LEARNING IMPULSE CONTROL IN A NOVEL ANIMAL MODEL: SYNAPTIC, CELLULAR, AND PHARMACOLOGICAL SUBSTRATES

Impulse control, an executive process that restrains inappropriate actions, is impaired in numerous psychiatric conditions. This thesis reports three experiments that utilized a novel animal model of impulse control, the response inhibition (RI) task, to examine the substrates that underlie learning this task. In the first experiment, rats were trained to withhold responding on the RI task, and then euthanized for electrophysiological testing. Training in the RI task increased the AMPA/NMDA ratio at the synapses of pyramidal neurons in the prelimbic, but not infralimbic, region of the medial prefrontal cortex. This enhancement paralleled performance as subjects underwent acquisition and extinction of the inhibitory response. AMPA/NMDA was elevated only in neurons that project to the ventral striatum. Thus, this experiment identified a synaptic correlate of impulse control. In the second experiment, a separate group of rats were trained in the RI task prior to electrophysiological testing. Training in the RI task produced a decrease in membrane excitability in prelimbic, but not infralimbic, neurons as measured by maximal spiking evoked in response to increasing current injection. Importantly, this decrease was strongly correlated with successful inhibition in the task. Fortuitously, subjects trained in an operant control condition showed elevated infralimbic, but not prelimbic, excitability, which was produced by learning an anticipatory signal that predicted imminent reward availability. These experiments revealed two cellular correlates of performance, corresponding to learning two different associations under distinct task conditions. In the final experiment, rats were trained on the RI task under three conditions: Short (4-s), long (60-s), or unpredictable (1-s to 60-s) premature phases. These conditions produced distinct errors on the RI task. Interestingly, amphetamine increased premature responding in the short and long conditions, but decreased premature responding in the unpredictable condition. This dissociation may arise from interactions between amphetamine and underlying cognitive processes, such as attention, timing, and conditioned avoidance. In summary, this thesis showed that learning to inhibit a response produces distinct synaptic, cellular, and pharmacological changes. It is hoped that these advances will provide a starting point for future therapeutic interventions of disorders of impulse control.

The uptake of silica during the spring bloom in the North East Atlantic Ocean

A full understanding of the biogeochemical cycling of silica in the North Atlantic is hampered by a lack of estimates of silica uptake by phytoplankton. We applied the ${}^{32}\text{Si}$ radiotracer incubation technique to determine silica uptake rates at 10 sites during the UK-(Natural Environment Research Council) Faroes-Iceland-Scotland hydrographic and environmental survey (FISHES) cruise in the Northeast Atlantic, May 2001. Column silica uptake rates ranged between 6 and 166 mmol Si $\text{m}^{-2}\ \text{d}^{-1}$; this data set was integrated with concurrent hydrographic, chemical, and primary productivity data to explain these changes in silica uptake in terms of the progress of the spring bloom. In order to interpret data covering a relatively large spatial and temporal scale, we used mean photic zone silica concentration as a proxy time-series measure of diatom bloom progression. Both absolute and specific silica uptake rates were highest at dissolved silica concentrations >2 mmol $\text{L}^{-1}$. Si and C uptake were vertically decoupled at those stations where surface silica was strongly depleted. Absolute primary productivity was not strongly correlated with dissolved silica concentrations, owing to either exhaustion of silica at diatom-dominated stations or to dominance of the community by other phytoplankton. Silica uptake as a function of increased substrate concentration was linear up to 25 $\mu \text{mol}\ \text{L}^{-1}$; we consider some possible reasons for the nonhyperbolic response.

High levels of genetic structuring as a result of population fragmentation in the tropical tree species Caesalpinia echinata Lam.

We have investigated levels of genetic diversity within and among seven remnant populations of Caesalpinia echinata Lam., an endangered species found as fragmented populations in three major areas around the coastal regions of Brazil. Using amplified fragment length polymorphism (AFLP) genetic markers, we detected levels of within-population genetic diversity ranging from 0.092 to 0.163, with the lowest values generally being found in the smallest populations. Estimates of between-population genetic differentiation were strongly correlated with geographical distance ( r = 0.884, p <0.001), which, along with a neighbour-joining phylogenetic analysis, strongly suggested high levels of genetic isolation by distance. Over half (62%) of the total genetic diversity was partitioned between populations, further highlighting the genetic distinctness of individual populations. Taken together, these results suggest that fragmentation has led to an increase in population differentiation between fragments of C. echinata. These formations will be of great value in the development of conservation plans for species exhibiting high levels of genetic differentiation due to fragmentation, such as indication of conservation unit size, which populations should be chosen as priority in conservation plans and which samples should be introduced in areas with a low number of individuals of brazilwood.

Measurement of Short-Range Correlations in Shock-Compressed Plastic by Short-Pulse X-Ray Scattering

We have performed short-pulse x-ray scattering measurements on laser-driven shock-compressed plastic samples in the warm dense matter regime, providing instantaneous snapshots of the system evolution. Time-resolved and angularly resolved scattered spectra sensitive to the correlation effects in the plasma show the appearance of short-range order within a few interionic separations. Comparison with radiation-hydrodynamic simulations indicates that the shocked plastic is compressed with a temperature of a few electron volts. These results are important for the understanding of the thermodynamic behavior of strongly correlated matter for conditions relevant to both laboratory astrophysics and inertial confinement fusion research.

Association of gene expression with sequential proliferation, differentiation and tumor formation in murine skin

Differential gene expression in two established initiation and promotion skin carcinogenesis models during promotion and tumor formation was determined by microarray technology with the purpose of distinguishing the genes more associated with neoplastic transformation from those linked with proliferation and differentiation. The first model utilized dimethylbenz[a]anthracene initiation and 12-O-tetradecanoylphorbol 13-acetate (TPA) promotion in the FVB/N mouse, and the second TPA promotion of the Tg.Ac mouse, which is endogenously initiated by virtue of an activated Ha-ras transgene. Comparison of gene expression profiles across the two models identified genes whose altered expression was associated with papilloma formation rather than TPA-induced proliferation and differentiation. DMBA suppressed TPA-induced differentiation which allowed identification of those genes associated more specifically with differentiation rather than proliferation. EASE (Expression Analysis Systemic Explorer) indicated a correlation between muscle-associated genes and skin differentiation, whereas genes involved with protein biosynthesis were strongly correlated with proliferation. For verification the altered expression of selected genes were confirmed by RT-PCR; Carbonic anhydrase 2, Thioredoxin 1 and Glutathione S-transferase omega 1 associated with papilloma formation and Enolase 3, Cystatin 6 and Filaggrin associated with TPA-induced proliferation and differentiation. In situ analysis located the papillomas Glutathione S-transferase omega 1 expression to the proliferating areas of the papillomas. Thus we have identified profiles of differential gene expression associated with the tumorigenesis and promotion stages for skin carcinogenesis in the mouse.

The relationship between the stockperson's personality and attitudes and the productivity of dairy cows

This study investigated the relationships amongst personality traits and attitudes of 311 dairy stockpeople and the milk yield they obtained. A questionnaire pack consisting of a big-five measure of personality (which includes the traits of extraversion, agreeableness, conscientiousness, emotional stability and intellect), a four-factor attitude questionnaire and associated demographic and production questions was posted out to Northern Ireland dairy farmers. Pearson correlations were used to assess the relationship between personality and attitudes and partial correlations were calculated between milk yield and these psychometric measures. The personality traits of agreeableness and conscientiousness were most strongly correlated to positive attitudes towards working with dairy cows. None of the stockpeople's personality traits were significantly correlated with the milk yield they obtained. Three of the attitude scales, however, were significantly correlated with milk yield; milk yield was related to higher levels of empathy and job satisfaction and lower levels of negative beliefs, These findings, along with previous research, suggest stockperson attitudes may be important in relation to dairy cow welfare and production.

Stochastic analysis of free surface flow through earth dams

This research investigated the unconfined flow through dams. The hydraulic conductivity was modeled as spatially random field following lognormal distribution. Results showed that the seepage flow produced from the stochastic solution was smaller than its deterministic value. In addition, the free surface was observed to exit at a point lower than that obtained from the deterministic solution. When the hydraulic conductivity was strongly correlated in the horizontal direction than the vertical direction, the flow through the dam has markedly increased. It is suggested that it may not be necessary to construct a core in dams made from soils that exhibit high degree of variability.

Climate drivers for peatland palaeoclimate records

Reconstruction of hydroclimate variability is an important part of understanding natural climate change on decadal to millennial timescales. Peatland records reconstruct 'bog surface wetness' (BSW) changes, but it is unclear whether it is a relative dominance of precipitation or temperature that has driven these variations over Holocene timescales. Previously, correlations with instrumental climate data implied that precipitation is the dominant control. However, a recent chironomid inferred July temperature record suggested temperature changes were synchronous with BSW over the mid-late Holocene. This paper provides new analyses of these data to test competing hypotheses of climate controls on bog surface wetness and discusses some of the distal drivers of large-scale spatial patterns of BSW change. Using statistically based estimates of uncertainty in chronologies and proxy records, we show a correlation between Holocene summer temperature and BSW is plausible, but that chronologies are insufficiently precise to demonstrate this conclusively. Simulated summer moisture deficit changes for the last 6000 years forced by temperature alone are relatively small compared with observations over the 20th century. Instrumental records show that summer moisture deficit provides the best explanatory variable for measured water table changes and is more strongly correlated with precipitation than with temperature in both Estonia and the UK. We conclude that BSW is driven primarily by precipitation, reinforced by temperature, which is negatively correlated with precipitation and therefore usually forces summer moisture deficit in the same direction. In western Europe, BSW records are likely to be forced by changes in the strength and location of westerlies, linked to large-scale North Atlantic ocean and atmospheric circulation. (C) 2009 Elsevier Ltd. All rights reserved.

Heritability of immune function in the caterpillar Spodoptera littoralis

Phenoloxidase (PO) is believed to be a key mediator of immune function in insects and has been implicated both in non-self recognition and in resistance to a variety of parasites and pathogens, including baculoviruses and parasitoids. Using larvae of the Egyptian cotton leafworm, Spodoptera littoralis, we found that despite its apparent importance, haemolymph PO activity varied markedly between individuals, even amongst insects reared under apparently identical conditions. Sib-analysis methods were used to determine whether individuals varied genetically in their PO activity, and hence in one aspect of immune function. The heritability estimate of haemolymph PO activity was high (h 2 = 0.690 +/- 0.069), and PO activity in the haemolymph was strongly correlated with PO activity in both the cuticle and midgut; the sites of entry for most parasites and pathogens. Haemolymph PO activity was also strongly correlated with the degree to which a synthetic parasite (a small piece of nylon monofilament) was encapsulated and melanized (r = 0.622 +/- 0.142), suggesting that the encapsulation response is also heritable. The mechanism maintaining this genetic variation has yet to be elucidated.

Transport, atom blockade and output coupling in a Tonks-Girardeau gas

Recent landmark experiments have demonstrated how quantum mechanical impurities can be created within strongly correlated quantum gases and used to probe the coherence properties of these systems. Here we present a theoretical model to simulate such an output coupler for a Tonks- Girardeau gas that shows excellent agreement with the experimental results for atom transport and output coupling. The solid theoretical basis our model provides allows us to explore non-equilibrium transport phenomena in ultra-cold quantum gases and leads us to predict a regime of atom blockade, where the impurity component becomes localised in the parent cloud despite the presence of gravity. We show that this provides a stable mixed-species quantum gas in the strongly correlated limit.

Probing magnetic order in ultracold lattice gases

A forthcoming challenge in ultracold lattice gases is the simulation of quantum magnetism. That involves both the preparation of the lattice atomic gas in the desired spin state and the probing of the state. Here we demonstrate how a probing scheme based on atom-light interfaces gives access to the order parameters of nontrivial quantum magnetic phases, allowing us to characterize univocally strongly correlated magnetic systems produced in ultracold gases. This method, which is also nondemolishing, yields spatially resolved spin correlations and can be applied to bosons or fermions. As a proof of principle, we apply this method to detect the complete phase diagram displayed by a chain of (rotationally invariant) spin-1 bosons.

BRCA1 transcriptionally regulates genes associated with the basal breast cancer phenotype

Background Ten to twenty per cent of breast tumours exhibit a basallike genetic profile and these tumours carry a poor prognosis. Breast tumours which contain germline mutations for BRCA1 commonly exhibit a molecular profile similar to basal breast tumours. BRCA1 is a tumour suppressor gene which is mutated in up to 5–10% of breast cancer cases and is involved in multiple cellular processes including DNA damage control, cell cycle checkpoint control, apoptosis, ubiquitination and transcriptional regulation.

Methods Microarray-based profiling was carried out using the HCC1937EV and HCC1937BR breast cancer cell lines. Basal gene and protein expression levels were analysed by qRT-PCR and western blotting. ChIP analyses were performed and demonstrated that BRCA1 regulates basal gene expression through a transcriptional mechanism involving c-myc.

Results We have previously carried out microarray-based expression profiling to examine differences in gene expression when BRCA1 is reconstituted in BRCA1 mutated HCC1937 breast cancer cells. We observed that p-cadherin and the cytokeratin 5 and cytokeratin 17 genes, which are strongly correlated with the basal phenotype, are differentially expressed when BRCA1 is reconstituted. In addition, qRT-PCR and ChIP analysis of BRCA1 reconstituted cells show that BRCA1 represses the expression of these basal genes by a transcriptional mechanism. Furthermore, abrogation of endogenous BRCA1 protein in the T47D cell line using siRNA results in reexpression of these basal genes, suggesting that BRCA1 expression levels may be important in basal gene expression. We have also demonstrated that BRCA1 is physically associated with the promoter regions of basal genes through an association with c-myc. Consequently, we have confirmed that siRNA inhibition of c-myc in T47D cells results in re-expression of these genes.

Conclusions Our results suggest that BRCA1 is involved in the transcriptional regulation of genes associated with the basal phenotype and that BRCA1 controls basal gene expression through a transcriptional mechanism involving c-myc. Further work is now concentrating on defining the relationship between BRCA1 and basal gene expression and how this may affect clinical responses to breast cancer chemotherapy.

LASING PROPERTIES OF THE J = 0-1 AND THE J = 2-1 LINES OF A NEON-LIKE GERMANIUM SOFT-X-RAY LASER

Lasing properties of a collisional-excitation Ne-like Ge soft-x-ray laser have been studied with exploding-foil, single-slab, and double-slab targets under identical pumping conditions. Experimental results for the angular intensity distributions and the temporal variations of the lasing intensities are examined with a hydrodynamic code and ray-trace calculations. The observed angular distribution are well reproduced by these analyses, and it is found that the effective gain regions are located on the high-density side of the expected gain regions. It is shown that the observed lasing intensity of the J = 0 to J = 1 line is strongly correlated with the temporal change of the calculated electron temperature for both the slab and the exploding-foil targets.

Size-selective fishing drives species composition in the Celtic Sea

Fishing alters community size structure by selectively removing larger individual fish and by changing the relative abundance of different-sized species. To assess the relative importance of individual-and species-level effects, two indices of fish community structure were compared, the relative abundance of large fish individuals (large fish indicator, LFI) and the relative abundance of large fish species (large species indicator, LSI). The two indices were strongly correlated for empirical data from the Celtic Sea and for data from simulated model communities, suggesting that much of the variability in the LFI is caused by shifts in the relative abundance of species (LSI). This correlation is explained by the observation that most of the biomass of a given species is spread over few length classes, a range spanning the factor 2 of individual length, such that most species contributed predominantly to either the small or the large component of the LFI. The results suggest that the effects of size-selective fishing in the Celtic Sea are mediated mainly through changes in community composition.

New prognostic markers, determined using gene expression analyses, reveal two distinct subtypes of chronic myelomonocytic leukaemia patients

Chronic myelomonocytic leukaemia (CMML) is a heterogeneous haematopoietic disorder characterized by myeloproliferative or myelodysplastic features. At present, the pathogenesis of this malignancy is not completely understood. In this study, we sought to analyse gene expression profiles of CMML in order to characterize new molecular outcome predictors. A learning set of 32 untreated CMML patients at diagnosis was available for TaqMan low-density array gene expression analysis. From 93 selected genes related to cancer and cell cycle, we built a five-gene prognostic index after multiplicity correction. Using this index, we characterized two categories of patients with distinct overall survival (94% vs. 19% for good and poor overall survival, respectively; P = 0.007) and we successfully validated its strength on an independent cohort of 21 CMML patients with Affymetrix gene expression data. We found no specific patterns of association with traditional prognostic stratification parameters in the learning cohort. However, the poor survival group strongly correlated with high-risk treated patients and transformation to acute myeloid leukaemia. We report here a new multigene prognostic index for CMML, independent of the gene expression measurement method, which could be used as a powerful tool to predict clinical outcome and help physicians to evaluate criteria for treatments.