Dual Effects of Adp and Adenylylimidodiphosphate on Cftr Channel Kinetics Show Binding to Two Different Nucleotide Binding Sites

The CFTR chloride channel is regulated by phosphorylation by protein kinases, especially PKA, and by nucleotides interacting with the two nucleotide binding domains, NBD-A and NBD-B. Giant excised inside-out membrane patches from Xenopus oocytes expressing human epithelial cystic fibrosis transmembrane conductance regulator (CFTR) were tested for their chloride conductance in response to the application of PKA and nucleotides. Rapid changes in the concentration of ATP, its nonhydrolyzable analogue adenylylimidodiphosphate (AMP-PNP), its photolabile derivative ATP-P3-[1-(2-nitrophenyl)ethyl]ester, or ADP led to changes in chloride conductance with characteristic time constants, which reflected interaction of CFTR with these nucleotides. The conductance changes of strongly phosphorylated channels were slower than those of partially phosphorylated CFTR. AMP-PNP decelerated relaxations of conductance increase and decay, whereas ATP-P3-[1-(2-nitrophenyl)ethyl]ester only decelerated the conductance increase upon ATP addition. ADP decelerated the conductance increase upon ATP addition and accelerated the conductance decay upon ATP withdrawal. The results present the first direct evidence that AMP-PNP binds to two sites on the CFTR. The effects of ADP also suggest two different binding sites because of the two different modes of inhibition observed: it competes with ATP for binding (to NBD-A) on the closed channel, but it also binds to channels opened by ATP, which might either reflect binding to NBD-A (i.e., product inhibition in the hydrolysis cycle) or allosteric binding to NBD-B, which accelerates the hydrolysis cycle at NBD-A

An approach to treating depressive and psychotic illness in Indigenous communities.

This study is one of the activities of a multi-site research program, the Australian Mental Health Initiative (AIMhi), funded by the National Health and Medical Research Council. AIMhi in the Northern Territory collaborated with Aboriginal mental health workers and Northern Territory remote service providers in developing a range of resources and strategies to promote improved Indigenous mental health outcomes. A brief intervention that combines the principles of motivational interviewing, problem solving therapy and chronic disease self-management is described. The intervention has been integrated into a randomised controlled trial. Early findings suggest that the strategy and its components are well received by clients with chronic mental illness, and their carers, in remote communities

Advanced Terahertz Data Processing for NDE Applications

Recently terahertz technology (THz) has emerged as a very powerful NDE tool for inspecting and characterizing dielectric materials. Due to its exceptional longitudinal and lateral resolutions, time-domain pulsed THz scan is particularly effective for inspecting thin layered dielectric media. This pulsed scanning produces multi-dimensional data for which advanced processing techniques are needed to extract and analyze the ample information within. In this presentation we conduct a comparable study of several renowned data processing techniques to determine their applicability and performance in processing THz data. These data processing techniques include an outlier detection algorithm based on minimum covariance determinant estimator, the popular partial least squares method in the field of chemometrics and a Bayesian classifier also known as probabilistic neural network in the fields of pattern recognition/machine learning. We will present the results on common simulated data as well as interface data obtained from fiber glass composites

CBT for people with intellectual disabilities : emerging evidence, cognitive ability and IQ effects

Historically people with intellectual disabilities have not been offered or received cognitive behavioural interventions that have been shown to be effective for mental health and emotional problems experienced by those without such disabilities. This is despite many people with intellectual disabilities having life experiences that potentially result in them having an increased risk to such problems. This paper discusses whether such therapeutic disdain is justified based on the evidence that is available and emerging concerning the application of cognitive behavioural interventions for this population. Issues concerning access to services, the ability of people with intellectual disabilities to engage in and benefit from the cognitive components of CBT, and the effect of cognitive abilities and IQ level on treatment effectiveness are explored in relation to this question

Pluralism about Knowledge

In this paper I consider the prospects for pluralism about knowledge, that is, the view that there is a plurality of knowledge relations. After a brief overview of some views that entail a sort of pluralism about knowledge, I focus on a particular kind of knowledge pluralism I call standards pluralism. Put roughly, standards pluralism is the view that one never knows anything simpliciter. Rather, one knows by this-or-that epistemic standard. Because there is a plurality of epistemic standards, there is a plurality of knowledge relations. In §1 I argue that one can construct an impressive case for standards pluralism. In §2 I clarify the relationship between standards pluralism, epistemic contextualism and epistemic relativism. In §3 I argue that standards pluralism faces a serious objection. The gist of the objection is that standards pluralism is incompatible with plausible claims about the normative role of knowledge. In §4 I finish by sketching the form that a standards pluralist response to this objection might take

Preconceptional, Gestational, and Lactational Exposure to an Unconventional Oil and Gas Chemical Mixture Alters Energy Expenditure in Adult Female Mice

Previous studies conducted in our laboratory have found altered adult health outcomes in animals with prenatal exposure to environmentally relevant levels of unconventional oil and gas (UOG) chemicals with endocrine-disrupting activity. This study aimed to examine potential metabolic health outcomes following a preconception, prenatal and postnatal exposure to a mixture of 23 UOG chemicals. Prior to mating and from gestation day 1 to postnatal day 21, C57BL/6J mice were developmentally exposed to a laboratory-created mixture of 23 UOG chemicals in maternal drinking water. Body composition, spontaneous activity, energy expenditure, and glucose tolerance were evaluated in 7-month-old female offspring. Neither body weight nor body composition differed in 7-month female mice. However, females exposed to 1.5 and 150 μg/kg/day UOG mix had lower total and resting energy expenditure within the dark cycle. In the light cycle, the 1,500 μg//kg/day group had lower total energy expenditure and the 1.5 μg/kg/day group had lower resting energy expenditure. Females exposed to the 150 μg/kg/day group had lower spontaneous activity in the dark cycle, and females exposed to the 1,500 μg/kg/day group had lower activity in the light cycle. This study reports for the first time that developmental exposure to a mixture of 23 UOG chemicals alters energy expenditure and spontaneous activity in adult female mice

Creativity and Autonomy in Swarm Intelligence Systems

This work introduces two swarm intelligence algorithms -- one mimicking the behaviour of one species of ants (\emph{Leptothorax acervorum}) foraging (a `Stochastic Diffusion Search', SDS) and the other algorithm mimicking the behaviour of birds flocking (a `Particle Swarm Optimiser', PSO) -- and outlines a novel integration strategy exploiting the local search properties of the PSO with global SDS behaviour. The resulting hybrid algorithm is used to sketch novel drawings of an input image, exploliting an artistic tension between the local behaviour of the `birds flocking' - as they seek to follow the input sketch - and the global behaviour of the `ants foraging' - as they seek to encourage the flock to explore novel regions of the canvas. The paper concludes by exploring the putative `creativity' of this hybrid swarm system in the philosophical light of the `rhizome' and Deleuze's well known `Orchid and Wasp' metaphor

Recombinant tissue-type plasminogen activator versus a novel dosing regimen of urokinase in acute pulmonary embolism: a randomized controlled multicenter trial

AbstractThrombolysis of acute pulmonary embolism can be accomplished more rapidly and safely with 100 mg of recombinant human tissue-type plasminogen activator (rt-PA) (Activase) than with a conventional dose of urokinase (Abbokinase) given as a 4,400-U/kg bolus dose, followed by 4,400 U/kg per h for 24 h. To determine the effects of a more concentrated urokinase dose administered over a shorter time course, this trial enrolled 90 patients with baseline perfusion lung scans and angiographically documented pulmonary embolism. They were randomized to receive either 100 mg/2 h of rt-PA or a novel dosing regimen of urokinase: 3 million U/2 h with the initial 1 million U given as a bolus injection over 10 min. Both drugs were delivered through a peripheral vein.To assess efficacy after initiation of therapy, repeat pulmonary angiograms at 2 h were performed in 87 patients and then graded in a blinded manner by a panel of six investigators. Of the 42 patients allocated to rt-PA therapy, 79% showed angiographic improvement at 2 h, compared with 67% of the 45 patients randomized to urokinase therapy (95% confidence interval for the difference in these proportions [rt-PA minus urokinase] is −6.6% to 30.4%; p = 0.11). The mean change in perfusion lung scans between baseline and 24 h was similar for both treatments. Three patients (two treated with rt-PA and one with urokinase) had an intracranial hemorrhage, which was fatal in one.The results indicate that a 2-h regimen of rt-PA and a new dosing regimen of urokinase exhibit similar efficacy and safety for treatment of acute pulmonary embolism