l-Stepholidine (SPD) is a tetrahydroprotoberberine alkaloid and a mixed dopamine D1 agonist/D2 antagonist. Preliminary clinical trials suggest that SPD improves both positive and negative symptoms of schizophrenia without producing significant extrapyramidal side effects. Here, we report that SPD mimics the effect of the atypical antipsychotic drug clozapine, preferentially increasing Fos expression in corticolimbic areas. Thus, at 10 mg/kg (i.p.), SPD induced Fos expression in the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and lateral septal nucleus (LSN) without significantly affecting the dorsolateral striatum (DLSt). At higher doses (20–40 mg/kg), SPD also increased Fos expression in the DLSt. The increase, however, was less pronounced than the increase seen in the NAc. Within the NAc, SPD also induced more Fos expression in the shell than in the core. In all subcortical areas examined, the Fos expression induced by SPD was mimicked by the D2 antagonist sulpiride and reversed by the D2 agonist quinpirole, suggesting that the effect is due to blockade of D2-like receptors by SPD. In the mPFC, however, the effect was not mimicked by sulpride or reversed by quinpirole. It was also not mimicked by the D1 agonist SKF38393 or SKF38393 plus sulpride, and not reversed by the D1 antagonist SCH23390. These results suggest that, in the mPFC, SPD may induce Fos expression through a non-DA mechanism. Whether the mechanism involves an interaction of SPD with other neurotransmitters such as 5-HT and norepinephrine remains to be determined.
l-Stepholidine (SPD) is a tetrahydroprotoberberine (THPB) alkaloid isolated from the Chinese herb Stephonia. Its biological activity was first examined in a rat hemiparkinsonian model, in which SPD produced an effect mimicked by dopamine (DA) D1 agonist SKF38393 and blocked by the D1 antagonist SCH23390 (Shi et al, 1984; Huang and Jin, 1992; Jin et al, 1992). Subsequent studies show that SPD binds directly to D1-like receptors (Ki=13 nM, Xu et al, 1989) and acts as a partial D1 agonist (Dong et al, 1997; Zou et al, 1997; see also reviews by Jin et al, 1987, 2002). Results also show that SPD binds to D2-like receptors as well (Ki=85 nM) and acts as a full D2 antagonist (Dong et al, 1997; Zou et al, 1997; see also reviews by Jin et al, 1987, 2002). To our knowledge, SPD is the first compound known to have mixed D1 agonist/D2 antagonist properties. Studies of the drug on non-DA receptors have been limited. Evidence suggests, however, that it differs from clozapine and haloperidol, exhibiting only low affinities for 5HT2 (Ki=300 nM), α2 (Ki=400 nM) (Jin and Sun, 1995), and α1 receptors (Ki=2.5 μM) (Lei et al, 1999), and having no effect on glutamate NMDA receptor-mediated Ca2+ entry into cells (Gu, Yang, Jin, and Shi, unpublished observation).
As a partial D1 agonist and D2 antagonist, SPD may offer some advantages over traditional antipsychotic drugs, most of which are DA antagonists relatively selective for D2- vs D1-like receptors. By blocking D2-like receptors, these drugs also remove the potent negative feedback mechanisms of DA neurons, resulting in an increase in DA release. With D2-like receptors blocked, this increase may lead to an unbalanced overstimulation of D1-like receptors. As a partial D1 agonist, SPD may prevent D1-like receptors from being overly activated and, at the same time, provide a submaximal stimulation of these receptors. Preliminary clinical trials suggest that SPD is an effective antipsychotic drug with a profile similar to that of clozapine (Wu et al, 2003). When co-administered, SPD also enhances the therapeutic effects and reduces the tardive dyskinesia induced by typical antipsychotic drugs (Cai et al, 1988).
With the data available, however, it remains uncertain how exactly the mixed D1 agonist/D2 antagonist property may contribute to the atypical profile of SPD. To begin to address this issue, this study examined the role of D1- and D2-like receptors in effects of SPD on Fos expression in forebrain areas that are thought to be involved in the therapeutic and side effects of antipsychotic drugs (Deutch, 1994; Fibiger, 1994). We asked whether SPD, like clozapine, preferentially increases Fos expression in the medial prefrontal cortex (mPFC), the nucleus accumbens (NAc), and the lateral septal nucleus (LSN), and has less effect on the dorsolateral striatum (DLSt). Using specific DA agonists and antagonists, we also examined whether both D1- and D2-like receptors play a role in effects of SPD on Fos expression in these areas.
Sprague–Dawley rats (Shanghai Animal Center, Chinese Academy of Sciences), weighing 250–300 g, were housed three per cage with free access to food and water and maintained in a 12-h light/dark cycle and temperature-controlled environment. To minimize Fos responses due to handling and injections, all animals were handled for 2–3 min and given an injection of saline per day for 4–7 days prior to drug administration. All experiments were in compliance with the Guide for the Care and Use of Laboratory Animals (National Research Council, 1996).
SPD (Shanghai Institute of Material Medical, Chinese Academy of Sciences) and clozapine (Shanghai Institute of Pharmaceutical Industry) were dissolved in 0.1 mM H2SO4 (10 mg/150 μl) and then diluted with distilled water to 10 mg/ml with the pH adjusted to 5.0 using 0.1 mM NaOH. Haloperidol ampoules were purchased from Shanghai Xudong Haipu Pharmaceutical Co. Ltd, China. SKF38393, sulpiride, SCH23390, and quinpirole (Sigma-RBI, CA, US) were dissolved in saline. All drugs were administered intraperitoneally (i.p.). Doses were 10–40 mg/kg for SPD, 10–20 mg/kg for clozapine, 0.3–1.0 mg/kg for haloperidol, 10 mg/kg for SKF38393, 0.5–1.5 mg/kg for SCH23390, 150 mg/kg for sulpiride, and 2 mg/kg for quinpirole. To control for the effect of SPD, additional animals were treated with vehicle (2 ml/kg, 15 μM H2SO4 with pH adjusted to 5.0 using 0.1 mM NaOH).
At 2 h after the final injection, rats were deeply anesthetized with chloral hydrate (500 mg/kg) and transcardially perfused with 0.9% saline, followed by 300 ml of 4% paraformaldehyde. The brains were post-fixed in the same fixative for 4–6 h and subsequently sunk in 30% sucrose (in 0.1 M PB) overnight at 4°C. Serial coronal sections (40 μm) were cut on a freezing microtome and stored at −20°C.
Free floating sections were washed three times with 0.01 M phosphate-buffered saline (PBS), permeabilized with 0.5% Triton X-100, and incubated for 48 h at 4°C with a primary rabbit polyclonal anti-Fos antibody directed against the amino-terminus of human c-Fos p62 (1:1000, Santa Cruz, CA). The sections were then incubated with biotinylated secondary antibody (donkey anti rabbit IgG, 1:200, Vector, CA) followed by avidin–biotin–horseradish peroxidase complex (ABC, 1:200, Vector, CA). Brown cytosolic products were obtained by a reaction with 3,3′-diaminobenzidine (DAB, 0.50 mg/ml) and 0.005% H2O2 for 5–10 min. Sections were then mounted, dehydrated, and coverslipped. To control for the specificity of immunostaining, some sections were processed as above but without the primary or secondary antibody. No specific staining was observed under either condition.
Sections were examined under bright-field illumination using an Olympus microscope (IX71). Images were captured on a CoolSNAP-Procf digital camera (Media Cybenetics, US). The average number of Fos-like immunoreactive (FLI) nuclei was calculated from 3–4 sections through each of the sampled areas (Figure 1, dark squares). Automated counts of FLI nuclei were obtained within a 373 × 373 μm2 area, with the help of Metamorph system (5.0, Universal Imaging Corp, Downingtown, PA). A constant-background intensity was maintained across different sections and animals such that a Fos-positive nucleus was counted only if it reached a defined optical density threshold above background. FLI counts from each of the areas were averaged and the mean was used for subsequent statistical analysis. The 'atypical index' was calculated using a method similar to that described previously (Robertson et al, 1994). First, the numbers of FLI neurons in the NAc and DLSt were averaged in vehicle-treated rats. The average number of each area was then subtracted from the value of that area in each individual rat treated with either a drug or vehicle. An atypical index could then be obtained from every animal by subtracting the corrected value of the DLSt from that of the NAc. Statistical comparisons were performed using one-way ANOVA followed by a post hoc Newman–Keuls test or two-way ANOVA followed by a Tukey HSD test. Numerical results are presented as mean±SEM.
Schematic drawings, adapted from Paxinos and Watson (1998), showing areas (squares) chosen for quantitative analysis of Fos expression. FLI nuclei in the mPFC and NAc were counted at anterior–posterior 2.60–2.80 mm, relative to bregma, and those in the LSN, DLSt, and the core and shell of the NAc were counted at anterior–posterior 2.10–2.30 mm, relative to bregma.
To study the effect of SPD, four groups of rats were used. One was treated with the vehicle (n=5, 0.015 mM H2SO4, pH 5.0, 2 ml/kg, see Materials and methods) and used as a control. The remaining three groups were injected (i.p.) with SPD at 10 mg/kg (n=6), 20 mg/kg (n=5), and 40 mg/kg (n=6), respectively. At 2 h after the injection, the animals were killed and the brains were processed for Fos immunostaining. The number of FLI nuclei was counted in four forebrain areas: the mPFC, NAc, LSN, and DLSt (Figure 1). Figure 2 shows representative photomicrographs of Fos immunostainings in the four areas after different doses of SPD. Figure 3 summarizes results from all rats. Compared to vehicle, all doses of SPD tested significantly increased FLI nuclei in the mPFC (F(3,18)=49.94, p<0.001; post hoc test—10 mg: p<0.05; 20 mg: p<0.001; 40 mg: p<0.001), NAc (F(3,18)=107.1, p<0.001; 10 mg: p<0.001; 20 mg: p<0.001; 40 mg: p<0.001), and LSN (F(3,18)=40.9, p<0.001; 10 mg: p<0.001; 20 mg: p<0.001; 40 mg: p<0.001) (Figures 2 and 3). SPD also significantly increased Fos expression in the DLSt (F(3,18)=57.36, p<0.001). Post hoc test showed, however, that the increase was significant at 20 (p<0.001) and 40 mg/kg (p<0.001), and not at 10 mg/kg of SPD (p=0.12).
Representative photomicrographs showing effects of SPD on Fos expression in the mPFC, NAc, LSN, and DLSt. Scale bar=200 μm. ac, anterior commissure; cc, corpus callosum; LV, lateral ventricle.
Summary bar graphs showing increases in the number of FLI nuclei in the mPFC, NAc, DLSt, and LSN induced by SPD (10, 20, and 40 mg/kg), haloperidol (Hal, 0.3 and 1 mg/kg), and clozapine (Cloz, 10 and 20 mg/kg), respectively. In this and the following figure, error bars are standard error of means. Note that, in the DLSt, the increase in Fos expression induced by 10 mg/kg of SPD was insignificant, and that haloperidol caused a small but significant decrease in Fos expression in the mPFC. *p<0.05, ***p<0.001 compared to vehicle group.
For comparison, effects of clozapine and haloperidol were also examined in separate animals (Figure 3). Consistent with previous studies (eg Deutch and Moghaddam, 1992; Robertson and Fibiger, 1992; Robertson et al, 1994), clozapine (20 mg/kg, n=6) significantly increased FLI neurons in mPFC, NAc, and LSN, and produced no increase in the DLSt. At a lower dose (10 mg/kg, n=5), it increased FLI nuclei in the NAc only (mPFC: F(2,13)=42.8, p<0.001; post hoc test—20 mg: p<0.001; 10 mg: p=0.40; NAc: F(2,13)=54.4, p<0.001; 20 mg: p<0.001; 10 mg: p<0.001; LSN: F(2,13)=114.9, p<0.001; 20 mg: p<0.001; 10 mg: p=0.8; DLSt: F(2,13)=31.3, p<0.001; 20 mg: p<0.001; 10 mg: p=0.65).
Unlike SPD and clozapine, haloperidol (0.3 mg/kg, n=6; 1 mg/kg, n=5, Figure 3) slightly decreased Fos expression in the mPFC (F(2,13)=4.883, p=0.026; post hoc test: 0.3 mg: p=0.02; 1 mg: p=0.015). In the same animals, haloperidol significantly increased FLI nuclei in the NAc (F(2,13)=78.8, p<0.001; 0.3 mg: p<0.001; 1 mg: p<0.001), LSN (F(2,13)=144.3, p<0.001; 0.3 mg: p<0.001; 1 mg: p<0.001), and DLSt (F(2,13)=220.2, p<0.001; 0.3 mg: p<0.001; 1 mg: p<0.001). Also, different from SPD and clozapine, haloperidol induced more FLI neurons in the DLSt than in the NAc, whereas SPD and clozapine preferentially increased Fos expression in the NAc. To illustrate this difference between drugs, the 'atypical index' was calculated for all animals including those in the vehicle-treated group (see Materials and methods). As shown in Figure 4a, atypical indexes of all three drugs were significantly different from that of vehicle (F(7,36)=55.85, p<0.001; post hoc test: SPD 10 mg: p<0.001; 20 mg: p<0.001; 40 mg: p<0.001; clozapine 10 mg: p<0.001; 20 mg: p<0.001; haloperidol 0.3 mg: p<0.001; 1 mg: p<0.001). They were, however, positive for SPD and clozapine, and negative for haloperidol (Figure 4a), confirming that SPD and clozapine induced more Fos expression in the NAc than DLSt, whereas haloperidol preferentially increased FLI nuclei in the DLSt.
SPD preferentially increases Fos expression in limbic structures. (a) Bar graph showing the 'atypical indexes' of SPD (10, 20, 40 mg/kg), haloperidol (0.3, 1 mg/kg), and clozapine (10, 20 mg/kg). The indexes are positive for SPD and clozapine and negative for haloperidol. ***p<0.001 compared to vehicle. (b) Summary bar graph showing the difference in the number of FLI nuclei induced by SPD (30 mg/kg) in the shell and core. **p<0.01, ***p<0.001 compared to vehicle, #p<0.05 compared to the shell. (c) Representative photomicrographs showing that SPD induced more FLI nuclei in the shell than in the core of the NAc. Scale bar=100 μm.
The NAc can be further divided into two subdivisions. The core of the NAc is more related to the extrapyramidal system, while the shell is more related to the limbic system. To examine whether SPD, like clozapine, preferentially increases Fos expression in the shell, two groups of rats were used, one treated with vehicle (n=5) and the other with SPD (30 mg/kg, n=5). As shown in Figure 4b, SPD increased Fos expression in both the shell and the core (F(1, 16)=62.61, p<0.001; post hoc test: shell: p<0.001; core: p<0.01 vs vehicle). However, the number of FLI nuclei in the shell induced by SPD was significantly higher than that in the core (F(1, 16)=20.0, p<0.001, shell vs core: p<0.05, Figure 4b and c).
To test whether part of the effect of SPD is due to blockade of D2-like receptors, four groups of rats were treated with vehicle (n=5), SPD (40 mg/kg, n=6), the D2 agonist quinpirole (2 mg/kg, n=5), and SPD plus quinpirole (n=6), respectively. As reported previously (Deutch and Duman, 1996; Alonso et al, 1999), quinpirole alone increased the number of FLI nuclei in the mPFC (p<0.01 vs vehicle) and had no significant effect in all subcortical areas examined (NAc shell: p=0.32; NAc core: p=0.80; LSN: p=0.29; DLSt: p=1.0, Figure 5 upper chart). When co-administered with SPD, quinpirole significantly reduced the effect of SPD in all subcortical regions (NAc shell: p<0.001; NAc core: p<0.001; LSN: p<0.001; DLSt: p<0.001 vs SPD alone, Figure 5). In the mPFC, co-administration of quinpirole with SPD produced an increase in Fos expression greater than that induced by either drug alone (p<0.01 vs quinpirole alone; p<0.05 vs SPD alone, Figure 5 upper chart).
Summary bar graphs showing that in subcortical regions, but not in the mPFC, the increase in Fos expression induced by SPD (40 mg/kg) was reversed by quinpirole (2 mg/kg, Quin, upper) and mimicked by sulpiride (150 mg/kg, lower). Note that quinpirole alone caused a significant increase in FLI cells in the mPFC. *p<0.05, **p<0.01, ***p<0.001 compared to vehicle; #p<0.05, ###p<0.001 compared to SPD alone.
To test whether blockade of D2-like receptors mimics the effect of SPD, the D2 antagonist sulpiride (150 mg/kg, n=5) was administered. Like SPD (30 mg/kg, n=5), sulpiride increased the number of FLI neurons in subcortical structures (NAc shell: p<0.001; NAc core: p<0.001; LSN: p<0.05; DLSt: p<0.001 vs vehicle, Figure 5 lower chart). Different from SPD, however, it produced no significant effect in the mPFC (p=0.10 vs vehicle; Figure 5 lower chart).
To determine whether SPD acts in part by stimulating D1-like receptors, effects of the D1 antagonist SCH23390 were examined. At 0.5 mg/kg (n=5), SCH23390 alone had no effect in the mPFC (p=0.054 vs vehicle), NAc shell (p=0.97 vs vehicle), NAc core (p=0.67 vs vehicle), and DLSt (p=0.87 vs vehicle), and increased FLI nuclei in the LSN (p<0.05 vs vehicle). At a higher dose (1.5 mg/kg, n=5), SCH23390 also produced an increase in the mPFC (p<0.05 vs vehicle, Figure 6 upper chart). When co-administered with SPD (40 mg/kg), both doses of SCH23390 failed to block the effect of SPD in the mPFC (0.5 mg: p=0.55; 1.5 mg: p=0.264 vs SPD alone), NAc shell (0.5 mg: p=0.52; 1.5 mg: p=0.67 vs SPD alone), NAc core (0.5 mg: p=0.99; 1.5 mg: p=0.88 vs SPD alone), and DLSt (0.5 mg: p=0.29; 1.5 mg: p=0.41 vs SPD alone). In the LSN, co-administration of SPD with the high dose of SCH23390 induced more FLI nuclei than either drug alone (p<0.01 vs SCH23390 alone; p<0.05 vs SPD alone; Figure 6 upper chart).
Summary bar graphs showing that effects of SPD (40 mg/kg) on Fos expression were not reversed by SCH23390 (1.5 mg/kg, SCH, upper). Effects of SPD (30 mg/kg) were also not mimicked by SKF38393 (10 mg/kg, SKF, lower). SKF38393 (10 mg/kg) plus sulpiride (150 mg/kg) mimicked SPD's effects in subcortical areas but not in the mPFC (lower). *p<0.05, ***p<0.001 compared to vehicle; #p<0.05 compared to SPD alone.
To test whether D1 activation mimics the effect of SPD, rats were treated with the D1 agonist SKF38393 (10 mg/kg, n=5). Unlike SPD (30 mg/kg, n=5), SKF38393 produced no significant effect in all regions examined (mPFC: p=0.60; NAc shell: p=1.0; NAc core: p=0.66; LSN: p=0.76; DLSt: p=1.0; Figure 6 lower chart). To determine further whether a combination of D1 activation and D2 blockade mimics the effect of SPD, rats were given both SKF38393 (10 mg/kg) and sulpiride (150 mg/kg, n=5). The treatment increased FLI neurons in all subcortical areas examined (NAc shell: p<0.001; NAc core: p<0.001; LSN: p<0.001; DLSt: p<0.001 vs vehicle), but not in the mPFC (p=0.63 vs vehicle, Figure 6 lower chart).
This study shows that SPD induces a pattern of Fos expression in forebrain areas similar to that induced by clozapine. Evidence further suggests that the effect of SPD in subcortical structures is mediated through the D2 blockade induced by the drug, whereas its effect in the mPFC is likely to involve more than D1 activation and/or D2 blockade.
The mPFC is believed to play a key role in the pathophysiology of negative symptoms and cognitive deficits in schizophrenia (see the review by Weinberger, 1988). All atypical antipsychotic drugs tested, including clozapine, increase Fos expression in the mPFC, whereas typical antipsychotic drugs such as haloperidol lack this effect. This finding has led to the suggestion that the increase in PFC Fos expression correlates the efficacy of an antipsychotic drug against negative symptoms (Robertson and Fibiger, 1992). This study confirmed that clozapine, but not haloperidol, increases Fos expression in the mPFC, and further showed that SPD mimicked the effect of clozapine. This finding is consistent with the clinical observation that SPD is effective in improving negative symptoms in schizophrenic patients (Wu et al, 2003).
SPD also dose-dependently increased Fos expression in the NAc, LSN, and DLSt. The effect in the NAc and LSN is shared by almost all clinical effective antipsychotic drugs tested (Robertson and Fibiger, 1992; Robertson et al, 1994) and may correspond to the ability of the drug to improve positive symptoms (Wu et al, 2003). Most antipsychotic drugs also increase Fos expression in the DLSt. The degree of increase, however, differs depending on the drug examined. Typical antipsychotic drugs usually induce more Fos expression in the DLSt than in the NAc, whereas atypical antipsychotic drugs preferentially affect the NAc, having either no effect or less effect in the DLSt (Dragunow et al, 1990; Miller, 1990; Robertson et al, 1994). Thus, a reduced effect in the DLSt may predict a low propensity of a drug to cause the extrapyramidal side effects. In this study, SPD, at 10 mg/kg, increased FLI neurons in the NAc without significantly affecting the DLSt. At higher doses, SPD also elevated Fos in the DLSt. The increase, however, was less pronounced compared to that in the NAc, giving rise to a positive 'atypical index' for SPD. Robertson and Fibiger (1992, 1996) evaluated 10 atypical and 8 typical antipsychotic drugs and found that the atypical index reliably differentiated the two classes of drugs, being positive for all atypical and negative for all typical antipsychotic drugs. The 'atypical' property of SPD is also reflected in its effect in the two subdivisions of the NAc. Functionally, the core of the NAc is more related to the extrapyramidal system, while the shell is more related to the limbic system (Brog et al, 1991; Deutch and Moghaddam, 1992). Like clozapine, SPD induced more FLI nuclei in the shell than in the core, whereas haloperidol preferentially increased FLI nuclei in the core. These results are consistent with the clinical finding that SPD at therapeutic doses has no significant extrapyramidal side effects (Wu et al, 2003).
In a previous study, however, low doses of SPD were shown to induce significant increases in Fos expression in the striatum (Guo et al, 1998). While the exact reason for the difference between studies is unclear, we noticed that in addition to a few darkly stained nuclei, SPD at 10 mg/kg induced many weak stainings in the DLSt. As they were only slightly above the background and so different from the darkly stained nuclei found in the same sections in the NAc and LSN, these weak stainings were not counted in the present study. Accurate counting of these stainings was in fact difficult using the computer-based imaging analysis system. In the study by Guo et al, these weak stainings may have been treated as FLI nuclei.
SPD is a mixed D1 agonist/D2 antagonist (see Introduction). Results of this study suggest that D2- but not D1-like receptors play a role in the Fos expression induced by SPD. Furthermore, the role of D2-like receptors seems to be restricted in subcortical regions. In these areas, the increase in Fos expression induced by SPD was reversed by the D2 agonist quinpirole and mimicked by the D2 antagonist sulpiride. The effect, however, was not blocked by the D1 antagonist SCH23390 or mimicked by the D1 agonist SKF38393. As discussed above, SPD preferentially increased Fos expression in the NAc. This preferential effect was also unaltered by SCH23390, suggesting that D1 activation is not critical to this 'atypical' property of SPD.
In the mPFC, neither D1- nor D2-like receptors seem to be critical in the Fos expression induced by SPD. In this cortical area, the increase in Fos expression induced by SPD was not blocked by the D1 antagonist SCH23390 or the D2 agonist quinpirole. It was also not mimicked by the D1 agonist SKF38393 and/or the D2 antagonist sulpiride. The lack of a role of D1-like receptors was unexpected because there is evidence that D1 activation can lead to an increase in Fos expression in the mPFC (Glickstein et al, 2002; Diaz Heijtz et al, 2004). One possibility is that both SPD and SKF38393 are partial D1 agonists and only a full D1 agonist can act through D1-like receptors to induce Fos expression in the mPFC. The finding that SCH23390 did not block the effect of SPD further supports the suggestion that D1-like receptors are unlikely to be involved in SPD-induced Fos expression.
As mentioned earlier, atypical antipsychotic drugs such as clozapine also increase Fos expression in the mPFC. The mechanism underlying the effect remains also elusive. A recent study suggests that adrenergic β receptors may play a role in the effect of clozapine and olanzapine because propranolol, a β antagonist, blocks the increase in Fos expression induced by both drugs (Ohashi et al, 2000). Preliminary results suggest that β receptors may also play a partial role in the effect of SPD in the mPFC.
In conclusion, this study shows that SPD, like clozapine, preferentially increases Fos expression in the mPFC and limbic structures. This finding is consistent with the clinical observation that SPD improves both positive and negative symptoms and has no significant extrapyramidal side effects. Results further suggest that SPD-induced Fos expression in subcortical areas is due to blockade of D2-like receptors, whereas its effect in the mPFC appears to involve more than D1 activation and/or D2 blockade. It is important to point out, however, that results of this study were all obtained after a single injection of SPD. To achieve significant levels of therapeutic effects, SPD, like other antipsychotic drugs, has to be administered chronically. Thus, to fully understand the role of D1- and D2-like receptors in the mechanism of action of SPD, studies using chronic treatment will be needed.
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Xu SX, Yu LP, Han YR, Chen Y, Jin GZ (1989). Effects of tetrahydroprotoberberines on dopamine receptor subtypes in brain . Zhongguo Yao Li Xue Bao 10: 104–110.
Zou LL, Liu J, Jin GZ (1997). Involvement of receptor reserve in D1 agonistic action of (−)-stepholidine in lesioned rats . Biochem Pharmacol 54: 233–240.
National Research Council (1996). Guide for the Care and Use of Laboratory Animals. National Academy Press: Washington, DC.
Paxinos G, Watson C (1998). The Rat Brain in Stereotaxic Coordinates. Academic Press: Sydney.
This work was supported by National Basic Research Program of China (973 Program) '2003CB515400', National Natural Science Fund '30230130' and '30271495'.


text:
Q: guardar datos en un objecto Utilizando FOR tengo este for, la idea es ir guardando los datos en el objecto:
 let data_array = {};
        for (var i = 0; i < data.length; i++) {
          //console.log("datos completos ->  " +  data[i].id_expediente);
          data_array = {
                    'id_expediente':data[i].id_expediente,
                    'demandado':data[i].demandado,
                    'direccion':data[i].direccion,
                    'status':"",
                    'fecha_asignada':data[i].fecha_asig,
                    'tipo_juicio':data[i].tipo_juicio,
                    'lat':"",
                    'lng':""
                };

        }

y al imprimir con
console.log("data->" + JSON.stringify(data_array));

solo me guarda el ultimo dato.
{
"id_expediente": "3",
"demandado": "JORGE AVILA BERRIO",
"direccion": "Barlovento 1",
"status": "",
"fecha_asignada": "2018-05-01 00:00:00",
"tipo_juicio": "1",
"lng": ""
}

Que es lo que tengo mal dentro del For ?, la intencion es generar este formato con los datos del For
{
"expedientes": [
{
  "id_expediente": "1",
  "demandado": "JORGE AVILA BERRIO",
  "direccion": "Barlovento 1",
  "status": "",
  "fecha_asignada": "2018-05-01 00:00:00",
  "tipo_juicio": "1",
  "lng": ""
},
{
  "id_expediente": "2",
  "demandado": "JORGE AVILA BERRIO",
  "direccion": "Barlovento 1",
  "status": "",
  "fecha_asignada": "2018",
  "tipo_juicio": "1",
  "lng": ""
},
{
  "id_expediente": "3",
  "demandado": "JORGE AVILA BERRIO",
  "direccion": "Barlovento 1",
  "status": "",
  "fecha_asignada": "2018",
  "tipo_juicio": "1",
  "lng": ""
}
]
}

A: Esto se debe a que constantemente estas sobreescribiendo data_array .
Lo ideal es que lo hagas de la siguiente manera:
data_array.push(data[i]);

A: Cambiando el let por un var, y haciendo push de los items al array.
  var data_array = {};
        for (var i = 0; i < data.length; i++) {
          //console.log("datos completos ->  " +  data[i].id_expediente);
          data_array.push({
                    'id_expediente':data[i].id_expediente,
                    'demandado':data[i].demandado,
                    'direccion':data[i].direccion,
                    'status':"",
                    'fecha_asignada':data[i].fecha_asig,
                    'tipo_juicio':data[i].tipo_juicio,
                    'lat':"",
                    'lng':""
                });
        }

redpajama_set_name: RedPajamaStackExchange


Aged in French oak for 12 months. Opaque dark red black colour with a vibrant purple red hue. Aromas of ripe red currants and mulberries are overlaid by dusty cedar characters with hints of black olive and spice following on. Medium bodied the palate possesses good mid palate richness with red and blackcurrant flavours mingling with ripe mulberries over dusty cedar characters, hints of tobacco and spicy bay leaf. Dryish but fine grained tannins provide a sturdy framework. Medium to long aftertaste of red and blackcurrant, mulberries, spicy dusted cedar, tobacco and bay leaf.


text:
Romance Biology – Now and Then
Guest blog by James Beers:
The following lurid prose is from a recent article about wolves in Yellowstone. It is foisted on the public as some sort of "scientific" factoid.
The following two paragraphs say all that need be said about the sad state of public information, public gullibility and government propaganda disguised as "science" today.
Regarding government-introduced wolves in Yellowstone National Park (totally isolated from the millions of acres surrounding the Park but who cares?) we are told:
"Photos taken in the early 1900s, when wolves roamed Yellowstone, reveal that young trees such as aspen and willow were abundant. In 30 years, after wolves were hunted out, the forest stopped regenerating. "Wolves are shaping what you see here," Douglas W. Smith, leader of the Yellowstone Wolf Project, told Scientific American magazine. "In 30 years, when you drive through the park, it will look very different."
Maybe more like it did a century ago. You can see the colour return to those black-and-white photos. If only Jack London had lived to read about this."
So "young trees" "were abundant" "in the early 1900's". So what? Is it written somewhere that "young trees" are better or necessary or belong in particular places? Are aspen and willow prettier or better for stream fish you either can't fish for or are being eradicated to be replaced by fish species that provide less fishing opportunity? Are the aspen and willows better for elk and moose that no longer provide hunting opportunity but only food for more wolves?
"After wolves were hunted out"? I thought job #1 for Park Rangers, since the Park was withheld by federal fiat from Wyoming, Montana and Idaho, was to prohibit all use (hunting, predator control, trapping, etc.) of animals in the Park?
"The forest stopped regenerating"? When the "Cedars of Lebanon" (of Biblical fame) were cut for Phoenician ships that ruled the Mediterranean economy for centuries, rural Lebanese folk set sheep and goats to graze on all the grasses, brush and young trees that suddenly were so abundant. Between the slopes and all that hard grazing (before folks realized how important and beneficial it was to manage grazing pressure) on lands that were communally-owned, soil eroded and soon only grasses and brush were present. For many centuries that modified landscape has supported and supports pastoral communities of villages and herders. THAT forest truly stopped "regenerating": Yellowstone merely began regenerating differently as it no doubt has done since time immemorial thanks to fires, diseases, predators, native impacts, drought, earthquakes, torrential rains, snows and snow melt, and all the other vagaries of nature. Thinking there is some absolute ideal picture that always was and always should be is as silly as saying wolves are benevolent and belong in settled landscapes such as The Lower 48 States.
Speaking of which, "Wolves are shaping what you see here," is certainly true. So too is the lack of former elk and moose numbers and the presence of tourists and campers and tourists feeding animals and etcetera, etcetera "shaping what you see here". That is merely an academic observation slanted to the observer's wishes. Is the Park "better" with no wolves and abundant elk in the meadows and moose in the ponds being observed enthusiastically by the "once-in-a-lifetime" tourists and harvested outside the Park each fall by thousands of hunters supporting rural economies and state conservation programs to the tune of Millions of dollars annually? Or is it "better" with only a rare tourist glimpse of an elk or moose or a wolf and the presence of all the dangers (disease, human safety, etc.) associated with the presence of wolves even in this tightly regulated and scripted government enclave where there are no dogs or livestock or kids walking alone to rural bus stops or old ladies walking to rural mailboxes for the wolves to menace.
So the head Pooh-Ba scientist tells a "Scientific" magazine that "In 30 years, when you drive through the park, it will look very different." Really? It looked different 50 years ago and it will look different 50 years hence despite all this twaddle about some mythical and sacred Park landscape that only government employees and environmental extremists with access to unlimited funding and political power can provide. The Park was set aside for "the People" as in "We the People", the first three words of our Constitution. Making it into a federal reserve differing from the lands of bygone monarchs only in being unmanaged estates of unused renewable natural resources lacking herbivores and stuffed with trees and undergrowth that yield catastrophic fires in surrounding settled landscapes is not only a travesty, it is a betrayal of "the People". It violates the Constitutional charge to a federal government to "establish justice, insure domestic Tranquility, …"promote the general Welfare, and secure the blessings of Liberty to ourselves and our Posterity".
For those unfamiliar with the spelling of color as "colour"; colour is the accepted British spelling. This anomaly may be attributable to the Yellowstone ecology author's (Bijoy Venugopal) background as likely somewhat distant from Yellowstone? You see, Romance Biology compositions are only limited by the imagination of the author. Experience or truth are neither required nor expected.
Finally we have the piece de resistance, "If only Jack London had lived to read about this." When I was young I greatly enjoyed Jack London's fiction. So I searched high and low to discover the reason for this reference but while I found that old Jack abandoned his wife and kids, was an alcoholic, ran unsuccessfully as a Socialist for Mayor of Oakland, was picked up for vagrancy in Niagara Falls and had visited Korea, Australia and England; nowhere could I find an interest in or visit to Yellowstone. Thinking it may have to do with his frequent mention of wolves in his writing, I searched those mentions and discovered that Jack London too could have been a successful Romance Biology writer today if only he "had lived to read about this". Perhaps it was due to passages like the following that Mr. London's name is evoked?
In "Love of Life" a prospector who has abandoned a friend and walked for hundreds of mile in N Canada to reach the Arctic Ocean endures unbelievable hardships with the thin hope of finding a ship to rescue him. As he lies almost dead on an Arctic beach a whaler appears on the horizon as he encounters a sick wolf. The account of this man and wolf interaction must surely be why Romance Biology authors everywhere admire Mr. London and why he must have a secure place in the Romance Biology Hall of Fame:
"The patience of the wolf was terrible. The man's patience was no less terrible. For half a day he lay motionless, fighting off unconsciousness and waiting for the thing that was to feed upon him and upon which he wished to feed. Sometimes the languid sea rose over him and he dreamed long dreams; but ever through it all, waking and dreaming, he waited for the wheezing breath and harsh caress of the tongue.
He did not hear the breath, and he slipped slowly from some dream to the feel of the tongue along his hand. He waited. The fangs pressed softly: the pressure increased: the wolf was exerting its last strength in an effort to sink teeth in the food for which it had waited so long. But the man had waited long, and the lacerated hand closed on the jaw. Slowly, while the wolf struggled feebly and the hand clutched feebly, the other hand crept across to a grip. Five minutes later the whole weight of the man's body was on top of the wolf. The hands had not sufficient strength to choke the wolf, but the face of the man was pressed close to the throat of the wolf and the mouth of the man was full of hair. At the end of half an hour the man was aware of a warm trickle in his throat. It was not pleasant. It was like molten lead being forced into his stomach, and it was forced by his will alone. Later the man rolled over on his back and slept."
In true Romance Biology fashion, the man on the beach is first seen from the whaler by "scientists" on a "scientific expedition" whereupon he is rescued. It doesn't get any better than that.
Yet, what would Jack London have thought if he "had lived to read about this", i.e. Yellowstone and wolves? My guess is he would have admired how fellow authors were making money from such silliness; he would have gotten a kick (do "Socialists" have a sense of humor?) out of a public so gullible as to believe even bigger tales than he wove; and finally he would have shook his head and wished to be back in his world where people knew the truth about things like wolves and understood that even a dying man couldn't kill a wolf with his teeth and then suck out wolf blood.
But, all Romance Biology today must have these propaganda chestnuts in them to qualify; besides the only difference is that people once merely enjoyed such fiction unlike today when they actually believe it.
Regardless of what these authors and their bureaucrat/radical friends tell you, wolves do NOT belong in the settled landscapes of The Lower 48 States, bombastic prose or not.
Jim Beers
If you found this worthwhile, please share it with others. Thanks.
Jim Beers is a retired US Fish & Wildlife Service Wildlife Biologist, Special Agent, Refuge Manager, Wetlands Biologist, and Congressional Fellow. He was stationed in North Dakota, Minnesota, Nebraska, New York City, and Washington DC. He also served as a US Navy Line Officer in the western Pacific and on Adak, Alaska in the Aleutian Islands. He has worked for the Utah Fish & Game, Minneapolis Police Department, and as a Security Supervisor in Washington, DC. He testified three times before Congress; twice regarding the theft by the US Fish & Wildlife Service of $45 to 60 Million from State fish and wildlife funds and once in opposition to expanding Federal Invasive Species authority. He resides in Eagan, Minnesota with his wife of many decades.
Jim Beers is available to speak or for consulting. You can receive future articles by sending a request with your e-mail address to: jimbeers7@comcast.net
Filed Under: history, National/World, Predators Tagged With: jack london, james beers, romance biology, wolves, yellowstone

redpajama_set_name: RedPajamaCommonCrawl


A 'one stop shop' for peeps following a primal way of life or ancestral diet. We promote a 'holistic' approach to health that offers a sustainable future.
Our 'web' community is where you can find like-minded people, share ideas and ask our vendors and experts for advice.
Our passion is to encourage a more responsible version of the ancestral diets where we consider and discuss the wider issues of sustainability and animal welfare along with great nutrition and wonderful recipes. We like a bit of silly fun too!


We're KASE Enterprises, a Brisbane based registered training organisation specialising in training and assesment for the Construction Materials Testing and Civil Construction industries. Although based in South-East Queensland, we travel Australia Wide and even overseas to provide quality face-to-face training and assessment to our trainees.
Our trainers each have over 30 years experience in their relevant fields of expertise. We're all passionate about the industry and pride ourselves on relating to the worker and the work environment by relaying knowledge through personal experience in the industry.
Our commitment is to hands on, relevant and useful training for individuals and organisations that results in better productivity on the job and a greater understanding of the construction materials and methods being used. Better productivity and a greater understanding on the job can only result in saving civil & construction companies time and money!


This topic was very well received by the 50 or so in-house counsel who attended from companies such as Northrop Grumman and Lockheed Martin, to name a few. We discussed how relocation of an employee from one country to another can expose the employer to liability in multiple jurisdictions, and how the structure of the relocation – such as temporary transfer, secondments, and local hire – can alter the potential liabilities in the event of a rupture in the employment relationship.
On February 12, I wrote about the amazing, personal story of King Peggy, a D.C. secretary who became the King of the Ghanaian village Otuam, and her vision for its future.
On May 31, Hogan Lovells will be holding an event "with a little help from its friends" to support King Peggy's vision for her village, along with that of Eleanor Herman, co-author (and "Queen Mother") of King Peggy: An American Secretary, Her Royal Destiny, and the Inspiring Story of How She Changed an African Village.
Since I first wrote my blog post in February, this nationally recognized book has been featured on NPR, CBS This Morning, and The Colbert Report, and it was a selection in Oprah's Book Club. CBS News has also covered King Peggy's story.
On May 3 the Latin America Practice Group Conference brought together nearly 70 clients, Hogan Lovells lawyers, and lawyers from our Latin American relationship firms to discuss the challenges and opportunities that exist for companies operating in Latin America.
The Conference hosted two panels composed of lawyers and executives entrenched in the region's corporate and financial development. Attendees also heard from keynote speaker Anthony Harrington, former U.S. Ambassador to Brazil, on the macro socio-economic outlook of the area.
• Krista Sweigart, The AES Corporation, Senior Corporate Counsel.
Although only 35 of the nation's Fortune 1000 companies are managed by women, at least one female CEO believes that number will double by 2017. Others echo the confidence of Maggie Wilderotter, head of Frontier Communications Corp., pointing to an increasingly strong pipeline of highly qualified female senior executives across all industries.
But who are the odds-on favorites to take over the corner office? Using the results of an informal poll, the Wall Street Journal this week released a top 10 list, selecting current managers who have the best shot at CEO in the next five years.
WSJ was quick to note that some of the more popular picks – including Sheryl Sandberg and Sherilyn McCoy – did not make the cut for varying reasons, including company size or decisions to head for greener pastures.
The list reflects a shift in traditional gender roles that our own Randy Segal detailed a few weeks ago – many had husbands who abandoned the fast track to support their wives' careers.
• Charlene Begley, General Electric Co.
• Rosalind Brewer, Wal-Mart Stores Inc.
• Juliana Chugg, General Mills Inc.
• Virginia "Gina" Drosos, Procter & Gamble Co.
• Jan Fields, McDonald's Corp.
• Michelle Gass, Starbucks Corp.
• Melanie Healey, Procter & Gamble Co.
• Marissa Mayer, Google Inc.
• Anne Sweeney, Walt Disney Co.


There is a certain beauty on listening the music in Spotify, for sure. One thing, is that you can discover new music, anytime. Music that you did not programmed to listen to, that you did not even expect it exists… There is far more music around, that you can hope to listen to, in all of your life!
Coming back to my little story: when the streaming of an album of Nick Kershaw was finished (an album that I already knew very well), the system began automatically to select "similar songs" to the ones contained in the album, just before I became aware it was actually finished and that I had to think about what to listen to, now.
Something which has a deep connection with a very simple word, "open". A simple word that it can disclose a whole world.
This Is Your Song proposes a very difficult task!
Posted on February 3, 2016 Categories musicTags dailypost, EurythmicsLeave a comment on Jennifer, where are you?
Posted on February 24, 2015 March 3, 2015 Categories ebookTags digital native, facebook, Kindle, readingLeave a comment on Are you (still) reading on paper?
I can relax only if I realize that things keeps happening in my life, even if sometimes I feel as I walked in a deep winter scenario. Even in those moment in which I feel like someone running under heavy rain, striving to be at home.
Besides, long before you physicists teached us that everything is movement and energy, Dante spoke of a "love that moves the sun and the other stars" and to him that was not a metaphor, but a real matter of fact. We are dealing with a difference of speed – the truths to which the poetic method leads are those a man needs in his life, whereas science takes sometimes thousands of years in order to succeed in analyzing some phenomena. Difference in speed and method therefore, (poetry knows by synthesis, by analogy, experiencing that state of knowledge through wonder and spiritual enlightenment that in science happens only sometimes), but not in the route nor in the final purpose. In fact, the language that scientists often use to indicate the primary or last realities they are looking for – in addition to the formulas – is composed of poetic metaphors. What is the "fossil light" that the recorders of the early events of the universe are analyzing? Isn't it a reality which we can explain using a poetic language?


text:
Q: problem with java.util.NoSuchElementException: No line found When I'm using Scanner to get character in java, compiler throws:
Exception in thread "main" java.util.NoSuchElementException: No line found
    at java.base/java.util.Scanner.nextLine(Scanner.java:1651)
    at ShoppingCartManager.getChar(ShoppingCartManager.java:37)
    at ShoppingCartManager.printMenu(ShoppingCartManager.java:56)
    at ShoppingCartManager.main(ShoppingCartManager.java:30)

Here's the part of code where exception is thrown
private static final Scanner scan = new Scanner(System.in);

public static void main(String[] args) {
    Scanner scnr = new Scanner (System.in);
    System.out.println("Enter Customer's Name:");
    String name = scnr.nextLine();
    System.out.println("Enter Today's Date:");
    String date = scnr.nextLine();
    System.out.println();

    ShoppingCart cart = new ShoppingCart(name, date);

    System.out.println("Customer Name: " + name);
    System.out.println("Today's Date: " + date + "\n");

    printMenu(cart);
    scan.close();

}

private static char getChar () {
    char option;

    while (true) {
        try {
           option = scan.next().charAt(0);
           break;
        } catch (Exception exc) {
           continue;
        }
    }
    return option;
}

public static void printMenu(ShoppingCart cart) {

    while(true) {
        System.out.println("MENU");
        System.out.println("g - Add Guitar to cart");
        System.out.println("c - Add Candy Bar to cart");
        System.out.println("s - Add Shoes to cart");
        System.out.println("d - Remove item from cart");
        System.out.println("n - Change item quantity");
        System.out.println("i - Output items' descriptions");
        System.out.println("o - Output shopping cart");
        System.out.println("q - Quit" + "\n");
        System.out.println("Choose an option:");

        char option = getChar();

        if (option == 'q') {
            return;

        } else if (option == 'g') {
            File guitar;
            Scanner iss;
            try {
                guitar = new File("Guitar.txt");
                iss = new Scanner(guitar);
                ItemToPurchase item = new ItemToPurchase();
                item.setName(iss.nextLine());
                item.setDescription(iss.nextLine());
                item.setPrice(Integer.parseInt(iss.nextLine()));
                item.setQuantity(Integer.parseInt(iss.nextLine()));
                cart.addItem(item);
                System.out.println("ADDED GUITAR TO CART");
                iss.close();
            } catch (IOException excp) {
                System.out.print(excp);
            }

        } else if (option == 'c') {
            File candyBar;
            Scanner iss;
            try {
                candyBar = new File("Candy_Bar.txt");
                iss = new Scanner(candyBar);
                ItemToPurchase item = new ItemToPurchase();
                item.setName(iss.nextLine());
                item.setDescription(iss.nextLine());
                item.setPrice(Integer.parseInt(iss.nextLine()));
                item.setQuantity(Integer.parseInt(iss.nextLine()));
                cart.addItem(item);
                System.out.println("ADDED CANDY BAR TO CART");
                iss.close();
            } catch (IOException excp) {
                System.out.print(excp);
            }

        } else if (option == 's') {
            File shoes;
            Scanner iss;
            try {
                shoes = new File("Shoes.txt");
                iss = new Scanner(shoes);
                ItemToPurchase item = new ItemToPurchase();
                item.setName(iss.nextLine());
                item.setDescription(iss.nextLine());
                item.setPrice(Integer.parseInt(iss.nextLine()));
                item.setQuantity(Integer.parseInt(iss.nextLine()));
                cart.addItem(item);
                System.out.println("ADDED SHOES TO CART");
                iss.close();
            } catch (IOException excp) {
                System.out.print(excp);
            }

        } else if (option == 'd') {

            System.out.println("REMOVE ITEM FROM CART");
            System.out.println("Enter name of item to remove");
            String item = scan.nextLine();
            cart.removeItem(item);

        } else if (option == 'n') {

            System.out.println("CHANGE ITEM QUANTITY");
            System.out.println("Enter the item name");
            String name = scan.nextLine();
            System.out.println("Enter the new quantity");
            int newQuantity = scan.nextInt();

            for (int i = 0; i < cart.cartItems.size(); i++) {
                if (cart.cartItems.get(i).getName().equals(name)) {
                    cart.cartItems.get(i).setQuantity(newQuantity);
                }

            }

        } else if (option == 'i') {

            System.out.println("OUTPUT ITEMS' DESCRIPTIONS");
            cart.printDescriptions();

        } else if (option == 'o') {

            System.out.println("OUTPUT SHOPPING CART");
            cart.printTotal();
        } else {
            continue;
        }

    }
}

}
what should I do?

A: You need also to check if there is a next line when you are using scanner, you can use hasNextLine() to perform this check.

A: with Scanner you need to check if there is a next line with hasNext()
so the loop becomes
while(sc.hasNext()){
str=sc.next().charAt(0);
//...

}
Something like this should work.
java.util.NoSuchElementException: No line found


It's normal to grill chicken, or even croutons for a salad, but lettuce? On the grill? You bet. Step out of your salad comfort zone with grilled romaine and buttermilk Caesar dressing!
Anchovy paste is a good substitute for real anchovies, but you can also leave the anchovies out of the mix completely. The dressing will still be excellent.
Preheat grill to medium-high heat. Brush grill rack with oil.
Combine 1/2 cup Asiago cheese, sour cream, anchovy paste, vinegar, Worcestershire sauce, garlic, dry mustard, salt, and pepper for the dressing in a small bowl. Whisk buttermilk into ingredients until smooth; cover and chill.
Brush both sides of bread and cut sides of romaine with oil; season with salt and pepper. Grill bread 2 minutes per side. Grill romaine until edges char and outer leaves wilt slightly and turn a deep, bright green, about 2 minutes per side. Rub one side of toasted bread slices with cut side of garlic clove, then cut bread into large cubes.
To assemble, cut romaine in half again lengthwise, then arrange two quarters on each of four serving plates. Top salads with sliced chicken, croutons, and dressing. Garnish with Asiago.
Whisk buttermilk into the ingredients for the dressing. It provides a thick consistency and tangy flavor.
Rinse the romaine, then remove any wilted outer leaves from the heads and slice them in half lengthwise.
Grill the romaine halves, cut sides down, until the edges begin to char. Turn romaine and grill the other sides.


text:
An April Fools' Gag That's Actually Funny, And Plausible: Check Out Funny Or Die's New 1.5-Second Creative Platform, Dips
"A second and a half is the optimal amount of time for creativity."
Adam McKay, Richard Linklater, and Mark Cuban
By Dan Solomon 1 minute Read
We all know that April Fools' Day pranks are the absolute worst, but some of them manage to also be pretty funny. Toning down the wackiness and the "check out our very traditional brand doing something zany!" element helps–as does having really funny people involved, and a target that's ripe for roasting.
Funny Or Die gets all of that–hence "Dips," their new (fake, but pretty close to being plausible) social network/video platform that plugs in all of the personal expression you could hope for into a second and a half ("the optimal amount of time for creativity").
In the pitch, Funny Or Die cofounder Adam McKay announces the launch of Dips, and then turns the mic over to Richard Linklater, who plugs Boyhood briefly, explaining that taking 12 years for a movie is done–now he only needs a second and a half. Somehow, the video ends with Shark Tank star/Dallas Mavericks owner Mark Cuban explaining why he gave McKay and Linklater $80,000,000 for Dips. Which he didn't, because it's a prank, and pranks are the worst–but occasionally, they're also pretty funny.
See the Dips here.
Dan Solomon lives in Austin with his wife and his dog. He's written about music for MTV and Spin, sports for Sports Illustrated, and pop culture for Vulture and the AV Club


Video: Investing – Safety, Liquidity Or Return?
Yesterday, during the Real Investment Hour, I discussed the three components of any investment – safety, liquidity or return. Importantly, as an investor, you can only have 2 of 3 components at any given time. Therefore, determining which components are the most important at any given time is key to the investment decision process.


Wagg's Builder is a high quality alkali for on-premise-laundries; it provides alkalinity and promotes detergency on all soil classifications. It is specially formulated to provide optimum results with our detergent, "Suds" or bour enzyme detergent, "Forward". It contains sequestrant and cmc and optical brighteners to prevent greying and discoloration.


Hey, foxy, we've got something as pretty as you are – a Fox body sticker set consisting of three identical sheets with a picture of the most beautiful woodland creature. We offer you a perfect design painted in watercolor. It's not just nice but also pretty romantic and dreamy. So if you like to daydream and adore the beauty of the autumn season, this temporary tattoos set will represent your state of mind just right.


text:
Film Review: Mesmerizing, Romantic Power of 'Ain't Them Bodies Saints'
Submitted by BrianTT on August 29, 2013 - 4:51pm
Ain't Them Bodies Saints
CHICAGO – Is a film automatically flawed if we can see its influences? We don't do it as quickly in music, in which it's often incredibly easy to determine a new artist's favorite bands as a kid. Authors that pull from a notable and recognizable literary history are often lauded for doing so.
Film Review: Terrence Malick's 'To the Wonder' Nearly Drowns in its Own Beauty
Submitted by mattmovieman on April 17, 2013 - 9:43am
Matt Fagerholm
To the Wonder
CHICAGO – Deservedly renowned as one of our greatest living filmmakers, Terrence Malick has a reputation for taking his time with each project. He won't make a picture unless he feels a burning desire to make it, and will put directing on the back burner for two decades, if necessary, in order to pursue other interests. He's never made what could be conceivably considered a minor work—until now.
Blu-ray Review: Terrence Malick's 'Badlands' Joins Criterion Collection
Submitted by BrianTT on April 3, 2013 - 7:15pm
CHICAGO – Any list of the most influential films of the '70s that doesn't include Terrence Malick's brilliant "Badlands" is incomplete. It's one of those cinematic works that's so important to its era and how it influenced filmmakers that saw it that it's hard to put into reviews in a brief review such as this one. It is iconic in the way Malick took the familiar (it's based on a true story that was well-known at the time) and made it artistic. It's also a great selection for The Criterion Collection, joining Malick's "Days of Heaven" and "The Thin Red Line" in the most important series of Blu-rays ever released.
Film News: Terrence Malick's 'The Tree of Life' Wins Four 2011 Chicago Film Critics Association Awards
Submitted by BrianTT on December 19, 2011 - 8:04am
Chicago Film Critics Association
Martha Marcy May Marle
CHICAGO – Terrence Malick's "The Tree of Life" led the way for film in the eyes of the Chicago Film Critics Association, as they have dubbed it the Best Picture of 2011. Malick also took Best Director for his long-delayed labor of love, while the CFCA also chose the cinematography and the work by Jessica Chastain as the Best Supporting Actress work of the year. "Drive" and "Martha Marcy May Marlene" came in second with two wins a piece.
Film News: Awards Season in Full Gear With LAFCA, NYFCO, SFFCC Winners
Submitted by TimBMartens on December 12, 2011 - 3:06pm
LAFCA
NYFCO
SFFCC
Tim Martens
CHICAGO – The winner announcements keep flying in as the award season for film swings into full gear. This past weekend, the Los Angeles Film Critics Association (LAFCA), New York Film Critics Online (NYFCO), and San Francisco Film Critics Circle (SFFCC) all took their turns awarding the best in film for 2011.
Blu-Ray Review: Poetic Vision of Terrence Malick's Beautiful 'The Tree of Life'
Submitted by BrianTT on October 22, 2011 - 4:38pm
Hunter McCracken
CHICAGO – Terrence Malick's "The Tree of Life" has stirred up a bit of controversy since its debut early in the Summer of 2011. You almost certainly saw the stories (or Facebook posts or tweets) about the audience walk-outs and signs at theaters that warned ticket buyers that they were about to see something unique.
Interview: John Michael McDonagh Takes Chances With 'The Guard'
Submitted by BrianTT on August 1, 2011 - 6:39pm
John Michael McDonagh
The Guard
CHICAGO – From a classic tradition of abrasive-but-lovable anti-heroes, the lead of writer/director John Michael McDonagh's "The Guard," Officer Boyle (Brendan Gleeson), is one of the most memorable leads of the year. Played with trademark wit by Gleeson, Boyle does drugs, sleeps with hookers, and simply doesn't care what you think about him.
Film Feature: All Things Shine in Terrence Malick's 'The Tree of Life'
Submitted by mattmovieman on June 3, 2011 - 6:23am
CHICAGO – "Where is it that we were together? Who were you that I lived with? The brother. The friend. Darkness, light. Strife and love. Are they the workings of one mind? The features of the same face? Oh, my soul. Let me be in you now.
DVD Review: Terrence Malick's Beloved 'The Thin Red Line' Joins Criterion
Submitted by BrianTT on October 12, 2010 - 12:04pm
Dash Mihok
CHICAGO – Whenever two power players in the world of cinephiles come together, it creates a critical buzz and such was the case when it was announced that The Criterion Collection had chosen Terrence Malick's "The Thin Red Line" for induction in their world-renowned series of DVDs and Blu-rays.
Academy Award-Nominated 'Beaufort' Ponders Question of Why We Fight
Submitted by HollywoodChicago.com on March 25, 2008 - 11:41pm
Itay Tiran
Ohad Knoller
Wolfgang Petersen
CHICAGO – History eludes us. It's what happens when we're busy making other plans. In his new film "Beaufort," director Joseph Cedar turns his lens toward the history and misery of a Mideastern soldier's outpost eight years ago that was both defended and attacked while highlighting the human element that has to endure when protecting the territory of warfare.


masterwelder had the most liked content!
A pallet jack dose a decent job of removing tires and spoke hub/drums as one.
41- is that using the cam out of the 400 motor or dose the 300 cam somehow have the ability for the straight key way?
Thank you for looking. That is interesting to have the same compression and use the same nozzles. Ill give the parts man a call tomorrow.
My 90 RB has a mechanical E7-300L, 12513 Eaton with 4.64 rears. I have a 91 CH with a mechanical E7-400. My question is could the parts from the 400 (pump, turbo, injectors) be put on the 300 block or are there internal differences like different pistons, compression etc. Would be nice to have more hp and rpm.
An '01 with less than 500k on a etech 350 mated to an 8ll...? One of the best combos ever. If takin care of even just a little should be good for awhile yet. My 01 ch with a 427 and a 15spd Eaton has 1.2 million in it and was only rebuilt once at 600k. The E-7 is a tough motor. Cams and liner issues are some if any of the "major" concerns. Rebuilding is reasonable when the time comes. And the best part- No emissions.
How's you're dad like the section of I88 between Oneonta and Cobleskill? To say it's rough would be kind!
Is it going to be put up for sale?
Almost a month, any update?
I've got a 20001CH with a setback front axle and my hood is in need of replacement. My question is does anyone know of a vision hood would work on this truck? My guess is it won't but maybe someone else has some definitive answers.
I don't think it matters what wires go to what terminals. It's a coil inside looking for ground to resist against, generate heat and in turn heat up your coolant.
Most of the time the thermometer is also a sight gauge, meaning the hydraulic fluid will be visible in the thermometer if at the same level.
If it's a Jake I think there a diagrams on there website.
We still know it's you! Mine got messed up to but luckily it's not my password to anything. I have confidence Barry will have things sorted out shortly. I can't even imagine trying to run a site like this.


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Commentary: Camp Good News is a Life Changing Experience
Written by Allie Sherwood on Sep 27, 2011
Allie Sherwood is a parishioner at Holy Trinity, Port Neches. Below is her account of her experience as a counselor at Camp Good News, a ministry at Camp Allen for children with parents in prison.
Lucy Nazro to Step Down as Head of St. Andrew's School, Austin
Written by EDOT Staff on Sep 26, 2011
After more than three decades as Head of School, Lucy Nazro will be stepping down as Head of School at St. Andrew's Episcopal School, Austin, at the end of this school year. During her tenure, Nazro has helped transform St. Andrew's from a small elementary school to a preeminent 1-12 college...
Resurrection, Austin, Completes Phase One of Renovation
The Episcopal Church of the Resurrection, Austin, recently completed Phase One of a three-phase renovation which began on June 5.
All Saints, Austin, to Host John Philip Newell for Bailey Lecture Series
All Saints', Austin, will host John Philip Newell for the Bailey Lecture Series, an annual endowed lectureship..
Of Love and Loss: Lessons from a Bastrop Firefighter
Written by Mark Gwin on Sep 22, 2011
This has been a long lesson in humility and hope. That it is not a story of futility and despair, I give thanks to my family, friends, coworkers and community, who have taken a devastating event and made it inspirational.
Hikers Released in Iran; Washington Bishop Highlights Religious Dialogue
The Sept. 21 release of U.S. hikers Shane Bauer and Josh Fattal from an Iranian prison "affirms the importance of the role of religious dialogue and its end product in this case, public diplomacy, as we seek ways to define common ground between our two countries," said Diocese of...
Rebuild Our Church in Haiti Announces New Resources
New and updated resources for dioceses and congregations who are about to launch campaigns to support the Rebuild Our Church in Haiti appeal are now available online. In addition to the practical tools, news, and progress reports already available, there are newly updated communications...
Bishop Doyle Elected to the Board of the College for Bishops
On Tuesday at the House of Bishops meeting in Quito, Ecuador, the Rt. Rev. Andy Doyle, Bishop of Texas was elected to a three year term on the board of the College for Bishops along with Honduras Bishop Lloyd Allen and Kansas Bishop Dean Wolf.