\u3cem\u3eCis\u3c/em\u3e-regulatory organization of the \u3cem\u3ePax6\u3c/em\u3e gene in the ascidian \u3cem\u3eCiona intestinalis\u3c/em\u3e

The Pax6 gene has attracted intense research interest due to its apparently important role in the development of eyes and the central nervous system (CNS) in many animal groups. Pax6 is also of interest for comparative genomics since it has not been duplicated in tetrapods, making for a direct orthology between the Ciona intestinalis gene CiPax6 and Pax6 in mammals. CiPax6 has been shown to be expressed in the anterior brain, caudal nerve cord, and in parts of the brain associated with the photoreceptive ocellus. This information was extended here using in-situ hybridization, and shows that CiPax6 transcripts mark the lateral regions of the nerve cord, remarkably similar to Pax6 expression in the mouse. As a means of dissecting the cis-regulation of CiPax6 we tested 8 kb of sequence using transient reporter transgene assays. Three separate regions were found that work together to drive the overall CiPax6 expression pattern. A 211 bp sequence 2 kb upstream of the first exon was found to be a major enhancer driving expression in the sensory vesicle (the anterior portion of the ascidian brain). Other upstream sequences were shown to work with the sensory vesicle enhancer to drive expression in the remainder of the CNS. An “eye enhancer” was localized to the first intron, which controls specific expression in the central portion of the sensory vesicle, including photoreceptor cells. The fourth intron was found to repress ectopic expression of the reporter gene in middle portions of the embryonic brain. Aspects of this overall regulatory organization are similar to the organization of the Pax6 homologs in mice and Drosophila, particularly the presence of intronic elements driving expression in the eye, brain and nerve cord

Reflection impulsivity in binge drinking: behavioural and volumetric correlates.

The degree to which an individual accumulates evidence prior to making a decision, also known as reflection impulsivity, can be affected in psychiatric disorders. Here, we study decisional impulsivity in binge drinkers, a group at elevated risk for developing alcohol use disorders, comparing two tasks assessing reflection impulsivity and a delay discounting task, hypothesizing impairments in both subtypes of impulsivity. We also assess volumetric correlates of reflection impulsivity focusing on regions previously implicated in functional magnetic resonance imaging studies. Sixty binge drinkers and healthy volunteers were tested using two different information-gathering paradigms: the beads task and the Information Sampling Task (IST). The beads task was analysed using a behavioural approach and a Bayesian model of decision making. Delay discounting was assessed using the Monetary Choice Questionnaire. Regression analyses of primary outcomes were conducted with voxel-based morphometry analyses. Binge drinkers sought less evidence prior to decision in the beads task compared with healthy volunteers in both the behavioural and computational modelling analysis. There were no group differences in the IST or delay discounting task. Greater impulsivity as indexed by lower evidence accumulation in the beads task was associated with smaller dorsolateral prefrontal cortex and inferior parietal volumes. In contrast, greater impulsivity as indexed by lower evidence accumulation in the IST was associated with greater dorsal cingulate and precuneus volumes. Binge drinking is characterized by impaired reflection impulsivity suggesting a deficit in deciding on the basis of future outcomes that are more difficult to represent. These findings emphasize the role of possible therapeutic interventions targeting decision-making deficits.The study was supported by theWellcome Trust grant to VV (093705/10/Z) and to NA Harrison. PB is supported by the Portuguese Foundation for Science and Technology (individual fellowship to PB: SFRH/BD/33889/ 2009). YW is supported by the Fyssen Fondation. MM is supported by the Welcome Trust and the Biomedical Research Centre.Wewould also like to thank theWolfson Brain Imaging Center staff for their expertise with collecting the imaging data and all the participants for their involvement in this study. The Behavioural and Clinical Neuroscience Institute is supported by the Wellcome Trust and Medical Research Council.This is the final published version. It first appeared from Wiley via http://dx.doi.org/10.1111/adb.1222

Body Weight Support on Anti-Gravity Treadmill Induces Less Physiological Strain While Running

The anti-gravity treadmill developed by AlterG® can be used as an alternative to traditional treadmill running. The AlterG® unloads an individual’s body weight through lower body positive pressure (LBPP) and can support up to 80% of an individual’s body weight. The cardiorespiratory response resulting from a bout of exercise on an AlterG® treadmill may be attenuated compared to similar exercise on a traditional treadmill. PURPOSE: The purpose of this study was to compare the physiological responses of running at 0%, 15%, 30%, and 45% of body weight support (BWS) on the AlterG® to a traditional treadmill. METHODS: Ten healthy, active males (n = 3) and females (n = 7) (mean ± SD; age 23 ± 3 yrs, weight 60 ± 9.4 kg, height 167.6 ± 6.4 cm) completed two separate treadmill sessions in a randomized order. The exercise sessions included running on an AlterG® treadmill at 6 mph and 1% grade with 0%, 15%, 30% and 45% BWS for 8 min each. The other exercise session included running on a traditional treadmill (TT) at 6 mph and 1% grade for 8 min. Oxygen consumption (VO2) and respiratory exchange ratio (RER) were measured every minute through indirect calorimetry. Heart rate (HR) was measured every minute with a heart rate monitor and values were averaged during the last five minutes of each exercise trial. Rating of perceived exertion (RPE) was measured every other minute. Multivariate ANOVA was used for statistical analysis for each dependent variable (p \u3c 0.05). RESULTS: BWS at 15%, 30% and 45% on the AlterG® treadmill significantly reduced VO2 18.5%, 28.3 and 33.7% compared to TT and 0%. Additionally, HR with BWS at 15%, 30% and 45% was significantly reduced 8.9%, 13.1% and 17.9% compared to TT and 0%. RER during 30% and 45% was significantly different (-8.6% and -7.4%) from TT. Perceived exertion during 45% BWS was significantly lower (10-20%) than all protocols. There was no significant difference in VO2 or HR reported between 30% and 45%. 0% BWS displayed no significant difference in VO2 or HR when compared to the traditional treadmill. CONCLUSION: Increasing the percentage of BWS while running on the AlterG® treadmill reduced VO2 and HR compared to TT and 0%. Greater levels of BWS (30% and 45%) resulted in lowered RER and perceived exertion (45% only). The AlterG® treadmill appears to lessen the physiological demands of running compared to a traditional treadmill

Predicting lymphatic filariasis transmission and elimination dynamics using a multi-model ensemble framework

Mathematical models of parasite transmission provide powerful tools for assessing the impacts of interventions. Owing to complexity and uncertainty, no single model may capture all features of transmission and elimination dynamics. Multi-model ensemble modelling offers a framework to help overcome biases of single models. We report on the development of a first multi-model ensemble of three lymphatic filariasis (LF) models (EPIFIL, LYMFASIM, and TRANSFIL), and evaluate its predictive performance in comparison with that of the constituents using calibration and validation data from three case study sites, one each from the three major LF endemic regions: Africa, Southeast Asia and Papua New Guinea (PNG). We assessed the performance of the respective models for predicting the outcomes of annual MDA strategies for various baseline scenarios thought to exemplify the current endemic conditions in the three regions. The results show that the constructed multi-model ensemble outperformed the single models when evaluated across all sites. Single models that best fitted calibration data tended to do less well in simulating the out-of-sample, or validation, intervention data. Scenario modelling results demonstrate that the multi-model ensemble is able to compensate for variance between single models in order to produce more plausible predictions of intervention impacts. Our results highlight the value of an ensemble approach to modelling parasite control dynamics. However, its optimal use will require further methodological improvements as well as consideration of the organizational mechanisms required to ensure that modelling results and data are shared effectively between all stakeholders

Projected free energies for polydisperse phase equilibria

A `polydisperse' system has an infinite number of conserved densities. We give a rational procedure for projecting its infinite-dimensional free energy surface onto a subspace comprising a finite number of linear combinations of densities (`moments'), in which the phase behavior is then found as usual. If the excess free energy of the system depends only on the moments used, exact cloud, shadow and spinodal curves result; two- and multi-phase regions are approximate, but refinable indefinitely by adding extra moments. The approach is computationally robust and gives new geometrical insights into the thermodynamics of polydispersity.Comment: 4 pages, REVTeX, uses multicol.sty and epsf.sty, 1 postscript figure include

Disease transmission promotes evolution of host spatial patterns

Ecological dynamics can produce a variety of striking patterns. On ecological time scales, pattern formation has been hypothesized to be due to the interaction between a species and its local environment. On longer time scales, evolutionary factors must be taken into account. To examine the evolutionary robustness of spatial pattern formation, we construct a spatially explicit model of vegetation in the presence of a pathogen. Initially, we compare the dynamics for vegetation parameters that lead to competition induced spatial patterns and those that do not. Over ecological time scales, banded spatial patterns dramatically reduced the ability of the pathogen to spread, lowered its endemic density and hence increased the persistence of the vegetation. To gain an evolutionary understanding, each plant was given a heritable trait defining its resilience to competition; greater competition leads to lower vegetation density but stronger spatial patterns. When a disease is introduced, the selective pressure on the plant's resilience to the competition parameter is determined by the transmission of the disease. For high transmission, vegetation that has low resilience to competition and hence strong spatial patterning is an evolutionarily stable strategy. This demonstrates a novel mechanism by which striking spatial patterns can be maintained by disease-driven selection

Effectiveness of a triple-drug regimen for global elimination of lymphatic filariasis : a modelling study

Background: Lymphatic filariasis is targeted for elimination as a public health problem by 2020. The principal approach used by current programmes is annual mass drug administration with two pairs of drugs with a good safety profile. However, one dose of a triple-drug regimen (ivermectin, diethylcarbamazine, and albendazole) has been shown to clear the transmissible stage of the helminth completely in treated individuals. The aim of this study was to use modelling to assess the potential value of mass drug administration with the triple-drug regimen for accelerating elimination of lymphatic filariasis in different epidemiological settings. Methods: We used three different transmission models to compare the number of rounds of mass drug administration needed to achieve a prevalence of microfilaraemia less than 1% with the triple-drug regimen and with current two-drug regimens. Findings: In settings with a low baseline prevalence of lymphatic filariasis (5%), the triple-drug regimen reduced the number of rounds of mass drug administration needed to reach the target prevalence by one or two rounds, compared with the two-drug regimen. For areas with higher baseline prevalence (10–40%), the triple-drug regimen strikingly reduced the number of rounds of mass drug administration needed, by about four or five, but only at moderate-to-high levels of population coverage (>65%) and if systematic non-adherence to mass drug administration was low. Interpretation: Simulation modelling suggests that the triple-drug regimen has potential to accelerate the elimination of lymphatic filariasis if high population coverage of mass drug administration can be achieved and if systematic non-adherence with mass drug administration is low. Future work will reassess these estimates in light of more clinical trial data and to understand the effect on an individual country's programme

Understanding the relationship between prevalence of microfilariae and antigenaemia using a model of lymphatic filariasis infection.

BACKGROUND: Lymphatic filariasis is a debilitating neglected tropical disease that affects impoverished communities. Rapid diagnostic tests of antigenaemia are a practical alternative to parasitological tests of microfilaraemia for mapping and surveillance. However the relationship between these two methods of measuring burden has previously been difficult to interpret. METHODS: A statistical model of the distribution of worm burden and microfilariae (mf) and resulting antigenaemic and mf prevalence was developed and fitted to surveys of two contrasting sentinel sites undergoing interventions. The fitted model was then used to explore the relationship in various pre- and post-intervention scenarios. RESULTS: The model had good quantitative agreement with the data and provided estimates of the reduction in mf output due to treatment. When extrapolating the results to a range of prevalences there was good qualitative agreement with published data. CONCLUSIONS: The observed relationship between antigenamic and mf prevalence is a natural consequence of the relationship between prevalence and intensity of adult worms and mf production. The method described here allows the estimation of key epidemiological parameters and consequently gives insight into the efficacy of an intervention programme

Biochemical systems theory and metabolic control theory: 2. the role of summation and connectivity relationships

Perhaps the major obstacle to recognizing the relatedness of Biochemical Systems Theory (BST) and a subsequently developed approach some have called Metabolic Control Theory (MCT) is the summation and connectivity relationships. These are the most visible and central features of the MCT approach to the understanding of intact biochemical systems, whereas in the BST approach they appear to be invisible and peripheral. Generalized versions of these relationships are shown to be inherent to BST, and it is shown how their role differs from that within MCT. The significance of summation and connectivity relationships is shown to be historical and secondary in the sense that one can understand fully the integrated behavior of complex biochemical systems in steady state with BST and never explicitly invoke these relationships. It also is shown that the summation and connectivity relationships in MCT have inherent limitations that make them inadequate as the basis for a general theory of biochemical systems. The results in this paper, together with those in the previous paper, clearly demonstrate that MCT is a special case of BST.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26551/1/0000090.pd

Biochemical systems theory and metabolic control theory: 1. fundamental similarities and differences

Biochemical Systems Theory (BST) was developed in the late 1960s to explicate the integrated behavior of intact biochemical systems--specific dynamic behavior as well as general principles of design--in relation to the properties of their underlying molecular elements. This approach was used successfully in a number of biochemical and other biological applications throughout the 1970s and 1980s. A related approach, Metabolic Control Theory (MCT), was proposed in the mid 1970s. Its developments generally have followed without reference the analogous developments in BST, and its proponents have treated the two approaches as if they were unrelated. Detailed comparison of the fundamental structures of BST and MCT shows that, although there are some superficial differences, both in fact are based upon the same underlying formalism. Molecular descriptions in MCT comprise a special case of those in BST. Systemic descriptions differ with respect to the level of aggregation assumed. The aggregation at the level of net increase or net decrease of each system constituent found in BST is shown to produce the more revealing and useful theory, and results presented elsewhere [41] suggest that this level of aggregation also provides a more accurate description of the system. At this fundamental level, MCT represents a special case of BST, for the content and range of validity of BST are more inclusive than those of MCT.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26550/1/0000089.pd