Pharmacogenomic Profiling and Pathway Analyses Identify MAPK-Dependent Migration as an Acute Response to SN38 in p53 Null and p53-Mutant Colorectal Cancer Cells.

The topoisomerase I inhibitor irinotecan is used to treat advanced colorectal cancer and has been shown to have p53-independent anticancer activity. The aim of this study was to identify the p53-independent signaling mechanisms activated by irinotecan. Transcriptional profiling of isogenic HCT116 p53 wild-type and p53 null cells was carried out following treatment with the active metabolite of irinotecan, SN38. Unsupervised analysis methods showed that p53 status had a highly significant impact on gene expression changes in response to SN38. Pathway analysis indicated that pathways involved in cell motility [adherens junction, focal adhesion, mitogen-activated protein kinase (MAPK), and regulation of the actin cytoskeleton] were significantly activated in p53 null cells, but not p53 wild-type cells, following SN38 treatment. In functional assays, SN38 treatment increased the migratory potential of p53 null and p53-mutant colorectal cancer cell lines, but not p53 wild-type lines. Moreover, p53 null SN38-resistant cells were found to migrate at a faster rate than parental drug-sensitive p53 null cells, whereas p53 wild-type SN38-resistant cells failed to migrate. Notably, cotreatment with inhibitors of the MAPK pathway inhibited the increased migration observed following SN38 treatment in p53 null and p53-mutant cells. Thus, in the absence of wild-type p53, SN38 promotes migration of colorectal cancer cells, and inhibiting MAPK blocks this potentially prometastatic adaptive response to this anticancer drug.

Non-targeted effects of ionising radiation-Implications for low dose risk

Non-DNA targeted effects of ionising radiation, which include genomic instability, and a variety of bystander effects including abscopal effects and bystander mediated adaptive response, have raised concerns about the magnitude of low-dose radiation risk. Genomic instability, bystander effects and adaptive responses are powered by fundamental, but not clearly understood systems that maintain tissue homeostasis. Despite excellent research in this field by various groups, there are still gaps in our understandfng of the likely mechanisms associated with non-DNA targeted effects, particularly with respect to systemic (human health) consequences at low and intermediate doses of ionising radiation. Other outstanding questions include links between the different non-targeted responses and the variations. in response observed between individuals and cell lines, possibly a function of genetic background. Furthermore, it is still not known what the initial target and early interactions in cells are that give rise to non-targeted responses in neighbouring or descendant cells. This paper provides a commentary on the current state of the field as a result of the non-targeted effects of ionising radiation (NOTE) Integrated Project funded by the European Union. Here we critically examine the evidence for non-targeted effects, discuss apparently contradictory results and consider implications for low-dose radiation health effects. (C) 2012 Elsevier B.V. All rights reserved.

Parainflammation, chronic inflammation, and age-related macular degeneration

Inflammation is an adaptive response of the immune system to noxious insults to maintain homeostasis and restore functionality. The retina is considered an immune-privileged tissue as a result of its unique anatomic and physiologic properties. During aging, the retina suffers from a low-grade chronic oxidative insult, which sustains for decades and increases in level with advancing age. As a result, the retinal innate-immune system, particularly microglia and the complement system, undergoes low levels of activation (parainflammation). In many cases, this parainflammatory response can maintain homeostasis in the healthy aging eye. However, in patients with age-related macular degeneration, this parainflammatory response becomes dysregulated and contributes to macular damage. Factors contributing to the dysregulation of age-related retinal parainflammation include genetic predisposition, environmental risk factors, and old age. Dysregulated parainflammation (chronic inflammation) in age-related macular degeneration damages the blood retina barrier, resulting in the breach of retinal-immune privilege, leading to the development of retinal lesions. This review discusses the basic principles of retinal innate-immune responses to endogenous chronic insults in normal aging and in age-related macular degeneration and explores the difference between beneficial parainflammation and the detrimental chronic inflammation in the context of age-related macular degeneration.

Achieving hypoxia-inducible gene expression in tumors

Hypoxia is an inevitable feature of solid tumors and a common cause of treatment failure. Hypoxia acts as a trigger to genetic instability, apoptosis and possibly metastases. The adaptive response to cellular hypoxia involves the modulation of the synthesis of multiple proteins controlling processes such as glucose homeostasis, angiogenesis, vascular permeability and inflammation. The hypoxia responsive element (HRE) sequences isolated from oxygen-responsive genes have been shown to selectively induce gene expression in response to hypoxia when placed upstream of a promoter. The levels of induced gene expression were dependent on the number of HRE copies and the oxygen tension. Hypoxia-mediated cancer gene therapy strategies may represent a promising mean to significantly improve the efficacy of standard radiation therapy and chemotherapy approaches.

Cellular and molecular phenotypes depending upon the RNA repair system RtcAB of Escherichia coli

RNA ligases function pervasively across the three kingdoms of life for RNA repair, splicing and can be stress induced. The RtcB protein (also HSPC117, C22orf28, FAAP and D10Wsu52e) is one such conserved ligase, involved in tRNA and mRNA splicing. However, its physiological role is poorly described, especially in bacteria. We now show in Escherichia coli bacteria that the RtcR activated rtcAB genes function for ribosome homeostasis involving rRNA stability. Expression of rtcAB is activated by agents and genetic lesions which impair the translation apparatus or may cause oxidative damage in the cell. Rtc helps the cell to survive challenges to the translation apparatus, including ribosome targeting antibiotics. Further, loss of Rtc causes profound changes in chemotaxis and motility. Together, our data suggest that the Rtc system is part of a previously unrecognised adaptive response linking ribosome homeostasis with basic cell physiology and behaviour.

Critical Role for STAT4 Activation by Type 1 Interferons in the Interferon-Y Response to Viral Infection

Interferons (IFNs) are essential for host defense. Although the antiviral effects of the type 1 IFNs IFN- and IFN- (IFN-/) have been established, their immunoregulatory functions, especially their ability to regulate IFN- production, are poorly understood. Here we show that IFN-/ activate STAT4 directly (STAT, signal transducers and activators of transcription) and that this is required for IFN- production during viral infections of mice, in concert with T cell receptor-derived signals. In contrast, STAT1 appears to negatively regulate IFN-/ induction of IFN-. Thus, type 1 IFNs, in addition to interleukin-12, provide pathways for innate regulation of adaptive immunity, and their immunoregulatory functions are controlled by modulating the activity of individual STATs.

Radiation-induced bystander and adaptive responses in cell and tissue models.

The use of microbeam approaches has been a major advance in probing the relevance of bystander and adaptive responses in cell and tissue models. Our own studies at the Gray Cancer Institute have used both a charged particle microbeam, producing protons and helium ions and a soft X-ray microprobe, delivering focused carbon-K, aluminium-K and titanium-K soft X-rays. Using these techniques we have been able to build up a comprehensive picture of the underlying differences between bystander responses and direct effects in cell and tissue-like models. What is now clear is that bystander dose-response relationships, the underlying mechanisms of action and the targets involved are not the same as those observed for direct irradiation of DNA in the nucleus. Our recent studies have shown bystander responses even when radiation is deposited away from the nucleus in cytoplasmic targets. Also the interaction between bystander and adaptive responses may be a complex one related to dose, number of cells targeted and time interval.

Adaptive Dialogue Strategy Selection through Imprecise Probabilistic Query Answering

In a human-computer dialogue system, the dialogue strategy can range from very restrictive to highly flexible. Each specific dialogue style has its pros and cons and a dialogue system needs to select the most appropriate style for a given user. During the course of interaction, the dialogue style can change based on a user’s response and the system observation of the user. This allows a dialogue system to understand a user better and provide a more suitable way of communication. Since measures of the quality of the user’s interaction with the system can be incomplete and uncertain, frameworks for reasoning with uncertain and incomplete information can help the system make better decisions when it chooses a dialogue strategy. In this paper, we investigate how to select a dialogue strategy based on aggregating the factors detected during the interaction with the user. For this purpose, we use probabilistic logic programming (PLP) to model probabilistic knowledge about how these factors will affect the degree of freedom of a dialogue. When a dialogue system needs to know which strategy is more suitable, an appropriate query can be executed against the PLP and a probabilistic solution with a degree of satisfaction is returned. The degree of satisfaction reveals how much the system can trust the probability attached to the solution.

A generalized functional response for predators that switch between multiple prey species

We develop a theory for the food intake of a predator that can switch between multiple prey species. The theory addresses empirical observations of prey switching and is based on the behavioural assumption that a predator tends to continue feeding on prey that are similar to the prey it has consumed last, in terms of, e.g., their morphology, defences, location, habitat choice, or behaviour. From a predator's dietary history and the assumed similarity relationship among prey species, we derive a general closed-form multi-species functional response for describing predators switching between multiple prey species. Our theory includes the Holling type II functional response as a special case and makes consistent predictions when populations of equivalent prey are aggregated or split. An analysis of the derived functional response enables us to highlight the following five main findings. (1) Prey switching leads to an approximate power-law relationship between ratios of prey abundance and prey intake, consistent with experimental data. (2) In agreement with empirical observations, the theory predicts an upper limit of 2 for the exponent of such power laws. (3) Our theory predicts deviations from power-law switching at very low and very high prey-abundance ratios. (4) The theory can predict the diet composition of a predator feeding on multiple prey species from diet observations for predators feeding only on pairs of prey species. (5) Predators foraging on more prey species will show less pronounced prey switching than predators foraging on fewer prey species, thus providing a natural explanation for the known difficulties of observing prey switching in the field. (C) 2013 Elsevier Ltd. All rights reserved.

Macroprudential Ideas and Contested Social Purpose: A Response to Terrence Casey

In response to Terrence Casey's argument that the emergence of macroprudential regulation since the financial crash can and should save neoliberalism we raise five objections. 1). The Debt-Driven Growth Hypothesis (DDG) and the Financial Instability Hypothesis (FIH), as Casey terms them, are just as likely to be complementary as they are oppositional and they are by no means incompatible. 2) Casey's empirics are too thin and static, drawn from the 1980s and 1990s, while Anglo Liberal Financialised Capitalism (ALFC) is a complex adaptive system that has continued to evolve throughout the 2000s. 3) Casey overlooks the dynamic relationship between potentially excessive financialisation and the performance of the wider economy, which is becoming a growing concern for many policy makers using the macroprudential frame. 4) Macroprudential as a series of ideas about the economy are often incompatible with neoliberal premises and their ontological foundations. 5) Many of the policy makers who have acted as the biggest champions of macroprudential regulation have also been highly critical of ALFC and view the macroprudential turn as making a contribution to a much needed deeper financial reformation that would over time transform some of the constituent economic and social relations of the existing political economy. We conclude that what we call the social purpose of macroprudential regulation (the question of whether it is intended to patch up or transform the existing system) is contested, and that macroprudential regulation has much potential beyond saving ‘neoliberalism’.

Synthesizable high performance adaptive equaliser and viterbi decoder for the class-IV PRML channel

The design and VLSI implementation of two key components of the class-IV partial response maximum likelihood channel (PR-IV) the adaptive filter and the Viterbi decoder are described. These blocks are implemented using parameterised VHDL modules, from a library of common digital signal processing (DSP) and arithmetic functions. Design studies, based on 0.6 micron 3.3V standard cell processes, indicate that worst case sampling rates of 49 mega-samples per second are achievable for this system, with proportionally high sampling rates for full custom designs and smaller dimension processes. Significant increases in the sampling rate, from 49 MHz to approximately 180 MHz, can be achieved by operating four filter modules in parallel, and this implementation has 50% lower power consumption than a pipelined filter operating at the same speed.

Improving E-Assessment Systems With A focus On Adaptive Feedback And Marking

Institutions involved in the provision of tertiary education across Europe are feeling the pinch. European universities, and other higher education (HE) institutions, must operate in a climate where the pressure of government spending cuts (Garben, 2012) is in stark juxtaposition to the EU’s strategy to drive forward and maintain a growth of student numbers in the sector (eurostat, 2015).

In order to remain competitive, universities and HE institutions are making ever-greater use of electronic assessment (E-Assessment) systems (Chatzigavriil et all, 2015; Ferrell, 2012). These systems are attractive primarily because they offer a cost-effect and scalable approach for assessment. In addition to scalability, they also offer reliability, consistency and impartiality; furthermore, from the perspective of a student they are most popular because they can offer instant feedback (Walet, 2012).

There are disadvantages, though.

First, feedback is often returned to a student immediately on competition of their assessment. While it is possible to disable the instant feedback option (this is often the case during an end of semester exam period when assessment scores must be can be ratified before release), however, this option tends to be a global ‘all on’ or ‘all off’ configuration option which is controlled centrally rather than configurable on a per-assessment basis.

If a formative in-term assessment is to be taken by multiple groups of
students, each at different times, this restriction means that answers to each question will be disclosed to the first group of students undertaking the assessment. As soon as the answers are released “into the wild” the academic integrity of the assessment is lost for subsequent student groups.

Second, the style of feedback provided to a student for each question is often limited to a simple ‘correct’ or ‘incorrect’ indicator. While this type of feedback has its place, it often does not provide a student with enough insight to improve their understanding of a topic that they did not answer correctly.

Most E-Assessment systems boast a wide range of question types including Multiple Choice, Multiple Response, Free Text Entry/Text Matching and Numerical questions. The design of these types of questions is often quite restrictive and formulaic, which has a knock-on effect on the quality of feedback that can be provided in each case.

Multiple Choice Questions (MCQs) are most prevalent as they are the most prescriptive and therefore most the straightforward to mark consistently. They are also the most amenable question types, which allow easy provision of meaningful, relevant feedback to each possible outcome chosen.
Text matching questions tend to be more problematic due to their free text entry nature. Common misspellings or case-sensitivity errors can often be accounted for by the software but they are by no means fool proof, as it is very difficult to predict in advance the range of possible variations on an answer that would be considered worthy of marks by a manual marker of a paper based equivalent of the same question.

Numerical questions are similarly restricted. An answer can be checked for accuracy or whether it is within a certain range of the correct answer, but unless it is a special purpose-built mathematical E-Assessment system the system is unlikely to have computational capability and so cannot, for example, account for “method marks” which are commonly awarded in paper-based marking.

From a pedagogical perspective, the importance of providing useful formative feedback to students at a point in their learning when they can benefit from the feedback and put it to use must not be understated (Grieve et all, 2015; Ferrell, 2012).

In this work, we propose a number of software-based solutions, which will overcome the limitations and inflexibilities of existing E-Assessment systems.