Prolactin Induces Tuberoinfundibular Dopaminergic Neurone Differentiation in Snell Dwarf Mice if Administered Beginning at 3 Days of Age

The hypothalamic tuberoinfundibular dopaminergic (TIDA) neurones secrete dopamine, which inhibits prolactin secretion. TIDA neurone numbers are deficient in Ames (df/df) and Snell (dw/dw) dwarf mice, which lack prolactin, growth hormone and thyroid-stimulating hormone. Prolactin therapy initiated before 21 days maintains normal-sized TIDA neurone numbers in df/df mice and, when initiated as early as 7 days, maintains the maximum TIDA neurone numbers observed in dw/dw development, which are decreased compared to those in normal mice. The present study investigated the effect of prolactin dose and species on TIDA neurone development. Snell dwarf and normal mice were treated with saline, 5 μg of ovine prolactin (oPRL), 50 μg of oPRL, or 50 μg of recombinant mouse prolactin (rmPRL) beginning at 3 days of age. Brains were analysed at 45 days using catecholamine histofluorescence, and immunohistochemistry for tyrosine hydroxylase or bromodeoxyuridine. Normal mice had greater (P ≤ 0.01) TIDA neurones than dw/dw, regardless of treatment. TIDA neurones in 50 μg oPRL-treated dw/dw mice were greater (P ≤ 0.05) than those in 5 μg oPRL- and rmPRL-treated dw/dw mice, which were greater (P ≤ 0.01) than those in saline-treated dw/dw mice. Fifty microgram oPRL-treated dw/dw mice also had greater (P < 0.01) TIDA neurone numbers than the maximum numbers observed in untreated dw/dw mice development. Among saline, 5 μg oPRL and 50 μg oPRL treatments, but not rmPRL, A14 neurone numbers were higher (P ≤ 0.01) in normal compared to in dw/dw mice. The mechanism of TIDA neurone recruitment was investigated using bromodeoxyuridine (BrdU) treatment at intervals after 21 days. Mice treated with rmPRL, but not oPRL, had increased BrdU incorporation in the periventricular area surrounding the third ventricle and median eminence and in the arcuate nucleus. The data obtained in the present study indicate that oPRL, but not rmPRL, when given at a high enough dose, induces TIDA neurone differentiation in dw/dw mice. This supports neurotrophic effects of prolactin on TIDA neurones in early postnatal development that extends beyond maintenance of the cell population

A Framework for Analysis of Case Studies of Reading Lessons

This paper focuses on the development and study of a framework to provide direction and guidance for practicing teachers in using a web-based case studies program for professional development in early reading; the program is called Case Studies Reading Lessons (CSRL). The framework directs and guides teachers’ analysis of reading instruction by focusing their attention to three critical dimensions of the process of teaching; in theory, analysis of a wide variety of reading lessons, using this framework, should contribute to teachers’ expertise. We report on a study of the Thinking Questions, which scaffold teachers’ analysis of the reading lessons, to determine the extent to which their responses meet theoretical expectations. Results suggest that teachers’ ratings of lessons tap their overall expertise in analysis of reading instruction, such that the three dimensions and features that represent these do not constitute separate factors. However, performance on the Thinking Questions differentiated more and less experienced teachers. As expected, less experienced teachers wrote longer and more specific comments about the instruction than more experienced teachers, who tended to highlight effective principles. The results suggest that an analytic framework of the kind used in CSRL holds promise as an effective component of a case-based professional development program. However, they also point to the need for further study of the framework and its influence on teachers’ own teaching practices

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Complexity of Bradley-Manna-Sipma Lexicographic Ranking Functions

In this paper we turn the spotlight on a class of lexicographic ranking functions introduced by Bradley, Manna and Sipma in a seminal CAV 2005 paper, and establish for the first time the complexity of some problems involving the inference of such functions for linear-constraint loops (without precondition). We show that finding such a function, if one exists, can be done in polynomial time in a way which is sound and complete when the variables range over the rationals (or reals). We show that when variables range over the integers, the problem is harder -- deciding the existence of a ranking function is coNP-complete. Next, we study the problem of minimizing the number of components in the ranking function (a.k.a. the dimension). This number is interesting in contexts like computing iteration bounds and loop parallelization. Surprisingly, and unlike the situation for some other classes of lexicographic ranking functions, we find that even deciding whether a two-component ranking function exists is harder than the unrestricted problem: NP-complete over the rationals and $\Sigma^P_2$-complete over the integers.Comment: Technical report for a corresponding CAV'15 pape

Free recall and forgetting of emotionally arousing words in autism spectrum disorder

Since the earliest descriptions of individuals with autism spectrum disorders (ASDs) abnormalities in affective behaviours have been considered a prominent feature in their clinical manifestations. What remains unclear, however, is whether these altered emotional behaviours are a mere facet of abnormalities in socio-cognitive processes or whether they constitute a primary feature of the condition. A number of studies now indicate that emotional processing atypicalities in ASD extend to domains outside the broader context of social cognition leading us to suggest that the disorder may be characterised by basic abnormalities in how psychophysiological and cognitive emotional responses modulate one another [Gaigg, S. B. & Bowler, D. M. (2007). Differential fear conditioning in Asperger's syndrome: Implications for an amygdala theory of autism. Neuropsychologia, 45, 2125–2134]. In the current study, we show that although individuals with ASD, like typical individuals, exhibit a free recall advantage for emotionally arousing and semantically related neutral as compared to unrelated neutral words, they do not show reduced forgetting rates for arousing stimuli as do typical individuals. These observations provide further support for the view that psychophysiological emotional responses do not modulate cognitive processes normally in ASD and further implicate abnormalities of amygdala connectivity (in particular with the hippocampus) in the neuropathology underlying this disorder

Is the disposition effect related to investors’ reliance on System 1 and System 2 processes or their strategy of emotion regulation?

We report research on investor susceptibility to the disposition effect, a financial decision-making bias where investors have a greater propensity to realize gains than realize losses. Despite theoretical arguments for the influence of emotions, research on susceptibility to this bias, on real investors, has relied primarily on socio-demographic explanations. Some experimental research on student populations has considered emotions more directly, but has not addressed differences in individual susceptibility and has not examined genuinely consequential investor behaviour in real markets. Our research addresses this gap by predicting susceptibility to the disposition effect based on investors’ reliance on intuitive (emotion mediated) cognition (System 1), analytical cognition (System 2) and the strategies they use to regulate their emotions. Using investors’ trading records from a UK sample, we measure their susceptibility to the disposition effect and assess, through a questionnaire, their reliance on Systems 1 and 2 cognitive processes and use of two emotion regulation strategies. Investors with higher reliance on System 1 processes have greater disposition effect, but reliance on System 2 processes is not related to the disposition effect. Investor reliance on reappraisal (an emotion regulation strategy of changing a situation’s meaning to alter its emotional impact) reduces their disposition effect. However, the use of expressive suppression (a strategy that inhibits emotion expressive behaviour) does not show a statistically significant relationship with this bias. These results suggest that investors’ intuitive emotional reactions explain susceptibility to bias, and that effective strategies of regulating emotions enable this bias to be overcome

Prolactin in man: a tale of two promoters

The pituitary hormone prolactin (PRL) is best known for its role in the regulation of lactation. Recent evidence furthermore indicates PRL is required for normal reproduction in rodents. Here, we report on the insertion of two transposon-like DNA sequences in the human prolactin gene, which together function as an alternative promoter directing extrapituitary PRL expression. Indeed, the transposable elements contain transcription factor binding sites that have been shown to mediate PRL transcription in human uterine decidualised endometrial cells and lymphocytes. We hypothesize that the transposon insertion event has resulted in divergent (pituitary versus extrapituitary) expression of prolactin in primates, and in differential actions of pituitary versus extrapituitary prolactin in lactation versus pregnancy respectively. Importantly, the TE insertion might provide a context for some of the conflicting results obtained in studies of PRL function in mice and man. BioEssays 28: 1051–1055, 2006. © 2006 Wiley Periodicals, Inc

Investigating the robustness of the classical enzyme kinetic equations in small intracellular compartments

<p>Abstract</p> <p>Background</p> <p>Classical descriptions of enzyme kinetics ignore the physical nature of the intracellular environment. Main implicit assumptions behind such approaches are that reactions occur in compartment volumes which are large enough so that molecular discreteness can be ignored and that molecular transport occurs via diffusion. Though these conditions are frequently met in laboratory conditions, they are not characteristic of the intracellular environment, which is compartmentalized at the micron and submicron scales and in which active means of transport play a significant role.</p> <p>Results</p> <p>Starting from a master equation description of enzyme reaction kinetics and assuming metabolic steady-state conditions, we derive novel mesoscopic rate equations which take into account (i) the intrinsic molecular noise due to the low copy number of molecules in intracellular compartments (ii) the physical nature of the substrate transport process, i.e. diffusion or vesicle-mediated transport. These equations replace the conventional macroscopic and deterministic equations in the context of intracellular kinetics. The latter are recovered in the limit of infinite compartment volumes. We find that deviations from the predictions of classical kinetics are pronounced (hundreds of percent in the estimate for the reaction velocity) for enzyme reactions occurring in compartments which are smaller than approximately 200 nm, for the case of substrate transport to the compartment being mediated principally by vesicle or granule transport and in the presence of competitive enzyme inhibitors.</p> <p>Conclusion</p> <p>The derived mesoscopic rate equations describe subcellular enzyme reaction kinetics, taking into account, for the first time, the simultaneous influence of both intrinsic noise and the mode of transport. They clearly show the range of applicability of the conventional deterministic equation models, namely intracellular conditions compatible with diffusive transport and simple enzyme mechanisms in several hundred nanometre-sized compartments. An active transport mechanism coupled with large intrinsic noise in enzyme concentrations is shown to lead to huge deviations from the predictions of deterministic models. This has implications for the common approach of modeling large intracellular reaction networks using ordinary differential equations and also for the calculation of the effective dosage of competitive inhibitor drugs.</p

Exposure to inflammatory cytokines selectively limits GM-CSF production by induced T regulatory cells

Interest in manipulating the immunosuppressive powers of Foxp3-expressing T regulatory cells as an immunotherapy has been tempered by their reported ability to produce proinflammatory cytokines when manipulated in vitro, or in vivo. Understanding processes that can limit this potentially deleterious effect of Treg cells in a therapeutic setting is therefore important. Here, we have studied this using induced (i) Treg cells in which de novo Foxp3 expression is driven by TCR-stimulation in vitro in the presence of TGF-β. We show that iTreg cells can produce significant amounts of three proinflammatory cytokines (IFN-γ, GM-CSF and TNF-α) upon secondary TCR stimulation. GM-CSF is a critical T-cell derived cytokine for the induction of EAE in mice. Despite their apparent capacity to produce GM-CSF, myelin autoantigen-responsive iTreg cells were unable to provoke EAE. Instead, they maintained strong suppressive function in vivo, preventing EAE induction by their CD4+Foxp3− counterparts. We identified that although iTreg cells maintained the ability to produce IFN-γ and TNF-α in vivo, their ability to produce GM-CSF was selectively degraded upon antigen stimulation under inflammatory conditions. Furthermore, we show that IL-6 and IL-27 individually, or IL-2 and TGF-β in combination, can mediate the selective loss of GM-CSF production by iTreg cells