Disrupted iron regulation in the brain and periphery in cocaine addiction

Stimulant drugs acutely increase dopamine neurotransmission in the brain, and chronic use leads to neuroadaptive changes in the mesolimbic dopamine system and morphological changes in basal ganglia structures. Little is known about the mechanisms underlying these changes but preclinical evidence suggests that iron, a coenzyme in dopamine synthesis and storage, may be a candidate mediator. Iron is present in high concentrations in the basal ganglia and stimulant drugs may interfere with iron homeostasis. We hypothesised that morphological brain changes in cocaine addiction relate to abnormal iron regulation in the brain and periphery. We determined iron concentration in the brain, using quantitative susceptibility mapping, and in the periphery, using iron markers in circulating blood, in 44 patients with cocaine addiction and 44 healthy controls. Cocaine-addicted individuals showed excess iron accumulation in the globus pallidus, which strongly correlated with duration of cocaine use, and mild iron deficiency in the periphery, which was associated with low iron levels in the red nucleus. Our findings show that iron dysregulation occurs in cocaine addiction and suggest that it arises consequent to chronic cocaine use. Putamen enlargement in these individuals was unrelated to iron concentrations, suggesting that these are co-occurring morphological changes that may respectively reflect predisposition to, and consequences of cocaine addiction. Understanding the mechanisms by which cocaine affects iron metabolism may reveal novel therapeutic targets, and determine the value of iron levels in the brain and periphery as biomarkers of vulnerability to, as well as progression and response to treatment of cocaine addiction

Computational Cancer Biology: An Evolutionary Perspective

ISSN:1553-734XISSN:1553-735

Autonomous transport and splitting of a droplet on an open surface

Pumpless transport of droplets on open surfaces has gained significant attention because of its applications starting from vapor condensation to Lab-on-a-Chip systems. Mixing two droplets on open surfaces can be carried out quickly by using wettability patterning. However, it is quite challenging to split a droplet in the absence of external stimuli because of the interfacial energy of the droplet. Here, we demonstrate a standalone power-free technique for transport and splitting of droplets on open surfaces using continuous wettability gradients. A droplet moves continuously from a low to a high wettability region on the wettability-gradient surface. A Y-shaped wettability-gradient track – laid on a superhydrophobic background – is used to investigate the dynamics of the splitting process. A three-dimensional phase-field Cahn-Hilliard model for interfaces and the Navier-Stokes equations for transport are employed and solved numerically using the finite element method. Numerical results are used to decipher the motion and splitting of droplet at the Y junction using the principle of energy conservation. It is observed that droplet splitting depends on the configuration of the Y junction; droplets split faster for the superhydrophobic wedge angle of 90∘ and the splitting ratio (ratio of the sizes of daughter droplets) depends on the widths of the Y branches. A critical branch-width ratio (w2w1=0.79) is identified below which the droplet does not split and moves towards the branch of higher width and settles there. The present study provides the required theoretical underpinnings to achieve autonomous transport and splitting of droplets on open surfaces, which has clear potential for applications in Lab-on-a-Chip devices

Disrupted iron regulation in the brain and periphery in cocaine addiction

Stimulant drugs acutely increase dopamine neurotransmission in the brain, and chronic use leads to neuroadaptive changes in the mesolimbic dopamine system and morphological changes in basal ganglia structures. Little is known about the mechanisms underlying these changes but preclinical evidence suggests that iron, a coenzyme in dopamine synthesis and storage, may be a candidate mediator. Iron is present in high concentrations in the basal ganglia and stimulant drugs may interfere with iron homeostasis. We hypothesised that morphological brain changes in cocaine addiction relate to abnormal iron regulation in the brain and periphery. We determined iron concentration in the brain, using quantitative susceptibility mapping, and in the periphery, using iron markers in circulating blood, in 44 patients with cocaine addiction and 44 healthy controls. Cocaine-addicted individuals showed excess iron accumulation in the globus pallidus, which strongly correlated with duration of cocaine use, and mild iron deficiency in the periphery, which was associated with low iron levels in the red nucleus. Our findings show that iron dysregulation occurs in cocaine addiction and suggest that it arises consequent to chronic cocaine use. Putamen enlargement in these individuals was unrelated to iron concentrations, suggesting that these are co-occurring morphological changes that may respectively reflect predisposition to, and consequences of cocaine addiction. Understanding the mechanisms by which cocaine affects iron metabolism may reveal novel therapeutic targets, and determine the value of iron levels in the brain and periphery as biomarkers of vulnerability to, as well as progression and response to treatment of cocaine addiction.This work was supported by the NIHR Cambridge Biomedical Research Centre and the Behavioural and Clinical Neuroscience Institute (which was supported by a joint award from the Medical Research Council and the Wellcome Trust). The Food Frequency Questionnaire and related analysis software were used in the study. These instruments were initially developed as part of the EPIC-Norfolk Study, which was supported by Cancer Research UK programme grant (C864/A8257)

Droplet dynamics on a wettability patterned surface during spray impact

Wettability patterning of a surface is a passive method to manipulate the flow and heat transport mechanism in many physical processes and industrial applications. This paper proposes a rational wettability pattern comprised of multiple superhydrophilic wedges on a superhydrophobic background, which can continuously remove the impacted spray droplets from the horizontal surface. We observed that the spray droplets falling on the superhydrophilic wedge region spread and form a thin liquid film, which is passively transported away from the surface. However, most of the droplets falling on the superhydrophobic region move towards the wedge without any flooding. The physics of the passive transport of the liquid film on a wedge is also delved into using numerical modelling. In particular, we elucidate the different modes of droplet transport in the superhydrophobic region and the interaction of multiple droplets. The observed droplet dynamics could have profound implications in spray cooling systems and passive removal of liquid from a horizontal surface. This study’s findings will be beneficial for the optimization of efficient wettability patterned surfaces for spray cooling application

Chronic koro-like symptoms – two case reports

BACKGROUND: Koro is a culture bound syndrome, which has been reported usually from Asian countries. It has been described as an acute, brief lasting illness, which often occurs in epidemics. There is no description in literature of a chronic form of this syndrome. CASE PRESENTATION: Two sporadic cases with koro-like symptoms from East India are presented where the illness had a chronic course with durations spanning more than ten years. In contrast to acute, good prognosis, psycho-education responsive form that is usually seen in epidemics; the chronic form, appeared to be associated with greater morbidity and poorer response to interventions. CONCLUSION: There is a possibility of a chronic form of koro syndrome

A new multi-anticipative car-following model with consideration of the desired following distance

We propose in this paper an extension of the multi-anticipative optimal velocity car-following model to consider explicitly the desired following distance. The model on the following vehicle’s acceleration is formulated as a linear function of the optimal velocity and the desired distance, with reaction-time delay in elements. The linear stability condition of the model is derived. The results demonstrate that the stability of traffic flow is improved by introducing the desired following distance, increasing the time gap in the desired following distance or decreasing the reaction-time delay. The simulation results show that by taking into account the desired following distance as well as the optimal velocity, the multi-anticipative model allows longer reaction-time delay in achieving stable traffic flows

Murine mesothelin: characterization, expression, and inhibition of tumor growth in a murine model of pancreatic cancer

Background Mesothelin has attracted much interest as a tumor specific antigen; it has been reported to promote tumor development and to be a good target for cancer treatment. Most studies to date have used human mesothelin in immunocompromised mice. Since these models do not allow for study of the natural immune response to mesothelin expressing tumors, we have undertaken the characterization of mouse mesothelin so the effects of this protein can be assessed in immunocompetent mouse strains. Methods We analyzed mouse mesothelin expression, tissue distribution, shedding and biochemistry. In addition we constructed stable mesothelin overexpressing lines of the pancreatic cancer line Panc02 by two methods and tested them for growth and tumorigencity in vitro and in vivo. Results We show here that mouse mesothelin is similar to human mesothelin in biochemical characteristics, tumor expression and tissue distribution, suggesting the mouse may be a suitable model for study of mesothelin. Stable overexpression of mesothelin in a pancreatic cancer cell line did not increase cell proliferation or anchorage-independent growth in vitro, suggesting that mesothelin is not necessarily a tumor progression factor. Surprisingly overexpression of mesothelin inhibited tumor formation in vivo in immunocompetent mice. Conclusion The mouse may be a good model for studying mesothelin in the context of an intact immune response. Mesothelin is not necessarily a tumor progression factor, and indeed mesothelin overexpression inhibited tumor growth in immunocompetent mice

Targeting cancer metabolism: a therapeutic window opens

Genetic events in cancer activate signalling pathways that alter cell metabolism. Clinical evidence has linked cell metabolism with cancer outcomes. Together, these observations have raised interest in targeting metabolic enzymes for cancer therapy, but they have also raised concerns that these therapies would have unacceptable effects on normal cells. However, some of the first cancer therapies that were developed target the specific metabolic needs of cancer cells and remain effective agents in the clinic today. Research into how changes in cell metabolism promote tumour growth has accelerated in recent years. This has refocused efforts to target metabolic dependencies of cancer cells as a selective anticancer strategy.Burroughs Wellcome FundSmith Family FoundationStarr Cancer ConsortiumDamon Runyon Cancer Research FoundationNational Institutes of Health (U.S.

Pathogenic marine microbes influence the effects of climate change on a commercially important tropical bivalve

There is growing evidence that climate change will increase the prevalence of toxic algae and harmful bacteria, which can accumulate in marine bivalves. However, we know little about any possible interactions between exposure to these microorganisms and the effects of climate change on bivalve health, or about how this may affect the bivalve toxin-pathogen load. In mesocosm experiments, mussels, Perna viridis, were subjected to simulated climate change (warming and/or hyposalinity) and exposed to harmful bacteria and/or toxin-producing dinoflagellates. We found significant interactions between climate change and these microbes on metabolic and/or immunobiological function and toxin-pathogen load in mussels. Surprisingly, however, these effects were virtually eliminated when mussels were exposed to both harmful microorganisms simultaneously. This study is the first to examine the effects of climate change on determining mussel toxin-pathogen load in an ecologically relevant, multi-trophic context. The results may have considerable implications for seafood safety