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

An electrochemical system for efficiently harvesting low-grade heat energy

Efficient and low-cost thermal energy-harvesting systems are needed to utilize the tremendous low-grade heat sources. Although thermoelectric devices are attractive, its efficiency is limited by the relatively low figure-of-merit and low-temperature differential. An alternative approach is to explore thermodynamic cycles. Thermogalvanic effect, the dependence of electrode potential on temperature, can construct such cycles. In one cycle, an electrochemical cell is charged at a temperature and then discharged at a different temperature with higher cell voltage, thereby converting heat to electricity. Here we report an electrochemical system using a copper hexacyanoferrate cathode and a Cu/Cu2+ anode to convert heat into electricity. The electrode materials have low polarization, high charge capacity, moderate temperature coefficients and low specific heat. These features lead to a high heat-to-electricity energy conversion efficiency of 5.7% when cycled between 10 and 60 degrees C, opening a promising way to utilize low-grade heat.open121

Reverse electrowetting as a new approach to high-power energy harvesting

Over the last decade electrical batteries have emerged as a critical bottleneck for portable electronics development. High-power mechanical energy harvesting can potentially provide a valuable alternative to the use of batteries, but, until now, a suitable mechanical-to-electrical energy conversion technology did not exist. Here we describe a novel mechanical-to-electrical energy conversion method based on the reverse electrowetting phenomenon. Electrical energy generation is achieved through the interaction of arrays of moving microscopic liquid droplets with novel nanometer-thick multilayer dielectric films. Advantages of this process include the production of high power densities, up to 103 W m−2; the ability to directly utilize a very broad range of mechanical forces and displacements; and the ability to directly output a broad range of currents and voltages, from several volts to tens of volts. These advantages make this method uniquely suited for high-power energy harvesting from a wide variety of environmental mechanical energy sources

A fast and accurate energy source emulator for wireless sensor networks

The capability to either minimize energy consumption in battery-operated devices, or to adequately exploit energy harvesting from various ambient sources, is central to the development and engineering of energy-neutral wireless sensor networks. However, the design of effective networked embedded systems targeting unlimited lifetime poses several challenges at different architectural levels. In particular, the heterogeneity, the variability, and the unpredictability of many energy sources, combined to changes in energy required by powered devices, make it difficult to obtain reproducible testing conditions, thus prompting the need of novel solutions addressing these issues. This paper introduces a novel embedded hardware-software solution aimed at emulating a wide spectrum of energy sources usually exploited to power sensor networks motes. The proposed system consists of a modular architecture featuring small factor form, low power requirements, and limited cost. An extensive experimental characterization confirms the validity of the embedded emulator in terms of flexibility, accuracy, and latency while a case study about the emulation of a lithium battery shows that the hardware-software platform does not introduce any measurable reduction of the accuracy of the model. The presented solution represents therefore a convenient solution for testing large-scale testbeds under realistic energy supply scenarios for wireless sensor networks

HPV16 E7-Dependent Transformation Activates NHE1 through a PKA-RhoA-Iinduced Inhibition of p38alpha

Background: Neoplastic transformation originates from a large number of different genetic alterations. Despite this genetic variability, a common phenotype to transformed cells is cellular alkalinization. We have previously shown in human keratinocytes and a cell line in which transformation can be turned on and followed by the inducible expression of the E7 oncogene of human papillomavirus type 16 (HPV16), that intracellular alkalinization is an early and essential physiological event driven by the up-regulation of the Na/H-+(+) exchanger isoform 1 (NHE1) and is necessary for the development of other transformed phenotypes and the in vivo tumor formation in nude mice.Methodology: Here, we utilize these model systems to elucidate the dynamic sequence of alterations of the upstream signal transduction systems leading to the transformation-dependent activation of NHE1.Principal Findings: We observe that a down-regulation of p38 MAPK activity is a fundamental step in the ability of the oncogene to transform the cell. Further, using pharmacological agents and transient transfections with dominant interfering, constitutively active, phosphorylation negative mutants and siRNA strategy to modify specific upstream signal transduction components that link HPV16 E7 oncogenic signals to up-regulation of the NHE1, we demonstrate that the stimulation of NHE1 activity is driven by an early rise in cellular cAMP resulting in the down-stream inhibition of p38 MAPK via the PKA-dependent phosphorylation of the small G-protein, RhoA, and its subsequent inhibition.Conclusions: All together these data significantly improve our knowledge concerning the basic cellular alterations involved in oncogene-driven neoplastic transformation

Comparison of data-merging methods with SVM attribute selection and classification in breast cancer gene expression

Background: DNA microarray data are used to identify genes which could be considered prognostic markers. However, due to the limited sample size of each study, the signatures are unstable in terms of the composing genes and may be limited in terms of performances. It is therefore of great interest to integrate different studies, thus increasing sample size.Results: In the past, several studies explored the issue of microarray data merging, but the arrival of new techniques and a focus on SVM based classification needed further investigation. We used distant metastasis prediction based on SVM attribute selection and classification to three breast cancer data sets.Conclusions: The results showed that breast cancer classification does not benefit from data merging, confirming the results found by other studies with different technique

Molecular biology of breast cancer metastasis: Inflammatory breast cancer: clinical syndrome and molecular determinants

Inflammatory breast cancer (IBC) is an aggressive form of locally advanced breast cancer (LABC) that effects approximately 5% of women with breast cancer annually in the USA. It is a clinically and pathologically distinct form of LABC that is particularly fast growing, invasive, and angiogenic. Nearly all women have lymph node involvement at the time of diagnosis, and approximately 36% have gross distant metastases. Despite recent advances in multimodality treatments, the prognosis of patients with IBC is poor, with a median disease-free survival of less than 2.5 years. Recent work on the genetic determinants that underlie the IBC phenotype has led to the identification of genes that are involved in the development and progression of this disease. This work has been aided by the establishment of primary human cell lines and animal models. These advances suggest novel targets for future interventions in the diagnosis and treatment of IBC

Hypoxia-Induced Invadopodia Formation Involves Activation of NHE-1 by the p90 Ribosomal S6 Kinase (p90RSK)

The hypoxic and acidic microenvironments in tumors are strongly associated with malignant progression and metastasis, and have thus become a central issue in tumor physiology and cancer treatment. Despite this, the molecular links between acidic pH- and hypoxia-mediated cell invasion/metastasis remain mostly unresolved. One of the mechanisms that tumor cells use for tissue invasion is the generation of invadopodia, which are actin-rich invasive plasma membrane protrusions that degrade the extracellular matrix. Here, we show that hypoxia stimulates the formation of invadopodia as well as the invasive ability of cancer cells. Inhibition or shRNA-based depletion of the Na+/H+ exchanger NHE-1, along with intracellular pH monitoring by live-cell imaging, revealed that invadopodia formation is associated with alterations in cellular pH homeostasis, an event that involves activation of the Na+/H+ exchange rate by NHE-1. Further characterization indicates that hypoxia triggered the activation of the p90 ribosomal S6 kinase (p90 RSK), which resulted in invadopodia formation and site-specific phosphorylation and activation of NHE-1. This study reveals an unsuspected role of p90RSK in tumor cell invasion and establishes p90RS kinase as a link between hypoxia and the acidic microenvironment of tumors

Neuropsychological patterns following lesions of the anterior insula in a series of forty neurosurgical patients

In the present study we investigated the effects of lesions affecting mainly the anterior insula in a series of 22 patients with lesions in the left hemisphere (LH), and 18 patients with lesions involving the right hemisphere (RH). The site of the lesion was established by performing an overlap of the probabilistic cytoarchitectonic maps of the posterior insula. Here we report the patients\u2019 neuropsychological profile and an analysis of their pre-surgical symptoms. We found that pre-operatory symptoms significantly differed in patients depending on whether the lesion affected the right or left insula and a strict parallelism between the patterns emerged in the pre-surgery symptoms analysis, and the patients\u2019 cognitive profile. In particular, we found that LH patients showed cognitive deficits. By contrast, the RH patients, with the exception of one case showing an impaired performance at the visuo-spatial planning test were within the normal range in performing all the tests. In addition, a sub-group of patients underwent to the post-surgery follow-up examination