae, are absent in Monocelididae. All minor nerve cords are closely connected to the peripheral nerve plexus. The postulated trends of condensation of plexal fibres to cords and/or the flexibility of the peripheral nerve plexus are discussed. In addition, the immunoreactivity (IR) pattern of NPF was compared to the IR patterns of the neuropeptide RFamide and the indoleamine, 5-HT (serotonin). Significant differences between the distribution of IR to NPF and to 5-HT occur. 5-HT-IR dominates in the submuscular and subepidermal plexuses. In the stomatogastric plexus of M. lineare, only peptidergic IR is observed in the intestinal nerve net. The distribution of NPF-IR in fibres and cells of the intestinal wall in M. lineare indicates a regulatory function for this peptide in the gut, while a relationship with ciliary and muscular locomotion is suggested for the 5-HT-IR occurring in the subepidermal and submuscular nerve plexuses. In M. lineare, the study revealed an NPF- and RFamide-positive cell pair, marking the finished development of new zooids. This finding indicates that constancy of these cells is maintained in this asexually reproducing and regenerating species.