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Cognitive deficits are critical determinants of schizophrenia morbidity. In this review, we offer a mechanistic perspective regarding schizophrenia-related changes observed in prefrontal cortical networks engaged in working memory. A body of earlier work converges on aberrations in putative macrocircuit stability and functional efficiency as the underlying pathophysiology of the cognitive deficits in schizophrenia. In parsing the dysfunctional prefrontal cortical dynamics of schizophrenia, recent functional magnetic resonance imaging and electoencephalography works suggest that in the context of reduced capacity for executive aspects of working memory, patients engage a larger network of cortical regions consistent with an interplay between reduced signal-to-noise components and the recruitment of compensatory networks. The genetic programming underlying these systems-level cortical interactions has been examined under the lens of certain schizophrenia susceptibility genes, especially catechol-o-methyltransferase (COMT) and GRM3. Variation in COMT, which presumably impacts on cortical dopamine signaling, translates into variable neural strategies for working memory and altering patterns of intracortical functional correlations. GRM3, which impacts on synaptic glutamate, interacts with COMT and exaggerates the genetic dissection of cortical processing strategies. These findings reveal novel insights into the modulation and parcellation of working memory processing in cortical assemblies and provide a mechanistic link between susceptibility genes and cortical pathophysiology related to schizophrenia.
Understanding the neurobiology of schizophrenia remains a significant challenge of public health importance. Cognitive dysfunction is a core feature of schizophrenia, and a key focus of investigation given its impact on functional outcome and chronic disease morbidity, largely unaffected by the present pharmacopoeia (Goldberg and Weinberger 1996; Green 1996). Working memory is a limited capacity system that enables us to temporarily hold, update, and work with relevant information; it underlies higher-order thinking, language, and goal-directed behavior (Baddeley 2003). It has been shown to be an important component underlying many cognitive deficits observed in schizophrenia (Goldberg et al. 1987; Goldman-Rakic 1994; Silver et al. 2003). There are several conceptual approaches to the study of working memory processes, though most agree that working memory involves a system of limited attentional capacity, peripheral information storage systems, and executive control processes (Baddeley 2003). In this review, we will examine recent systems-level findings in the in vivo prefrontal cortical networks engaged by working memory and related cognitive processes in patients with schizophrenia, as well as in healthy individuals with susceptibility genes for schizophrenia. As we attempt to synthesize a coherent perspective on the interplay of cortical macrocircuits implicated in these processes, we will speculate on implications for the dynamic adaptations occurring in the brain in schizophrenia, and for future work on the neurodevelopmental pathophysiology of the disorder.
Prefrontal Cortex, Working Memory, and Schizophrenia
The prefrontal cortex is involved in working memory and related higher-cognitive processes like planning and goal-directed activity (Goldman-Rakic 1995, 1996; Fuster 2000). Seminal work on single-unit recording in nonhuman primates shows that neurons located around the principal sulcus in the dorsolateral prefrontal cortex exhibit delay-related activity during delay-match-to-sample paradigms (Goldman-Rakic 1987, 1990). Pharmacological manipulations of the dorsolateral prefrontal cortex, particularly involving the dopamine (DA) D1 receptor, also modulate working memory (Sawaguchi and Goldman-Rakic 1991, 1994; Williams and Goldman-Rakic 1995). Numerous functional neuroimaging studies have since elaborated the key role of the prefrontal cortex in human working memory. It is also clear that the neural system supporting working memory does not reside only in the prefrontal cortex, but extends beyond it to involve other distant cortical areas. These include the posterior parietal cortex, the inferotemporal cortex, the cingulate gyrus, and hippocampus—all of which have anatomical connections with the prefrontal cortex (Petrides and Pandya 1984; Selemon and Goldman-Rakic 1985; Goldman-Rakic 1988, 1999; Cavada and Goldman-Rakic 1989; Fuster 1997; Jonides et al. 1998).
There is abundant evidence that the prefrontal cortex and working memory are abnormal in schizophrenia. Postmortem studies have shown increased neuronal density in the dorsolateral prefrontal cortex of patients with schizophrenia (Garey et al. 1998; Harrison 1999; Selemon and Goldman-Rakic 1999; Glantz and Lewis 2000). Cognitive deficits, including working memory, may occur before the onset of psychosis (Jones et al. 1994; Davidson et al. 1999; Cannon et al. 2002; Fuller et al. 2002; Ang and Tan 2004), and are certainly present by the first-episode and thereafter (Goldberg and Weinberger 1988; Park and Holzman 1992; Keefe et al. 1995; Gold et al. 1997; Bilder et al. 2000; Weickert et al. 2000). An extensive body of functional imaging experiments is consistent with prefrontal cortical physiological dysfunction in schizophrenia (Weinberger et al. 1986; Andreasen et al. 1992; Fletcher et al. 1998; Manoach et al. 1999, 2000; Callicott et al. 2000; Barch et al. 2001; Meyer-Lindenberg et al. 2001; Perlstein et al. 2001; Callicott, Mattay, et al. 2003; Manoach 2003; Schlosser, Gesierich, Kaufmann, Vucurevic, Hunsche, et al. 2003; Schlosser, Gesierich, Kaufmann, Vucurevic, Stoeter 2003; Tan et al. 2005, 2006). This is characterized by abnormal activation relative to healthy controls. As we will elaborate, emerging studies argue that the directionality of the findings (i.e., too much or too little prefrontal activity) depend on the specific task paradigm utilized, disease-related differences in behavioral performance, and capacity constraints of task load (Callicott et al. 1999, 2000; Ramsey et al. 2002; Callicott, Mattay, et al. 2003; Manoach 2003), and possibly the engagement of dysfunctional and compensatory macrocircuits (Tan et al. 2005, 2006). Contemporary functional neuroimaging therefore affords the opportunity to further elaborate the dynamics of these complex pathophysiological processes underlying what appears to be inefficient brain function in schizophrenia.
Dysfunctional Prefrontal Cortical Dynamics in Schizophrenia
Early functional imaging studies in schizophrenia have documented reduced frontal-lobe regional cerebral blood flow at rest and during complex tasks involving executive function (for review, see Callicott and Weinberger 1999). Recent work examining more specific processes involved in working memory and executive cognition have also often found reduced blood-oxygen-level–dependent activation in the prefrontal cortex in patients with schizophrenia (Callicott et al. 1998; Carter et al. 1998; Stevens et al. 1998; Barch et al. 2001, 2002, 2003; Perlstein et al. 2001, 2003). One important approach has been to examine the encoding, maintenance, and the application of contextual information in cognitive control (Braver et al. 1999; Barch et al. 2001). In one such study, patients with schizophrenia performed worse on such trials but did relatively better on trials where successful maintenance of contextual information interfered with subsequent task behavior. Both of these behavioral deficits were accompanied by reduced functional magnetic resonance imaging (fMRI) activation of the dorsolateral prefrontal cortex (Barch et al. 2001). Furthermore, the patients in this study were neuroleptic-naïve and at their first psychotic episode—thus potential confounds related to illness chronicity and treatment were not applicable to these findings. In neuroimaging studies using the N-back task, which engaged a number of storage and executive processes related to working memory, patients with schizophrenia also exhibited decreased performance accuracy and reaction time relative to healthy controls, along with decreased prefrontal activation (Callicott et al. 1998; Menon et al. 2001; Meyer-Lindenberg et al. 2001; Perlstein et al. 2001). This pattern of executive processing deficits appears to be relatively specific to schizophrenia, as suggested by comparisons between patients with schizophrenia and affective disorders, where the former were found to perform worse in executive function tasks and had more dorsolateral prefrontal cortical activation deficits (Berman et al. 1993; Barch et al. 2003; MacDonald et al. 2005).
A concern has often been raised regarding the impact of patients' poorer performance on cortical activation differences per se, as well as how this might reflect differences in the capacity limitation of working memory between patients and controls. Capacity limitation, a key feature of working memory, is usually reflected in cognitive testing as decreasing performance in response to increasing working memory load (Shallice 1988; Just and Carpenter 1996; Fuster 1997). In addressing the dynamic range of physiological responses that presumably underlie variations in capacity during an N-back working memory task with increasing cognitive load, it was found that regions within the healthy dorsolateral prefrontal cortex evinced a nonlinear "inverted-U" shaped physiological response (Callicott et al. 1999; Mattay et al. 2003; Jansma et al. 2004). Thus, areas of prefrontal cortical activation increased with task load and difficulty, alongside decreased accuracy and slower reaction time. This occurred to an extent defined by the individual's working memory capacity, after which continued increase in task load resulted in decreased prefrontal cortical activation. This is analogous to findings with single-unit recordings in monkeys (Goldman-Rakic 1990) and with EEG evoked potentials in humans (Gevins et al. 1997), that is, that memory error is associated with failure of engagement of the appropriate cortical response network. It has been suggested that the working memory capacity of schizophrenia patients is relatively reduced to account for their deficits in cognitive performance and their tendency to disengage prefrontal cortical activation when their performance is failing (Fletcher et al. 1998; Callicott, Mattay, et al. 2003; Jansma et al. 2004). Patients therefore seem to fall off the information processing "treadmill" at a lower cognitive load, possibly as a reflection of underlying neuronal pathology (Weinberger et al. 2001).
These considerations, however, still leave unresolved the possibility that nonspecific factors like psychological disengagement or lack of effort could confound the finding of reduced working memory capacity and prefrontal activation in patients (Weinberger and Berman 1996). A complementary approach, therefore, has been to study patients whose working memory performance is at or near normal, or to account for performance deficits by analyzing only correct trials within an event-related study design. This approach often yielded the intriguing finding of regions with intact or relatively increased prefrontal cortical activation (Curtis et al. 1999; Manoach et al. 1999, 2000; Callicott et al. 2000; Ramsey et al. 2002; Callicott, Mattay, et al. 2003; Manoach 2003; MacDonald et al. 2005; Tan et al. 2005, 2006), which cannot easily be interpreted as reflecting nonspecific disengagement, lack of effort, or poor performance. Instead, the results of these studies suggest that when patients are able to keep up with the processing demands, they tend to do so less efficiently by engaging greater cerebral metabolic activity or a less focused cortical activity state. This might be analogous to the recruitment of extraneous neural activity in the early phases of a variety of learning paradigms, when the optimal cognitive strategy has not been arrived at, and when the task might conceivably be found to be more difficult (Andreasen et al. 1995; Shadmehr and Holcomb 1997; Petersen et al. 1998; Rypma and D'Esposito 1999; Ramsey et al. 2004). It might also parallel the reorganization in neural strategy following cortical injury with the redistribution of increased activity to functionally related healthy brain regions (Johansen-Berg et al. 2002). Indeed, if performance is preserved, then at least part of the increased or intact activation might serve to compensate for some underlying neural dysfunction, even as the overall network architecture might be inefficient. EEG evoked potential studies have suggested that this loss of an efficient or tuned response may represent a decrease in signal to noise or a failure of response stability within the cortical microcircuits that support these cognitive operations (Winterer, Egan, et al. 2006). This concept has recently been extended in an fMRI study of simple choice reaction time in patients with schizophrenia, in which signal to noise and independent component analyses revealed greater noise and more independent components within medial prefrontal cortex during the establishment of even this simple response (Winterer, Musso, et al. 2006).
Dysfunctional and Compensatory Cortical Networks in Schizophrenia
The conceptualization that there might be an interplay of dysfunctional and compensatory cortical regions or networks in schizophrenia gains traction in view of recent trends to examine specific working memory subprocesses that engage combinations of prefrontal subregions and associated nodes in the extended working memory network. As alluded to by previous behavioral (Goldberg et al. 1998; Kim et al. 2004) and imaging (Barch et al. 2001; MacDonald et al. 2005; Tan et al. 2005, 2006) studies, the executive aspects of working memory (e.g. the application of appropriate contextual information, or manipulation of information within working memory) appear selectively vulnerable in schizophrenia, relative to the maintenance of information. Executive processes hierarchically engage more dorsal (Brodmann Areas BAs 9, 10, and 46) than ventral regions (BAs 44, 45, 47) in the prefrontal cortex, whereby higher-order processes in the dorsolateral prefrontal cortex are suggested to exert control on more ventrolateral regions responsible for less complex processes (Fuster 1997; D'Esposito et al. 1999; Koechlin et al. 2003), such as rehearsal of information within working memory (Paulesu et al. 1993; Awh et al. 1996). Correspondingly, for patients with schizophrenia who have working memory deficits, regions of decreased activation (Barch et al. 2001; Callicott, Mattay, et al. 2003; MacDonald et al. 2005; Tan et al. 2005) or reduced functional connectivity (Kim et al. 2003; Meyer-Lindenberg, Olsen, et al. 2005; Tan et al. 2006) have often been localized to the dorsolateral prefrontal cortex in tasks engaging executive aspects of working memory that seem to exceed capacity in patients at reduced loads.
Conversely, schizophrenia patients with near normal working memory performance sometimes have shown activation patterns in the ventrolateral prefrontal cortex that were either intact (Barch et al. 2001; Perlstein et al. 2001; Kim et al. 2003; Meyer-Lindenberg, Olsen, et al. 2005), or increased (Callicott, Mattay, et al. 2003; Glahn et al. 2005; MacDonald et al. 2005; Tan et al. 2005, 2006), possibly in compensation for the dysfunctional dorsolateral prefrontal response. A series of recent fMRI findings examining brain–behavior correlations and frontoparietal functional connectivity support this interpretation (Tan et al. 2006): working memory performance was correlated with dorsolateral prefrontal cortical activation in healthy controls, but this relationship occurred at the ventrolateral prefrontal cortex in patients; and although healthy controls had relatively greater frontoparietal functional connectivity with the dorsolateral prefrontal cortex, schizophrenia patients evinced increased ventrolateral frontoparietal functional connectivity that was reciprocally related to deficits in the dorsal regions (Fig. 1). Thus, although healthy controls optimally utilized the dorsolateral prefrontal cortex in executive working memory tasks, schizophrenia patients were unable to do so but engaged greater ventrolateral prefrontal cortex involvement instead. Furthermore, poorer performing patients activated another region in the ventrolateral prefrontal cortex more than better performing patients, suggesting that this compensatory strategy might not always result in improved performance (Tan et al. 2006). The compensatory response may thus reflect a relative loss of hierarchical functional specialization in the diseased prefrontal cortex, where optimum dorsolateral prefrontal function is compromised and accompanied by a greater reliance on less efficient ventrolateral prefrontal engagement. Although resulting in a limited restoration of performance through a reweighting of the distributed neuronal architecture, the overall neural circuitry is likely to be unstable, may have a more limited functional capacity, and may eventually fail to maintain cognitive performance (i.e., reach capacity at lower levels of cognitive complexity). Still, how might these systems-level prefrontal cortical interactions relate to the core biology of schizophrenia in terms of key neurotransmitter complexes and the genes that program the wiring of this circuitry?
Imaging Genetics of Working Memory and Risk for Schizophrenia
DA-ergic and glutamatergic abnormalities have long served as major theoretical frameworks for understanding the pathophysiology as well as pharmacology of schizophrenia and its cognitive deficits, particularly working memory (Weinberger et al. 1988; Lisman et al. 1998; Carlsson et al. 2001; Egan, Goldberg, Kolachana, et al. 2001; Coyle et al. 2003; Laruelle et al. 2003; Moghaddam 2003; Sesack et al. 2003; Tamminga et al. 2003; Egan et al. 2004; Honey et al. 2004; Seamans and Yang 2004; Harrison and Weinberger 2005; Krystal et al. 2005). DA-ergic, glutamatergic, and GABAergic (gamma-amino-butyric acidergic) receptor systems are also central in the prefrontal neural dynamics mediating working memory (Sawaguchi and Goldman-Rakic 1991; Williams and Goldman-Rakic 1995; Lisman et al. 1998; Wang 1999; Durstewitz and Seamans 2002; Seamans and Yang 2004). Locally sustained activity of prefrontal neurons that are crucial in the maintenance of relevant information during the delay period of working memory tasks (Goldman-Rakic 1987, 1990) appear to be protected against distracters and instability by DA-mediated mechanisms (Durstewitz et al. 2000), which likely act by stabilizing the inhibitory architecture (Winterer and Weinberger 2004). This is likely to be critically dependent on DA D1-receptors (Williams and Goldman-Rakic 1995) and their role in enhancing N-methyl-D-aspartic acid (NMDA) receptor–mediated postsynaptic currents in prefrontal pyramidal and GABAergic neurons active during the delay period (Seamans, Durstewitz, et al. 2001; Wang and O'Donnell 2001). Concurrently, the D1-receptor appears to cause a tonic increase in the firing of GABAergic inhibitory interneurons, allowing a relative exaggeration of task-relevant activity compared with nontask related activity, thus increasing signal-to-noise (Seamans, Gorelova, et al. 2001). Of significance to the series of functional neuroimaging studies examining this process described below, the dose–response signature of prefrontal DA upon related signaling appears to follow an inverted-U curve (Williams and Goldman-Rakic 1995; Seamans and Yang 2004; Vijayraghavan et al. 2007).
These molecular and single-neuron paradigms resonate with suggestions that the functional architecture of the lateral prefrontal cortex could be hierarchically organized, whereby the more anterior and dorsal regions are thought to be engaged in higher-order executive processing (D'Esposito et al. 1999; Koechlin et al. 2003), wherein manipulation of information in memory has recently been modeled in integrate-and-fire networks to engage more inhibitory processing (Deco et al. 2004; Deco and Rolls 2005). Thus, it would be conceivable that changes in signal-to-noise processing through the DA-ergic D1-receptor or related NMDA or GABA receptor systems in the prefrontal cortex would tend to enhance or to degrade working memory predictably along the inverted-U shaped tuning curve (Williams and Goldman-Rakic 1995; Seamans and Yang 2004), and that executive aspects of working memory would be more sensitive to these variable effects.
Indeed, extensions of these hypotheses to the more complex in vivo human cortex have, in recent years, supported these possibilities (Egan, Goldberg, Kolachana, et al. 2001; Weinberger et al. 2001; Mattay et al. 2003; Egan et al. 2004; Bertolino et al. 2004; Blasi et al. 2005; Meyer-Lindenberg, Kohn, et al. 2005). This has been facilitated by examining the effects of an increasing set of putative schizophrenia candidate genes (particularly COMT and GRM3) using neuroimaging of working memory. Although these genes by themselves have modest effects on schizophrenia risk per se (Harrison and Weinberger 2005), their influence on key DA-ergic and glutamatergic neurotransmitter signaling pathways implicated in more constrained intermediate phenotypes such as working memory provides a powerful approach to examine the relationships between the biology of schizophrenia risk and specific brain function in vivo (Meyer-Lindenberg and Weinberger 2006).
The study of catechol-o-methyltransferase (COMT) is an important example of recent studies linking genes to cortical physiologic organization. COMT is a major enzyme in synaptic DA catabolism with a critical role in prefrontal cortical DA signaling because of the relative lack of DA transporters in this region (Seasack et al. 1998; Lewis et al. 2001; Chen et al. 2004). A common polymorphism in the COMT gene resulting from a valine-to-methionine Val(108/158)Met substitution gives rise to a significant reduction in its enzymatic activity in the prefrontal cortex and in peripheral tissues (Lotta et al. 1995; Lachman et al. 1996; Chen et al. 2004). This is thought to correspond to reduced prefrontal DA in proportion to Val-allele load—the allele that has been weakly associated with risk for schizophrenia and psychosis. Located on chromosome 22q11, this susceptibility locus has been implicated in meta-analyses of linkage to schizophrenia (Badner and Gershon 2002; Lewis et al. 2003). COMT is also deleted in velocardiofacial syndrome, a condition that has a 20 times increased risk for schizophrenia (Murphy 2002). However, the effect on risk for schizophrenia of the specific COMT Val(108/158)Met polymorphism is small and inconsistent (Glatt et al. 2003; Fan et al. 2005). This is not surprising given the manifold factors associated with schizophrenia pathogenesis, such as the interaction of genes and environmental conditions (Caspi et al. 2005).
In contrast, investigations of the effect of the COMT Val(108/158)Met polymorphism on working memory have converged with that predicted by cellular models of prefrontal DA previously described. Reduced prefrontal DA in COMT Val-carriers, presumably through decreased tonic D1-receptor activation, would be expected to result in firstly, reduced cortical signal-to-noise; secondly, a relatively inefficient and detuned prefrontal cortical activation map if performance accuracy is still maintained; and ultimately, reduced working memory and executive function. Each of these predictions have been borne out, and COMT genotypes were found to account for about 3–4% of the variance in performance on frontal-lobe tests, with poorer performance in subjects carrying the Val- rather than the Met-allele, even in normal subjects (Egan, Goldberg, Kolachana, et al. 2001; Malhotra et al. 2002; Goldberg et al. 2003; Nolan et al. 2004; de Frias et al. 2006). Analogous results were obtained in normal children (Diamond et al. 2004). Correspondingly, using fMRI to study cortical activity, healthy Val-allele carriers engaged relatively greater N-back prefrontal cortical activation, consistent with the conclusion that Val carriers are relatively less efficient (Egan, Goldberg, Kolachana, et al. 2001; Mattay et al. 2003; Meyer-Lindenberg et al. 2006). As might be predicted by the greater dependence on dorsolateral prefrontal cortical processing of higher-executive tasks (D'Esposito et al. 1999; Koechlin et al. 2003; Deco et al. 2004; Deco and Rolls 2005), these COMT effects in dorsolateral prefrontal cortex were more prominent at higher working memory loads (Mattay et al. 2003). The study by Mattay et al. (2003) also showed that the putatively inefficient prefrontal cortical activation in Val-homozygotes could be improved by the dopamimetic amphetamine, resulting in a more focused reduction of dorsolateral prefrontal activation as it became more optimally modulated, or closer to its peak on the inverted-U prefrontal DA tuning curve (Mattay et al. 2003). Conversely, Met-homozygotes, who were presumably already at the peak at baseline, appeared to be pushed off the peak of the curve by amphetamine, resulting in the adoption of a relatively inefficient (increased) cortical activation pattern (Fig. 2). Using an EEG evoked potential analysis based on signal-to-noise during the P300 oddball paradigm, it was recently demonstrated that COMT Val-allele load was associated with poorer signal-to-noise during this paradigm in prefrontal cortex, in patients with schizophrenia, in their healthy siblings, and also in normal subjects (Winterer, Egan, et al. 2006). These studies strongly indicate that this functional polymorphism in COMT impacts on the stability and tuning of cortical circuitry during working memory processing.
Cortical information processing, especially in prefrontal cortex, impacts on the regulation of DA activity in the mesencephalon (Winterer and Weinberger 2004). This is probably important in learning as it is reasonable to assume that reward signals emanating from brainstem DA neuronal firing must correspond to prefrontal cortical executive action for learning to take place. COMT, presumably via its actions at the cortical level, appears to impact on DA activity in the brainstem. In a study of normal postmortem human brainstem, individuals with a COMT Val/Val genotype had twice the expression of the messenger RNA for tyrosine hydroxylase, the rate limiting biosynthetic enzyme for DA (Akil et al. 2003). Remarkably, this relationship has been confirmed in a positron emission tomography imaging study of normal living subjects. COMT Val-carriers were shown to have relatively increased midbrain DA synthesis (measured with f-18 flurodopa uptake) that correlated negatively with N-back dorsolateral prefrontal cortical activation (measured with O-15 H2O regional cerebral blood flow), whereas prefrontal activation in Met-homozygotes positively correlated with midbrain DA synthesis (Meyer-Lindenberg, Kohn, et al. 2005). These reciprocal relationships fit tightly to the inverted-U tuning curve of prefrontal DA whereby increased midbrain DA synthesis in COMT Val-carriers with lower prefrontal DA tends to help restore more efficient cortical activation, whereas COMT Met-homozygotes are at risk to become less efficient with increased midbrain DA synthesis.
Like DA, glutamatergic abnormalities are important in schizophrenia and working memory function, and it follows that disease-related mutations in glutamate signaling could similarly impair its function. This has been found to be the case for GRM3 (Egan et al. 2004), a heteroceptor modulating NMDA-receptor transmission, and located on chromosome 7q21–22 (Moghaddam and Adams 1998; Egan et al. 2004; Harrison and Weinberger 2005). A polymorphism in intron 2 and related haplotypes were significantly associated with schizophrenia in several samples (Martí et al. 2002; Egan et al. 2004; Fallin et al. 2005; Chen et al. 2005), though negative studies also have been reported (Norton et al. 2005). GRM3 regulates synaptic glutamate via a presynaptic mechanism and by regulating the expression of the glial glutamate transporter, which inactivates synaptic glutamate. Risk variants in GRM3 may be a factor influencing alternative splicing of the GRM3-receptor (Sartorius et al. 2006). In postmortem brain, the risk allele is associated with reduced prefrontal glial glutamate transporter EAAT2, a protein modulating synaptic glutamate (Egan et al. 2004). Consistent with the role of the glutamatergic system in schizophrenia and working memory, the risk allele was associated with inefficient prefrontal cortical fMRI activation and reduced working memory performance even in normal subjects (Egan et al. 2004).
Critically, given the tight relationships governing DA-ergic, and glutamatergic (and GABAergic) dynamics in the biology of working memory (Sawaguchi and Goldman-Rakic 1991; Williams and Goldman-Rakic 1995; Lisman et al. 1998; Wang 1999; Durstewitz and Seamans 2002; Seamans and Yang 2004), and their putatively greater involvement in executive aspects of working memory at the dorsolateral prefrontal cortex (D'Esposito et al. 1999; Koechlin et al. 2003; Mattay et al. 2003; Deco et al. 2004; Deco and Rolls 2005), we would expect that higher-order working memory processes taxing dorsolateral prefrontal cortex might be more vulnerable to the combined effect of suboptimal DA-ergic and glutamatergic influence. If these processes were related to the prefrontal deficits associated with schizophrenia, a similar pattern of inefficiently increased dorsolateral prefrontal cortical activation might occur in the context of relatively preserved cognitive performance (Curtis et al. 1999; Manoach et al. 1999, 2000; Callicott et al. 2000; Ramsey et al. 2002; Callicott, Mattay, et al. 2003; Manoach 2003; Tan et al. 2005, 2006). Moreover, this pattern of relatively increased activation predicted during suboptimal DA-ergic and glutamatergic function might also be associated with reduced frontoparietal functional connectivity as found in schizophrenia (Tan et al. 2006). Correspondingly, putative compensatory activation from the ventrolateral prefrontal cortical regions (Barch et al. 2001; Perlstein et al. 2001; Callicott, Mattay, et al. 2003; Kim et al. 2003; Glahn et al. 2005; MacDonald et al. 2005; Meyer-Lindenberg, Olsen, et al. 2005; Tan et al. 2005, 2006) would be engaged with reciprocal increased activation and frontoparietal functional connectivity. Consistent with the interplay of cortical macrocircuits suggested by these possibilities, a recent fMRI study revealed that the integrity of higher-executive areas in the dorsolateral prefrontal cortex could be disproportionately compromised and inefficient in the presence of combined deleterious COMT and GRM3 genotypes in normal subjects, with a reweighting of activity to the ventrolateral prefrontal cortex if performance was maintained (Fig. 3) (Tan et al., 2007).
If confirmed, these findings could extend putative brain DA-ergic and glutamatergic cross-talk to the level of in-vivo neural systems interactions in cortical circuits implicated in working memory dysfunction and in schizophrenia. To the extent that these complex genetic associations mimic biological phenomena related to schizophrenia, they suggest that the neurobiology of schizophrenia involves dynamic changes to cortical systems as they adapt to these adverse neurobiological environments through the additional engagement of related cortical networks—possibly those usually engaged by processes lower in the cognitive processing hierarchy such as the ventrolateral prefrontal cortex. This example of putative disease-related functional plasticity appears at least in part genetically driven, and dissociable. The disproportionately inefficient prefrontal response associated with the combined deleterious genotypes of COMT and GRM3 also underlies an important concept in complex genetic diseases—that of epistatic interactions between genes, each of small individual effect. Thus, COMT, GRM3, and/or closely related downstream molecular events could play leading roles in human working memory and the pathogenesis of schizophrenia and could provide a foothold for other clinically relevant investigations.
Future Directions
Future work will need to elaborate on these early leads in several major areas—particularly in elaborating the related molecular events, and the developmental pathophysiology of schizophrenia. It would be critical to improve upon the resolution of how genetic variation (and indeed haplotypic variation; The International HapMap Consortium 2005) in COMT and GRM3, and other related schizophrenia susceptibility genes impacting neurotransmission (such as neuregulin, dysbindin, DISC1, RGS4, and G72) translate to molecular mechanisms that could account for these systems-level blood-oxygen-level–dependent observations in fMRI. We speculate that higher synaptic DA in COMT Met-homozygotes favorably enables the engagement of frontoparietal networks to handle the executive demands of complex working memory tasks, possibly with optimal D1 and NMDA-receptor–mediated signal-to-noise processing (Sawaguchi and Goldman-Rakic 1991; Moghaddam and Adams 1998; Durstewitz and Seamans 2002; Seamans and Yang 2004), and associated increased neural firing synchronicity (Wang 2001; Spencer et al. 2004) indexed by functional connectivity. Conversely, less efficient and noisier processing in the context of lower synaptic DA in COMT Val-homozygotes and more deleterious glutamatergic states, as well as in disease states, could require the additional recruitment of parallel inhibitory networks from the ventrolateral prefrontal cortex. These might have computational properties required to supplement dysfunctional dorsolateral prefrontal cortical executive processes. However, a mechanistic explanation for how the engagement of additional networks occurs in response to the relative loss of function of others is unknown. Clearly, not all brain regions are affected to the same degree in schizophrenia. But beyond the important finding that cellular abnormalities may occur at the dorsolateral prefrontal cortex but not at more ventrolateral regions (Selemon et al. 2003), relatively little is known about how some of these network changes could be grounded in terms of its neuropathology. Promising ideas along the lines of neural modeling (Deco et al. 2004; Deco and Rolls 2005), and other paradigms related to cortical plasticity and response to injury (Corbetta et al. 2005; Serrien et al. 2006) could be helpful in future investigational efforts to further resolve the critical molecular events influencing macrocircuitry changes in schizophrenia.
Another major avenue of future work is to consider these networks in terms of their neurodevelopmental phases. Core cognitive deficits, in which working memory plays a leading role, are likely to have begun before the first psychotic episode (Jones et al. 1994; Davidson et al. 1999; Cannon et al. 2002; Fuller et al. 2002; Ang and Tan 2004). Healthy siblings of schizophrenia patients have working memory deficits (Egan, Goldberg, Gscheidle, et al. 2001), as well as prefrontal cortical activation abnormalities (Callicott, Egan, et al. 2003). The prefrontal cortex is one of the last structures to mature in humans, and key changes occur in prefrontal cortical neurons around adolescence, particularly in terms of the enhanced inhibition critical for executive function (Lewis et al. 2004). These developmental changes might therefore be both temporally and causally related to the onset of prodromal symptoms and the first psychotic episode, which tend to occur at late adolescence and early adulthood (Weinberger 1987; McGlashan and Hoffman 2000; Lewis et al. 2004). However, relatively little is understood about how the functional architecture of working memory, genes, and brain developmental trajectories interact, and how this might lead to a decompensation in those destined to develop psychosis, although some data on language deficits are emerging from longitudinal studies of high-risk subjects (Whalley et al. 2004, 2006). It might be conceivable that subtle cortical network physiological differences exist vis-à-vis recent findings of cortical thickness changes during longitudinal neurodevelopmental studies in schizophrenia, velocardiofacial syndrome, Williams syndrome, and attention-deficit-hyperactivity disorder (Thompson et al. 2001; Toga et al. 2006).
Finally, understanding how schizophrenia susceptibility alleles influence working memory in the brain could provide clues about biomarkers and targets for novel treatment and preventative strategies. The COMT genotype was recently demonstrated to influence improvement in working memory following antipsychotic treatment. Individuals homozygous for the COMT Met-allele improved more in working memory after antipsychotic treatment (Bertolino et al. 2004; Weickert et al. 2004). Notably, this was reflected by a more efficient dorsolateral prefrontal cortical function following treatment (Bertolino et al. 2004). Better understanding of how COMT and other factors associated with disease neurodevelopment and medication response intersect as a function of brain DA could serve as a starting point in identifying novel treatment targets. Indeed, a study of tolcapone, a central nervous system penetrant COMT inhibitor, has found a salutary effect of this drug on working memory performance in healthy volunteer subjects, especially in COMT Val-allele carriers, and also an improvement in prefrontal cortical efficiency measured with fMRI (Apud et al. 2007). The results of tolcapone in patients with schizophrenia are eagerly anticipated. The emerging data also suggest that dynamic changes in cortical systems occur as they adapt to adverse neurobiological conditions, perhaps through the engagement of additional cortical networks, and resulting in an overall less efficient neural architecture that is ultimately dysfunctional (Callicott, Mattay, et al. 2003; Corbetta et al. 2005; Tan et al. 2005, 2006, unpublished manuscript). Further evaluation of the effects of treatments on these processes should be warranted through the study of disease susceptibility genes, in combination with longitudinal follow-up, advances in experimental task design, and the use of multimodal neuroimaging. There are potentially powerful synergies in linking fMRI with the temporal resolution of megnetoencephalography or EEG (Horwitz and Poeppel 2002) and the enhanced structural connectivity measurements of diffusion-tensor imaging (Kim DS and Kim M 2005). These developments will herald an era of rapid bidirectional dataflow between cellular molecular models, and the in-vivo human brain in health and disease, leading perhaps toward cures and prevention (Insel and Scolnick 2006).
This work was supported by the US National Institute of Mental Health Intramural Research Program, and a National Institutes of Health Visiting Fellowship (to H.Y.T.). Conflict of Interest: None declared.


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SL.CCS.1/2/3/4 Grades 6-12: An essay of a current news event is provided for discussion to encourage participation, but also inspire the use of evidence to support logical claims using the main ideas of the article. Students must analyze background information provided about a current event within the news, draw out the main ideas and key details, and review different opinions on the issue. Then, students should present their own claims using facts and analysis for support.
California city aims at Happy Meals in nutrition push: 'Food cops' or health defenders?
See if you can find a recent restaurant review, recipe or any type of food-related item. Are nutritional balance or healthfulness addressed?
Look for diet or health news, including coverage of fitness activities in your area.
Pick an ad for a restaurant, grocer or snack and discuss whether words and images promote sensible eating.
Health experts, schools, parents and even First Lady Michelle Obama are working to combat childhood obesity, which means being seriously overweight and is pronounced oh-BEE-city. Now San Francisco has a new approach: Its leaders want to bar fast-food restaurants from enticing children to unhealthy food with toys or other gimmicks.
"I do believe that toys and other incentives attached to foods that are high in sugar, fat and calories are a major reason for the alarming rise for childhood obesity," says Supervisor Eric Mar -- father of a fifth-grade daughter -- who proposed the law. The board, which has enough votes to bypass a threatened mayoral veto, is expected to formally approve the measure in a final reading this Tuesday, Nov. 9. Mar and others hope the measure, first of its kind for a big city, spurs similar standards across the country. "It's courageous of the supervisors to put the health of the city's children above food company profits," comments Marion Nestle, professor of nutrition at New York University and author of a book titled "Food Politics."
Critics say the move undercuts business rights and parents' ability to make choices for their families. "Someone doesn't have to travel very far -- a mile outside San Francisco -- to get the traditional McDonald's Happy Meals experience," complains Scott Rodrick, owner-operator of 10 McDonald's restaurants in the city. A California Restaurant Association representative says: "It's insulting to parents and it's more generating headlines than trimming waist lines. There's been absolutely no proof that this will impact the way people eat."
Backer says: "We're part of a movement that is moving forward an agenda of food justice." -- Eric Mar, San Francisco board sponsor of the new policy
Critic says: "When George Orwell wrote about government control in his novel 1984, McDonald's hadn't even invented the Happy Meal yet. . . . Supervisor Eric Mar's own words could have come straight from Orwell's pen." -- Luanne Hays, teacher from Red Oak, Texas, guest-blogging in Dallas Morning News
McDonald's says: "Parents tell us it's their right and responsibility -- not the government's -- to make their own decisions and to choose what's right for their children." -- Danya Proud, corporate spokeswoman
Front Page Talking Points is written by Alan Stamm for NIEonline.com, Copyright 2017
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The president's team: Six cabinet seats remain empty more than a month after Trump took office
A big U.S. employment challenge comes from automation, not just foreign competition
High school students value First Amendment safeguards on speech and media, survey shows
Supreme Court nominee Neil Gorsuch awaits Senate review and confirmation vote
Trump temporarily bans all refugees, plus citizens from 7 nations with Muslim majorities
Climate data from 2016 shows need to reduce fossil fuel emissions, experts say
Presidential swearing-in: Ceremonies, parade and dancing on a historic Friday in Washington, D.C.
Fake news, Part 2: How to be a smart reader who isn't tricked by viral nonsense
Fake news, Part 1: Made-up stories shared widely online can have a real impact, 2016 events show
Energy and environment: Tribe wins North Dakota oil pipeline fight -- for now


text:
Digital Director - Entertainment Client - £70K
- Recruiter
- Ultimate Asset Limited
- Location
- England, London
- Salary
- £65000 - £70000 per annum + Great Agency Benefits
- Posted
- 11 Nov 2016
- Closes
- 09 Dec 2016
- Ref
- AS/DigStrat
- Marketing Disciplines
- Digital / Online Marketing, Strategy
- Industry Sector
- Digital / Online
- Contract Type
- Permanent
- Work Experience Level
- Director
- Agency-side or Client-side
- Agency Side
- Job Role
- Head of Digital
Media Agency, London - £70,000/£75,000
So this is a pretty good role for a strong Digital Director who wants to focus on strategy more than overseeing implementation. Reporting directly into the Head of Strategy, you'll be leading a huge amount of brand activity for two pretty special and important clients.
One operates in the entertainment/gaming space and being honest they are considered one of the world's largest computer games producers, with huge titles and big launches! There will be a big focus on the development of their digital ecosystem, as a digital/tech business they require someone who will lead innovation and drive creative ideas.
The second is a major global drinks brand, they work with them both on a local and global level and this role will be only UK focused. They are in the process of quite a big transformation and now are at a point of spending more on digital than any other channel. So this for this part of the role, it will be building on from what's been achieved and setting out a guideline for them to really kick start some interesting digital campaigns.
The agency aren't bad either! Yes they are a network but they have a good culture and the people are nice, your job is to work closely with these people, specifically the Business Director & Strategy Director on both of the accounts. They are solid media specialists who need that extra bit of digital knowledge to bolster their clients execution.
I think by this point, you've probably got a good idea whether or not you're interested in this type of role. However I just want to be a bit more specific on the type of person that i'm looking for. This role won't be for someone who wants to sit behind a computer all day, the clients need a voice in the room that can be heard and isn't afraid to challenge them or push back.
More essentially it's the background I need, so if you've spent quite some time media agency side, worked with some major clients, led digital strategy then I think it's worth us having a chat!
For more information on this role, please feel free to reach out to me on 07912000448 or firstname.lastname@example.com


text:
Is Pookaari - Online Fashion Accessories Portal incorrect or missing key business information? Update your Hotfrog listing today.
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Products & services
Pookaari brings online fashion accessory with handcrafted scarves, curated scarves. Buy scarves at http://pookaari.com/scarves.html. Read more
Pookaari is an online fashion accessories portal. Buy handcrafted bags, handcrafted designer bags and curated bags at http://pookaari.com/bags.html. Read more
Pookaari is an online fashion accessories portal. It provides you one of the top and remarkable fashion accessories collections from top class designers. Shop fashion accessories for women at http:/… Read more
Pookaari brings online fashion accessory with fashion jewelry. Shop fashion jewelry collections at http://pookaari.com/fashion-jewelry.html Read more
Pookaari is an online fashion accessories portal. We are providing handcrafted jewelry and curated jewelry. Shop the jewelry collections at http://pookaari.com/handcrafted-jewelry.html Read more
Is Pookaari - Online Fashion Accessories Portal in Pookaari, Kg House, Old No.86, New No.126, Arts College Road Racecourse, Coimbatore Tamil Nadu 641018 your business? Claim your listing and attract more leads by adding more content, photos and other business details.
We have more Fashion Accessories services in Coimbatore Tamil Nadu available on Hotfrog INDIA. You can update your search for Coimbatore Fashion Accessories by location, keyword or service options.
SB ROAD NANJAPPA ROAD/RACE COURCE Coimbatore Tamil Nadu 641018
62,MASTHI STREET PEELAMEDU Coimbatore Tamil Nadu 641004
29 M.K.P COLONY GANAPATHY Coimbatore Tamil Nadu 641006
3698 DR NANJAPPA ROA NANJAPPA ROAD/RACE COURCE Coimbatore Tamil Nadu 641018
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text:
- Affiliations:
1 Department of Photonics Engineering, Technical University of Denmark
2 Optical Microsensors and Micromaterials, Department of Photonics Engineering, Technical University of Denmark
3 Department of Energy Conversion and Storage, Technical University of Denmark
4 Electrofunctional materials, Department of Energy Conversion and Storage, Technical University of Denmark
- 10.1007/s00339-013-8207-0
- Abstract:
- Nanosecond pulsed laser deposition of different metals (Ag, Cu, Sn, Zn) has been studied in high vacuum at a laser wavelength of 355 nm and pulse length of 6 ns. The deposition rate is roughly similar for Sn, Cu and Ag, which have comparable cohesive energies, and much higher for the deposition of Zn which has a low cohesive energy. The deposition rate for all metals is strongly correlated with the total ablation yield, i.e., the total mass ablated per pulse, reported in the literature except for Sn, for which the deposition rate is low, but the total ablation yield is high. This may be explained by the continuous erosion by nanoparticles during deposition of the Sn films which appear to have a much rougher surface than those of the other metals studied in the present work.
- Type:
- Journal article
- Language:
- English
- Published in:
- Applied Physics a, 2014, Vol 117
- Main Research Area:
- Science/technology
- Publication Status:
- Published
- Review type:
- Peer Review
- Submission year:
- 2014
- Scientific Level:
- Scientific
- 259759760


text:
South 75 Storage
Self-storage Units, Special Warehousing And Storage, Residential Storage
South 75 Storage in Tulsa Hill, Oklahoma is one of the top choices when it comes to storage buildings. We offer the right storage solutions that meet whatever needs you have. Conveniently located at 91st and Union Avenue, (91st and Highway 75), one mile south of the Tulsa Hills shopping district, Tuscany Hills and Nickel Creek Apartments, we serve South Tulsa, Jenks, Sapulpa, Glenpool and surrounding locations.
Website - None provided
Email - none provided
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Tom's Ditching And Backhoe Inc
excavation, 24/7 emergency excavation services, trenching, dump truck hauling, cable plowing, horizo
Website: http://www.tomsditching.com
Contact: 620-879-9989
24/7 emergency service. Excavating contractor. Excavation. Trenching. Dump truck hauling. Cable plowing. Horizontal drilling. Call 620-879-9989
UNHCR Your generous support to the UN Refugee Agency will provide protection, shelter, clean water ...


text:
KAPOW! by Cameron Francis and Liam Montier - DVD£27.69 £18.99
Allow 2-3 working days for dispatch
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Radisson Blu Royal Hotel, Stavanger, Stavanger
- Free full breakfast and WiFi
Main amenities
- 215 smoke-free guestrooms
- Near the beach
- 2 restaurants
- Indoor pool
- Ski storage
- Fitness center
- Self parking
- Spa services
- 24-hour business center
- In-room childcare
- 24-hour front desk
- Coffee/tea in a common area
For families
- Free cribs/infant beds
- In-room childcare (surcharge)
- Babysitting or childcare (surcharge)
- Rollaway/extra beds (surcharge)
- Connecting/adjoining rooms available
- Private bathroom
What's around
- Heart of Stavanger
- Stavanger Cathedral (0.2 mi / 0.4 km)
- Stavanger Museum (0.4 mi / 0.6 km)
- Museum of Archaeology (0.4 mi / 0.6 km)
- Norwegian Petroleum Museum (0.6 mi / 0.9 km)
- Telecom Museum (0.2 mi / 0.3 km)
Radisson Blu Royal Hotel, Stavanger, Stavangerfrom $107
- Standard Room
- Standard Guest Room
- Suite
- Business Room
- Business Room
- Standard Single Room
- Standard Room
- Standard Guest Room
- Business Class Room
- Business Class Room
- Business Room
More great choices
At a glance
Key facts
Hotel size
- This hotel has 215 rooms
- This hotel is arranged over 6 floors
- Check-in time starts at 2 PM
- Check-out time is noon
- Express check-in/out
Required at check in
- Credit card or cash deposit required
- Government-issued photo ID required
Travelling with others
- Children (12 years old and younger) stay free when occupying the parent or guardian's room, using existing bedding
- Babysitting/childcare *
- Pets not allowed
- Free WiFi in public areas
- Free WiFi in rooms
- Self parking *
Other information
- Smoke-free property
Nearby Four Star Stavanger hotels
In the hotel
- In-room childcare (surcharge)
- Free full breakfast daily
- 2 restaurants
- Bar/lounge
- 24-hour room service
- Coffee/tea in a common area
- Indoor pool
- Ski storage
- Fitness facilities
- Spa services on site
- Spa tub
- Bicycle rentals nearby
- Golfing nearby
- Hiking/biking trails nearby
- Sauna
- 24-hour business center
- Number of meeting rooms - 6
- Conference space
- Meeting rooms
- Conference space size (feet) - 5197
- Conference space size (meters) - 483
- 24-hour front desk
- Concierge services
- Dry cleaning/laundry service
- Laundry facilities
- Free newspapers in lobby
- Luggage storage
- Wedding services
- Multilingual staff
- Number of buildings/towers - 1
- Year Built 1987
- Elevator/lift
- Safe-deposit box at front desk
- Fireplace in lobby
- Accessible bathroom
- In-room accessibility
In the room
- Air conditioning
- Minibar
- Coffee/tea maker
- Iron/ironing board
- Hypo-allergenic bedding available
- Blackout drapes/curtains
- Private bathroom
- Bathtub or shower
- Free toiletries
- Hair dryer
- Pay movies
- Premium TV channels
- Desk
- Free weekday newspaper
- Free WiFi
- Daily housekeeping
- In-room safe (laptop compatible)
- Connecting/adjoining rooms available
Top Stavanger hotels
Recently reviewed hotels in Stavanger
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"The room was clean and comfortable and the bus stop to the city center was literally right out front, which was a bonus when you're carrying giant backpacks. The heliport for the…"Sep 17, 2016
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Nearby hotels
Also popular with travelers from the USA
Special features
Dining26 North - This restaurant specializes in Scandinavian cuisine and serves dinner only. Guests can enjoy drinks at the bar. Open daily.
Atrium - This restaurant specializes in Scandinavian cuisine and serves breakfast and lunch. Open daily.
Awards and affiliations
Green / Sustainable Property
This property participates in Green Key (nogle), a program that measures the property's impact on one or more of the following: environment, community, cultural-heritage, the local economy.
Radisson Blu Royal Hotel, Stavanger, Stavanger's small print
Also known as
- Hotel Radisson Blu Stavanger
- Stavanger Radisson Blu
- Radisson Blu Royal Hotel, Stavanger Hotel Stavanger
- Radisson Stavanger
- Stavanger Radisson
- Radisson Blu Hotel Stavanger
- Radisson Blu Royal Hotel Stavanger
- Radisson Blu Royal Stavanger
- Radisson Blu Royal Stavanger Hotel
- Radisson Blu Stavanger
- Radisson Blu Stavanger Royal
- Royal Hotel Stavanger
- Royal Stavanger
The property has connecting/adjoining rooms, which are subject to availability and can be requested by contacting the property using the number on the booking confirmation.
Optional extras
Self parking costs NOK 180 per night
Rollaway beds are available for an additional charge
Babysitting/childcare is available for an extra charge
We have included all charges provided to us by this hotel. However, charges can vary, for example, based on length of stay or the room you book.
Recent reviews
Excellent 4.4 /5 from 580 reviews
Staff was extremely pleasant and made for an inviting start to our time in stavanger. The room was clean and comfortable. A great value for the cost. The breakfast is also fantastic!
It was a beautiful hotel and had a very friendly stuff. Also close to the center
Having lived in Stavanger, Norway for 7 years as expatriates, we are very familiar with what used to be called the SAS Hotel. As the Radisson-Blu now, the standards have been maintained. The sink in the bathroom may be ultra-modern but it is very impractical, as it is 2" deep and about 15" long. We were very pleased with service in the hotel and found the included breakfast to be of top quality with a nice variety of dishes and pastries on offer.
Overall a very pleasent experience
Great location, just about eight minutes from train station by walk. And the reception is also very friendly, i'm actually arrived at the hotel at 7:00 AM, and to have available room to checking, that is so sweet, and they are also provided a free breakfast in this morning, and the breakfast is very awesome. Above all it worth better than you pay.
Is the description of this hotel not correct? Tell us


text:
40 Interview Questions Every Social Worker Needs to Know
Funny - I just spent the day working on a brand new outcome management system with my co-workers! Its a pain but this quote helps!
Self care infographic …
Social Work Memes. I like this idea but it's not just for mental illness. Don't give up on people...period!
Social Work More
高校の出席、1910年から1937年に増加します。 midmonthly調査:ソーシャルワークのジャーナル。 1939年5月。
"When little people are overwhelmed by big emotions, it's our job to share our calm, not to join their chaos." - L.R. Knost
Via Social Work Helper. Never underestimate the power of a social worker! More
Keep calm and check out the Colorado State University School of Social Work!
Dang, y'all. I'd heard this years back, and then on one Letterboard Friday I shared it. And it took off. Because I think it's something we all needed to hear. Now all we've gotta do is go be it. ... D


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- Last Activity:
- Sep 5, 2016
- Joined:
- Dec 7, 2013
- Messages:
- 10
- Likes Received:
- 53
- Trophy Points:
- 60
- Gender:
- Female
- Location:
- United States
Mistress Michelle
Member, Female, from NW Montana
Just arrived in Negril Jamaica man and I'm having no problems. Feb 2, 2014
- Mistress Michelle was last seen:
- Sep 5, 2016
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41 year old curvy HOTWIFE. I'm still learning the ropes and hope to find the help of a black BULL with a very large cock. If you think you could fill that role, please write me so we can figure out if we want to set something up.
- Location:
- NW Montana
We're headed to Hedonism in Jamaica in February. We arrive on the 1st and leave on the 9th. On the 5th of February we will be renewing our wedding vows and taking new vows for our cuckold relationship on the nude beach (though we will be clothed). I'm hoping to find someone there who can be our "best man."
We've been married 20 years and are very sure of our desire to have a cuckold relationship.
The right bull for us would be smart, in decent shape (nothing wrong with a few extra pounds), reasonably attractive (just not distractingly odd looking), mildly aggressive, not into extreme cuck humiliation, and willing to take the time to get to know each other just a little bit before jumping in to bed. The times I've slept with someone I knew nothing about were never good. I need to be attracted to the whole person.


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text:
Special Day Wedding Photos
wedding photography, wedding photographer, professional wedding photographer
Devon wedding photographers Special Day Wedding Photos offer unobtrusive wedding photography in Devon, Cornwall, Somerset the whole of the Southwest and beyond. If you are looking for an natural style wedding photographer in Devon, please do not hesitate to contact me.
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If you would like Devon wedding photographers, Special Day Wedding Photos, to capture your special day, please do not hesitate to contact me.
I look forward to talking to you soon.
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Fauquier.com, Tue, Feb 21 2017 @ 09:51 AM
Will reading teach teen vandals empathy?
Amidst the chaos in Washington and the ricocheting anger around the country, the following item should supply most of us - book-lovers especially - with a level of comfort that is hard to come by these days. A Virginia judge recently ordered five vandals to read 35 books as a punishment for covering a historic African-American schoolhouse with racist, obscene and anti-Semitic graffiti.
Tri-cityherald.com, Tue, Feb 21 2017 @ 05:03 AM
new Va. student charged with filming undressed classmates
A student at Freedom High School in Chantilly, Virginia, is charged as a juvenile with five felonies after investigators say he recorded video of other students while they were undressed. The five counts of illegally filming people under the age of 18 include two cases of "upskirting," and more charges may be coming.
WTOP-FM Washington, Fri, Feb 17 2017 @ 07:46 PM
Sterling dance instructor charged with child sex crimes
A Sterling man and dance instructor is behind bars at the Loudoun County Adult Detention Center after being charged with sexual assault of a minor.
Loudoun Times, Fri, Feb 17 2017 @ 01:25 PM
Freedom High School student charged with unlawful filming, a upskirtinga
A Chantilly 16-year-old was charged Friday with unlawfully filming his classmates in various stages of undress at Freedom High School.
Loudoun Times, Fri, Feb 17 2017 @ 05:20 PM
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Antoninus pius
Explore related topics
Roman gold coin depicting Antoninus Pius
Portrait of Antoninus Pius. Antoninus Pius, was Roman Emperor from 138 to 161.
Marcus Aurelius was Roman Emperor from 161 to 180. He ruled with Lucius Verus as co-emperor from 161 until Verus' death in 169. He was the last of the Five Good Emperors, and is also considered one of the most important Stoic philosophers.
Portrait of Emperor Antoninus Pius, 138–161; Antonine Roman Marble Source: Portrait of the emperor Antoninus Pius [Roman] (33.11.3) | Heilbrunn Timeline of Art History | The Metropolitan Museum of Art
A marble bust of Roman emperor Antoninus Pius, r. 138-161 CE. (The Vatican Museums, Rome).
Antoninus Pius (Titus Aurelius Fulvus Boionius Arrius Antoninus Pius) 19 Sept. 86 – 7 March 161
Ancient Roman relief, Apotheosis of Antoninus Pius and Faustina, base of the Column of Antoninus Pius, 161 AD
Roman marble bust of Antoninus Pius. Antoninus Pius was born in 86 AD and died in 161 AD. He was Roman Emperor from 138 AD through to his death, and was happily married to Faustina the Elder. Together they bore four children (two sons and two daughters); one of the daughters was Faustina the Younger, who went on to marry emperor Marcus Aurelius, who succeeded Antoninus' title
NYC - Metropolitan Museum of Art: Bust of Emperor Antoninus Pius | Roman, Antonine period, A.D. 138-161
antoninus pius | File:Antoninus Pius BM Sc1463.jpg - Wikipedia, the free encyclopedia


text:
Twilight cast to have hand prints immortalised
Robert Pattinson, Kristen Stewart and Taylor Lautner will make impressions at the Grauman's Chinese Theater in Hollywood
From next month, you'll be able to visit Robert Pattinson, Kristen Stewart and Taylor Lautner any time you visit LA!
Well, sort of. They're going to be putting their handprints and footprints in cement at the famous Grauman's Chinese Theatre in Hollywood, alongside celebs like Marilyn Monroe, Johnny Depp and Audrey Hepburn.
The trio of Twilight stars will take part in the ceremony as they promote the next movie in the franchise, Breaking Dawn: Part 1, alongside newlywed Nikki Reed and the rest of their castmates.
Edward Cullen will live on forever, and now RPattz is having his chance to as well!


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Look Back in Anger: Faber Modern ClassicsBy: John Osborne (author), David Hare (contributor), Michael Billington (contributor)Paperback
1 - 2 weeks availability
DescriptionLook Back in Anger transformed the face of British theatre; legend has it that audiences gasped at the sight of an ironing board on a London stage. John Osborne's play launched the 'angry young men' movement, writers from working or middle class background who had become disillusioned with British society, were sick of contemporary theatre's escapism, and wanted their work to reflect life as they knew it. The play tells the story of a love triangle between Jimmy, an intelligent and educated man of working class background, his upper-middle-class wife Alison, and her superior and disdainful best-friend Helena. Jimmy hates his wife's background, almost as much as he hates himself. Dark and savage, Look Back in Anger makes readers and audiences re-examine what was once called 'the good life'.
Create a review
About AuthorJohn Osborne was born in London in 1929. Before becoming a playwright he worked as a journalist, assistant stage manager and repertory theatre actor. Seeing an advertisement for new plays in The Stage in 1956, Osborne submitted Look Back in Anger. Not only was the play produced, but it was to become considered as the turning point in post-war British theatre. Osborne's protagonist, Jimmy Porter, captured the rebelliousness of an entire post-war generation of 'angry young men'. His other plays include The Entertainer (1957), Luther (1961), Inadmissible Evidence (1964), and A Patriot for Me (1966). He also wrote two volumes of autobiography, A Better Class of Person (1981) and Almost a Gentleman (1991) published together as Looking Back: Never Explain, Never Apologise. His last play, Deja Vu (1991), returns to the characters of Look Back in Anger, over thirty years later. Both Look Back in Anger and The Entertainer were adapted for film, and in 1963 Osborne won an Academy Award for his screenplay for Tom Jones. John Osborne died on 24 December 1994.
Product Details
- publication date: 02/04/2015
- Format: Paperback
- Number Of Pages: 144
- weight: 143
Delivery Information
- Saver Delivery: Yes
- 1st Class Delivery: Yes
- Courier Delivery: Yes
- Store Delivery: Yes


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The benefit of education is not simply a long-term financial reward for those prepared, or wealthy enough, to take on a commercial risk early in life. It is a benefit to the community as a whole, and as a community we should be prepared to pay for it.
It is in all our interests that there are enough doctors, engineers and teachers, when we need professional assistance. It is also in our interests that we have a community with an appreciation of social issues, as well as science and technology, able to make balanced judgments. I would prefer to buy my Big Mac from a history graduate, than there to be no history graduates at all.
Richard Evans
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- More about:
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Select Language Home |
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Home » 1 BHK Builder Flats for Sale in Kalamboli, Navi Mumbai, Maharashtra
Property ID: 82421, Posted on: 03-Mon-2016
1 BHK Builder Flats for Sale in Kalamboli, Navi Mumbai, Maharashtra
Property Total Price : 24lac 16thousand
Washroom(s): 1
Built Area:636  sq-ft
Plot Area:606   sq-ft
Age of Property:0-1 years old
Floor Number:1
Total Floors:7
Transaction Type:New Property
Type of Ownership:Freehold
Annual Dues :24lac 16thousand
Property Amenities:
Property Description:
1. Easy access to Panvel-Taloja MIDC Road and Panvel-Kalyan Road via Kalamboli Highway. 2.10 mins distance from Panvel Railway Station. 3. 3 mins walking distance from Kalamboli Railway Station. 4. A very established area with all necessary social infrastructures in the vicinity. 5. The proposed Panvel-Badlapur link road is set to boost the connectivity to even further. Early entrants in reputed projects always enjoy a substantial upside as compared to investors who enter at later stages
Property Individual Details
sachin tambe
Address: New Panvel, Navi Mumbai-, Maharashtra,
Contact To Property Individual
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Property ID : 82421
Contact To Property Individual
sachin tambe
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text: To dream of winter when it isn't is a promise of financial improvement. Also, click to see other meanings of this dream.Winter Figurative of cold, hard timesWinter 1. One is going through or suspects he/she will be going through a bad time. 2. Death. 3. Old age. 4. The lost or forgotten.Winter Symbolic of peace, tranquility, or a late stage in a person's life


text:
David Mills and family followed their celluloid dreams to California, but found the real adventures in the endless oddities of American life
Standing on the Golden Gate Bridge, we finally conceded: July and August is the worst time to visit San Francisco. Oh, and Wednesdays are not good either. I thought I knew what to expect from America, but I was wrong. That's the trouble with the unexpected: it's so unpredictable.
It had begun so well too. We had managed to work the children up into something approaching enthusiasm (sullen resignation) for a visit to the Museum of Modern Art. "Look at this photograph. It's an amazing building." They looked dubious. "And we'll get some sweets on the way." It's-a-deal expressions all


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Product no. 137539_8717418292584
Disney's Toy Story 3 Blu-ray
When their owner clears out his bedroom in preparation for starting college, Woody, Buzz and the rest of the toy-box gang are dumped in the donations box at a local nursery school and find themselves at the mercy of a horde of wild, sticky-fingered toddlers. As they struggle to stay together while coping with the chaos, the gang meet a new bunch of toys led by pink teddy bear Lotso, while Barbie is at last united with her male counterpart, Ken. The yearning to return home cannot be ignored, however, and many comical adventures ensue as the toys make a series of elaborate escape attempts.
Duration (mins): 103
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Hotel IN RED ROOF GREENWOOD
Service & facilities
|Earliest check-in
Service & facilities
Hotel facilities
- Hotel-owned car park
- Whirlpool
Room facilities
In-house services
- Pets permitted
- Laundry service
Style of hotel and ambience
- From ind - indianapolis intl airport, from indianapolis international airport:, merge onto airport expy via the ramp to, i-70-i-465. Take the exit onto i-465 s-i-74 e, toward i-70. Take exit 53b to merge onto i-65 s., Take exit 99 toward greenwood. Turn right at co rd, 950 n-e main st. Take the 1st left onto sheek rd., The red roof inn will be on the right., ., - From cus - columbus municipal airport, from columbus municipal airport:, head south on andrews st. Take the 2nd right onto, arnold st. Turn right at bakalar dr-n warren dr., Turn right at river rd. Turn left at e 400 n. Turn, right at n us-31. Merge onto i-65 n via the ramp, to indianapolis. Take exit 99 toward greenwood., Turn left at county rd-950 n-e main st. Take the, 1st left onto county rd-125 e-sheek rd. The red, roof inn will be on the right., ., ., -Additional driving directons, ., Traveling on i-65:, exit at e main st exit 99. Travel west on e main, st and at the 1st light turn left onto sheek rd., The red roof inn is on the right side of the road., ., Located 2.1 miles east of downtown greenwood and, 13.4 miles south of indianapolis., ., Corporate locations-, marsh stores incorporated 24.9 MI- 40.1 KM
Hotel data
Trade fair/conference hotel, child-friendly hotel
Service times
Earliest check-in:
Accepted payment methods
- Diners Club
- Visa
- Eurocard/MasterCard
- American Express
- Japan Credit Bureau (JCB Intl.)
110 SHEEK RD, 46143 Greenwood -
- 3.53 km
- 21.95 km


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The Puli Hotel And Spa, Shanghai
- Free WiFi
Main amenities
- 229 guestrooms
- Restaurant and bar/lounge
- Full-service spa
- Indoor pool
- Breakfast available
- WiFi in the lobby
- Health club
- 24-hour business center
- Airport shuttle
- 24-hour front desk
- Coffee/tea in a common area
- Air conditioning
For families
- Cribs/infant beds (surcharge)
- Sofa bed
- Separate bathtub and shower
- Garden
- Daily housekeeping
- Laundry facilities
What's around
- In Jing'an
- Jing An Temple (0.2 mi / 0.4 km)
- French Concession (1.1 mi / 1.8 km)
- Jade Buddha Temple (1.7 mi / 2.7 km)
- People's Square (1.9 mi / 3 km)
- Flower, Bird, Fish & Insect Market (2.4 mi / 3.9 km)
The Puli Hotel And Spa, Shanghaifrom €253
- Club Deluxe Room
- Deluxe Suite, 1 King Bed
- Club Grand Room
- Deluxe Room, 1 King Bed
- Junior Suite, 1 King Bed
- Grand Room
- Deluxe Twin Room
- Grand Studio
More great choices
At a glance
Key facts
Hotel size
- This hotel has 229 rooms
- This hotel is arranged over 26 floors
- Check-in time starts at 2 PM
- Check-out time is noon
- Express check-in/out
Required at check in
- Credit card deposit required
- Government-issued photo ID required
Travelling with others
- Children (10 years old and younger) stay free when occupying the parent or guardian's room, using existing bedding
- Pets not allowed
- WiFi in public areas *
- Free WiFi in rooms
- Airport shuttle (available 24 hours) *
Nearby Five Star Shanghai hotels
In the hotel
- Breakfast (surcharge)
- Restaurant
- Bar/lounge
- 24-hour room service
- Coffee/tea in a common area
- Indoor pool
- Health club
- Full-service spa
- Spa treatment room(s)
- Steam room
- Sauna
- 24-hour business center
- Meeting rooms 6
- 24-hour front desk
- Concierge services
- Tours/ticket assistance
- Limo or Town Car service available
- Dry cleaning/laundry service
- Laundry facilities
- Multilingual staff
- Porter/bellhop
- Number of buildings/towers - 1
- Elevator/lift
- Safe-deposit box at front desk
- Designated smoking areas
- Garden
- Library
- Fireplace in lobby
- Accessible bathroom
- In-room accessibility
In the room
- In-room climate control (air conditioning)
- Air conditioning
- Espresso maker
- Bathrobes
- Slippers
- Iron/ironing board (on request)
- Hypo-allergenic bedding available
- Pillow menu
- Down comforter
- Blackout drapes/curtains
- Turndown service
- Sofa bed
- Individually decorated
- Individually furnished
- Partially open bathroom
- Jetted bathtub
- Rainfall showerhead
- Hair dryer
- 32-inch LCD TV
- Satellite TV channels
- IPod docking station
- DVD player
- Desk
- Free WiFi
- Phone
- Daily housekeeping
- In-room safe (laptop compatible)
Top Shanghai hotels
Recently reviewed hotels in Shanghai
- Holiday Inn Express Shanghai Zhenping
"Breakfast is not servered on time."Dec 25, 2016
- Gallery SuitesFrom
"Unique hotel, not just the usual chain hotel. Staff very friendly and attentive, most spoke English. Lovely Art Deco features. Great location in the former French concession,…"Sep 14, 2016
- Oriental Riverside Hotel - Shanghai Int'l Convention CenterFrom
"Stayed three nights for a conference/exhibition. The room was nice and everything worked well. Breakfast had a lot of choices both western and Asian. Right next to the conference…"May 13, 2016
- Narada Boutique Hotel Shanghai BundFrom
Nearby hotels
Recommended hotels
Special features
The Puli Hotel And Spa has a full-service spa featuring massage/treatment rooms and facials.
DiningLong Bar - Onsite bar.
Awards and affiliations
- This hotel is listed in the 2010 Condé Nast Traveler Hot List.
- The property is a member of the Leading Hotels of the World.
The Puli Hotel And Spa, Shanghai's small print
Also known as
- Hotel Puli
- Puli Hotel
- Puli Hotel Shanghai
- Puli Shanghai
- The Puli Hotel Shanghai
Optional extras
Breakfast is offered for an extra charge of CNY 230 per person (approximately)
Cribs/Infant beds are available for an extra charge
Airport shuttle service is offered for an extra charge of CNY 950 per vehicle (one-way)
WiFi is available in public areas for CNY 0.00 per night (rates may vary)
We have included all charges provided to us by this hotel. However, charges can vary, for example, based on length of stay or the room you book.
Recent reviews
Outstanding 4.8 /5 from 289 reviews
A wonderful retreat, a convenient location, a awsome lobby, a great SPA and very nice rooms. The ultimate address In Shanghai
Very very nice stay!
We had a lovely one night stay at the Puli. The service at the hotel is really outstanding - from the polite doormen and front desk to the staff at the fitness center - we were really impressed by the level of service provided. We were upgraded to a Club room, and as it was our first time at the hotel, I am unable to offer direct comparisons between a standard room and a Club room. However, I do know the Club room was very comfortable, spacious and well laid-out. We also liked the "freebies" offered by the hotel, such as home-made chocolate and other pastries. It made our stay feel more special! Just a few suggested areas for improvement: - The comforter was very thick and we woke up all sweaty, so would suggest including a flat sheet for greater comfort - Loved the fitness center and how clean and well-equipped it was. However, the jacuzzi button at the fitness center (women's room) is really hard to activate. Is there a way to make it more user-friendly? Overall, we had a really enjoyable stay and would not hesitate to book again or recommend to friends / family!
The epitome of good design but with no loss of comfort or service. The room had everything and was lovely to be in. The staff could not have been more obliging and friendly. The food is outstanding. As good as any hotel I've stayed in.
Great value. Beautiful hotel.
Is the description of this hotel not correct? Tell us


text:
"We must reject the idea that every time a law's broken, society is guilty rather than the lawbreaker. It is time to restore the American precept that each individual is accountable for his actions."
Related quotes
"We're seriously looking at getting these banks charged with aiding and abetting someone who's a criminal. Illegal aliens are criminals."
"There are addicts who commit crimes, and criminals who use dope, ... We have to learn the difference with these sociopaths."
"The biggest target of home invasions are criminals. They have drugs and cash. They get whacked all the time."


text:
Managing Your Grant : Nuts, Bolts, Coffee
Everyone is elated! All the planning and research paid off and your organization has been awarded its first grant. Whether it's a $500,000 grant from the US government or a $10,000 grant from a private foundation, now's the time to lay essential groundwork to ensure grant funds will be spent and accounted for as required and that program obligations will be met. Welcome to the world of grants management.
The Initial Paperwork
As you might imagine, government grants come with more red tape than foundation or corporate grants. For government grants, your top executive officer or board chairperson must usually sign and return documents accepting the grant award and agreeing to reporting and fund draw-down requirements, as well as any other special requirements that have been attached to the funding. This is strictly a business transaction—there's no need to send along a warm letter of appreciation. Be sure to return paperwork by the required deadline.
Corporations and foundations sometimes require that officers sign a letter accepting the grant award, but often they don't—a check simply arrives in the mail with a letter of congratulations laying out the expected reporting requirements. If you're expected to return a signed acceptance document, do so promptly and be sure to include a letter expressing appreciation, acknowledging any reporting requirements, and inviting the funder for a visit. While this is a business transaction, it's also a starting point for building an ongoing relationship of trust, commitment, and support.
Establish both an electronic and hard-copy file for each grant your organization receives. Since so much business done electronically, be sure that e-documents and emails are organized for easy access–and be sure electronic documents are backed-up in case of a failure in technology.
Place copies of signed grant documents in a hard-copy file, and keep the file updated with subsequent correspondence related to the grant. When an e-document is of particular importance, print it out and file it here as well.


text: Today mine was that her middle child, the one that that plays piano and fiddle had managed to dislocate her finger playing rugby. Yes, the sport that I'd assured after the last time one of "her" children had been hurt that it was unlikely to happen again. No, I hadn't bothered to take her to a hospital, as I had undislocated it myself! Looks like being a quiet night in the house the night!


text:
Hunter Sight Gameplay 1 iOS / Android
Hunter Sight
By: Wishnee
Genre: Arcade
Video Tips
Let's play Hunter Sight! This is part 1 of my walkthrough for the iOS and Android game Hunter Sight.
Still need help to finish Hunter Sight gameplay?
I will update this post with more tips and tricks, so please bookmark this page and keep on checking in!
If you have any questions, feel free to ask for extra help in the comments section.
Hit like if this helped you!
Visit Hunter Sight walkthrough page for level videos, tutorials, cheats and more.


text:
Is LGC Electric incorrect or missing key business information? Update your Hotfrog listing today.
Contact details
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Hotfrog Philippines provides information regarding LGC Electric in Caloocan Metro Manila. LGC Electric is located at 78, 5th Avenue, Caloocan Metro Manila 1406 and provides Electrical Equipment services. Contact them on (02) 364 4581.
Is LGC Electric in 78, 5th Avenue, Caloocan Metro Manila 1406 your business? Claim your listing and attract more leads by adding more content, photos and other business details.
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Apartment in the heart of Vilnius
Find Hotel Rates
Recent Searches
Wego searches multiple travel sites so you can find and compare the best rates.
Apartment in the heart of Vilnius Hotel Reviews
Based on reviews from across the web.
Apartment in the heart of Vilnius Hotel Details
Check-in: 14:00
Check-out: 12:00
Rotunda Street Apartaments offers self-catering accommodation located in Vilnius the centre of the city. Free Wi-Fi access is available. The Old Town is a short walk away. The apartments will provide you with a seating area and a TV with satellite channels. There is a fully equipped kitchenette with a refrigerator, a stove and an electric kettle. Featuring a shower, private bathrooms also come with a hairdryer and free toiletries. Some of the properties have a safety deposit box and ironing facilities. The Museum of Applied Art s is 1.6 km and Vilnius Airport is located 5 km away. The property offers free parking.


text:
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Customers who interact with a global enterprise want to know they will have the same service experience whether they are in Dubai, the UK, or Bangkok. Hear how a world-wide travel agency used a customer needs analysis to re-design their global training for customer service, and incorporated a new service standard into their culture and brand, brought to life by their talent. Discover how they successfully deliver a consistent customer experience that also respects customers' cultural preferences. You'll learn how your pivotal service talent, whether they are interacting with procurement or individual customers around the globe, can demonstrate aligned service competencies to expand your brand and marketshare.
Don't miss these webcast take aways: