Phosphatidylinositol 4,5‐bisphosphate (PI4,5P2) is a key lipid signaling molecule that regulates a vast array of biological activities. PI4,5P2 can act directly as a messenger or can be utilized as a precursor to generate other messengers: inositol trisphosphate, diacylglycerol, or phosphatidylinositol 3,4,5‐trisphosphate. PI4,5P2 interacts with hundreds of different effector proteins. The enormous diversity of PI4,5P2 effector proteins and the spatio‐temporal control of PI4,5P2 generation allow PI4,5P2 signaling to control a broad spectrum of cellular functions. PI4,5P2 is synthesized by phosphatidylinositol (...) phosphate kinases (PIPKs). The array of PIPKs in cells enables their targeting to specific subcellular compartments through interactions with targeting factors that are often PI4,5P2 effectors. These interactions are a mechanism to define spatial and temporal PI4,5P2 synthesis and the specificity of PI4,5P2 signaling. In turn, the regulation of PI4,5P2 effectors at specific cellular compartments has implications for understanding how PI4,5P2 controls cellular processes and its role in diseases. (shrink)

Reactive oxygen species (ROS) are known as toxic metabolic products in plants and other aerobic organisms. An elaborate and highly redundant plant ROS network, composed of antioxidant enzymes, antioxidants and ROS-producing enzymes, is responsible for maintaining ROS levels under tight control. This allows ROS to serve as signaling molecules that coordinate an astonishing range of diverse plant processes. The specificity of the biological response to ROS depends on the chemical identity of ROS, intensity of the signal, sites of production, plant (...) developmental stage, previous stresses encountered and interactions with other signaling molecules such as nitric oxide, lipid messengers and plant hormones. Although many components of the ROS signaling network have recently been identified, the challenge remains to understand how ROS-derived signals are integrated to eventually regulate such biological processes as plant growth, development, stress adaptation and programmed cell death. (shrink)

The recent discovery and structure determination of a novel ubiquitin‐like dimerization domain in protein kinase D (PKD) has significant implications for its activation. PKD is a serine/threonine kinase activated by the lipid second messenger diacylglycerol (DAG). It is an essential and highly conserved protein that is implicated in plasma membrane directed trafficking processes from the trans‐Golgi network. However, many open questions surround its mechanism of activation, its localization, and its role in the biogenesis of cargo transport carriers. In (...) reviewing this field, the focus is primarily on the mechanisms that control the activation of PKD at precise locations in the cell. In light of the new structural findings, the understanding of the mechanisms underlying PKD activation is critically evaluated, with particular emphasis on the role of dimerization in PKD autophosphorylation, and the provenance and recognition of the DAG that activates PKD. (shrink)

SummaryMuch excitement surrounded the proposal that a family of endo‐lysosomal channels, the two‐pore channels (TPCs) were the long sought after targets of the Ca2+‐mobilising messenger, nicotinic acid adenine dinucleotide phosphate (NAADP). However, the role of TPCs in NAADP signalling may be more complex than originally envisaged. First, NAADP may not bind directly to TPCs but via an accessory protein. Second, two papers recently challenged the notion that TPCs are NAADP‐regulated Ca2+ channels by suggesting that they are highly selective Na+ (...) channels regulated by the lipid phosphatidylinositol 3,5‐bisphosphate and by ATP. This paper aims critically to evaluate the evidence for TPCs as NAADP targets and to discuss how the new findings fit in with what we know about endo‐lysosomal Ca2+ stores. (shrink)

The respiration of oxygen, while essential to aerobic organisms for the generation of energy, leads to the formation of reactive oxygen intermediates (ROIs) as harmful byproducts. ROIs damage nucleic acids, lipids and proteins. Therefore, protective mechanisms against elevated intracellular ROI levels, referred to as oxidative stress, have evolved. These include the activation of transcription factors which elevate the expression of protective enzymes. Eukaryotic cells have also evolved the ability to specifically generate ROIs are used as second messengers to activate gene (...) expression. Here we will discuss both prokaryotic and eukaryotic transcription factors that respond to ROIs. In addition, transcription factors will be described that are activated by either exposure to antioxidants, which reduce the intracellular ROI concentration, or by hypoxia, the absence of oxygen. (shrink)

Adipose tissue plays an important role in mammalian energy equilibrium not only as a lipid‐dissipating, i.e. energy‐storing, tissue (white adipose tissue), but also as an energy‐dissipating one (brown adipose tissue). Brown adipocytes have the ability of facultative heat production due to a unique mitochondrial protein, the uncoupling protein (UCP). Differentiation of white and (to a lesser extent) brown adipocytes has been studied in different cell culture systems, which has led to the identification of external inducers, second messenger pathways (...) and transcription factors involved in adipocyte differentiation. Functional differentiation of white adipocytes implies adipose conversion, whereas in brown adipocytes it insinuates additionally the development of a thermogenic function. This review discusses recent advances in the elucidation of the pathways responsible for, and the molecular bases of, adipose conversion on the one hand and development of the thermogenic properties of brown adipocytes on the other. (shrink)

Cell signalling mediators derived from membrane phospholipids are frequent participants in biological processes. The family of phosphoinositide 3-kinases (PI3Ks) phosphorylate the membrane lipid phosphatidylinositol, generating second messengers that direct diverse responses. These PI3K products are fundamental for leukocyte migration or chemotaxis, a pivotal event during the immune response. This system is therefore of significant biomedical interest. This review focuses on the biochemistry and signalling pathways of PI3K, with particular emphasis on chemokine (chemotactic cytokine)-directed responses. The key objectives of chemotaxis (...) are motility and direction. The latter—direction—requires distinct events at the front and back of a cell. In light of this, the coordinated localisation of signalling factors, an event choreographed by a sharp intracellular gradient of PI3K-derived products, is a common theme. BioEssays 27:153–163, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

In their environment, plants are continuously submitted to natural stimuli such as wind, rain, temperature changes, wounding, etc. These signals induce a cascade of events which lead to metabolic and morphogenetic responses. In this paper the different steps are described and discussed starting from the reception of the signal by a plant organ to the final morphogenetic response. In our laboratory two plants are studied: Bryonia dioica for which rubbing the internode results in reduced elongation and enhanced radial expansion and (...) Bidens pilosa for which the response occurs at distance, hence pricking the cotyledon of a plantlet induces the growth inhibition of both the hypocotyl and the axillary bud of the pricked cotyledon. Reception of the signal and transmission of the message. In Bryonia the signal is received by epidermal cells while in Bidens they are the cells adjacent to the midrib of the cotyledon which receive the mechanical signal. In both plants the message is transmitted via a wave of electric depolarization. This latter is composed of an action potential associated with a slow wave whose transmission rates are respectively 1cm s−1 and 1 mm s−1. Recent results have shown the involvement of Ca2+ in the triggering of the slow wave and the role of the H+ pump during the slow wave. Transient and fast biochemical responses. An entry of extraceilular Ca2+ into the cells and a transient increase in IP3 occur within seconds following the mechanical stimulus. At the same time, the membrane becomes more fluid, correlated with qualitative changes in phospholipids. The rapid increase in the concentration of peroxidated lipids may be correlated with ethylene biosynthesis which is stimulated after rubbing. Other parameters such as cytoplasmic pH, relative water content, hydric potential, membrane potential and modifications of K+, Mg2+-ATPase and Ca2+-ATPase activities, play a key role in the early responses induced by the traumatisms. Irreversible-biochemical responses. The mechanical stimulus performed on a Bryonia internode induces an acceleration of: i) enzymatic activities related to the lignification, ii) esterification of phenolic acids in the cell wall. Consequently the lignification process is accelerated. Storage of the information. After being received by the target cells the information can be stored during several days before being expressed. At the level of cotyledonary bud, the first message, previously stored, can be expressed or not by a second treatment. Bidens thus behaves as if it was able to “store” and to “retrieve” morphogenetic messages, using a sort of rudimentary memory. The nuclei of the bud cells of the pricked cotyledon show that these cells, initially in G2 phase, divide and then remain in the G1 phase. In Bryonia, calli derived from young stimulated internodes, keep thigmomorphogenetic characteristics during several weeks. In the last part of this paper the particularity of our plant model which permits a study of the transmission and storage of the message, is underlined. The links between the different steps induced by the stimulus are discussed. Special attention is devoted to second messengers and to the amplification of the message. (shrink)

The implicit learning account of syntactic priming proposes that the same mechanism underlies syntactic priming and language development, providing a link between a child and adult language processing. The present experiment tested predictions of this account by comparing the persistence of syntactic priming effects in children and adults. Four‐year‐olds and adults first described transitive events after hearing transitive primes, constituting an exposure phase that established priming effects for passives. The persistence of this priming effect was measured in a test phase (...) as participants described further transitive events but no longer heard primes. Their production of passives was compared to a baseline group who described the same pictures without any exposure to primes. Neither immediate nor long‐term priming effects differed between children and adults but both children and adults showed significant immediate and persistent effects of the priming when the test phase occurred immediately after the exposure phase and when a short delay separated the exposure and test phase. The implications of these results for an implicit learning account of syntactic priming are discussed. (shrink)

Messenger, Dally The renowned and popular philosopher, Alain de Botton, TV-and-radio crawled Australia in February 2012 promoting his new book, Religion for Atheists: a non-believers guide to the uses of religion. It was a thesis which many, including me, welcomed as sensible and constructive. Basically his message was that the human wisdom and artistry which has evolved over thousands of years though the various religious movements is part of everyone's heritage, and should be culturally assimilated and used by us, (...) to affect human behaviour for the better. (shrink)

Messenger, Dally The unique Australian Civil Celebrant program was and is a great social and political initiative. For over forty years it has enabled secular humanists to free themselves from religious connections. Unfortunately, in the last ten years this program has been partially destroyed, and certainly greatly diminished by hostile public servants and politicians.

There has never been a greater need for reliable, truthful news to help citizens navigate and assess the veracity of what they are reading and viewing, especially on social media. Widespread concerns around ‘fake’ news demonstrate an enduring requirement for curated and trustworthy children’s news that addresses children as young citizens with certain rights. Drawing on recent UK events, we discuss the case for children’s news provision by public service broadcasting from a communication rights perspective by analyzing the BBC’s 2019 (...) plans to reduce the broadcast presence and originated hours of its flagship news service, Newsround, in favor of online distribution. (shrink)

This book has been considered by academicians and scholars of great significance and value to literature. This forms a part of the knowledge base for future generations. So that the book is never forgotten we have represented this book in a print format as the same form as it was originally first published. Hence any marks or annotations seen are left intentionally to preserve its true nature.

Recent arguments claim that behavioral science has focused – to its detriment – on the individual over the system when construing behavioral interventions. In this commentary, we argue that tackling economic inequality using both framings in tandem is invaluable. By studying individuals who have overcome inequality, “positive deviants,” and the system limitations they navigate, we offer potentially greater policy solutions.

In the mammalian central nervous system (CNS), each neuron receives signals from other neurons through numerous synapses located on its cell body and dendrites. Molecules involved in the postsynaptic signaling pathways need to be targeted to the appropriate subcellular domains at the right time during both synaptogenesis and the maintenance of synaptic functions. The presence of messenger RNAs (mRNAs) in dendrites offers a mechanism for synthesizing the appropriate molecules at the right place in response to local extracellular stimuli. Several (...) dendritic mRNAs have been identified, and the mechanisms controlling their localization are beginning to be understood. In many cell types, controls on mRNA stability play an important role in the regulation of gene expression, but it is unclear to what extent this type of control operates in dendrites. The regulation of protein synthesis and the control of mRNA stability in dendrites could have important implications for neuronal function. BioEssays 20:70–78, 1998. © 1998 John Wiley & Sons, Inc. (shrink)

In the mammalian central nervous system (CNS), each neuron receives signals from other neurons through numerous synapses located on its cell body and dendrites. Molecules involved in the postsynaptic signaling pathways need to be targeted to the appropriate subcellular domains at the right time during both synaptogenesis and the maintenance of synaptic functions. The presence of messenger RNAs (mRNAs) in dendrites offers a mechanism for synthesizing the appropriate molecules at the right place in response to local extracellular stimuli. Several (...) dendritic mRNAs have been identified, and the mechanisms controlling their localization are beginning to be understood. In many cell types, controls on mRNA stability play an important role in the regulation of gene expression, but it is unclear to what extent this type of control operates in dendrites. The regulation of protein synthesis and the control of mRNA stability in dendrites could have important implications for neuronal function. BioEssays 20:70–78, 1998. © 1998 John Wiley & Sons, Inc. (shrink)

The language of Seneca’s messenger speeches concentrates preceding patterns of imagery into grotesquely violent action. In three tragedies – Phaedra, Thyestes, and Trojan Women – the report of an anonymous messenger dominates an entire act. All three scenes describe gruesome deaths: the impalement of Hippolytus on a tree trunk in Phaedra, Atreus’ butchering of his nephews in Thyestes, and the slaughter of Astyanax and Polyxena in Trojan Women. In portraying violence, these messenger speeches repurpose language established in (...) earlier scenes to realize and deform a dominant theme of each play: distorted sexuality, appetite, and moral dissolution. (shrink)

Representational accounts of painful experiences, which characterize contents of pain in indicative terms, face a serious problem known as the Messenger-Shooting Objection. This problem arises from the fact that indicative representational accounts do not seem to be able to accommodate the observation that painful experiences rationalize actions aimed towards their own removal. I present a novel representational account of painful experiences which can solve the Messenger-Shooting Objection while still being an indicative representational theory. I argue that the proposed (...) account is also coherent with the contemporary scientific paradigm concerning pains. (shrink)

According to strong representationalism it is in virtue of having a particular representational content that an experience has the specific phenomenal character that it has. This paper argues that representationalism does not have the resources to explain the most salient aspect of the phenomenal character of pain – it is bound to leave out the painfulness of pain or its negative affect. Its central argument proceeds by analysing the rationalising role of pains. According to it, representationalism is committed to a (...) false picture on which a subject who knowingly acts so as to get rid of her pain without thereby getting rid of the bodily condition it represents always behaves irrationally – in so acting she is shooting the messenger. Thus, there can be no viable representationalist account of the phenomenal character of pain. (shrink)

The molecular pathways for insulin's signal transduction from its cell surface receptor to the cell's interior metabolic machinery remain in many ways uncharted. Lately two molecules have been proposed as second messengers transducing the insulin signal into the target cell. One is a phospholigosaccharide/inositolphosphoglycan and the other is diacylglycerol, both deriving from the same plasma membrane glycolipid, which is hydrolysed in response to insulin treatment. The phospho‐oligosaccharide appears to mediate many metabolic effects of insulin through control of the phosphorylation state (...) of key regulatory metabolic enzymes. Diacylglycerol may mediate insulin's stimulation of glucose transport over the plasma membrane. The glycolipid precursor of these putative second messengers, as well as the receptor for insulin, appear to be localized in caveolae microdomains of the plasma membrane, and glucose transporters accumulate in caveolae in response to insulin treatment, suggesting a focal role for caveolae in insulin signalling. (shrink)

Unpleasant sensations possess a unique ability to make certain aversive actions seem reasonable to us. But what is it about these experiences that give them that ability? According to some recent evaluationist accounts, it is their representational content: unpleasant sensations represent a certain event as bad for one. Unfortunately evaluationism seems unable to make sense of our aversive behavior to the sensations themselves, for it appears to entail that taking a painkiller is akin to shooting the messenger, and is (...) every bit as unreasonable. In this paper I distinguish two versions of the shooting-the-messenger challenge: First, how do we account for the badness of unpleasant sensation? And second, how do we account for our access to that badness? I suggest plausible responses to the first question, but I also argue that the seriousness of the second has not been appreciated. I then propose a solution to the second: when we introspect our pains we also turn our emotional distress inwards, enabling them to represent our pains as bad. (shrink)

The translation of the Guru Granth Sahib (GGS), or Sikh ‘scripture’, within the discourse of (European) colonial/modernity was enacted by the use of hermeneutics—which oversaw the shift from the openness of praxis to the closure of representation and knowledge. Such a shift demoted certain indigenous interpretive frames, wherein the GGS is assumed to enunciate an excess that far transcends the foreign demand to fix the text’s ‘call’ into singular meanings (beyond time), but rather transforms the hermeneutic desire into a process (...) of learning (Sikhi) through multiple meanings (in time). Thus the GGS is not translated according to a particular life-world, but actively transforms the life-world of those that respond to its excessive call. How should hermeneutics be reformed in this case? If the GGS as text demands interpretation, then the text as Guru demands engagement, and together they would necessarily call forth a radicalization of hermeneutics via a certain poetic reticence to all philosophical messengers. (shrink)

Movement of leukocytes from peripheral blood into tissues, also called leukocyte extravasation, is absolutely essential for immunity in higher organisms. Over the past decade, our understanding of the molecular mechanisms involved in white blood cell extravasation during both normal immune surveillance and the generation of protective immune responses has taken a great leap forward with the discovery of the chemokine gene superfamily. Chemokines are low-molecular-weight cytokines whose major collective biological activity appears to be that of chemotaxis of both specific and (...) overlapping subsets of leukocytes. They are therefore likely to play a critical role in the directed movement of leukocytes from the bloodstream into tissue. These molecules are almost exclusively secreted and act as extracellular messengers for the immune system. However, emerging data also show that various members of the chemokine gene superfamily exert other biological effects outside the immune system. All nucleated cells and all tissues examined to date are capable of expressing at least some chemokines, and it seems likely therefore that by the time all the chemokines are identified, and all their biological functions elucidated, we will find that, as a family, these molecules perform an extracellular messenger role in all tissues and systems of the body. BioEssays 1999;21:17–28. © 1999 John Wiley & Sons, Inc. (shrink)

The interconversion of key regulatory proteins between phosphorylated and dephosphorylated forms is an extremely versatile mechanism for reversible altering their activities, and in mammalian cells may be almost as common as allosteric regulation. It is now evident that protein phosphorylation is the basis of a complex network of interlocking systems which allow a variety of hormones and other extracellular signals, acting through just a few second messengers to coordinate biochemical functions.