Aluminium and breast cancer: sources of exposure, tissue measurements and mechanisms of toxicological actions on breast biology

This review examines recent evidence linking exposure to aluminium with the aetiology of breast cancer. The human population is exposed to aluminium throughout daily life including through diet, application of antiperspirants, use of antacids and vaccination. Aluminium has now been measured in a range of human breast structures at higher levels than in blood serum and experimental evidence suggests that the tissue concentrations measured have the potential to adversely influence breast epithelial cells including generation of genomic instability, induction of anchorage-independent proliferation and interference in oestrogen action. The presence of aluminium in the human breast may also alter the breast microenvironment causing disruption to iron metabolism, oxidative damage to cellular components, inflammatory responses and alterations to the motility of cells. The main research need is now to investigate whether the concentrations of aluminium measured in the human breast can lead in vivo to any of the effects observed in cells in vitro and this would be aided by the identification of biomarkers specific for aluminium action.

Protease-activated receptors: mechanisms by which proteases sensitize TRPV channels to induce neurogenic inflammation and pain

Proteolytic enzymes comprise approximately 2 percent of the human genome [1]. Given their abundance, it is not surprising that proteases have diverse biological functions, ranging from the degradation of proteins in lysosomes to the control of physiological processes such as the coagulation cascade. However, a subset of serine proteases (possessing serine residues within their catalytic sites), which may be soluble in the extracellular fluid or tethered to the plasma membrane, are signaling molecules that can specifically regulate cells by cleaving protease-activated receptors (PARs), a family of four G-protein-coupled receptors (GPCRs). These serine proteases include members of the coagulation cascade (e.g., thrombin, factor VIIa, and factor Xa), proteases from inflammatory cells (e.g., mast cell tryptase, neutrophil cathepsin G), and proteases from epithelial tissues and neurons (e.g., trypsins). They are often generated or released during injury and inflammation, and they cleave PARs on multiple cell types, including platelets, endothelial and epithelial cells, myocytes, fibroblasts, and cells of the nervous system. Activated PARs regulate many essential physiological processes, such as hemostasis, inflammation, pain, and healing. These proteases and their receptors have been implicated in human disease and are potentially important targets for therapy. Proteases and PARs participate in regulating most organ systems and are the subject of several comprehensive reviews [2, 3]. Within the central and peripheral nervous systems, proteases and PARs can control neuronal and astrocyte survival, proliferation and morphology, release of neurotransmitters, and the function and activity of ion channels, topics that have also been comprehensively reviewed [4, 5]. This chapter specifically concerns the ability of PARs to regulate TRPV channels of sensory neurons and thereby affect neurogenic inflammation and pain transmission [6, 7].

Mechanisms of protease-activated receptor 2-evoked hyperexcitability of nociceptive neurons innervating the mouse colon

Agonists of protease-activated receptor 2 (PAR(2)) evoke hyperexcitability of dorsal root ganglia (DRG) neurons by unknown mechanisms. We examined the cellular mechanisms underlying PAR(2)-evoked hyperexcitability of mouse colonic DRG neurons to determine their potential role in pain syndromes such as visceral hyperalgesia. Colonic DRG neurons were identified by injecting Fast Blue and DiI retrograde tracers into the mouse colon. Using immunofluorescence, we found that DiI-labelled neurons contained PAR(2) immunoreactivity, confirming the presence of receptors on colonic neurons. Whole-cell current-clamp recordings of acutely dissociated neurons demonstrated that PAR(2) activation with a brief application (3 min) of PAR(2) agonists, SLIGRL-NH(2) and trypsin, evoked sustained depolarizations (up to 60 min) which were associated with increased input resistance and a marked reduction in rheobase (50% at 30 min). In voltage clamp, SLIGRL-NH(2) markedly suppressed delayed rectifier I(K) currents (55% at 10 min), but had no effect on the transient I(A) current or TTX-resistant Na(+) currents. In whole-cell current-clamp recordings, the sustained excitability evoked by PAR(2) activation was blocked by the PKC inhibitor, calphostin, and the ERK(1/2) inhibitor PD98059. Studies of ERK(1/2) phosphorylation using confocal microscopy demonstrated that SLIGRL-NH(2) increased levels of immunoreactive pERK(1/2) in DRG neurons, particularly in proximity to the plasma membrane. Thus, activation of PAR(2) receptors on colonic nociceptive neurons causes sustained hyperexcitability that is related, at least in part, to suppression of delayed rectifier I(K) currents. Both PKC and ERK(1/2) mediate the PAR(2)-induced hyperexcitability. These studies describe a novel mechanism of sensitization of colonic nociceptive neurons that may be implicated in conditions of visceral hyperalgesia such as irritable bowel syndrome.

Demand side response: patterns in Europe and future policy perspectives under capacity mechanisms

Demand Side Response (DSR) has been slow to emerge in European electricity markets. This paper aims to both examine the reasons for low levels of DSR in Europe and reflect on factors that might affect the participation of DSR in capacity mechanisms. It relies on available evidence from the literature, secondary data on existing DSR programmes and energy aggregator's data from industries participating in DSR. Findings show that changes to the duration of contracted loads under existing or new programmes might increase the penetration of DSR. The introduction of capacity mechanisms may increase DSR from demand turn down if longer response times were available.

Recovery mechanisms of Arctic summer sea ice

We examine the recovery of Arctic sea ice from prescribed ice-free summer conditions in simulations of 21st century climate in an atmosphere–ocean general circulation model. We find that ice extent recovers typically within two years. The excess oceanic heat that had built up during the ice-free summer is rapidly returned to the atmosphere during the following autumn and winter, and then leaves the Arctic partly through increased longwave emission at the top of the atmosphere and partly through reduced atmospheric heat advection from lower latitudes. Oceanic heat transport does not contribute significantly to the loss of the excess heat. Our results suggest that anomalous loss of Arctic sea ice during a single summer is reversible, as the ice–albedo feedback is alleviated by large-scale recovery mechanisms. Hence, hysteretic threshold behavior (or a “tipping point”) is unlikely to occur during the decline of Arctic summer sea-ice cover in the 21st century.

Effects and mechanisms of ginseng and ginsenosides on cognition

Reviewed here is the existing evidence for the effects of ginseng extracts and isolated ginsenosides relevant to cognition in humans. Clinical studies in healthy volunteers and in patients with neurological disease or deficit, evidence from preclinical models of cognition, and pharmacokinetic data are considered. Conditions under which disease modification may indirectly benefit cognition but may not translate to cognitive benefits in healthy subjects are discussed. The number of chronic studies of ginseng effects in healthy individuals is limited, and the results from acute studies are inconsistent, making overall assessment of ginseng's efficacy as a cognitive enhancer premature. However, mechanistic results are encouraging; in particular, the ginsenosides Rg 3 , Rh 1 , Rh 2 , Rb 1 , Rd, Rg 2 , and Rb 3 , along with the aglycones protopanaxadiol and protopanaxatriol, warrant further attention. Compound K has a promising pharmacokinetic profile and can affect neurotransmission and neuroprotection. Properly conducted trials using standardized tests in healthy individuals reflecting the target population for ginseng supplementation are required to address inconsistencies in results from acute studies. The evidence summarized here suggests ginseng has potential, but unproven, benefits on cognition.

Performance analysis and deployment of VoLTE mechanisms over 3GPP LTE-based networks

Long Term Evolution based networks lack native support for Circuit Switched (CS) services. The Evolved Packet System (EPS) which includes the Evolved UMTS Terrestrial Radio Access Network (E-UTRAN) and Evolved Packet Core (EPC) is a purely all-IP packet system. This introduces the problem of how to provide voice call support when a user is within an LTE network and how to ensure voice service continuity when the user moves out of LTE coverage area. Different technologies have been proposed for the purpose of providing a voice to LTE users and to ensure the service continues outside LTE networks. The aim of this paper is to analyze and evaluate the overall performance of these technologies along with Single Radio Voice Call Continuity (SRVCC) Inter-RAT handover to Universal Terrestrial Radio Access Networks/ GSM-EDGE radio access Networks (UTRAN/GERAN). The possible solutions for providing voice call and service continuity over LTE-based networks are Circuit Switched Fall Back (CSFB), Voice over LTE via Generic Access (VoLGA), Voice over LTE (VoLTE) based on IMS/MMTel with SRVCC and Over The Top (OTT) services like Skype. This paper focuses mainly on the 3GPP standard solutions to implement voice over LTE. The paper compares various aspects of these solutions and suggests a possible roadmap that mobile operators can adopt to provide seamless voice over LTE.

Diverse mechanisms underlying the regulation of ion channels by carbon monoxide

Carbon monoxide is firmly established as an important, physiological signalling molecule as well as a potent toxin. Through its ability to bind metal-containing proteins it is known to interfere with a number of intracellular signalling pathways, and such actions can account for its physiological and pathological effects. In particular, CO can modulate the intracellular production of reactive oxygen species, nitric oxide and cGMP levels, as well as regulate MAP kinase signalling. In this review, we consider ion channels as more recently discovered effectors of CO signalling. CO is now known to regulate a growing number of different ion channel types, and detailed studies of the underlying mechanisms of action are revealing unexpected findings. For example, there are clear areas of contention surrounding its ability to increase the activity of high conductance, Ca2+ -sensitive K+ channels. More recent studies have revealed the ability of CO to inhibit T-type Ca2+ channels and have unveiled a novel signalling pathway underlying tonic regulation of this channel. It is clear that the investigation of ion channels as effectors of CO signalling is in its infancy, and much more work is required to fully understand both the physiological and the toxic actions of this gas. Only then can its emerging use as a therapeutic tool be fully and safely exploited.

Towards a resolution of ‘the paradox of the plankton’: a brief overview of the proposed mechanisms

In plankton ecology, it is a fundamental question as to how a large number of competing phytoplankton species coexist in marine ecosystems under a seemingly-limited variety of resources. This ever-green question was first proposed by Hutchinson [Hutchinson, G.E., 1961. The paradox of the plankton. Am. Nat. 95, 137–145] as ‘the paradox of the plankton’. Starting from Hutchinson [Hutchinson, G.E., 1961. The paradox of the plankton. Am. Nat. 95, 137–145], over more than four decades several investigators have put forward varieties of mechanisms for the extreme diversity of phytoplankton species. In this article, within the boundary of our knowledge, we review the literature of the proposed solutions and give a brief overview of the mechanisms proposed so far. The proposed mechanisms that we discuss mainly include spatial and temporal heterogeneity in physical and biological environment, externally imposed or self-generated spatial segregation, horizontal mesoscale turbulence of ocean characterized by coherent vortices, oscillation and chaos generated by several internal and external causes, stable coexistence and compensatory dynamics under fluctuating temperature in resource competition, and finally the role of toxin-producing phytoplankton in maintaining the coexistence and biodiversity of the overall plankton population that we have proposed recently. We find that, although the different mechanisms proposed so far is potentially applicable to specific ecosystems, a universally accepted theory for explaining plankton diversity in natural waters is still an unachieved goal.

Mechanisms of motivation-cognition interaction: challenges and opportunities

There has been a recent rejuvenation of interest in studies of motivation-cognition interactions arising from many different areas of psychology and neuroscience. The current issue of Cognitive, Affective, and Behavioral Neuroscience provides a sampling of some of the latest research from a number of these different areas. In this introductory paper, we provide an overview of the current state of the field, in terms of key research developments and candidate neural mechanisms receiving focused investigation as potential sources of motivation-cognition interaction. However, our primary goal is conceptual: to highlight the distinct perspectives taken by different research areas in terms of how motivation is defined, the relevant dimensions and dissociations that are emphasized, and the theoretical questions being targeted. Together, these distinctions present both challenges and opportunities for efforts aiming towards a more unified and cross-disciplinary approach. We identify a set of pressing research questions calling out for this sort of cross-disciplinary approach, with the explicit goal of encouraging integrative and collaborative investigations directed towards them.

Mechanisms for AMOC variability simulated by the NEMO model

We have investigated mechanisms for the Atlantic Meridional Overturning Circulation (AMOC) variability at 26.5° N (other than the Ekman component) that can be related to external forcings, in particular wind variability. Resolution dependence is studied using identical experiments with 1° and 1/4° NEMO model runs over 1960–2010. The analysis shows that much of the variability in the AMOC at 26° N can be related to the wind strength over the North Atlantic, through mechanisms lagged on different timescales. At ~ 1-year lag the January–June difference of mean sea level pressure between high and mid-latitudes in the North Atlantic explains 35–50% of the interannual AMOC variability (with negative correlation between wind strength and AMOC). At longer lead timescales ~ 4 years, strong (weak) winds over the northern North Atlantic (specifically linked to the NAO index) are followed by higher (lower) AMOC transport, but this mechanism only works in the 1/4° model. Analysis of the density correlations suggests an increase (decrease) in deep water formation in the North Atlantic subpolar gyre to be the cause. Therefore another 30% of the AMOC variability at 26° N can be related to density changes in the top 1000 m in the Labrador and Irminger seas occurring ~ 4 years earlier.

Distinction between semantic and episodic memory: The underlying mechanisms for autonoetic consciousness

In 1972, episodic and semantic memories were considered to reflect different types of knowledge (Tulving, 1972). However, these early definitions encountered many difficulties. Now, Episodic and semantic memories are discussed in terms of awareness associated with retrieval (Wheeler, Stuss, & Tulving, 1997): Autonoetic consciousness (i.e., feeling of remembering) is considered associated with retrieval from the episodic memory system, while noetic consciousness (i.e., feeling of knowing) is considered characterized by retrieval from the semantic memory system. The present article investigated determinants of autonoetic consciousness in order to clarify characteristics of perceptual knowledge that is being recalled, the more strongly the individual feels autonoetic consciousness during retrieval, and that autonoetic consciousness is based on rich sensory-perceptual knowledge. Furthermore, we suggested that the parietal and frontal lobes mediate the process of generating autonoetic consciousness. This suggested that sensory-perceptual knowledge, the parietal lobe and the frontal lobe are important factors for discriminating episodic memory afrom semantic memory.