C-Jun N-terminal kinase (JNK) isoforms play differing roles in otitis media

BACKGROUND: Innate immunity and tissue proliferation play important roles in otitis media (OM), the most common disease of childhood. CJUN terminal kinase (JNK) is potentially involved in both processes. RESULTS: Genes involved in both innate immune and growth factor activation of JNK are upregulated during OM, while expression of both positive and negative JNK regulatory genes is altered. When compared to wildtypes (WTs), C57BL/6 mice deficient in JNK1 exhibit enhanced mucosal thickening, with delayed recovery, enhanced neutrophil recruitment early in OM, and delayed bacterial clearance. In contrast, JNK2(−/−) mice exhibit delayed mucosal hyperplasia that eventually exceeds that of WTs and is slow to recover, delayed recruitment of neutrophils, and failure of bacterial clearance. CONCLUSIONS: The results suggest that JNK1 and JNK2 play primarily opposing roles in mucosal hyperplasia and neutrophil recruitment early in OM. However, both isoforms are required for the normal resolution of middle ear infection. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12865-014-0046-z) contains supplementary material, which is available to authorized users

Let's plan it deductively!

AbstractThe paper describes a transition logic, TL, and a deductive formalism for it. It shows how various important aspects (such as ramification, qualification, specificity, simultaneity, indeterminism etc.) involved in planning (or in reasoning about action and causality for that matter) can be modelled in TL in a rather natural way. (The deductive formalism for) TL extends the linear connection method proposed earlier by the author by embedding the latter into classical logic, so that classical and resource-sensitive reasoning coexist within TL. The attraction of a logical and deductive approach to planning is emphasized and the state of automated deduction briefly described

Towards a Computational Model of Anaphora in Discourse: Reference to Events and Actions

When people talk or write, they refer to things, objects, events, actions, facts and/or states that have been mentioned before. Such context-dependent reference is called anaphora. In general, linguists and researchers working in artificial intelligence have looked at the problem of anaphora interpretation as that one of finding the correct antecedent for anaphor - that is, the previous words or phrases to which the anaphor is linked. Lately, people working in the area of anaphora have suggested that in order for anaphors to be interpreted correctly, they must be interpreted by reference to entities evoked by the previous discourse rather than in terms of their antecedents. In this recent work, people have focused on entities of type concrete individual (an x) or set of such individuals (some xs) or generic class of such individuals (xs). This proposal focuses on anaphora interpreted as referring to entities of type event and action. It considers four issues: (i) what aspects of the discourse give evidence of the events and actions the speaker is talking about, (ii) how actions and events are represented in the listener\u27s discourse model, (iii) how to delimit the set of events and actions which correspond to possible choices for a particular anaphor, and (iv) how to obtain the speaker\u27s intended referent to an action or event from that set of possible choices. Anaphoric forms that are used to refer to entities of type action and event include sentential-it, sentential-that pronominalizations as well as do it, do that, and do this forms. I will concentrate on the four previously mentioned issues along with other mechanisms that will provide us with better tools for the successful interpretation of anaphoric reference in discourse

PHYSIOLOGY OF A BASAL VERTEBRATE, THE SEA LAMPREY (PETROMYZON MARINUS): OSMOREGULATION AND CORTICOSTEROID ACTION

Lamprey represent the most basal living example of a vertebrate animal which regulates its internal fluid and ion homeostasis. This phylogenetic position among vertebrates makes lamprey an important model organism for understanding the basal state, and thus the evolution, of physiological systems such as the mechanisms of osmo- and ionoregulation and the endocrine factors controlling them. Sea lamprey (Petromyzon marinus) are an anadromous fish, migrating from freshwater (FW) to seawater (SW) as juveniles, then returning back upstream as mature adults to spawn. Surviving this transition from a solute-poor FW environment to a solute-concentrated SW environment requires many changes to osmo- and ionoregulatory mechanisms, which are driven, in part, by signaling from corticosteroid hormones. Much of this dissertation examines the molecular mechanisms for osmo- and ionoregulation in the lamprey gill and intestine and how corticosteroids control osmoregulatory processes in these tissues. Additionally, effect of temperature on osmoregulation, and the corticosteroid response to handling and thermal stressors are also examined. I report the results of experiments that were designed to identify molecular and organismal processes driving physiological acclimation to FW or SW residence. Special attention was given to understanding the endogenous nature of sea lamprey physiology, particularly regarding the development of the ability to survive and osmoregulate in SW that occurs during the larvae-to-juvenile metamorphosis. In Chapter 1, I offer an introduction to basic sea lamprey biology and physiology, including background on osmoregulation and corticosteroid action in fishes. In Chapter 2, I functionally characterize a critical ion transporter in the gills of SW-acclimated fishes responsible for Cl- secretion, the Na+/K+/2Cl- cotransporter (NKCC1). I demonstrate that (i) a membrane-bound NKCC1 is upregulated in the gills of sea lamprey during metamorphosis in preparation for SW migration; (ii) the timing of gill NKCC1 upregulation corresponds to the upregulation of another critical ion transporter and biomarker of ionoregulatory activity in fish gills, Na+/K+-ATPase (NKA), as well as the acquisition of SW tolerance; and (iii) pharmacological inhibition of NKCC1 markedly decreases SW tolerance in juvenile sea lamprey. In Chapter 3, I describe branchiometric changes that occur during the sea lamprey metamorphosis and SW acclimation, such as an increase in the branchiosomatic index (percentage of total body weight contributed by the gills) and a redistribution of the gill pouch-specific contribution to total gill NKA activity. In Chapters 4 and 5, I characterize 11-deoxycortisol as the endogenous corticosteroid hormone that controls osmo- and ionoregulation in the gills and intestine of sea lamprey. I show that (i) 11-deoxycortisol and its corticosteroid receptor (CR) are upregulated during metamorphosis and after exposure to SW; (ii) that the CR present in the gill and intestine are highly specific to binding by 11-deoxycortisol; and (iii) only 11-deoxycortisol (and not deoxycorticosterone, the other endogenous corticosteroid in lamprey blood) can upregulate osmo- and ionoregulatory mechanisms and SW tolerance in metamorphosing sea lamprey. In Chapter 6, I describe the glucose stimulating action of 11-deoxycortisol. I demonstrate that (i) lamprey responding to acute stress upregulate circulating 11-deoxycortisol and glucose in the blood plasma; (ii) only treatment with 11-deoxycortisol (and not deoxycorticosterone) increases plasma glucose; and (iii) among other tissues, the kidney uniquely expresses the transcriptional markers of steroidogenesis. Finally, in Chapter 7, I investigate the osmoregulatory capacity of post-metamorphic juvenile sea lamprey throughout springtime water warming and assess thermal tolerance of juvenile sea lamprey. I report that (i) elevated levels of gill NKA activity and SW tolerance persist well into the spring; (ii) survival after SW entry in late-spring is affected by temperature; and (iii) that juvenile sea lamprey can tolerate temperatures above 30 °C but begin showing signs of thermal stress, such as upregulation of heat shock proteins, at temperatures below their critical thermal maximum. Taken together, this dissertation contributes a substantial body of work regarding mechanisms of epithelial ion transport and corticosteroid action in the most basal vertebrate group. This dissertation describes that a single endogenous corticosteroid, 11-deoxycortisol, has a critical role in promoting the development of osmo- and ionoregulatory mechanisms during metamorphosis that confer survival in SW. This work will be of interest to scientists from a range of disciplines including physiology, endocrinology, evolutionary biology, developmental biology, and ecology, as well as conservationists and managers working with sea lamprey

Beyond dynamic risk factors: Towards a comprehensive explanation of offending

The current conceptualisation of dynamic risk factors (DRF) for criminal offending is problematic. There have been significant conceptual issues highlighted in this domain, however, until recently addressing these has not been a priority for researchers. Instead, research has predominantly focused on the success of DRF in predicting reoffending and the effectiveness of treatment programmes that target these factors. DRF are typically defined as aspects of individuals and their environments that are associated with an increased likelihood of reoffending, and they are widely considered ‘plausible causes’ of criminal behaviour. It is acknowledged that this definition encompasses a wide range of individual characteristics, social processes, behaviours, and environmental features, and that these vary in their ability to explain and predict offending. The more recent interest in features that reduce risk has prompted similar discussions about the concept of protective factors (PF). Given the frequent use of, and interest in, these foundational concepts it is timely to investigate them in depth, and to address two key issues. First, both DRF and PF are broad category labels that encompass a diverse (and largely unspecified) range of psychological and contextual features and processes. Second, without a clear understanding of what exactly these constructs are, it is difficult to effectively link them to correctional research and practice. I will begin this thesis by setting out the problems with the reliance on DRF to explain offending. I will do this by exploring recent empirical findings concerning their relationship with recidivism and outlining numerous conceptual problems which make DRF poor candidates for causal explanation. I will then suggest a shift in focus, from these crime correlates to human nature and agency, and argue that this perspective is essential in explaining any behaviour. I will present a preliminary model based on agency and demonstrate the utility of this perspective in reconceptualising DRF as aspects of goal-directed behaviour. Next, I will develop a framework for continuing this theoretical research and adding depth to theories of agency. Finally, I will discuss the implications of agency theories for forensic interventions, including their integration with widely used rehabilitation models. I will conclude with an evaluation of the approaches developed throughout this thesis and make some suggestions for future research. This research holds promise in directing the field away from the otherwise inevitable theoretical ‘dead end’

An experimental examination of object-directed ritualized action in children across two cultures.

Ritualized actions are common in daily life, and prevalent across cultures. Adults have been shown, under experimental conditions, to treat objects subjected to ritualized action as special and different relative to objects subjected to non-ritualized action. Similarly, children as young as 4, are sensitive to ritualized actions-frequently reproducing such actions at high fidelity. The current cross-cultural experiment attempts to extend existing findings among two culturally distinct groups of children with regard to object-directed rituals. We predicted that children's preference for a reward would be influenced by ritualized action (but not non-ritualized action). Over two trials we presented children in Australia (N = 93; mean age = 6.03 years, SD = 2.07 years) and Vanuatu (N = 109; mean age = 6.13 years, SD = 1.96 years) with two identical rewards, which was either subjected to ritualized action or non-ritualized action. Contrary to previous findings among adults, ritualized action did not influence children's preference for a reward. We frame the current results in the context of socially relevant group rituals, and discuss the implications for both wider theory and methods. We conclude with a call for pre-registered replications

Beyond dynamic risk factors: Towards a comprehensive explanation of offending

The current conceptualisation of dynamic risk factors (DRF) for criminal offending is problematic. There have been significant conceptual issues highlighted in this domain, however, until recently addressing these has not been a priority for researchers. Instead, research has predominantly focused on the success of DRF in predicting reoffending and the effectiveness of treatment programmes that target these factors. DRF are typically defined as aspects of individuals and their environments that are associated with an increased likelihood of reoffending, and they are widely considered ‘plausible causes’ of criminal behaviour. It is acknowledged that this definition encompasses a wide range of individual characteristics, social processes, behaviours, and environmental features, and that these vary in their ability to explain and predict offending. The more recent interest in features that reduce risk has prompted similar discussions about the concept of protective factors (PF). Given the frequent use of, and interest in, these foundational concepts it is timely to investigate them in depth, and to address two key issues. First, both DRF and PF are broad category labels that encompass a diverse (and largely unspecified) range of psychological and contextual features and processes. Second, without a clear understanding of what exactly these constructs are, it is difficult to effectively link them to correctional research and practice. I will begin this thesis by setting out the problems with the reliance on DRF to explain offending. I will do this by exploring recent empirical findings concerning their relationship with recidivism and outlining numerous conceptual problems which make DRF poor candidates for causal explanation. I will then suggest a shift in focus, from these crime correlates to human nature and agency, and argue that this perspective is essential in explaining any behaviour. I will present a preliminary model based on agency and demonstrate the utility of this perspective in reconceptualising DRF as aspects of goal-directed behaviour. Next, I will develop a framework for continuing this theoretical research and adding depth to theories of agency. Finally, I will discuss the implications of agency theories for forensic interventions, including their integration with widely used rehabilitation models. I will conclude with an evaluation of the approaches developed throughout this thesis and make some suggestions for future research. This research holds promise in directing the field away from the otherwise inevitable theoretical ‘dead end’