Reciprocal Actions Research Articles

Reciprocal actions of ATF5 and Shh in proliferation of cerebellar granule neuron progenitor cells

Precise regulation of neuroprogenitor cell proliferation and differentiation is required for successful brain development, but the factors that contribute to this are only incompletely understood. The transcription factor ATF5 promotes proliferation of cerebral cortical neuroprogenitor cells and its down regulation permits their differentiation. Here, we examine the expression and regulation of ATF5 in cerebellar granule neuron progenitor cells (CGNPs) as well as the role of ATF5 in the transition of CGNPs to postmitotic cerebellar granule neurons (GCNs). We find that ATF5 is expressed by proliferating CGNPs in both the embryonic and postnatal cerebellar external granule layer (EGL) and in the rhombic lip, the embryonic structure from which the EGL arises. In contrast, ATF5 is undetectable in postmitotic GCNs. In highly enriched dissociated cultures of CGNPs and CGNs, ATF5 is expressed only in CGNPs. Constitutive ATF5 expression in CGNPs does not affect their proliferation or exit from the cell cycle. In contrast, in presence of sonic hedgehog (Shh), a mitogen for CGNPs, constitutively expressed ATF5 promotes CGNP proliferation and delays their cell cycle exit and differentiation. Conversely, ATF5 loss-of-function conferred by a dominant-negative form of ATF5 significantly diminishes Shh-stimulated CGNP proliferation and promotes differentiation. In parallel with its stimulation of CGNP proliferation, Shh enhances ATF5 expression by what appeared to be a posttranscriptional mechanism involving protein stabilization. These findings indicate a reciprocal interaction between ATF5 and Shh in which Shh stimulates ATF5 expression and in which ATF5 contributes to Shh-stimulated CGNP expansion.

Coaxing Climate Policy Leadership

The United States and China have recently been called upon to exercise more leadership in developing an effective international policy response to climate change, but without giving attention to either the risks inherent in taking on such a role or the mechanism by which leading can mobilize others to act in response. Here, I understand leadership as action by a sufficiently powerful actor in a cooperative scheme that is capable of triggering reciprocal actions by followers on behalf of that scheme, and argue that such leadership can be coaxed by potential followers through pledges of reciprocal action that are made conditional upon prior action undertaken by a leader. In the context of the current international impasse over post-Kyoto climate change mitigation commitments, I identify means by which leadership by the U.S. or China might be induced by such conditional pledges, potentially allowing some obstacles to international collective action on climate change mitigation to be overcome.

SATB Homeobox Proteins Regulate Trophoblast Stem Cell Renewal and Differentiation

The morphogenesis of the hemochorial placenta is dependent upon the precise expansion and differentiation of trophoblast stem (TS) cells. SATB homeobox 1 (SATB1) and SATB2 are related proteins that have been implicated as regulators of some stem cell populations. SATB1 is highly expressed in TS cells, which prompted an investigation of SATB1 and the related SATB2 as regulators of TS cells. SATB1 and SATB2 were highly expressed in rat TS cells maintained in the stem state and rapidly declined following induction of differentiation. SATB proteins were also present within the rat placenta during early stages of its morphogenesis and disappeared as gestation advanced. Silencing Satb1 or Satb2 expression decreased TS cell self-renewal and increased differentiation, whereas ectopic expression of SATB proteins promoted TS cell expansion and blunted differentiation. Eomes, a key transcriptional regulator of TS cells, was identified as a target for SATB proteins. SATB knockdown decreased Eomes transcript levels and promoter activity, whereas SATB ectopic expression increased Eomes transcript levels and promoter activity. Electrophoretic mobility shift assay as well as chromatin immunoprecipitation analyses demonstrated that SATB proteins physically associate with a regulatory site within the Eomes promoter. We conclude that SATB proteins promote TS cell renewal and inhibit differentiation. These actions are mediated in part by regulating the expression of the TS cell stem-associated transcription factor, EOMES.

The complex dialogue between (myo)fibroblasts and the extracellular matrix during skin repair processes and ageing

The fibroblasts and the myofibroblasts are key players for maintaining skin homeostasis and for orchestrating physiological tissue repair. The (myo)fibroblasts are embedded in a sophisticated extracellular matrix (ECM) that they secrete, and a complex and interactive dialogue exists between (myo)fibroblasts and their microenvironment. The composition of the ECM around (myo)fibroblasts is variable depending on the situation and, in addition to the secretion of the ECM, the (myo)fibroblasts, by secreting matrix metalloproteinases and tissue inhibitors of metalloproteinases can remodel this ECM. The (myo)fibroblasts and their microenvironment form a changing network with reciprocal actions leading to cell differentiation, proliferation, quiescence or apoptosis, and also acting on growth factor biodisponibility. In pathological situations (such as chronic wounds or excessive scarring), or during ageing, especially due to ultraviolet exposition, this dialogue between the (myo)fibroblasts and their microenvironment is disrupted, leading to repair defects or to skin injuries with unaesthetic alterations such as wrinkles. Knowing the intimate exchanges between the (myo)fibroblasts and their microenvironment represents a fascinating domain important not only for characterizing new targets and drugs able to prevent pathological developments but also for interfering with skin alterations observed during ageing.

Managing Software Outsourcing Relationships in Emerging Economies: An Empirical Study of the Chinese Small- and Medium-Sized Enterprises

Small- and medium-sized enterprises (SMEs) are facing great challenges in their information systems (IS) outsourcing relationship management, especially with customized software outsourcing under conditions of technological uncertainty and transaction-specific investments. The problem may be even critical for Chinese SMEs in emerging economies characterized by institutional instability. This article draws on multiple theories to examine antecedents and consequences of the effectiveness of three important interorganizational governance mechanisms, namely, contractual-based and relational-based governance and vendor-specific investments. The results of a survey on 83 software outsourcing projects indicate some interesting patterns that Chinese SMEs use to manage their outsourcing relationships. We found that contractual governance is found to be the only effective mechanism when the outsourcing firm (client) perceives technological uncertainty. On the other hand, with the transaction-specific investments, relational governance, and reciprocal-specific investments by IS vendor would be preferred as effective mechanisms by the outsourcing firm. Our analyses also show that Chinese SMEs in emerging economies would rely on multiple governance mechanisms to enhance outsourcing success. Overall, the findings are in line with the studies stressing the importance of building partnership-style relationships and seeking reciprocal actions in sourcing exchanges.

Memory encoding in hippocampal ensembles is negatively influenced by cannabinoid CB1 receptors

It has previously been demonstrated that the detrimental effect on the performance of a delayed nonmatch to sample (DNMS) memory task by exogenously administered cannabinoid (CB1) receptor agonist, WIN 55212-2 (WIN), is reversed by the receptor antagonist rimonabant. In addition, rimonabant administered alone elevates DNMS performance, presumably through the suppression of negative modulation by released endocannabinoids during normal task performance. Other investigations have shown that rimonabant enhances encoding of DNMS task-relevant information on a trial-by-trial, delay-dependent basis. In this study, these reciprocal pharmacological actions were completely characterized by long-term, chronic intrahippocampal infusion of both agents (WIN and rimonabant) in successive 2-week intervals. Such long-term exposure allowed extraction and confirmation of task-related firing patterns, in which rimonabant reversed the effects of CB1 agonists. This information was then utilized to artificially impose the facilitatory effects of rimonabant and to reverse the effects of WIN on DNMS performance, by delivering multichannel electrical stimulation in the same firing patterns to the same hippocampal regions. Direct comparison of normal and WIN-injected subjects, in which rimonabant injections and ensemble firing facilitated performance, verified reversal of the modulation of hippocampal memory processes by CB1 receptor agonists, including released endocannabinoids.

A dual action of saturated fatty acids on electrical activity in rat pancreatic β‐cells. Role of volume‐regulated anion channel and KATP channel currents

Free fatty acids (FFAs) exert complex actions on pancreatic β-cells. Typically, an initial potentiation of insulin release is followed by a gradual impairment of β-cell function, the latter effect being of possible relevance to hyperlipidaemia in type 2 diabetes mellitus. The molecular actions of FFAs are poorly understood. The present study investigated the acute effects of saturated FFAs on electrophysiological responses of rat pancreatic β-cells. Membrane potential and KATP channel activity were recorded using the perforated patch technique. Volume-regulated anion channel (VRAC) activity was assessed from conventional whole-cell recordings. Cell volume regulation was measured using a video-imaging technique. Addition of octanoate caused a transient potentiation of glucose-induced electrical activity, followed by a gradual hyper-polarisation and a prolonged inhibition of electrical activity. Octanoate caused an initial increase in VRAC activity followed by a secondary inhibition coinciding with increased KATP channel activity. Similar effects were observed with palmitate and 2-bromopalmitate whereas butyrate was virtually ineffective. Octanoate and palmitate also exerted a dual effect on electrical activity evoked by tolbutamide. Octanoate significantly attenuated cell volume regulation in hypotonic solutions, consistent with VRAC inhibition. It is concluded that medium and long chain FFAs have a dual action on glucose-induced electrical activity in rat pancreatic β-cells: an initial stimulatory effect followed by a secondary inhibition. These effects appear to be the result of reciprocal actions on VRAC and KATP channel currents, and could contribute towards the stimulatory and inhibitory actions of FFAs on pancreatic β-cell function.

The neurobiofeedback cumulative effect on the electroencephalographic indexes in the high qualified athletes with the dominance of metabolic modulation of heart rate variability

The aim was to investigate the electroencephalography indexes dynamic caused by neurofeedback in athletes. The main results are that the neurobiofeedback cumulative effect on the electroencephalographic indexes in the high qualified athletes with the dominance of metabolic modulation of heart rate variability is carried out. The conclusions are that the interlobar reciprocal actions reorganization in a brain and the general changing of quantitative electroencephalogram indexes of all standard diapasons of frequency are revealed both in the locus of biofeedback control and overall brain convex surface.

Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5

Interleukin 2 (IL-2), a cytokine linked to human autoimmune disease, limits IL-17 production. Here we found that deletion of the gene encoding the transcription factor STAT3 in T cells abrogated IL-17 production and attenuated autoimmunity associated with IL-2 deficiency. Whereas STAT3 induced IL-17 and the transcription factor RORγt and inhibited the transcription factor Foxp3, IL-2 inhibited IL-17 independently of Foxp3 and RORγt. STAT3 and STAT5 bound to multiple common sites across the locus encoding IL-17. The induction of STAT5 binding by IL-2 was associated with less binding of STAT3 at these sites and the inhibition of associated active epigenetic marks. 'Titration' of the relative activation of STAT3 and STAT5 modulated the specification of cells to the IL-17-producing helper T cell (T(H)17 cell) subset. Thus, the balance rather than the absolute magnitude of these signals determined the propensity of cells to make a key inflammatory cytokine.

Effects of Varenicline on Smoking Cue–Triggered Neural and Craving Responses

Varenicline, an effective smoking cessation medication, functions as an α4β2 nicotinic acetylcholine receptor partial agonist. It indirectly affects the dopaminergic reward system by reducing withdrawal symptoms during abstinence and by decreasing the reinforcement received from nicotine while smoking. We hypothesize that varenicline would have a third mechanism to blunt responses to smoking cues in the reward-related ventral striatum and medial orbitofrontal cortex and would be associated with a reduction in smoking cue–elicited craving. A laboratory model of conditioned responding and arterial spin-labeled perfusion functional magnetic resonance imaging, a biomarker of regional brain activity, was used to test our hypothesis. Perfusion functional magnetic resonance imaging is quantitative and stable across time, facilitating the measurement of medication-induced neural modifications in the brain in response to a challenge (smoking cue exposure) and in the brain in the resting condition (without provocation). Smokers were imaged during rest and during smoking cue exposure before and after a 3-week randomized placebo-controlled medication regimen. Subjects were nonabstinent to explicitly examine the effects of varenicline on cue reactivity independent of withdrawal. Center for the Study of Addictions, University of Pennsylvania, Philadelphia. Subjects Subjects were nicotine-dependent smokers who responded to advertisements placed on local radio and Listservs to participate in a medication-related research study that specifically stated "this is not a Quit Smoking Study" and "smokers may be contemplating but not currently considering quitting." Prerandomization smoking cues vs nonsmoking cues activated the ventral striatum and medial orbitofrontal cortex (t = 3.77) and elicited subjective reports of craving (P = .006). Craving reports correlated with increased activity in the posterior cingulate (t = 4.11). Administration of varenicline diminished smoking cue–elicited ventral striatum and medial orbitofrontal cortex responses (t values from –3.75 to –5.63) and reduced self-reported smoking cue–elicited craving, whereas placebo-treated subjects exhibited responses similar to those observed prior to randomization. Varenicline-induced activation of lateral orbitofrontal cortex in the brain at rest (t = 5.63) predicted blunting of smoking cue responses in the medial orbitofrontal cortex (r = –0.74). Varenicline's reciprocal actions in the reward-activated medial orbitofrontal cortex and in the reward-evaluating lateral orbitofrontal cortex underlie a diminished smoking cue response, revealing a distinctive new action that likely contributes to its clinical efficacy.

Unbalanced Reciprocities: Cooperation on Readmission in the Euro-Mediterranean Area

This short volume starts with a paradox. Over the last fifteen years or so, the number of bilateral readmission treaties concluded by the EU Member States with third countries has skyrocketed. This is quite extraordinary given the unbalanced reciprocities characterizing such treaties. Despite their being framed in a reciprocal context, readmission treaties incur asymmetric costs and benefits for the two contracting parties, particularly given they do not share the same interests in the removal of unauthorized aliens. With specific reference to the Euro-North African context, the authors set out to explain the cumulative factors and the overriding driving forces that have contributed to the growth and geographical expansion of the cobweb of bilateral agreements linked to readmission. They also highlight the gaps that may exist between reciprocal commitments and effective actions as well as between the drive for operability and the respect for human rights.

Glucose Regulates Steady-state Levels of PDX1 via the Reciprocal Actions of GSK3 and AKT Kinases

The pancreatic beta cell is sensitive to even small changes in PDX1 protein levels; consequently, Pdx1 haploinsufficiency can inhibit beta cell growth and decrease insulin biosynthesis and gene expression, leading to compromised glucose-stimulated insulin secretion. Using metabolic labeling of primary islets and a cultured beta cell line, we show that glucose levels modulate PDX1 protein phosphorylation at a novel C-terminal GSK3 consensus that maps to serines 268 and 272. A decrease in glucose levels triggers increased turnover of the PDX1 protein in a GSK3-dependent manner, such that PDX1 phosphomutants are refractory to the destabilizing effect of low glucose. Glucose-stimulated activation of AKT and inhibition of GSK3 decrease PDX1 phosphorylation and delay degradation. Furthermore, direct pharmacologic inhibition of AKT destabilizes, and inhibition of GSK3 increases PDX1 protein stability. These studies define a novel functional role for the PDX1 C terminus in mediating the effects of glucose and demonstrate that glucose modulates PDX1 stability via the AKT-GSK3 axis.

Explaining educational experience: On one- and two-handed gestures as semiotic entities and the flexibility of their use

This article studies hand gestures and specifies four different possible uses: (1) one-handed gestures; (2) symmetrical two-handed gestures; (3) symmetrical two-handed gestures in which the hands alternately perform the same movement ; (4) asymmetrical two-handed gestures. The paper shows how a speaker employs various hand gestures to explain her teaching experiences and views the concurrence ofgestures with speech, body posture, shrugs, gaze, and facial expressions as reciprocal actions to an interlocutor's responses. The final section of the paper discusses the flexibility of hand gestures and the different ways in which it is revealed.

Le Capteur plan veut son indépendance

Converging evidence indicates the hypothalamus–pituitary–adrenal axis and serotonergic neurons exert reciprocal modulatory actions. Likewise, brain-derived neurotrophic factor (BDNF) has been implicated as a growth and differentiation factor in the development of serotonergic neurons. The aim of this study was to examine the interaction of cortisol and BDNF on serotonin transporter (SERT) in bipolar disorder (BD). Twenty-eight BD and 28 age- and gender-matched healthy controls (HCs) were recruited. 123I-ADAM with single-photon emission computed tomography (SPECT) was applied for measurement of SERT availability in the brain, which included the midbrain, thalamus, putamen and caudate. Ten milliliters of venous blood was withdrawn, when the subject underwent SPECT, for the measurement of the plasma concentration of cortisol and BDNF. SERT availability was significantly decreased in the midbrain and caudate of BD compared with HCs, whereas plasma concentration of cortisol and BDNF did not show a significant difference. The linear mixed-effect model revealed that there was a significant interaction of group and cortisol on SERT availability of the midbrain, but not BDNF. Linear regression analyses by groups revealed that cortisol was associated with SERT availability in the midbrain in the HCs, but not in BD. Considering previous studies, which showed a significant association of cortisol with SERT availability in the HCs and major depressive disorder (MDD), our result replicated a similar finding in HCs. However, the negative finding of the association of cortisol and SERT availability in BD, which was different from MDD, suggests a different role for cortisol in the pathophysiology of mood disorder.

Molecular Physiology of the WNK Kinases

Mutations in the serine-threonine kinases WNK1 and WNK4 cause a Mendelian disease featuring hypertension and hyperkalemia. In vitro and in vivo studies have revealed that these proteins are molecular switches that have discrete functional states that impart different effects on downstream ion channels, transporters, and the paracellular pathway. These effects enable the distal nephron to allow either maximal NaCl reabsorption or maximal K+ secretion in response to hypovolemia or hyperkalemia, respectively. The related kinase WNK3 has reciprocal actions on the primary mediators of cellular Cl(-) influx and efflux, effects that can serve to regulate cell volume during growth and in response to osmotic stress as well as to modulate neuronal responses to GABA. These findings define a versatile new family of kinases that coordinate the activities of diverse ion transport pathways to achieve and maintain fluid and electrolyte homeostasis.

The Kennedy Experiment Revisited

Many of the critical issues and conflicts in international relations today bear a significant resemblance to the geopolitical circumstances that led to the development of a theorem the author published in these pages forty years ago. This theorem points toward a course of (1) unilateral, (2) reciprocal, and (3) symbolic actions between mutually mistrustful agents as the best road to travel toward the possibility of “normal” negotiations. Looking back at the events of 1962—1963, the author finds (as he found in his article forty years ago) that the unilateral-reciprocal approach led to reduced tensions between the United States and the Union of Soviet Socialist Republics. Although his theorem has received the kind of varied and relevant observations those who formulate theorems aspire to, the author regrets that there have been very few attempts to apply this theorem to subsequent international conflicts as a tension-reducing tactic.

Online interaction readiness: conceptualisation and measurement

Relationship marketing suggests a need to better understand and more actively involve consumers in the marketing process. This is especially the case with the Internet channel, because of its unique capability for two-v\/ay communication compared with traditional mass media. Existing research, however, has paid limited attention to consumers' general tendency to engage in online interaction. This paper brings together critical thinking in relationship marketing, Internet marketing, and communication to propose a new construct, online interaction readiness, that captures a consumer's willingness to engage in reciprocal actions through the Internet. Following recommended scale development procedures, a 10-item scale measuring interaction readiness (IRSCALEl is developed. Evidence regarding the dimensionality, validity, and reliability of the IRSCALE is provided. The relevance of interaction readiness to business strategy is illustrated through its impact on consumers' online shopping behaviour and communication channel preferences.

Functional studies of motor cortex.

Defining functions for neural elements becomes more difficult the more remote they are, in synaptic linkages, from motor neurons. The precentral motor cortex contains a corticomotoneuronal projection system, only one synapse removed from motor neurons. Corticomotoneuronal fibres produce monosynaptic excitation of spinal motor neurons, which is more powerful for those acting distally, innervating extensor muscles of the fingers and intrinsic hand muscles. Latencies and time-course of corticomotoneuronal excitation are defined. Amplitudes of unitary corticomotoneuronal excitatory postsynaptic potentials are very small. Many corticomotoneuronal cells converge on a given motor neuron. Some motor neurons innervating proximally acting muscles appear to receive no corticomotoneuronal excitation. Disynaptic inhibitory actions are produced by corticospinal volleys via the common Ia inhibitory interneuron--possibly reciprocal actions produced over collaterals of corticomotoneuronal fibres. Anatomical divergence of projections of collaterals of an identified corticomotoneuronal fibre is extensive enough to provide both for delivery of synapses to a large number of motor neurons and for the dispersion of specific projections to inhibitory interneurons, to fusimotor neurons and to other interneurons. Functions of corticomotoneuronal elements in motor cortex whose targets have been identified and whose excitatory or inhibitory actions have been specified by cross-correlation have been studied by Fetz & Cheney (J Neurophysiol 1980; 44:751-772).

Reciprocal Actions of Platelet-Secreted TGF-??1 on the Production of VEGF and HGF by Human Tendon Cells

Autologous platelet-rich matrices can be an aid in surgery by promoting and accelerating tissue healing because of the release of growth factors including transforming growth factor (TGF)-beta1 and platelet-derived growth factor (PDGF) from platelet alpha-granules. PDGF and TGF-beta1 were quantified in supernatants collected from platelet-rich matrices prepared in vitro (n = 45 donors) and they correlated with the number of platelets and showed a constant ratio (p < 0.05). Tendon cells in culture were exposed to the supernatants (n = 4 donors) from either platelet-rich or platelet-poor matrices, differing in their content of platelet-secreted molecules. These treatments were modified by either neutralizing or adding PDGF or TGF-beta1. Effects were compared in terms of proliferation, procollagen I, vascular endothelial growth factor (VEGF), and hepatocyte growth factor (HGF) production. PDGF was a partial contributor to cell proliferation, whereas exogenous TGF-beta1 acted as a negative modulator (p < 0.05). The production of type I collagen was similar regardless of differences in the concentration of TGF-beta1. Moreover, addition of exogenous TGF-beta1 promoted a significant increase in collagen synthesis only in the absence of other platelet-released substances (p < 0.05). Exogenous TGF-beta1 increased the synthesis of VEGF and simultaneously abolished the production of HGF. Furthermore, antibody-mediated neutralization of TGF-beta1 induced a decrease in VEGF synthesis and concomitantly a substantial production of HGF (p < 0.05). The balance between TGF-beta1 and the pools of platelet-secreted molecules may have important therapeutic implications in the control of angiogenesis and fibrosis.

Roles of Volume-Sensitive Chloride Channel in Excitotoxic Neuronal Injury

Excitotoxicity is associated with stroke, brain trauma, and a number of neurodegenerative disorders. In the brain, during excitotoxic insults, neurons undergo rapid swelling in both the soma and dendrites. Focal swellings along the dendrites called varicosities are considered to be a hallmark of acute excitotoxic neuronal injury. However, it is not clear what pathway is involved in the neuronal anion flux that leads to the formation and resolution of excitotoxic varicosities. Here, we assessed the roles of the volume-sensitive outwardly rectifying (VSOR) Cl- channel in excitotoxic responses in mouse cortical neurons. Whole-cell patch-clamp recordings revealed that the VSOR Cl- channel in cultured neurons was activated by NMDA exposure. Moreover, robust expression of this channel on varicosities was confirmed by on-cell and nystatin-perforated vesicle patch techniques. VSOR channel blockers, but not blockers of GABA(A) receptors and Cl- transporters, abolished not only varicosity resolution after sublethal excitotoxic stimulation but also necrotic death after sustained varicosity formation induced by prolonged NMDA exposure in cortical neurons. The present slice-patch experiments demonstrated, for the first time, expression of the VSOR Cl- channels in somatosensory pyramidal neurons. NMDA-induced necrotic neuronal death in slice preparations was largely suppressed by a blocker of the VSOR Cl- channel but not of the GABA(A) receptor. These results indicate that VSOR Cl- channels exert dual, reciprocal actions on neuronal excitotoxicity by serving as major anionic pathways both for varicosity recovery after washout of an excitotoxic stimulant and for persistent varicosity formation under prolonged excitotoxic insults leading to necrosis in cortical neurons.