A new principle for tight junction modulation based on occludin peptides

The aim of this study was to investigate whether peptides from the extracellular loops of the tight junction protein occludin could be used as a new principle for tight junction modulation. Peptides of 4 to 47 amino acids in length and covering the two extracellular loops of the tight junction protein occludin were synthesized, and their effect on the tight junction permeability in Caco-2 cells was investigated using [C-14] mannitol as a paracellular marker. Lipopeptide derivatives of one of the active occludin peptides (OPs), synthesized by adding a lipoamino acid containing 14 carbon atoms (C-14-) to the N terminus of the peptide, were also investigated. Peptides corresponding to the N terminus of the first extracellular loop of occludin increased the permeability of the tight junctions without causing short-term toxicity. However, the peptides had an effect only when added to the basolateral side of the cells, which could be partly explained by degradation by apical peptidases and aggregate formation. By contrast, the lipopeptide C-14-OP90-103, which protects the peptide from degradation and aggregation, displayed a rapid apical effect. The L- and D-diastereomers of C-14-OP90-103 had distinctly different effects. The D-isomer, which releases intact OP90-103 from the lipoamino acid, displayed a rapid and transient increase in tight junction permeability. The L- isomer, which releases OP90-103 more rapidly, gave a more sustained increase in tight junction permeability. In conclusion, C-14-OP90-103 represents a prototype of a new class of tight junction modulators that act on the extracellular domains of tight junction proteins.

The prospects for immunotherapy in smoking cessation

Context Smoking is a major preventable cause of death and disability that is maintained by dependence on nicotine. Smoking cessation reduces mortality and morbidity. Although existing pharmacological aids to smoking cessation and relapse prevention (nicotine replacement therapy and bupropion) improve on unassisted quitting and behavioural methods, they are only modestly effective. More effective pharmacological methods are required that improve compliance, reduce side-effects, and can be used in combination with existing cessation methods. Starting point A nicotine vaccine is a promising immunotherapeutic approach to smoking cessation and relapse prevention. Such a vaccine would induce the immune system to form specific antibodies to nicotine to prevent it from crossing the blood-brain barrier to act on receptor sites in the central nervous system. Recent studies in rats provide proof of principle by showing that nicotine-specific antibodies can prevent the reinstatement of nicotine self-administration (N Lindblom et al, Respiration 2002; 69: 254–60) and block dopamine release in the shell of the nucleus accumbens (Sde Villiers et al, Respiration 2002; 69: 247–53). A phase 1 trial of a human cocaine vaccine has also recently been successfully completed (T Kosten et al, Vaccine 2002; 20: 1196–204). A safe and effective human nicotine vaccine would potentially have fewer side-effects and better compliance than existing smoking-cessation pharmacotherapies. It could also be used in combination with some of them (eg, bupropion). Where next? The most promising clinical application of a human nicotine vaccine is likely to be in relapse prevention in abstinent smokers. A vaccine may also have a role in preparing smokers to quit. Clinical trials of safety and efficacy in human smokers and ex-smokers are warranted. If a nicotine vaccine proves to be safe and effective, the health-care system will need to ensure that it is registered for clinical use and that the poorer members of the community (among whom smoking prevalence is now highest in developed countries) have access to the vaccine. The community will need to be appropriately informed about the role of a nicotine vaccine to ensure that it is not prematurely used for preventive purposes in children and adolescents.

Fault-tolerant quantum computation with cluster states

The one-way quantum computing model introduced by Raussendorf and Briegel [Phys. Rev. Lett. 86, 5188 (2001)] shows that it is possible to quantum compute using only a fixed entangled resource known as a cluster state, and adaptive single-qubit measurements. This model is the basis for several practical proposals for quantum computation, including a promising proposal for optical quantum computation based on cluster states [M. A. Nielsen, Phys. Rev. Lett. (to be published), quant-ph/0402005]. A significant open question is whether such proposals are scalable in the presence of physically realistic noise. In this paper we prove two threshold theorems which show that scalable fault-tolerant quantum computation may be achieved in implementations based on cluster states, provided the noise in the implementations is below some constant threshold value. Our first threshold theorem applies to a class of implementations in which entangling gates are applied deterministically, but with a small amount of noise. We expect this threshold to be applicable in a wide variety of physical systems. Our second threshold theorem is specifically adapted to proposals such as the optical cluster-state proposal, in which nondeterministic entangling gates are used. A critical technical component of our proofs is two powerful theorems which relate the properties of noisy unitary operations restricted to act on a subspace of state space to extensions of those operations acting on the entire state space. We expect these theorems to have a variety of applications in other areas of quantum-information science.

Processing of urinary pheromones in Antechinus stuartii (Marsupialia: Dasyuridae): Functional magnetic resonance imaging of the brain

Little is known of the neural mechanisms of marsupial olfaction. However, functional magnetic resonance imaging (fMRI) has made it possible to visualize dynamic brain function in mammals without invasion. In this study, central processing of urinary pheromones was investigated in the brown antechinus, Antechinus stuartii, using fMRI. Images were obtained from 18 subjects (11 males, 7 females) in response to conspecific urinary olfactory stimuli. Significant indiscriminate activation occurred in the accessory olfactory bulb, entorhinal, frontal, and parietal cortices in response to both male and female urine. The paraventricular nucleus of hypothalamus, ventrolateral thalamic nucleus, and medial preoptic area were only activated in response to male urine. Results of this MRI study indicate that projections of accessory olfactory system are activated by chemo-sensory cues. Furthermore, it appears that, based on these experiments, urinary pheromones may act on the hypothalamo-pituitary-adrenocortical axis via the paraventricular nucleus of the hypothalamus and may play an important role in the unique life history pattern of A. stuartii. Finally, this study has demonstrated that fMRI may be a powerful tool for investigations of olfactory processes in mammals.

Targeted! Population segmentation, electronic surveillance and governing the unemployed in Australia

Targeting is increasingly used to manage people. It operates by segmenting populations and providing different levels of opportunities and services to these groups. Each group is subject to different levels of surveillance and scrutiny. This article examines the deployment of targeting in Australian social security. Three case studies of targeting are presented in Australia's management of benefit overpayment and fraud, the distribution of employment services and the application of workfare. In conceptualizing surveillance as governance, the analysis examines the rationalities, technologies and practices that make targeting thinkable, practicable and achievable. In the case studies, targeting is variously conceptualized and justified by calculative risk discourses, moral discourses of obligation and notions of welfare dependency Advanced information technologies are also seen as particularly important in giving rise to the capacity to think about and act on population segments.

The formal representation of process system modelling assumptions and their implications

In order to analyse the effect of modelling assumptions in a formal, rigorous way, a syntax of modelling assumptions has been defined. The syntax of modelling assumptions enables us to represent modelling assumptions as transformations acting on the set of model equations. The notion of syntactical correctness and semantical consistency of sets of modelling assumptions is defined and methods for checking them are described. It is shown on a simple example how different modelling assumptions act on the model equations and their effect on the differential index of the resulted model is also indicated.

National audit of anaesthesia for major abdominal surgery

A postal survey was conducted of all hospitals in Australia known to have a department of anaesthesia and an intensive care or high dependency unit. Each hospital was asked to report the anaesthetic and postoperative analgesic techniques used for the last ten cases of four common major surgical procedures-aorto-femoral bypass, repair of an abdominal aortic aneurysm, hemicolectomy and anterior resection of the rectum. Half of 76 hospitals sent a survey form completed and returned it. Responding hospitals were larger on average, than non-responding ones, but otherwise typical of them in terms of university affiliation and metropolitan versus rural location. For each of the procedures studied the proportion of cases in which epidural block was used intra- or postoperatively varied from 0% to 100%. Depending on the procedure, between 65% and 85% of hospitals used epidural block sometimes, with between 10% and 90% of patients in these hospitals being managed with this technique. There is wide variation in the use of epidural block, intra- and postoperatively, in Australia, variation that is unlikely to be explained by systematic differences between institutions in the patients seen or their suitability for one or other technique. This pattern of practice mirrors the lack of agreement about the proper place for epidural techniques evident in the recent literature. There is a widespread belief among clinicians that this is a question of great importance. Accordingly, we believe that anaesthetists and surgeons share an ethical responsibility to enter suitable patients in an appropriately designed randomized controlled trial in order to resolve this question.

Up-regulation of p21(WAF1)/(CIP1) by histone deacetylase inhibitors reduces their cytotoxicity

Histone deacetylase inhibitors show promise as chemotherapeutic agents and have been demonstrated to block proliferation in a wide range of tumor cell lines. Much of this antiproliferative effect has been ascribed to the up-regulated expression of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1). In this article, we report that p21 expression was up-regulated by relatively low doses of the histone deacetylase inhibitor azelaic bishydroxamic acid (ABHA) and correlated with a proliferative arrest. Higher doses of ABHA were cytotoxic. Cells that did not up-regulate p21 expression were hypersensitive to killing by ABHA and died via apoptosis, whereas up-regulation of p21 correlated with reduced sensitivity and a block in the apoptotic mechanism, and these cells seemed to die by necrosis. Using isogenic p21(+/+) and p21(-/-) cell lines and direct inhibition of caspase activity, we demonstrate that the reduced sensitivity to killing by ABHA is a consequence of inhibition of apoptosis by up-regulated p21 expression. These data indicate the enormous potential of therapeutic strategies that bypass the cytoprotective effect of p21 and act on the same molecular targets as the histone deacetylase inhibitors.

Genetic sources of covariation among P3(00) and online performance variables in a delayed-response working memory task

Genetic and environmental sources of covariation among the P3(00) and online performance elicited in a delayed-response working memory task, and psychometric IQ assessed by the multidimensional aptitude battery, were examined in an adolescent twin sample. An association between frontal P3 latency and task performance (phenotypic r = -0.33; genotypic r = -0.49) was indicated, with genes (i.e. twin status) accounting for a large part of the covariation ( > 70%). In contrast, genes influencing P3 amplitude mediated only a small part (2%) of the total genetic variation in task performance. While task performance mediated 15% of the total genetic variation in IQ (phenotypic r = 0.22; genotypic r = 0.39) there was no association between P3 latency and IQ or P3 amplitude with IQ. The findings provide some insight into the inter-relationships among psychophysiological, performance and psychometric measures of cognitive ability, and provide support for a levels-of-processing genetic model of cognition where genes act on specific sub-components of cognitive processes.

NPS-2143 - Treatment of osteoporosis - Calcilytic

Efforts to discover new treatments for osteoporosis led to the identification of the potent and selective, small-molecule calcium receptor antagonist NPS-2143. NPS-2143 is the prototype calcilytic drug, designed to act on calcium receptors on the surface of parathyroid glands, stimulating the release of the body's own stores of native parathyroid hormone (PTH). In osteopenic ovariectomized rats, daily oral administration of NPS-2143 resulted in moderate but sustained increases in plasma PTH levels and marked increases in bone formation and resorption, with no net bone gain or loss. The combination of NPS-2143 and estrogen increases bone formation and density to a greater extent than either agent alone. These results suggest that NPS-2143 may be useful in the treatment of established osteoporosis.

Ethical issues in using a cocaine vaccine to treat and prevent cocaine abuse and dependence

A cocaine vaccine'' is a promising immunotherapeutic approach to treating cocaine dependence which induces the immune system to form antibodies that prevent cocaine from crossing the blood brain barrier to act on receptor sites in the brain. Studies in rats show that cocaine antibodies block cocaine from reaching the brain and prevent the reinstatement of cocaine self administration. A successful phase 1 trial of a human cocaine vaccine has been reported. The most promising application of a cocaine vaccine is to prevent relapse to dependence in abstinent users who voluntarily enter treatment. Any use of a vaccine to treat cocaine addicts under legal coercion raises major ethical issues. If this is done at all, it should be carefully trialled first, and only after considerable clinical experience has been obtained in using the vaccine to treat voluntary patients. There will need to be an informed community debate about what role, if any, a cocaine vaccine may have as a way of preventing cocaine addiction in children and adolescents.

Local therapy for restenosis

The durability of all forms of open or percutaneous revascularisation is affected by the development of localised stenoses within the bypass graft or at the site of endarterectomy, stent or angioplasty. The reported incidence of significant restenosis has varied dependent on initial procedure, site, case mix and definition, but is greatest during the first 12 months (Table 1).1 Over the last 40 years tens of thousands of studies have been carried out in an effort to understand or reduce the incidence of restenosis, with two major mechanisms identified as being responsible for the luminal narrowing, namely intimal hyperplasia and constrictive remodelling. Intimal hyperplasia is provoked by changes in the balance of local cytokines controlling vascular smooth muscle cell (VSMC) proliferation, apoptosis and migration, brought about by endothelial or medial injury and alterations in haemodynamic forces. The overall vessel diameter reduction that occurs in constrictive remodelling is less well defined, but likely involves matrix turnover under the control of proteinases, particularly metalloproteinases.

Animal migration: is there a common migratory syndrome?

Ornithologists, and especially northern hemisphere ornithologists, have traditionally thought of migration as an annual return movement of populations between regular breeding and non-breeding grounds. Problems arise because selection does not ordinarily act on populations and because organisms of many taxa (including birds) are clearly migrants, but fail to undertake movements of the kind described. There are also extensive return movements that are not migratory. I propose that it is more useful to think of migration as a syndrome of behavioral and other traits that function together within individuals, and that such a syndrome provides a common ground across taxa from aphids to albatrosses. Large-scale return movements of populations are one outcome of the syndrome. Similar behavioral and physiological traits serve both to define migration and to provide a test for it. I use two insect (Hemipteran) examples to illustrate migratory syndromes and to demonstrate that, in many migrants, behavior and physiology correlate with life history and morphological traits to form syndromes at two levels. I then compare the two Hemipterans with migration in birds, butterflies, and fish to assess the question of whether there are migratory syndromes in common between these diverse migrants. Syndromes are more similar at the level of behavior than when morphology and life history traits are included. Recognizing syndromes leads to important evolutionary questions concerning migration strategies, trade-offs, the maintenance of genetic variance and the responses of migratory syndromes to both similar and different selective regimes.

Axillary bud outgrowth: sending a message

Mutants that branch profusely in the presence of a growing shoot tip have highlighted the role of graft-transmissible signals that are produced in roots and stem. Orthologous genes in Arabidopsis, pea and petunia are involved in the transmission of a novel long-distance message. These genes show varying degrees of regulation by auxin and an auxin-independent feedback system, and encode enzymes that might act on carotenoid-like substrates. Axillary bud outgrowth is under homeostatic control, involving developmental stages or checkpoints. Perturbation of the long-range messaging and auxin depletion does not guarantee that bud outgrowth will ensue at a particular node.

Potencies of human immunodeficiency virus protease inhibitors in vitro against Plasmodium falciparum and in vivo against murine malaria

Parasite resistance to antimalarial drugs is a serious threat to human health, and novel agents that act on enzymes essential for parasite metabolism, such as proteases, are attractive targets for drug development. Recent studies have shown that clinically utilized human immunodeficiency virus (HIV) protease inhibitors can inhibit the in vitro growth of Plasmodium falciparum at or below concentrations found in human plasma after oral drug administration. The most potent in vitro antimalarial effects have been obtained for parasites treated with saquinavir, ritonavir, or lopinavir, findings confirmed in this study for a genetically distinct P. falciparum line (3D7). To investigate the potential in vivo activity of antiretroviral protease inhibitors (ARPIs) against malaria, we examined the effect of ARPI combinations in a murine model of malaria. In mice infected with Plasmodium chabaudi AS and treated orally with ritonavir-saquinavir or ritonavir-lopinavir, a delay in patency and a significant attenuation of parasitemia were observed. Using modeling and ligand docking studies we examined putative ligand binding sites of ARPIs in aspartyl proteases of P. falciparum (plasmepsins II and IV) and P. chabaudi (plasmepsin) and found that these in silico analyses support the antimalarial activity hypothesized to be mediated through inhibition of these enzymes. In addition, in vitro enzyme assays demonstrated that P. falciparum plasmepsins II and IV are both inhibited by the ARPIs saquinavir, ritonavir, and lopinavir. The combined results suggest that ARPIs have useful antimalarial activity that may be especially relevant in geographical regions where HIV and P. falciparum infections are both endemic.