gemmatalis larvae midgut as PolyP-rich organelles Our data sugge

gemmatalis larvae midgut as PolyP-rich organelles. Our data suggest that bafilomycin A1 or vanadate-sensitive transporters play a role during metal uptake and metals are stored as phosphate and PolyP salts, possibly serving as a detoxification mechanism. We suggest a mechanism of detoxification involving binding of metals to PolyP and release of spherites content. Immobilization of metals in vesicles named spherites is a widespread strategy that has been shown in several arthropods (Delakorda et al., 2008, Lipovsek et al., 2002, Pinheiro Dde et al., 2008 and Words, Obeticholic Acid 2002). In that regard, spherites of fifth instar A. gemmatalis larvae were identified by their

elemental profile using X-ray microanalysis as type A spherites ( Hopkin, 1989 and Kôhler, 2002).

Homogeneous electron-dense type A spherites have been found among other Lepidoptera, including Diatracea saccharalis ( Pinheiro Dde et al., 2008) and Manduca sexta ( Dow et al., 1984), and in cells of the mite Xenillus tegeocranus ( Pigino et al., 2006). X-ray microanalysis has been previously used to find PolyP-rich organelles in the eggs of the cockroach Periplaneta americana and other animal models where they remain associated with metallic cations ( Gomes et al., 2008, Ramos et al., 2010a and Ramos et al., 2010b). The similarity of elemental profile between spherites and egg PolyP granules suggests storage of PolyP inside spherites and shared physiological routes of metal uptake. Accordingly, detection of PolyP by fluorescence probes confirmed that spherites are PolyP-rich compartments. Also, metal check details uptake of spherites was modulated in vitro by addition of V- or P-ATPase inhibitors, similarly to what has been described for the PolyP-rich organelles from protozoans ( Miranda et al., 2005, Scott et al., 1998, Scott et al., 1995b and Vercesi et al., 1994). Both spherites and PolyP stores have been described

as metal-buffering agents (Keasling, 1997a, Keasling and Hupf, 1996 and Lichko et al., 1982). Here, calcium, magnesium, sodium, phosphorous and zinc were continually found, while manganese and iron were only periodically detected. Except for manganese, all elements were previously described Smoothened in PolyP granules from other models (Miranda et al., 2000, Miranda et al., 2004a and Miranda et al., 2004b). Nevertheless, the presence of manganese is not a striking feature as a Ca2+/Mn2+-ATPase isoform has been recently suggested to be present in Drosophila spherites ( Southall et al., 2006) and the yeast Vtc4p has been shown to possess a PolyP polymerase activity which is Mn2+-dependent and localized in the yeast vacuole, a PolyP-rich organelle ( Hothorn et al., 2009). We have suggested a link between PolyP mobilization and metal homeostasis in the eggs of P. americana. In this model, PolyP mobilization coincides with an increase in free calcium levels during early egg development ( Gomes et al., 2008).

They are related to and associated with socially constructed valu

They are related to and associated with socially constructed values, preferences and interests. But science can help to determine which probable or possible consequences the different options may have (“recursive model”, cf. Weingart, 1999). By answering “if–then” questions and dealing with options of decision making, science can contribute valuably to quality of life, both in terms of “making sense” of a complex environment and practical management. This is particularly so with respect

to coastal sea systems. The body of potentially useful knowledge about the state, the development of the coast, about options for managing the coast, needs a sustainably managed infrastructure. This infrastructure comprises coastal observatories, process and simulation models, tools for dynamical click here and statistical analysis of change, interdisciplinary exchange between the involved disciplines from physics to geology, from engineering to ecology, and socio-economic this website assessment methods for the

integration of relevant data and expert judgments. Useful coastal science must be based on a solid scientific basis. But such a basis is not enough for making coastal science “useful”. The attribute “scientific” is not sufficient for an analysis to gain acceptance in the public and among stakeholders. This is clearly demonstrated by the public debate about the reality of man-made climate change. Instead, scientifically legitimized knowledge is just one form of knowledge, which has to compete with other forms of knowledge in the public domain (von Storch, 2009). Stakeholders,

including the public and media, are often confronted with developments and events in coastal environments that appear hazardous, alarming or promising. Some events are noticed only by a few decision makers, who ask for intensity, spatial and temporal extension, for options, systematic changes and perspectives. In other cases, the Protirelin general public is getting involved, and the issue becomes a legal or political one. In both cases, coastal science is asked for answers, orientation and, when societal interests are involved, provision of a broader context. However, stakeholders have already knowledge what is going on; sometimes this understanding is consistent with scientific insights, but often it is partially or even completely inconsistent. For placing consolidated scientific knowledge in such a “knowledge-environment”, scientific actors need to understand these “other” knowledge about the dynamics, statistics and conditioning of the coastal sea environment. We come back to this issue in the concluding section. For this purpose, we not only need “border organizations”, which identify the utility of scientific achievements for societal needs, but also apprehend societally relevant questions. These border organizations nowadays go often with the concept of “services”.

An example of this situation is shown in Figure 1b – R99p for the

An example of this situation is shown in Figure 1b – R99p for the warm season. The regional time series of R95 and R99 are produced by summing the numbers of events at all stations in the region: 7 stations belong to the western region, 13 to the central region and 20 to the eastern region. The 99th percentiles of daily precipitation

distributions for Estonian stations vary between 18.9 mm and 25.3 mm in the warm season (Figure 1b) and 9.9 mm and 15.8 mm in the cold season (Figure 1a); the corresponding 95th percentiles are 9.3–13.1 mm and 5.2–8.8 mm. The R99p and R95p for the whole year fall into the 15.7–20.6 mm and 7.7–10.4 mm ranges this website respectively. Approximately the same values can be seen in Figures 2a and 2b, which show histograms of the daily precipitation see more distributions at the Viljandi and Vilsandi stations, together with the annual values R95p and R99p. These stations were selected as examples of typical stations with low (Vilsandi) and high (Viljandi) percentile values. Figures 3a, 3b and 3c show the interannual variability of R99 and

R95 at Viljandi. The R95 and R99 usually go hand in hand from one year to the next. The reason for this synchronous movement is that during years with a lot of extreme events, both very wet days and extremely wet days occur more often, and also that extremely wet days are counted among the very wet days. In Figure 3, especially in Figure 3b for the cold season, two different periods between 1961 and 2008 can be distinguished: one with lower values beginning from 1961 (or before) and ending around 1980, and the

Bortezomib cell line other with higher values beginning in the 1980s and lasting till the present day. This pattern is also apparent in the other time-series. Among the temporal changes in the series from individual stations, tendencies were evident in both directions as regards very wet and extremely wet days, but none of the falling trends was significant. Whereas summing the events over the whole country yields more stable trends (see Table 1), grouping the stations in regions allows us to refer to regions where these trends are more pronounced. If we look at the trends of the Estonian mean, then they are all significant at least at the 5% level. The trends for very wet days are always larger than for extremely wet days. This is also the case in all the regions taken separately. As we can see in Figure 4a, the number of very wet days in the warm season has increased by 5.2% at a significance level of α = 0.05. On average, events over R95p take place 9.3 times during the warm season, so the 5% increase is relatively small in absolute terms. Even more so, the same scenario applies to values over R99p during the warm season. As on average there are 1.9 events over R99p per station during the warm season, its 2.2% increase at α = 0.01 is not especially remarkable.

6 and 2 8, respectively Defibrinating activity was tested using

6 and 2.8, respectively. Defibrinating activity was tested using the method of Gene (Gene et al., 1989), with slight modifications. Briefly, four Swiss mice (18–20 g) were intraperitoneally (i.p.) injected with 50 μg of moojenin dissolved in 200 μL of saline buffer; control animals received only 200 μL of saline buffer. After 1 h, animals were sacrificed by an overdose of ketamine/xylazine and bled by cardiac puncture. Whole blood was placed in tubes and kept at 25–30 °C until clotting occurred. Hemorrhagic activity was determined by the method of Nikai et al. (1984). In

this method, different doses of moojenin (5–50 μg) were injected subdermically into the dorsum of Swiss mice (20–25 g). After 3 h the animals were AZD0530 ic50 sacrificed, the skins were removed, and the area of hemorrhage on the underside of the skin was measured. To evaluate systemic effects, the experimental animals (n = 4) were Ibrutinib chemical structure injected i.p. with 50 μg of moojenin dissolved in sterile saline (50 μL). The myotoxic activity was evaluated by intramuscular injection of moojenin (50 μg/50 μL sterile saline) in the gastrocnemius muscle of mice. A control

group received 50 μL of sterile saline under identical conditions. After 24 h, mice were euthanized by an overdose of ketamine/xylazine and the heart, lung, liver, kidney and gastrocnemius muscle were dissected out. For histological analysis, tissues were placed in 10% formaldehyde and processed routinely for embedding in paraffin. Thick sections (5 μm) were prepared and stained with hematoxylin–eosin (HE) for light microscopic observation. Since the 60′s, Nahas and colleagues have shown that Bothrops venoms coagulate plasma either via direct action on fibrinogen or via activation of factors II and X ( Nahas et al., 1964). In this work, we describe the isolation see more and partial characterization of a fibrinogenolytic metalloproteinase with coagulant activity from B. moojeni venom. Fractionation of crude B. moojeni venom (400 mg) by ion-exchange chromatography on a DEAE-Sephacel column produced eight major protein peaks named D1 to D8 ( Fig. 1A). The main coagulant

activity was detected in fractions D3 and D7 (data not shown). The D7 fraction was further fractionated over a Sephacryl S-300 column ( Fig. 1B). This chromatographic procedure was able to isolate a fibrinogenolytic enzyme, which was named moojenin. Non-reducing SDS-PAGE indicated that the moojenin showed a high degree of purity and consisted of a single polypeptide chain of about 45 kDa ( Fig. 1B1), corresponding to the mass range of other PIII SVMPs (37–75 kDa) ( Terra et al., 2009). Afterward, the moojenin was submitted to SDS-PAGE under reducing conditions, presenting a single band of about 30 kDa ( Fig. 1B1, line 3). Furthermore, the degree of purity of the isolated moojenin was verified by reverse-phase FPLC on a C2/C18 column, disclosing a single peak ( Fig. 1C).

04 02 (Agilent Technology, USA) and the following operating condi

04.02 (Agilent Technology, USA) and the following operating conditions: HP-5 column (30 m find more x 0.32 mm x 0.25 μm film thickness, cross-linked 5% PH ME siloxane);

injector in split-less mode operated at 250 °C; oven temperature (column) at 100 °C for 1 min, then changed to 250 °C with 25 °C/min ramp rate, then changed to 280 °C with 5 °C/min ramp rate, held at 280 °C for 5 min, and post run at 290 °C for 5 min. Oxygen free nitrogen as make-up gas and helium as carrier gas were from TIG, Bangkok. The limit of detection for α-cypermethrin was 0.1 μg/kg tissue. Pooled liver samples spiked with α-cypermethrin (80 μg/kg) and analysed along the study samples gave intra-batch (n = 8) and inter-batch (n = 10) coefficients of variation of 8.5% and 13.7%, respectively. All statistical analyses were performed using SPSS software (SPSS Inc., Chicago, IL; Version 11.5) and Selleckchem Protease Inhibitor Library GraphPad Prism 5 for Mac OS X (version 5.0c; GraphPad Software, Inc., La Jolla, CA, USA). All data are given as mean with standard deviation. Differences between groups were assessed by means of one-way ANOVA with Bonferroni’s multiple comparisons test and considered significant at P <0.05. The toxic and pro-oxidative

effects of the pesticide α-cypermethrin have been investigated in rats [3], [9], [11], [12], [13], [23], [27], [30], [32], [38] and [41]. A major problem that limits the power of these studies to simulate the situation in humans is the fact that they did not study continuous low-level dietary exposure but a less realistic oral intake of individual high doses of the pesticide once per day. We thus designed the current experiment to investigate if the more realistic scenario of a continuous intake Olopatadine of small α-cypermethrin doses spread-out over the day [33], amounting to a total daily intake comparable to the doses applied in previous studies [9], [12] and [32], would lead

to impaired antioxidant defence mechanisms and increased lipid peroxidation and if so, whether or not dietary curcumin might counteract these harmful effects. Curcumin was chosen as test compound because of its antioxidant activity in various model systems in addition to its reported safety for human consumption, even at high doses (curcumin is generally recognized as safe by the US Food and Drug Administration), its widespread use as a colorant by the food industry and the high acceptance of this natural plant compound by the consumers [21]. The daily α-cypermethrin intake in the current study was in the range of 20-35 mg/kg bodyweight (BW) and thus 8-14% of the acute oral LD50 for adult rats, which is 250 mg/kg bodyweight [3]. Since rats consume their feed in approximately 14-18 meals over the course of one day [31] and [42], the individual doses were much lower and below 1% LD50.

001, data combined over the 7 months) Soil dilution amendment di

001, data combined over the 7 months). Soil dilution amendment did not affect plant growth and there buy MS-275 were no significant interactions between the factors (dilution, AMF, month of harvest). In the T-RFLP analysis, 68 bacterial TRFs (terminal restriction fragments) were observed

in total: Over the 7 month period 14 TRFs were present in all treatments (i.e. in bare soil, mycorrhizal and non-mycorrhizal planted soils at both dilution treatments across all harvests); 13 TRFs were present only in soils treated with the 10−1 dilution of soil slurry and absent from the 10−6 dilution treatments (planted and unplanted combined) and 14 TRFs were present in the planted treatments and absent from the macrocosms containing bare soil (dilution treatments combined). Six bacterial TRFs were associated with the planted arbuscular mycorrhizal (AM) treatment but not with the planted non-mycorrhizal (NM) treatment. A greater number of fungal TRFs were observed overall (97 TRFs): buy I-BET-762 over the 7 month period 15 fungal TRFs were present in all treatments; 28 TRFs were observed in planted macrocosms but not in those containing bare soil and 10 fungal TRFs were observed in the planted AM treatments compared

to the planted NM macrocosms. Of the fungal TRFs, 17 were present in soil treated with the 10−1 soil slurry dilution but absent from the 10−6 treatments. In any one dilution/planting regime per month, an overall average (grand mean) of 11 bacterial and 12 fungal TRFs were observed in sufficient

abundance to be included in the analysis. The number of bacterial TRFs identified (TRF richness) was lower in the bare unplanted and the NM planted soils amended with the 10−6 dilution than in the equivalent treatments amended with the 10−1 soil dilution one month after the experiment was established. This trend became less clear over the duration of the investigation until after 7 months the effect of dilution treatment was no longer evident, although TRF richness in the Atezolizumab molecular weight NM soils was greater than in the soil which had AM fungi present (ANOVA: dilution × planting regime × month effect, F6,50 = 3.72, P = 0.004, LSD = 6.3, Fig. 2a). In months 3 and 5, the number of TRFs in the 10−1 AMF treatment was greater than in the 10−6 AMF treatment (data not shown) but by month 7 differences had disappeared ( Fig. 2a). Fungal TRF richness followed similar trends ( Fig. 2b) although data were more variable. Unplanted (bare) soil contained fewer fungal TRFs than planted soils (planting regime, F2,47 = 5.03, P = 0.010) overall. The number of fungal TRFs remained constant over all 7 months whereas the number of bacterial TRFs fell from an average (across all treatments) of 16 in month one to an average of 10 in month 7 (month as a single factor, F3,50 = 15.62, P < 0.001). PCA analysis of the microbial communities illustrated the complexity of these interactive effects.

1 nmol Our previous report showed that 10 nmol of serofendic aci

1 nmol. Our previous report showed that 10 nmol of serofendic acid with intracerebroventricular treatment was required CHIR-99021 to exhibit the protective effect on ischemic neuronal damage (Nakamura et al., 2008). Thus, we predicted that serofendic acid may fail to protect

the brain from ischemia-reperfusion injury when administered intravenously. Contrary to our expectations, intravenous administration of serofendic acid exerted protective effects on cerebral ischemia-reperfusion injury without affecting rCBF and physiological parameters. While serofendic acid has a relatively low ability to penetrate the blood brain barrier (BBB), it can be detected in the brain after intravenous administration (Terauchi et al., 2007). We assume that its low concentration in the brain is able to exert a protective effect since a low dose (10–30 nmol) of intracerebroventricularly administered serofendic acid was effective on cerebral ischemia-reperfusion injury (Nakamura et al., 2008). Thus, the small amount of serofendic acid that penetrates into the brain tissue may be sufficient to protect cells from ischemia-reperfusion injury. Since cerebral ischemia-reperfusion injury leads to the breakdown of Alectinib order BBB, molecules that cannot infiltrate the BBB in normal conditions

may be able to do so more in case of cerebral ischemia-reperfusion injury (Haile et al., 2010 and Michalski et al., 2010). It is possible that serofendic acid may pass through the injured BBB more easily click here than under normal conditions. Further studies are needed to determine whether BBB disruption is required for a sufficient amount of serofendic acid to pass through. In the present

study, three administrations of serofendic acid exerted protective effects on cerebral ischemia-reperfusion injury, whereas single administration did not protect from ischemia-reperfusion injury. In our previous study, serofendic acid exhibited a high clearance value when administered intravenously (T1/2: 0.65 h) ( Terauchi et al., 2007). Thus, the protective effects from three administrations of serofendic acid are not because of the total dose (30 mg/kg) but because of persistent blood concentrations. We showed that protective effect of serofendic acid administrated intravenously requires pretreatment before ischemia, whereas serofendic acid intracerebroventricularly administered at 30 min after the onset of ischemia protected brain from ischemia-reperfusion injury ( Nakamura et al., 2008). This difference may have occurred owing to the poor ability of serofendic acid to penetrate BBB or be retained in the brain tissue. Regulation of pharmacokinetics of serofendic acid may enable serofendic acid administered intravenously after the onset of ischemia to exert protective effect on ischemia-reperfusion injury.

The twospotted spider mite, Tetranychus urticae Koch (Acari: Tetr

The twospotted spider mite, Tetranychus urticae Koch (Acari: Tetranychidae), is a worldwide pest of numerous crops with tomato, bean and cucurbit crops being attacked most often ( Jepson et al., 1975) while the tomato red spider mite, Tetranychus

evansi Baker & Pritchard (Acari: Tetranychidae) attacks host plants such as nightshade, tomato, eggplant and potato ( Moraes et al., 1987). However, both spider mites are web spinning and occur during prolonged, hot and dry periods ( Huffaker et al., 1969, Moraes et al., 1987 and Knapp et al., 2003). Because of difficulties associated with their control and huge economic losses thereof, there is much interest in the search for alternative

control measures especially biological control. Effort is currently being devoted Veliparib in vitro to the search for natural enemies of T. evansi because most predatory phytoseiids used in the control of other spider mites such as T. urticae are not effective for its control especially in regions where it is considered exotic ( Moraes and selleck products McMurtry, 1985, Moraes and McMurtry, 1986, Fiaboe et al., 2006, Furtado et al., 2006 and Furtado et al., 2007). Interest in the use of acaropathogenic fungi for the control of spider mites has also increased in recent years ( Chandler et al., 2000, Van der Geest et al., 2000 and Wekesa et al., 2005). However, biological control can be challenging as spider mites are known

to perform differently on different host-plant species in terms of survival and fecundity ( Gould, 1978). For instance, Agrawal (2000) collected several hundred T. urticae from cotton, bean, roses, and morning glory (Convolvulus arvensis L.) and maintained them on cotton ADP ribosylation factor and cucumber (Cucumis sativus L.) for several generations before using the reversion lines on cotton and concluded that local adaptation to host plants may be genetically correlated with reduced performance on other hosts and with altered host-plant preference. Generally, most herbivorous arthropods are restricted to feeding on relatively few plant families, and it is believed that this host-range limitation may be due to fitness costs associated with alternative hosts ( Fox and Morrow, 1981). Trade-offs in fitness arises from differential adaptations to plant defenses such as ability to detoxify toxic allelochemicals and the benefits derived from these chemicals ( Gould, 1979). Neozygites floridana (Weiser and Muma) Remaudiére and S. Keller (Zygomycetes: Neozygitaceae) is a fungal pathogen that is an important natural enemy of T. urticae and T. evansi and it is a major mortality factor that causes decline in field populations of T. urticae attacking different crops such as corn ( Smitley et al., 1986), peanuts ( Boykin et al., 1984), soybean ( Klubertanz et al.

Therefore, the GPS may be considered insufficient for prognostica

Therefore, the GPS may be considered insufficient for prognostication. There is selleck an increasing evidence that platelet count and NLR can be used for prognostication in patients with several types of cancer [11] and [12]. Recently, Ishizuka et al. [13] showed that COP-NLR is considered to be a useful predictor of postoperative survival in patients with colorectal cancer. They showed that COP-NLR is easy to measure routinely because of its low cost and convenience [13]. Therefore, we conducted a study to determine whether COP-NLR is useful for predicting long-term survival in patients with ESCC. In our study, we demonstrated

that COP-NLR (P = .003) was significantly associated with CSS. Moreover, our study showed a similar HR between COP-NLR and GPS. In addition, the AIC and BIC values were similar between COP-NLR and GPS, indicating that COP-NLR predicts survival in ESCC similar to GPS. The potential limitations of the present study include the use of a retrospective analysis and the Akt inhibitor short duration of the mean follow-up duration. In addition, we excluded patients who had adjuvant chemotherapy and/or radiotherapy, which may have influenced our analysis. Furthermore, AIC and BIC values were not correct if follow-up differed between patients, and the results of the study should therefore be regarded with caution. Thus, larger prospective studies will need to be performed to confirm

these preliminary results. In summary, our study showed that both GPS and COP-NLR are associated with tumor progression and can be considered as independent markers in patients with ESCC. We conclude that COP-NLR predicts survival in ESCC similar to GPS. However, larger prospective studies will need to be performed to confirm these preliminary results. The authors declare that they have no competing interests. “
“Melanoma is a malignant tumor of melanocytes, with a high potential to develop metastases. In the last few decades, the incidence of melanoma has increased Immune system substantially worldwide [1] and [2].

The annual growth rate of incidence is approximately 3% to 5%. Genetic, phenotypical, and environmental factors are involved in melanoma developing [3]. The manifestation and prognosis are significantly different between Asian and white populations. The subtype of superficial spreading melanoma is common in white patients, which is clearly associated with sunlight exposure [4]. Studies have confirmed that mutations of p16 located in the chromosome 9 or CDKN2A is the main genetic susceptibility of melanoma [5]. However, the most frequent subtypes of melanoma in Asian patients are acral lentiginous melanoma (AM) and mucosal melanoma (MM) [6] and [7]. The primary lesions were not always exposed to the ultraviolet, so the specific causative factor for increasing melanoma incidence in China was still unclear [6]. Lysosome-associated protein transmembrane 4 beta (LAPTM4B), is a new gene first cloned in hepatocellular carcinoma [8].

Otherwise, the gate is closed and irrelevant information is kept

Otherwise, the gate is closed and irrelevant information is kept from needlessly occupying Ribociclib concentration capacity. Several computational models of working memory have achieved this gating dynamic using cortico-striatal mechanisms analogous to those described for the motor system. Just

as a cortically represented motor action could cause Go cells to fire via corticostriatal projections, thereby facilitating thalamic-motoneuron information flow for movement programming (as described above), a cortically represented stimulus could also cause Go cells to fire, again via corticostriatal projections, and thereby facilitate thalamic-prefrontal information flow for working memory updating. By contrast, distracting sensory see more representations would trigger NoGo cells and so would have negligible thalamoprefrontal influence. By this scheme, updating is favored (and stable maintenance prevented) by input to Go cells, whereas updating is prevented (and stable maintenance favored) by input to

NoGo cells. Thus, the Go/NoGo system is a potent means of circumventing stability/flexibility tradeoffs that plague single-component systems. Several features of this and related striatal input gating models are supported by human neuroscience evidence. First, there is evidence that D1-expressing Go cells support the rapid updating of information in working memory. Striatal activation in fMRI, thought to be driven primarily by D1 receptor activation [24] is a common observation during working memory tasks that require updating

(Figure 2a). Training of updating transfers to other tasks involving overlapping striatal BOLD responses [25]; this transfer is accompanied by alterations in the striatal hemodynamic response to updating challenges [26] and results in increased striatal dopamine receptor binding [27] (Figure 2b) as assessed via PET. Shifting the striatal balance toward Go firing (via blockade of D2 receptors with PRKACG haloperidol) also enhances working memory updating [28]. Second, there is evidence that D2-expressing NoGo cells act to limit the rapid updating of information in working memory. For example, the ‘attentional blink’ is more pronounced among individuals with enhanced D2/D3 receptor binding in the BG [29•] (Figure 2c). Likewise, the depletion of central dopamine due to Parkinson’s disease counterintuitively enhances resistance to distraction in these patients, while producing deficits in the updating of working memory [30]. In summary, a variety of recent evidence strongly implicates BG-mediated input gating in working memory updating. It is important to note that BG-mediated gating is unlikely to be the only mechanism by which working memory is updated. For example, dopaminergic projections might directly ‘toggle’ prefrontal ensembles from a labile state to a more stable one, and hence act as a second kind of gating mechanism [21].