DNA double strand break repair: a radiation perspective

SIGNIFICANCE:
Ionizing radiation (IR) can induce a wide range of unique deoxyribonucleic acid (DNA) lesions due to the spatiotemporal correlation of the ionization produced. Of these, DNA double strand breaks (DSBs) play a key role. Complex mechanisms and sophisticated pathways are available within cells to restore the integrity and sequence of the damaged DNA molecules.
RECENT ADVANCES:
Here we review the main aspects of the DNA DSB repair mechanisms with emphasis on the molecular pathways, radiation-induced lesions, and their significance for cellular processes.
CRITICAL ISSUES:
Although the main characteristics and proteins involved in the two DNA DSB repair processes present in eukaryotic cells (homologous recombination and nonhomologous end-joining) are reasonably well established, there are still uncertainties regarding the primary sensing event and their dependency on the complexity, location, and time of the damage. Interactions and overlaps between the different pathways play a critical role in defining the repair efficiency and determining the cellular functional behavior due to unrepaired/miss-repaired DNA lesions. The repair pathways involved in repairing lesions induced by soluble factors released from directly irradiated cells may also differ from the established response mechanisms.
FUTURE DIRECTIONS:
An improved understanding of the molecular pathways involved in sensing and repairing damaged DNA molecules and the role of DSBs is crucial for the development of novel classes of drugs to treat human diseases and to exploit characteristics of IR and alterations in tumor cells for successful radiotherapy applications.

Neural pathways mediating cross education of motor function

Cross education is the process whereby training of one limb gives rise to enhancements in the performance of the opposite, untrained limb. Despite interest in this phenomenon having been sustained for more than a century, a comprehensive explanation of the mediating neural mechanisms remains elusive. With new evidence emerging that cross education may have therapeutic utility, the need to provide a principled evidential basis upon which to design interventions becomes ever more pressing. Generally, mechanistic accounts of cross education align with one of two explanatory frameworks. Models of the 'cross activation' variety encapsulate the observation that unilateral execution of a movement task gives rise to bilateral increases in corticospinal excitability. The related conjecture is that such distributed activity, when present during unilateral practice, leads to simultaneous adaptations in neural circuits that project to the muscles of the untrained limb, thus facilitating subsequent performance of the task. Alternatively, 'bilateral access' models entail that motor engrams formed during unilateral practise, may subsequently be utilised bilaterally - that is, by the neural circuitry that constitutes the control centres for movements of both limbs. At present there is a paucity of direct evidence that allows the corresponding neural processes to be delineated, or their relative contributions in different task contexts to be ascertained. In the current review we seek to synthesise and assimilate the fragmentary information that is available, including consideration of knowledge that has emerged as a result of technological advances in structural and functional brain imaging. An emphasis upon task dependency is maintained throughout, the conviction being that the neural mechanisms that mediate cross education may only be understood in this context. © 2013 Ruddy and Carson.

Power and the Construction of Independence in ICTD Organizations

How do powerful vested interests continue to influence ICT for development (ICTD) projects? In this paper, instead of adopting a macro-level analysis, I take an in-depth, ethnographic approach to focus on work practices at one NGO involved in producing information and communication technologies for use in developing countries. Staff decisions at this NGO were influenced by particular powerful organizations, and I draw on theoretical insights from organization studies in order to understand this. The approach yields surprising results. Staff members appeared able to "stand back" from the pressures coming from donors and other influential parties, and to critically reflect upon these. Paradoxically, rather than fueling resistance, this sense of independence appeared to reinforce dependency on these powerful organizations. Moreover, the fact that this NGO was engaged in ICTD work further heightened these effects. This study extends existing understandings of how power operates within ICTD organizations, by highlighting the ways in which a sense of independence can paradoxically exacerbate donor influence over work activities.

Documents and Dependencies: an Exploration of Vector Space Models for Semantic Composition

In most previous research on distributional semantics, Vector Space Models (VSMs) of words are built either from topical information (e.g., documents in which a word is present), or from syntactic/semantic types of words (e.g., dependency parse links of a word in sentences), but not both. In this paper, we explore the utility of combining these two representations to build VSM for the task of semantic composition of adjective-noun phrases. Through extensive experiments on benchmark datasets, we find that even though a type-based VSM is effective for semantic composition, it is often outperformed by a VSM built using a combination of topic- and type-based statistics. We also introduce a new evaluation task wherein we predict the composed vector representation of a phrase from the brain activity of a human subject reading that phrase. We exploit a large syntactically parsed corpus of 16 billion tokens to build our VSMs, with vectors for both phrases and words, and make them publicly available.

Counselling for sight loss: Using systematic case study research to build a client informed practice model

There is compelling evidence to suggest that acquired sight loss negatively impacts on emotional well-being. Despite increasing recognition of the need to provide emotional support for people with sight loss, we still do not fully understand what counselling interventions help and why they help. The aim of this study was to examine the process and outcome of counselling for a 70-year-old client who had experienced complete, irreversible, post-operative sight loss in order to gain a deeper understanding of client-defined helpful aspects of therapy. A Hermeneutic Single-Case Efficacy Design study was undertaken having received ethical approval from the University's Research Ethics Committee. The client received six sessions of counselling from a vision-impaired counsellor working within a pluralistic framework. Measures were completed by the client at every session, as well as at pre-and post-counselling. All sessions were recorded and transcribed. The client also participated in pre-and post-counselling interviews. Data formed a rich case record that was analysed by a quasi-judicial enquiry team. Results suggested that this was a successful outcome case. Client-defined helpful aspects of therapy were (1) feeling understood; (2) being able to express emotions around the loss of sight; (3) finding a new identity; (4) finding ways to cope with fear, loss, dependency, and other people's perceptions; (5) exploring the possibility of a positive future without sight; (6) making sense of things; and (7) finding ways to become more socially connected. Relevant therapeutic tasks are proposed, and four key aspects of therapy are identified, which may have implications for the development of a practice model.

Review of constitutive models for describing the time dependent behaviour of soft clays

Different classes of constitutive models have been proposed to capture the time-dependent behaviour of soft soil (creep, stress relaxation, rate dependency). This paper critically reviews many of the models developed based on understanding of the time dependent stress-strain-stress rate-strain rate behaviour of soils and viscoplasticity in terms of their strengths and weaknesses. Some discussion is also made on the numerical implementation aspects of these models. Typical findings from numerical analyses of geotechnical structures constructed on soft soils are also discussed. The general elastic viscoplastic (EVP) models can roughly be divided into two categories: models based on the concept of overstress and models based on non-stationary flow surface theory. Although general in structure, both categories have their own strengths and shortcomings. This review indicates that EVP analysis is yet to be vastly used by the geotechnical engineers, apparently due to the mathematical complication involved in the formulation of the constitutive models, unconvincing benefit in terms of the accuracy of performance prediction, requirement of additional soil parameter(s), difficulties in determining them, and the necessity of excessive computing resources and time. © 2013 Taylor & Francis.

Crisis Cartels:Non-Economic Values, the Public Interest and Institutional Considerations

This paper considers the use of non-economic considerations in Article 101(3) analysis of industrial restructuring agreements, using the Commission's Decisions in Synthetic Fibres, Stichting Baksteen, and the recent UK Dairy Initiative as examples. I argue that contra to the Commission's recent economics-based approach; there is room for non-economic considerations to be taken into account within the framework of the European Treaties. The competition law issue is whether the provisions of Article 101(3) can save such agreements.
I further argue that there is legal room for non-economic considerations to be considered in evaluating these restructuring agreements, it is not clear who the appropriate arbiter of these considerations should be given the institutional limitations of courts (which have no democratic mandate), specialised competition agencies (which may be too technocratic in focus) and legislatures (which are susceptible to capture by rent-seeking interest groups).

Geographies of Communality, Colonialism, and Capitalism: Ecology and the World-System

Drawing upon recent reworkings of world systems theory and Marx’s concept of metabolic rift, this paper attempts to ground early nineteenth-century Ireland more clearly within these metanarratives, which take the historical-ecological dynamics of the development of capitalism as their point of departure. In order to unravel the socio-spatial complexities of Irish agricultural production throughout this time, attention must be given to the prevalence of customary legal tenure, institutions of communal governance, and their interaction with the colonial apparatus, as an essential feature of Ireland’s historical geography often neglected by famine scholars. This spatially differentiated legacy of communality, embedded within a country-wide system of colonial rent, and burgeoning capitalist system of global trade, gave rise to profound regional differentiations and ecological contradictions, which became central to the distribution of distress during the Great Famine (1845-1852). Contrary to accounts which depict it as a case of discrete transition from feudalism to capitalism, Ireland’s pre-famine ecology must be understood through an analysis which emphasises these socio-spatial complexities. Consequently, this structure must be conceptualised as one in which communality, colonialism, and capitalism interact dynamically, and in varying stages of development and devolution, according to space and time.

Fracture strength of machined ceramic crowns as a function of tooth preparation design and the elastic modulus of the cement

Objectives: To determine, by means of static fracture testing the effect of the tooth preparation design and the elastic modulus of the cement on the structural integrity of the cemented machined ceramic crown-tooth complex. 
Methods: Human maxillary extracted premolar teeth were prepared for all-ceramic crowns using two preparation designs; a standard preparation in accordance with established protocols and a novel design with a flat occlusal design. All-ceramic feldspathic (Vita MK II) crowns were milled for all the preparations using a CAD/CAM system (CEREC-3). The machined all-ceramic crowns were resin bonded to the tooth structure using one of three cements with different elastic moduli: Super-Bond C&B, Rely X Unicem and Panavia F 2.0. The specimens were subjected to compressive force through a 4 mm diameter steel ball at a crosshead speed of 1 mm/min using a universal test machine (Loyds Instrument Model LRX.). The load at the fracture point was recorded for each specimen in Newtons (N). These values were compared to a control group of unprepared/unrestored teeth. 
Results: There was a significant difference between the control group, with higher fracture strength, and the cemented samples regardless of the occlusal design and the type of resin cement. There was no significant difference in mean fracture load between the two designs of occlusal preparation using Super-Bond C&B. For the Rely X Unicem and Panavia F 2.0 cements, the proposed preparation design with a flat occlusal morphology provides a system with increased fracture strength. 
Significance: The proposed novel flat design showed less dependency on the resin cement selection in relation to the fracture strength of the restored tooth. The choice of the cement resin, with respect to its modulus of elasticity, is more important in the anatomic design than in the flat design. © 2013 Academy of Dental Materials.

The Map Defines the Territory: Remodelling NGO Partnerships for Knowledge Translation in Transition Contexts

The initial impetus for a theoretical exploration of organisational relationships is based on case study research on a Bulgarian NGO's implementation of values and goals into practices under a guiding relationship from a very experienced UK organisation in the same field. Findings diverged from conventional accounts of developing NGOs' dependence on more developed counterparts and that case study findings characterised the inter- dependency between the two organisations as more alike to a collaborative knowledge ...

Deep impact: in situ functional responses reveal context-dependent interactions between vertically migrating invasive and native mesopredators and shared prey

The ecological effects of invasive species depend on myriad environmental contexts, rendering understanding problematic. Functional responses provide a means to quantify resource use by consumers over short timescales and could therefore provide insight into how the effects of invasive species vary over space and time. Here, we use novel in situ microcosm experiments to track changes in the functional responses of two aquatic mesopredators, one native and the other an invader, as they undergo diel vertical migrations through a lake water column.
The Ponto–Caspian mysid, Hemimysis anomala, a known ecologically damaging invader, generally had higher a functional response towards cladoceran prey than did a native trophic analogue, Mysis salemaai. However, this differential was spatiotemporally dependent, being minimal during the day on the lake bottom, and increasing at night, particularly inshore.
Because the functional response of the native predator was spatiotemporally consistent, the above pattern was driven by changes in the invader functional response over the diel cycle. In particular, the functional response of H. anomala was significantly reduced on the lake bottom during the daytime relative to night, and predation was especially pronounced in shallow surface waters.
We demonstrate the context dependency of the effects of an invasive predator on prey populations and emphasise the utility of functional responses as tools to inform our understanding of predator–prey interactions. In situ manipulations integrate experimental rigour with field relevance and have the potential to reveal how impacts manifest over a range of spatiotemporal scales.

Kinetostatic-model-based Stiffness Analysis of Exechon PKM

As a comparative newly-invented PKM with over-constraints in kinematic chains, the Exechon has attracted extensive attention from the research society. Different from the well-recognized kinematics analysis, the research on the stiffness characteristics of the Exechon still remains as a challenge due to the structural complexity. In order to achieve a thorough understanding of the stiffness characteristics of the Exechon PKM, this paper proposed an analytical kinetostatic model by using the substructure synthesis technique. The whole PKM system is decomposed into a moving platform subsystem, three limb subsystems and a fixed base subsystem, which are connected to each other sequentially through corresponding joints. Each limb body is modeled as a spatial beam with a uniform cross-section constrained by two sets of lumped springs. The equilibrium equation of each individual limb assemblage is derived through finite element formulation and combined with that of the moving platform derived with Newtonian method to construct the governing kinetostatic equations of the system after introducing the deformation compatibility conditions between the moving platform and the limbs. By extracting the 6 x 6 block matrix from the inversion of the governing compliance matrix, the stiffness of the moving platform is formulated. The computation for the stiffness of the Exechon PKM at a typical configuration as well as throughout the workspace is carried out in a quick manner with a piece-by-piece partition algorithm. The numerical simulations reveal a strong position-dependency of the PKM's stiffness in that it is symmetric relative to a work plane due to structural features. At the last stage, the effects of some design variables such as structural, dimensional and stiffness parameters on system rigidity are investigated with the purpose of providing useful information for the structural optimization and performance enhancement of the Exechon PKM. It is worthy mentioning that the proposed methodology of stiffness modeling in this paper can also be applied to other overconstrained PKMs and can evaluate the global rigidity over workplace efficiently with minor revisions.

Does wave exposure determine the interactive effects of losing key grazers and ecosystem engineers?

The consequences of biodiversity loss in the face of environmental change remain difficult to predict, given the complexity of interactions among species and the context-dependency of their functional roles within ecosystems. Predictions may be enhanced by studies testing how the interactive effects of species loss from different functional groups vary with important environmental drivers. On rocky shores, limpets and barnacles are recognised as key grazers and ecosystem engineers, respectively. Despite the large body of research examining the combined effects of limpet and barnacle removal, it is unclear how their relative importance varies according to wave exposure, which is a dominant force structuring intertidal communities. We tested the responses of algal communities to the removal of limpets and barnacles on three sheltered and three wave-exposed rocky shores on the north coast of Ireland. Limpet removal resulted in a relative increase in microalgal biomass on a single sheltered shore only, but led to the enhanced accumulation of ephemeral macroalgae on two sheltered shores and one exposed shore. On average, independently of wave exposure or shore, ephemeral macroalgae increased in response to limpet removal, but only when barnacles were removed. On two sheltered shores and one exposed shore, however, barnacles facilitated the establishment of fucoid macroalgae following limpet removal. Therefore, at the scale of this study, variability among individual shores was more important than wave exposure per se in determining the effect of limpet removal and its interaction with that of barnacles. Overall, these findings demonstrate that the interactive effects of losing key species from different functional groups may not vary predictably according to dominant environmental factors.

גבול (Border)

This paper is a reexamination of the concept of the geopolitical border through a critical analysis of prevalent conceptualizations of borders, as they are articulated in the fields of geopolitics, political theory and international relations. Suggesting that thinking of borders as the derivative of territorial definitions disregards the dependency of territoriality and sovereign space on the praxes of border making, this paper offers an analytic distinction between normative articulations of borders and the border as a political practice. This distinction enables the identification of partial and incoherent border making processes. Consequently, the creation of borders can be analyzed as an effect of a multiplicity of performative praxes, material, juridical and otherwise discursive, that operate in relation to the management of space and attribute it with geopolitical distinctions. Furthermore, the paper suggests that these praxes, which appear in dispersed sites and in a wide variety of loci, are intrinsically linked to different spatial practices of population management, of governmentality. Thus, I offer a reading of borders as a praxis which manages binary differentiations of matrixes of governmentality, which create schisms in the population as a totality, through the deployment of the evocation of sovereignty as the legitimizing source of this differentiation or for the means necessary for its sustainment.

Genetic Background and Light-Dependent Progression of Photoreceptor Cell Degeneration in Prominin-1 Knockout Mice

PURPOSE: Mutations in the Prominin-1 (Prom1) gene are known to cause retinitis pigmentosa and Stargardt disease, both of which are associated with progressive photoreceptor cell death. There are no effective therapies for either disorder. The aim of this study was to investigate the mechanism of the retinal degeneration in Prom1-deficient mouse models.

METHODS: We constructed Prom1 knockout mice with two distinct genetic backgrounds of C57BL/6 and C57BL/6xCBA/NSlc, and investigated the photoreceptor degeneration by means of histology and functional tests.. In addition, we examined the effect of light on the Prom1(-/-) retina by rearing the mice in the normal light/dark cycle and completely dark conditions. Finally, we investigated if the retinoic-acid derivative Fenretinide slowed the pace of retinal degeneration in these mouse models.

RESULTS: The Prom1(-/-)-knockout mice with both backgrounds developed photoreceptor degeneration after eye opening, but the CB57/BL6-background mice developed photoreceptor cell degeneration much faster than the C57BL/6xCBA/NSlc mice, demonstrating genetic background dependency.. Interestingly, our histologic and functional examination showed that the photoreceptor cell degeneration of Prom1-knockout mice was light-dependent, and was almost completely inhibited when the mutant mice were kept in the dark. The Prom1-knockout retina showed strong downregulation of expression of the visual cycle components, Rdh12 and Abca4. Furthermore, administration of Fenretinide, which lowers the level of the toxic lipofuscin, slowed the degeneration of photoreceptor cells.

CONCLUSIONS: These findings improve our understanding of the mechanism of cell death in Prominin-1-related disease and provide evidence that fenretinide may be worth studying in human disease.