Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkâ

Focuses on the reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of IkB kinase beta (IKKbeta) Definition of insulin resistance; Recognition of the IKKbeta pathway as the target for insulin sensitization; Impact of the increase of IKKbeta activity on obese rodents.

Sex reversal in Nile tilapia (Oreochromis niloticus Linnaeus) by androgen immersion

Two experiments were conducted to investigate the efficacy of three androgens applied through immersion treatments on the sex ratio of Nile tilapia (Oreochromis niloticus L.) fry. In experiment 1, 14 days post-hatching (DPH) larvae were exposed to a single immersion treatment in 17α-methyltestosterone (MT), 17α-methyldihydrotestosterone (MDHT) or 17α-ethynyltestosterone (ET) at 200, 600 and 1800 μg L⁻¹ over 4 h (130 larvae per treatment). In experiment 2, Nile tilapia larvae were exposed to the higher androgen concentration (1800 μg L⁻¹) applied as either a single immersion (14 DPH) or double immersion (10 and 14 DPH) over 4 h (125 larvae per treatment). Change in sex proportion within each experiment as well as between experiments was analysed by the chi-square test. In experiment 1, MT, MDHT and ET were equally effective in significantly increasing the proportion of males when applied at 1800 μg L⁻¹ (86.0%, 90.0% and 86.7% respectively). At 200 μg L⁻¹ none of the androgens altered sex ratio. At 600 μg L⁻¹, only MDHT slightly, but significantly skewed the sex ratio towards males (73.0%). In experiment 2, a single immersion treatment at 14 DPH (1800 μg L⁻¹) significantly increased the proportion of males, but at this time the response was significantly hormone dependent (MDHT, 100.0%; MT, 91.6%; ET, 76.9%). When compared with a single immersion, two-immersion treatments significantly increased the proportion of males in the MT-treated group (from 91.6% to 98.3%), decreased the proportion of males in the MDHT group (from 100.0% to 93.4%) and had no significant effect the ET-treated group (change from 76.9% to 82.5%). The overall comparison of the sex ratio among same treatments from different experiments (a single immersion in 1800 μg L⁻¹) was not significantly different.

Reversal of vascular macrophage accumulation and hypertension by a CCR2 antagonist in deoxycorticosterone/salt-treated mice

Infiltration of macrophages into the artery wall plays detrimental roles during hypertension by promoting vascular inflammation and endothelial dysfunction, and it occurs via a chemo-attractant action of chemokines on macrophage cytokine receptors. We sought to identify the key chemokine receptors associated with macrophage infiltration into the vascular wall during deoxycorticosterone acetate (DOCA)/salt-induced hypertension in mice and to evaluate the impact of pharmacological inhibition of these receptors on blood pressure and leukocyte accumulation. Mice treated with DOCA/salt for 21 days displayed markedly elevated systolic blood pressure (158±2 versus 114±5 mm Hg in sham group; P<0.0001). Polymerase chain reaction screening via a gene array of 20 chemokine receptors indicated an increased expression of CCR2 in aortas of DOCA/salt-treated mice. Real-time polymerase chain reaction confirmed mRNA upregulation of CCR2 in aortas from DOCA/salt-treated animals and of the CCR2 ligands CCL2, CCL7, CCL8, and CCL12 (all >2-fold versus sham; P<0.05). Flow cytometry revealed 2.9-fold higher macrophage numbers (ie, CD45+ CD11b+ F4/80+ cells) in the aortic wall of DOCA/salt versus sham-treated mice. Intervention with a CCR2 antagonist, INCB3344 (30 mg/kg per day, IP), 10 days after the induction of hypertension with DOCA/salt treatment, reduced the aortic expression of CCR2 mRNA and completely reversed the DOCA/salt-induced influx of macrophages. Importantly, INCB3344 substantially reduced the elevated blood pressure in DOCA/salt-treated mice. Hence, our findings highlight CCR2 as a promising therapeutic target to reduce both macrophage accumulation in the vascular wall and blood pressure in hypertension.

Cocaine use severity and cerebellar gray matter are associated with reversal learning deficits in cocaine-dependent individuals

Cocaine addiction involves persistent deficits to unlearn previously rewarded response options, potentially due to neuroadaptations in learning-sensitive regions. Cocaine-targeted prefrontal systems have been consistently associated with reinforcement learning and reversal deficits, but more recent interspecies research has raised awareness about the contribution of the cerebellum to cocaine addiction and reversal. We aimed at investigating the link between cocaine use, reversal learning and prefrontal, insula and cerebellar gray matter in cocaine-dependent individuals (CDIs) varying on levels of cocaine exposure in comparison with healthy controls (HCs). Twenty CDIs and 21 HCs performed a probabilistic reversal learning task (PRLT) and were subsequently scanned in a 3-Tesla magnetic resonance imaging scanner. In the PRLT, subjects progressively learn to respond to one predominantly reinforced stimulus, and thenmust learn to respond according to the opposite, previously irrelevant, stimulus-reward pairing. Performance measureswere errors after reversal (reversal cost), and probability of maintaining response after errors. Voxel-based morphometry was conducted to investigate the association between gray matter volume in the regions of interest and cocaine use and PRLT performance. Severity of cocaine use correlated with gray matter volume reduction in the left cerebellum (lobule VIII), while greater reversal cost was correlated with gray matter volume reduction in a partially overlapping cluster (lobules VIIb and VIII). Right insula/inferior frontal gyrus correlated with probability of maintaining response after errors. Severity of cocaine use detrimentally impacted reversal learning and cerebellar gray matter.

Role of muscarinic receptors in the activity of N-desmethylclozapine: reversal of hyperactivity in the phospholipase C knockout mouse

Activity of the cholinergic muscarinic system is associated with modulation of locomotor activity, although the precise mechanism remains unclear. The phospholipase C-[beta]1 knockout mouse displays both M1 muscarinic receptor dysfunction and a hyperactive locomotor phenotype. This mouse serves as an ideal model for the analysis of muscarinic modulation of locomotor activity. The clozapine metabolite N-desmethylclozapine (NDMC) has shown some promise as an alternative or adjunct treatment for psychotic disorders. NDMC shows strong muscarinic acetylcholine receptor affinities, which may contribute to the clinical efficacy of clozapine and account for the correlation between NDMC/clozapine ratio and treatment response. Administration of NMDC reversed a striking hyperactive phenotype in the phospholipase C-[beta]1 knockout mouse, whereas no significant effects were observed in wild-type animals. This highlights the potential role of muscarinic activity in the behavioural response to NDMC. The M1 muscarinic antagonist pirenzepine, however, also reduced the hyperactive phenotype of these mice, emphasizing the importance of muscarinic function in the control of locomotor behaviour, but also calling into question the specific mechanism of action of NMDC at muscarinic receptors.

Pliocene reversal of late Neogene aridification.

The Pliocene epoch (5.3-2.6 Ma) represents the most recent geological interval in which global temperatures were several degrees warmer than today and is therefore considered our best analog for a future anthropogenic greenhouse world. However, our understanding of Pliocene climates is limited by poor age control on existing terrestrial climate archives, especially in the Southern Hemisphere, and by persistent disagreement between paleo-data and models concerning the magnitude of regional warming and/or wetting that occurred in response to increased greenhouse forcing. To address these problems, here we document the evolution of Southern Hemisphere hydroclimate from the latest Miocene to the middle Pliocene using radiometrically-dated fossil pollen records preserved in speleothems from semiarid southern Australia. These data reveal an abrupt onset of warm and wet climates early within the Pliocene, driving complete biome turnover. Pliocene warmth thus clearly represents a discrete interval which reversed a long-term trend of late Neogene cooling and aridification, rather than being simply the most recent period of greater-than-modern warmth within a continuously cooling trajectory. These findings demonstrate the importance of high-resolution chronologies to accompany paleoclimate data and also highlight the question of what initiated the sustained interval of Pliocene warmth.

Pricing segmentation and MBA course choice

The consensus from studies of the price-demand relationship for higher education is that this relationship is negative but small. This paper investigates the circumstances in which demand for an MBA is positive to price increases. A survey of currently enrolled MBA students, and prospective MBA students, found that most students displayed the expected price elasticity in a conjoint analysis of hypothetical MBA course ratings. However, 12 per cent of respondents exhibited “reversal” behaviour regarding price. Profiling these respondents using discriminant analysis suggested that “reversals” seemed prepared to pay more for a course at a high prestige university, if they could study off-campus using print-based materials.

Patterns of coronary heart disease mortality over the 20th century in England and Wales : possible plateaus in the rate of decline

Background
Coronary heart disease (CHD) rates in England and Wales between 1950 and 2005 were high and reasonably steady until the mid 1970s, when they began to fall. Recent work suggests that the rate of change in some groups has begun to decrease and may be starting to plateau or even reverse.

Methods
Data for all deaths between 1931 and 2005 in England and Wales were grouped by year, sex, age at death and contemporaneous ICD code for CHD as cause of death. CHD mortality rates by calendar year and birth cohort were produced for both sexes and rates of change were examined.

Results
The pattern of increased burden of CHD mortality within older age groups has only recently emerged in men, whereas it has been established in women for far longer. CHD mortality rates among younger people showed little variation by birth cohort. For younger women (49 and under), the rate of change in CHD mortality has reversed in the last 20 years, indicating a future plateau and possible reversal of previous improvement in CHD mortality rates. Among younger men the rate of change in CHD mortality has been consistent for the past 15 years indicating that rates in this group have continued to fall steadily.

Conclusion
Although CHD mortality rates continue to drop in older age groups the actual burden of coronary heart disease is increasing due to the ageing of the population. The rate of improvement in CHD mortality appears to be beginning to decline and may even be reversing among younger women.

Increased food energy supply is more than sufficient to explain the US epidemic of obesity

Background: The major drivers of the obesity epidemic are much debated and have considerable policy importance for the population-wide prevention of obesity.

Objective: The objective was to determine the relative contributions of increased energy intake and reduced physical activity to the US obesity epidemic.

Design: We predicted the changes in weight from the changes in estimated energy intakes in US children and adults between the 1970s and 2000s. The increased US food energy supply (adjusted for wastage and assumed to be proportional to energy intake) was apportioned to children and adults and inserted into equations that relate energy intake to body weight derived from doubly labeled water studies. The weight increases predicted from the equations were compared with weight increases measured in representative US surveys over the same period.

Results: For children, the measured weight gain was 4.0 kg, and the predicted weight gain for the increased energy intake was identical at 4.0 kg. For adults, the measured weight gain was 8.6 kg, whereas the predicted weight gain was somewhat higher (10.8 kg).

Conclusions: Increased energy intake appears to be more than sufficient to explain weight gain in the US population. A reversal of the increase in energy intake of 2000 kJ/d (500 kcal/d) for adults and of 1500 kJ/d (350 kcal/d) for children would be needed for a reversal to the mean body weights of the 1970s. Alternatively, large compensatory increases in physical activity (eg, 110–150 min of walking/d), or a combination of both, would achieve the same outcome. Population approaches to reducing obesity should emphasize a reduction in the drivers of increased energy intake.

Control of ovarian development in the yabby (Cherax destructor)

A study under controlled conditions of ovarian development and rematuration in the yabby (Cherax destructot) was undertaken. The purpose of the study was to improve fundamental understanding of the reproductive biology of the species and provide a basis for application to hatchery management in culture. A review was made of the current status of yabby culture in Australia and the present understanding of reproductive biology of decapod Crustacea. The review emphasised factors controlling several aspects of ovarian development, in particular the processes of vitellogenesis. The subsequent study was designed within the context of current hatchery practice and was based on existing knowledge of decapod reproduction, The sexual differentiation of the yabby after hatching was investigated by serial histological sections, and experiments were carried out to investigate the possibility of sex reversal of males. Most of this Investigation was concerned with removing the influence of the androgenic gland in directing male development, with the intent of observing the development of the elementary gonadal tissue into ovary. It was found that in contrast to other crustacean species, the sex of the yabby becomes fixed before the development of external secondary sexual characteristics, and before the androgenic gland can be discerned. Ovarian tissue developed in females at less than 8 weeks after hatching. A preliminary examination was undertaken for feminising parasites in gonadal tissue of a hermaphrodite yabby. Investigation of the ovary after spawning demonstrated that whilst the female was held under constant conditions of temperature and photoperiod, little rematuration occurred. Except for generation of previtellogenic oocytes during the first two days, the gonaciosomatic index remained low for up to 5 months after spawning. If the temperature of the female was reduced to 10°C and maintained constant, the previtellogenic oocytes were partially resorbed over a three week period. Rematuration then commenced, albeit at a low rate because of the reduced temperature, A method for standardising gonadosomatic indices was developed which took into account differences in hepatopancreatic nutrient reserves of individuals and loss of one or more appendages. This part of the study also considered constraints to rematuration and developed a method of accounting for differences in the ability of females to remature after spawning. Experiments were carried out to investigate the effect of crowding and temperature manipulation on initiating ovarian rematuration and to determine the rate of rematuration at 22°C once initiated. The duration of low temperature had no effect on rematuration; an overnight cooling was sufficient to initiate the process, Rematuration to the end of stage 2 vltellogenesis was substantially complete within 10 days. Crowding of females suppressed rematuration, but less than ideal water quality was not found to have any effect. The presence of a male initiated rematuration at a similar rate, but also led to stage 3 vitetlogenesis and spawning. A study was made of the pheromonal influence of the male through water borne factors without success. Rematuration could not be induced in ovigerous females. The literature review indicated that ovarian rematuration was under the control of an ovary stimulating hormone produced by the thoracic nerve ganglia. Attempts were therefore made to stimulate ovarian rematuration by incorporating the thoracic nerve into the diet of females. Attempts were also made to induce the release of ovary stimulating hormone from the thoracic nerve with 5-hydroxytryptamine, and also with octopamine. No effects were found, but a significant difference between the neurophysiology of the yabby and northern hemisphere crayfish was observed, and the implications of this finding are discussed. The study did not produce any conclusive evidence of an ovary stimulating hormone for the yabby. A model of ovarian rematuration which collects the findings of the experimental investigations was developed, and was used to suggest a hatchery broodstock management protocol. This model differs from existing models in that rematuration triggers and nutritional status are considered.

Tariff protection and politics : Castlemaine 1870-1901

This study, set within the contextual background of Victorian politics, ‘seeks to identify the economic, political and social implications of tariff protection for the Castlemaine region from 1870-1901. The introduction of the Victorian tariff in 1865 precipitated a reversal of earlier attitudes towards protection by politicians and their constituents. Reasons are sought for changes in the perceptions of the Castlemaine electorate and its political representatives towards the tariff between 1870 and Federation. An examination has been made of the role of the tariff in the creation of employment in the region’s primary and secondary industries together with its influence on politicians, primary and secondary industry leaders and workers. Also explored is the relative impact of the tariff on the economic performance of Castlemaine industries, whether producing for export or domestic markets.

Repair and tolerance of DNA damage in higher plants

DNA repair mechanisms constitute an essential cellular response to DNA damage arising either from metabolic processes or from environmental sources such as ultraviolet radiation. Repair of these lesions may be via direct reversal, or by processes such as nucleotide excision repair (NER), a coordinated pathway in which lesions and the surrounding nucleotides are excised and replaced via DNA resynthesis. The importance of repair is illustrated by human disease states such as xeroderma pigmentosum and Cockayne's syndrome which result from defects in the NER system arising from mutations in XP- genes or XP- and CS- genes respectively Little detail is known of DNA damage repair processes in plants, despite the economic and ecological importance of these organisms. This study aimed to expand our knowledge of the process of NER in plants, largely via a polymerase chain reaction (PCR)-based approach involving amplification, cloning and characterisation of plant genomic DNA and cDNA. Homologues of the NER components XPF/RAD1 and XPD/RAD3 were isolated as both genomic and complete cDNA sequences from the model dicotyledonous plant Arabidopsis thaliana. The sequence of the 3'-untranslated region of atXPD was also determined. Comparison of genomic and cDNA sequences allowed a detailed analysis of gene structures, including details of intron/exon processing. Variable transcript processing to produce three distinct transcripts was found in the case of atXPF. In an attempt to validate the proposed homologous function of these cDNAs, assays to test complementation of resistance to ultraviolet radiation in the relevant yeast mutants were performed. Despite extensive amino acid sequence conservation, neither plant cDNA was able to restore UV-resistance. As the yeast RAD3 gene product is also involved in vivo in transcription, and so is required for viability, the atXPD cDNA was tested in a complementation assay for this function in an appropriate yeast mutant. The plant cDNA was found to substantially increase the viability of the yeast mutant. The structural and functional significance of these results is discussed comparatively with reference to yeast, human and other known homologues. Other putative NER homologues were identified in A. thaliana database sequences, including those of ERCC1/RAD10 and XPG/ERCC5/RAD2, and are now the subjects of ongoing investigations. This study also describes preliminary investigations of putative REVS and RAD30 translesion synthesis genes from A. thaliana.

An analysis of microband orientation in hot deformed aluminium alloy AA5052 using forward and reverse torsion

The effects of strain path reversal on the macroscopic orientation of microbands in AA5052 have been studied using high resolution electron backscatter diffraction. Deformation was carried using two equal steps of forward/forward or forward/reverse torsion at a temperature of 300°C and strain rate of 1s-1 to a total equivalent tensile strain of 0.5. In both cases microbands were found in the majority of grains examined with many having more than one set. The microbands appear to cluster at specific angles to the macroscopic deformation. For the forward/forward condition microbands clustered around -20° and +45° to the maximum principle stress direction and at ± 30-35° to the principal strain direction. For the forward/reverse condition significantly more spread in microband angle was observed though peaks were visible at ±35° with respect to principal stress direction and at -40° and +30° with respect to the principal strain direction of the reverse torsion. This suggests the microbands formed in the forward deformation have or are dissolving and any new microbands formed are related to the deformation conditions of the final strain path.