Endogenous cholinergic inputs and local circuit mechanisms govern the phasic mesolimbic dopamine response to nicotine

Nicotine exerts its reinforcing action by stimulating nicotinic acetylcholine receptors (nAChRs) and boosting dopamine (DA) output from the ventral tegmental area (VTA). Recent data have led to a debate about the principal pathway of nicotine action: direct stimulation of the DAergic cells through nAChR activation, or disinhibition mediated through desensitization of nAChRs on GABAergic interneurons. We use a computational model of the VTA circuitry and nAChR function to shed light on this issue. Our model illustrates that the α4β2-containing nAChRs either on DA or GABA cells can mediate the acute effects of nicotine. We account for in vitro as well as in vivo data, and predict the conditions necessary for either direct stimulation or disinhibition to be at the origin of DA activity increases. We propose key experiments to disentangle the contribution of both mechanisms. We show that the rate of endogenous acetylcholine input crucially determines the evoked DA response for both mechanisms. Together our results delineate the mechanisms by which the VTA mediates the acute rewarding properties of nicotine and suggest an acetylcholine dependence hypothesis for nicotine reinforcement.Peer reviewe

QCD and strongly coupled gauge theories : challenges and perspectives

We highlight the progress, current status, and open challenges of QCD-driven physics, in theory and in experiment. We discuss how the strong interaction is intimately connected to a broad sweep of physical problems, in settings ranging from astrophysics and cosmology to strongly coupled, complex systems in particle and condensed-matter physics, as well as to searches for physics beyond the Standard Model. We also discuss how success in describing the strong interaction impacts other fields, and, in turn, how such subjects can impact studies of the strong interaction. In the course of the work we offer a perspective on the many research streams which flow into and out of QCD, as well as a vision for future developments.Peer reviewe

Biflorin: an o-naphthoquinone of clinical significance

Biflorin is an o-naphthoquinone with proven cytotoxic effects on tumor cells showing antimicrobial, antitumor and antimutagenic activities. Biflorin is an isolated compound taken from the roots of the plant Capraria biflora L. (Schrophulariaceae), indigenous of the West Indies and South America, which is located in temperate or tropical areas. This compound has shown to be strongly active against grampositive and alcohol-acid-resistant bacteria. It has been efficient in inhibiting the proliferation tumor cell lines CEM, HL-60, B16, HCT-8 and MCF-7. Recently, SK-Br3 cell line was treated with biflorin showing important cytotoxic effects. In this article, information related to the first structural characterization studies are presented, as well as the latest reports concerning the biological activity of this molecule

Effect of knee replacement on flexion deformity

One of the objectives of knee replacement is to correct flexion deformity, the frequent consequence of rheumatoid arthritis and osteoarthritis. A review of 697 primary and revision replacements carried out between 1969 and 1985 and followed up from 1 to 16 years found that such deformity was present in 61% of knees before the primary operation. Replacement reduced this to 17% and the improvement was usually maintained. The deformity was present in only 21% of the replacements which required revision and the second operation reduced this to 8%. Flexion contractures affected rheumatoid knees more often and more seriously than osteoarthritic knees, but arthroplasty was more successful in correcting the deformity in the former. All of the 11 types of prosthesis used achieved some degree of correction, but the Walldius hinge and the variants of the Freeman condylar design were the most successful. Surprisingly, the best outcome, in terms of pain and reduced need for revision, was found in the rheumatoid knees most seriously deformed before operation, but this association was absent in the osteoarthritic knees. Postoperative deformity in knees without pain or extreme weakness did not appear to influence the patients' ability to walk or to use stairs or a chair, as measured by unexacting tests in the clinic. </jats:p