text:
Appointment of New Minister
Date Published: 27/02/2018
On 13 February 2018, the Industry and Technology Development (ITD) Act 1998, was transferred to the Hon. Mark McGowan, Premier; Minister for Public Sector Management; State Development, Jobs and Trade; Federal-State Relations.
Economic Growth, Diversity and New Energy Technologies - July 2017
Date Published: 16/01/2018
TIAC has drafted an Energy Report that looks at key strategic energy issues from a business end-user perspective. The report looks at the need for a network and generation transition strategy to enable efficient, effective and secure energy models reflective of these technology trends and cost structures.
TIAC Annual Activity Report 2016 - 2017
Date Published: 14/09/2017
The TIAC Annual Activity Report 2016-2017 is now complete and was tabled in the Western Australian Legislative Assembly in September 2017. The report lists achievements and activities for the last financial year and includes as an appendix the recently TIAC commissioned 'Accessing Commonwealth Grant Funding Paper.
2017 Machinery of Government changes
Date Published: 15/08/2017
The Department of Jobs, Tourism, Science and Innovation was formed on 1 July 2017. The department comprises the former Department of State Development; the Industry Development division from the former Department of Commerce; the Western Australian Tourism Commission; and the former Office of Science. It also has responsibility for international education and innovation.
Project Paper: Accessing Commonwealth Grant Funding
Date Published: 15/08/2017
TIAC has drafted an Accessing Commonwealth Grant Funding Project Paper by way of identifying the types of support offered and government interventions to assist WA in accessing Commonwealth competitive funding.
TIAC has added its voice in support of agencies and applicants in approaching the Commonwealth Government in relation to funding for innovation in WA. Members acknowledged that WA does not perform well in accessing Commonwealth competitive funding programs and in particular the poor performance of WA researchers in accessing important Commonwealth funding such as Cooperative Research Centres (CRCs), Australian Research Council (ARC) and National Health and Medical Research Council (NHMRC) grants. WA also performs poorly in accessing infrastructure funding. By way of example of the poor level of access, until March 2017, when a CRC was awarded for honey bee products, no CRC's were headquartered in WA.
WA Innovation Summit
Date Published: 22/08/2016
The Western Australian Innovation Summit held in Perth on the 28 July 2016, brought together some of the State's brightest minds to discuss, challenge, debate and collectively position Western Australia to prosper in this era of rapid global change. Summit outcomes will inform the formulation of the State's 5 year Innovation Strategy.
Stimulating innovation: Comparative and competitive advantages and the role of competencies
Date Published: 22/08/2016
TIAC has drafted a Comparative and Competitive Advantages Paper by way of defining the true meaning of what generic competencies are and how they relate to the Western Australia economy. The Council will consider how this topic aligns with or impacts the outcomes of the Innovation Summit.
Comments and feedback are being sought on the Comparative and Competitive Advantages Paper. If you have a question or would like to leave a comment or provide feedback, please contact firstname.lastname@example.com.
Office of Science
Date Published: 22/08/2016
The Office of Science (OOS) was established in 2013 as a stand-alone office within the Department of Premier and Cabinet reflecting the importance of science and a science culture to the future development of the State. TIAC member Professor Shaun Collin has been working with the OOS with the Premier's Round Table Forums and the Blueprint for Marine Science Initiative.
The Blueprint for Marine Science Initiative Implementation Strategy 2016-2018
Date Published: 1/08/2016
On the 21 June 2016 the Blueprint for Marine Science Initiative was released. Some of Western Australia's most influential government, industry, science and community members have joined forces to launch the implementation strategy that will steer the state's marine science for sustainable economic development and environmental protection over the coming decades.


text: Categories Most RecentArchivesBath & SpaBirthdayBoardingDayCareFirst DayObediencePlayStaffUncategorized DayCare Tera F. gives kisses to her favorite dog handler, Sadie. Tags: Daycare, Dog Handler, Kisses, Sadie, Tera F., March 13, 2018 DayCare Cuddling for warmth Tags: Cold Weather, Jojo M., Lucy Sm., Ruby Bo, staff, Winter, February 16, 2018 DayCare Carhart-wearing dog handlers stay warm! Tags: Cold Weather, staff, Winter, February 16, 2018 DayCare Playing on a nice winter day. Tags: Dance, Emma O., outdoor play, Play, February 16, 2018 Staff Ryan Evans (with Kendall S.) Tags: Kendall S., Ryan E., staff, January 2, 2018 Staff Sadie Sanchez (with Beanie and Tera F.) Tags: Beanie F., Sadie S., staff, Tera F., January 2, 2018 Staff Emma Thiede (with Miko B.) Tags: Emma T., Miko B., staff, January 2, 2018 Staff Brad Snell (with Pippi A., Pandora A., & Bruin L.) Tags: Brad Snell, Bruin L., Pandora A., Pippi A., staff, March 30, 2016 Staff Mary Beth McTaggart (with Motley W.) Tags: Mary Beth, Motley W., staff, February 12, 2016 Staff Travis Drahozal (with Cooper F.) Tags: Cooper F., staff, Travis D., December 31, 2014 Staff Stephanie Barriero (with Dublin) Tags: Dublin, staff, Stephanie Barriero, August 28, 2012 Staff Larry Coppey (with Emma) Tags: Emma C, Larry Coppey, staff, August 25, 2012

subset: commoncrawl


text:
"Action may not always bring happiness; but there is no happiness without action." ~Benjamin Disraeli
Although laziness is common and a natural part of life, it has the potential to completely consume us.
I personally have times where laziness causes me to feel trapped. No matter what I do, I cannot seem to shake it off. I feel tired, fall asleep constantly during the day, sit around a lot and feel unable to be active, avoid doing anything productive, and put on hold things that I want to accomplish.
I believe there are two kinds of laziness. First, there's the kind where you have been working your butt off for weeks and finally, after all your hard work, all you want to do is be lazy and do nothing.
But then there's the kind of laziness where you struggle to find motivation. Every time you think of something you would like to do or achieve, you cannot find the energy or drive to work toward it. This is the kind of laziness that I am talking about.
Being lazy is actually quite draining and depressing. I know because I regularly find myself feeling so lethargic that even the simplest task seems like a challenge. I'm sure I'm not alone in this struggle.
I have found five effective ways to overcome my laziness that I want to share with you so you can win your personal battle too.
1. Focus on just a few things at a time.
We often create a big list of things that we want to do and achieve. Focusing on two or three things at a time will allow you to feel less overwhelmed. Instead, you will feel motivated, as your goals will now seem so much more achievable.
Out of the two sets of six-month goals below, which set gets you more motivated?
Learn to play guitar, do well at work, and get fit.
Learn to play guitar, do well at work, get fit, build big muscles, get better at singing, get top marks at school, learn how to draw better, and write a book.
When I see the second list, I feel overwhelmed. When my life looks a bit like this, I usually don't know where to start or if I can succeed at anything I've set out to do.
This has been a big learning curve for me. When success seems like it is just around the corner, suddenly I get an amazing rush of energy where I feel liberated and excited to achieve bigger things.
Set yourself two or three easy to achieve goals at a time and you will notice that you will naturally gain inspiration and motivation.


text:
Top-down shooters don't get much attention these days, but there was a time when the genre dominated the arcade landscape. The Raiden franchise had its decade in the sun through the 1990s, spanning multiple releases that included three Raiden Fighters games towards the turn of the millennium. Those three can now be had on one disc at the budget price of just $19.99. While these aren't the greatest top-down shooters of all time and a little bit more could have been done to bring the package up to date, Raiden Fighters Aces is a good compilation of old-school gaming.
Though most top-down shooters have found their way to Xbox 360 via Xbox Live Arcade, Raiden Fighters Aces has made its home on disc and on store shelves. That gives it a few advantages over its XBLA brethren, most notably the full set of 1,000 Achievement points and a robust set of options for tweaking the gameplay.
All three Raiden Fighters games have been faithfully recreated for play on Xbox 360 -- straight down to the broken English. Online leaderboards and a replay save option have been added, but other than those additions this is a straightforward port. The visuals and sound haven't been updated which makes this one of the most technically inferior Xbox 360 releases.
There is little difference between the three Raiden Fighters games. Each has a good selection of ships, each carrying their own stats and special weapons. Once the game starts, it's a matter of dodging bullets amidst all of the chaos that goes on. Power-ups can be grabbed to add slave ships a la Galaga or to increase your firing power. Like all top-down shooters, the game is more about memorizing enemy patterns than any other skill set. The games are rather short, though beating them without continuing to get all of the Achievements is quite challenging.
Each game can be played co-operatively, but only offline with another player. The two-player game can get rather hectic after adding a second bullet-spewing ship onto the screen, so it isn't really my cup of tea. Still, the lack of any Xbox Live multiplayer features is disappointing.
In fact, the Xbox Live integration as a whole is a bit odd. There are leaderboards, but you have to select the Xbox Live tab on the main menu to play a game where your scores will be registered. There you'll find a more restrictive option set to keep everyone on the same playing field, but even if you play under the default settings on the normal "Game Play" tab you'll find that your scores aren't uploaded to the leaderboards.
The same goes for saved videos -- another feature added for Xbox 360. Only while playing an Xbox Live game can you save a video that can be shared online. You're free to save videos in other modes, but they can only be viewed locally.
Even with these small points of contention, Raiden Fighters Aces still has an impressive set of options and features. Plenty of sliders and filters exist for getting your visuals just right, including fully customizable controls and the ability to rotate the screen so you can get the full use of your widescreen television.
The Verdict
Raiden Fighters Aces is a good deal for anybody that loves top-down shooters or has nostalgic memories for Raiden. The budget price and good assortment of options leave little to be desired, though the absence of online multiplayer is a letdown. As a package of arcade games, the actual content is still rather slim and anybody looking for a visual showcase on their 360 should look elsewhere.


text:
What Happens After Forgiveness?
Forgiveness is essential in any relationship. God commands it. And not only does he command it, He commands that we do it over and over again. I find little trouble in forgiving someone, especially someone I love. If someone asks me to forgive them I will say, "I forgive you." Just knowing it is God's command is enough for me.
What I do struggle with is what comes after forgiveness. After the offender is set free with forgiveness I am left with this hurt that I find difficult to stop thinking about. And you can say "forgive and forget" but it is just impossible. Just because I forgave someone does not mean that all is erased and everything is as if nothing happened in the first place. I struggle with that. I wonder if anyone else does, too.
What happens when I struggle with forgetting the past? I think about it. I wake up thinking about it. I go to sleep thinking about it. When I see the person who hurt me in the first place those original feelings of anger and hurt bubble up again even though all has been forgiven. Any of this starting to sound familiar?
Now those feelings are back and I begin to think about what my flesh would have liked to say instead of "I forgive you." I start to think of what I should have done to make myself feel better instead of saying "I forgive you." I begin to resent that person for ever asking me to forgive them. I feel angry that they no longer have to deal with this but I am still struggling with the effects of it. I feel angry that this doesn't continue to cause them pain, too. Am I beginning to get close?
The truth is, whether we want to admit it or not, we have probably all struggled with these feelings at one point or another. But it is not spiritual to talk about how we feel after forgiveness. After all, we are to forgive and forget, right? Well, let me talk to you about what happened to me after forgiveness. Well, I guess I already have. Everything I described above I have felt personally. And it hurts. It is heavy. It is sadness. And it brings me down. I bring myself down when I allow those feelings to rule.
I had to come to a point where I chose not to think about it. I didn't allow myself. This took practice. I would put on the tv or music. I would start a conversation with someone. I would not allow my mind to reenact the whole situation over again. Make no room for the devil.
I would purposely show acts of love to the individual that hurt me. This helped the most. I found ways to show them that I still loved them and that I wasn't going to let what happened stand between our friendship. Because, let's be honest, every moment that I am harboring that anger I am putting more distance between myself and the "offender."
I waited. You can't instantly get rid of these feelings. And if you are on the offending side you shouldn't expect your friend or spouse or whoever it is to instantly feel fine about what happened. Give it time. And time does heal if you are taking the above steps to help the healing. Time, in itself, won't do it.
I prayed. You can't expect to fight feelings like anger, hurt, jealousy, etc on your own. You simply need the Lord's help. And praise the Lord He is ready, willing, and fully capable to help us out of the miry clay and set our feet on a rock.
I am so thankful to say that I am in the "waiting" stage. I used to be praising the Lord hour by hour that I didn't think about it. Now, by His grace, I am praising the Lord as month to month I can go without ever thinking about what happened to me.
Let's be honest now. Where are you at?


text:
The antipsychotic drug zotepine [ZTP; 2-[(8-chlorodibenzo[b,f]thiepin-10-yl)oxy]-N,N-dimethylethan-1-amine] is known to have not only atypical antipsychotic effects but also antidepressive effects in schizophrenia patients. Norzotepine [norZTP; N-desmethylzotepine, 2-[(8-chlorodibenzo[b,f]thiepin-10-yl)oxy]-N-methylethan-1-amine] has been postulated to be a major metabolite of ZTP in humans. Here, we characterized norZTP through several in vitro studies and in animal models of psychosis, depression, and extrapyramidal symptoms (EPS) and compared the pharmacological profiles with those of ZTP. Although both compounds showed similar overall neurotransmitter receptor binding profiles, norZTP showed 7- to 16-fold more potent norepinephrine reuptake inhibition than ZTP. In a pharmacokinetic study, both ZTP and norZTP showed good brain permeability when administered individually in mice, although norZTP was not detected in either plasma or brain after intraperitoneal injection of ZTP. In the methamphetamine-induced hyperlocomotion test in mice, norZTP and ZTP showed similar antipsychotic-like effects at doses above 1 mg/kg i.p. In contrast, unlike ZTP, norZTP did not induce catalepsy up to 10 mg/kg i.p. norZTP significantly antagonized the hypothermia induced by reserpine [(3β,16β,17α,18β,20α)-11,17-dimethoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]yohimban-16-carboxylic acid methyl ester], suggesting in vivo inhibition of the norepinephrine transporter. In the forced-swim test, norZTP exerted an antidepressant-like effect at the effective doses for its antipsychotic action, whereas ZTP neither antagonized reserpine-induced hypothermia nor showed antidepressant-like effect. These results collectively demonstrate that norZTP exerts more potent inhibitory action than ZTP on norepinephrine transporters both in vitro and in vivo, presumably accounting for its antidepressant-like effect and low EPS propensity. Given that norZTP is the major metabolite observed in humans, norZTP may contribute to the unique clinical profiles of its mother compound, ZTP.
Zotepine [ZTP; 2-[(8-chlorodibenzo[b,f]thiepin-10-yl)oxy]-N,N-dimethylethan-1-amine; brand name: Lodopin, Zoleptil, or Nipolept] is an antipsychotic drug with low extrapyramidal symptom (EPS) liability (Petit et al., 1996; Cooper et al., 2000; Davis et al., 2003). Since ZTP was originally developed and launched in Japan in 1982, it has been available as a pharmacotherapeutic agent in treating schizophrenia patients in Germany, the United Kingdom, and 10 other countries in Europe and Asia. Although the term "atypical antipsychotics" did not exist at its development, ZTP was later proposed to be classified as such (Meltzer et al., 1989b; Stockmeier et al., 1993), along with other drugs exerting antipsychotic activity with low EPS liability, such as clozapine [8-chloro-11-(4-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine] (Meltzer et al., 1989a). Indeed, ZTP is a dopamine D2 receptor antagonist and serotonin 5-HT2A receptor antagonist like olanzapine [2-methyl-4-(4-methylpiperazin-1-yl)-10H-thieno[2,3-b][1,5]benzodiazepine] and risperidone [3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl}-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one] (Schotte et al., 1996; Prakash and Lamb, 1998).
In clinical settings, ZTP has been reported to show not only antipsychotic but also antidepressive and anxiolytic effects in schizophrenia patients (Fleischhacker et al., 1989; Kondo et al., 1993). Furthermore, ZTP is also known to exert a rapid antimanic effect without inducing depression in severe mania patients (Amann et al., 2005). In addition to its antagonistic activity on D2 and 5-HT2 receptors, ZTP displays binding affinity for the norepinephrine transporter (NET) with potency comparable with that of conventional antidepressants (Leysen et al., 1993; Prakash and Lamb, 1998; Tatsumi et al., 1999).
Shiraga et al. (1999) reported that incubation of ZTP with human liver microsomes produced four metabolites: N-desmethylzotepine, 3-hydroxyzotepine, zotepine S-oxide, and 2-hydroxyzotepine. A fifth metabolite, zotepine N-oxide, was also detected, but could not be quantified. N-desmethylzotepine and zotepine S-oxide are formed via metabolism by CYP3A4, whereas 3-hydroxyzotepine and 2-hydroxyzotepine are formed via metabolism by CYP2D6 and CYP1A2, respectively (Shiraga et al., 1999). Among these metabolites, the N-desmethyl metabolite of zotepine [norzotepine, norZTP; N-desmethylzotepine, 2-[(8-chlorodibenzo[b,f]thiepin-10-yl)oxy]-N-methylethan-1-amine] is known to be a main metabolite of zotepine in humans (the chemical structures are shown in Fig. 1). Some reports have been published regarding plasma concentration of norZTP in humans. In one study conducted with 12 young healthy subjects, plasma concentration of norZTP was measured, and Cmax value of norZTP was approximately 30% of the parent compound in plasma (ZTP at 12.7 ng/ml versus norZTP at 3.79 ng/ml) after administration of 50 mg of ZTP (Velagapudi et al., 1997). Similar results were observed in a schizophrenia patient (Chou et al., 2005). These results suggest that norZTP may contribute considerably to the clinical therapeutic effects of its mother compound ZTP, provided norZTP is pharmacologically active.
Pharmacological properties of metabolites of ZTP have not been fully elucidated, and there have been few pharmacological investigations on the profile of norZTP published to date. Albeit only in conference abstracts, it was shown that norZTP and 3-hydroxyzotepine have potent affinity to 5-HT2A receptors although other metabolites did not show such affinities (Ohki et al., 1999), and norZTP has affinities to D1, D2, D3, D4, and D5 receptors (Heal and Needham, 1996).
Here, to characterize the pharmacological action of norZTP and compare its profile with that of ZTP, we evaluated norZTP via in vitro studies and in vivo animal models of psychosis (methamphetamine-induced hyperlocomotion), depression (forced-swim test), and EPS (catalepsy). Furthermore, norZTP was tested by using the apomorphine hydrochloride [APO; (6aR)-5,6,6a,7-tetrahydro-6-methyl-4H-dibenzo[de,g]quinoline-10,11-diol hydrochloride hydrate (2:2:1)]-induced climbing test to assess in vivo D2 antagonist activity and using reserpine [(3β,16β,17α,18β,20α)-11,17-dimethoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]yohimban-16-carboxylic acid methyl ester]-induced hypothermia to assess in vivo NET inhibitory activity.
Materials and Methods
Drugs and Drug Treatment.
norZTP was synthesized at Astellas Pharma Inc. (Tsukuba, Japan), and ZTP was obtained from Astellas Tokai Inc. (Shizuoka, Japan). Olanzapine (brand name: Ziprexa) was purchased from Eli Lilly & Co. (Indianapolis, IN). Ziprasidone [5-{2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-yl]ethyl}-6-chloro-1,3-dihydro-2H-indol-2-one] and (+)-(S,S)-reboxetine [(+)-(2S)-2-[(S)-(2-ethoxyphenoxy)(phenyl)methyl]morpholine methanesulfonate] were purchased from Pfizer Inc. (New York, NY) as Geodon and Edronax, respectively, and all of the compounds were extracted by Astellas Pharma Inc. The antipsychotics amisulpride [4-amino-N-[(1-ethylpyrrolidin-2-yl) methyl]-5-(ethylsulfonyl)-2-methoxybenzamide] and risperidone were purchased from Sequoia Research Products, Ltd. (Pangbourne, UK). Haloperidol [4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-1-(4-fluorophenyl)butan-1-one], clozapine, chlorpromazine [3-(2-chloro-10H-phenothiazin-10-yl)-N,N-dimethylpropan-1-amine]; paroxetine hydrochloride [(–)-(3S,4R)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine hydrochloride (antidepressant, serotonin selective reuptake inhibitor), desipramine hydrochloride [3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N-methylpropan-1-amine hydrochloride] (antidepressant), imipramine hydrochloride [3-(10,11-dihydro-5H-dibenzo[b,f]-azepin-5-yl)-N,N-dimethylpropan-1-amine] (antidepressant), and APO hydrochloride (D2/D1 agonist) were purchased from Sigma-Aldrich (St. Louis, MO). Methamphetamine hydrochloride [MAP; (αS)-N,α-dimethylbenzeneethanamine hydrochloride (1:1)] and reserpine were purchased from Dainippon Sumitomo Pharma Co., Ltd. (Osaka, Japan) and Daiichi Sankyo Co., Ltd. (Tokyo, Japan), respectively.
Drug doses were corrected for salt content (except for desipramine hydrochloride, paroxetine hydrochloride, MAP, and APO). For in vivo tests, MAP was dissolved in saline and injected subcutaneously. APO was dissolved with 0.1% sodium disulfite in distilled water and injected subcutaneously. Reserpine ampoules were opened just before use and also injected subcutaneously. ZTP, norZTP, and olanzapine were dissolved with a drop of hydrochloric acid and diluted with distilled water, and risperidone was dissolved with a drop of 1% tartaric acid and diluted with distilled water. Amisulpride was dissolved with 0.3% lactic acid, and desipramine hydrochloride was dissolved with distilled water. ZTP, norZTP, olanzapine, risperidone, amisulpride, and desipramine were administered by intraperitoneal injection. Paroxetine hydrochloride was dissolved with 0.5% methylcellulose in distilled water and administered orally. All injection volumes were 10 ml/kg.
Receptor Binding Assays.
Initial receptor binding screens were conducted with duplicate samples of 1 μM ZTP and norZTP evaluated for binding to neurotransmitter receptors, a transporter, ion channels and enzymes by using radioligand assays (performed at Sekisui Medical Inc., Tokyo, Japan). Subsequent dose-response studies for D1, M1, H1, α1A, α2A, and 5-HT6 were also conducted at Sekisui Medical Inc. Receptor binding assays for D2, 5-HT1A, 5-HT2A, 5-HT7, and 5-HT2C were conducted at Astellas Pharma Inc.
Norepinephrine and Serotonin Uptake Inhibition Assays.
Mouse and human NET and serotonin transporter (SERT) were transiently expressed in human embryonic kidney (HEK) 293 cells, and cells were cultured overnight 24 h after gene transfection. Cells were washed with Krebs-Ringer's assay buffer (125 mM NaCl, 4.8 mM KCl, 1.2 mM MgSO4, 1.2 mM KH2PO4, 25 mM HEPES, 5.6 mM glucose, 1 mg/ml bovine serum albumin, 1 mM ascorbic acid, 0.1 mM pargyline) and incubated for 30 min with either 100 nM [3H]NE [LEVO-[RING-2,5,6-3H]-norepinephrine; PerkinElmer Life and Analytical Sciences, Waltham, MA] or 50 nM [3H]5-HT [5-[1,2-3H(N)]-hydroxytryptamine creatinine sulfate; PerkinElmer Life and Analytical Sciences] in the presence of test compounds. After incubation, cells were washed with assay buffer, and intracellular radio activity was measured. Nonspecific uptake was measured with duloxetine (15 μM). Imipramine, desipramine, paroxetine, and (+)-(S,S)-reboxetine were used as positive controls.
Histamine H1 Receptor Antagonist Assay.
Chinese hamster ovary cells stably expressing H1 receptors were cultivated overnight (7.5 × 103 cells/well on a 384-well plate), and stimulated with histamine (1000 nM) in the presence of test compounds, and intracellular calcium release was measured by calcium flux assay using a fluorescent dye (Fluo-4AM; Dojindo Laboratories, Kumamoto, Japan). All compounds were dissolved by using dimethyl sulfoxide, with a final concentration of 1% dimethyl sulfoxide in the assay buffer.
For pharmacokinetic measurements and the forced-swim test, adult male DBA/2N mice were purchased from Charles River Japan (Yokohama, Japan) and used at 13 to 14 weeks of age. For other behavioral experiments, male ICR mice were purchased from Japan SLC, Inc. (Shizuoka, Japan) and used at 4 to 8 weeks of age. Mice were maintained 10 per cage in plastic cages with ALPHA-dri chip bedding (LSG Corporation, Tokyo, Japan). Mice were housed in a temperature- and humidity-controlled colony room (23 ± 3°C and 55 ± 15%, respectively) under a 12-h light/dark cycle with water and laboratory chow supplied ad libitum. All in vivo experimental procedures were performed during the light cycle. Procedures involving animals and their care were conducted in accordance with the institutional guidelines that are in compliance with international laws and policies (International Guiding Principles for Biomedical Research Involving Animals developed by the Council for International Organization of Medical Science). All experiments were also conducted in accordance with the Astellas Pharma Inc. guidelines for the care and use of animals and under approved protocols from the Institutional Animal Care and Use Committee of Astellas Pharma Inc.
Pharmacokinetic Study in Mice.
For pharmacokinetic analysis, 3.2 mg/kg ZTP or norZTP was administered intraperitoneally to 14-week-old male DBA/2N mice, and plasma and brain samples were collected at 0.5, 1, 2, and 4 h after drug administration and stored at −20°C until use. ZTP and norZTP in plasma and brain were quantified by using high-performance liquid chromatography (HPLC)/tandem mass spectrometry assay. In brief, plasma samples (50 μl) were treated by protein precipitation with the addition of acetonitrile (200 μl) containing diazepam [7-chloro-1-methyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one] (Wako Pure Chemicals, Tokyo, Japan) as internal standard (final concentration; 20 ng/ml). After centrifugation (1500g, 10 min, 15°C), the supernatant was separated and used for analysis. Brain samples were homogenized with a sodium bicarbonate solution. After addition of internal standard and t-butyl methyl ether, the mixture was shaken for 15 min and centrifuged. The organic layer was then separated, evaporated to dryness under nitrogen, and reconstituted in mobile phase for assay. ZTP and norZTP extracted from plasma and brain were analyzed with an API 3200TM Triple Quadrupole Mass Spectrometer (Applied Biosystems, Tokyo, Japan) coupled to a Shimadzu HPLC system (Shimadzu Scientific Instruments, Kyoto, Japan). Samples were injected into an HPLC column (XTerra MS C18, 5 μm, 4.6 × 50 mm; Waters, Tokyo, Japan) and eluted at 40°C. The mobile phase, pumped at 0.4 ml/min, was a mixture of 20 mM ammonium acetate-acetonitrile [30:70 (v:v)]. The Kp value was the ratio of drug concentration in brain (ng/g brain) to plasma (ng/ml) at 30 min after drug injection.
Apomorphine-Induced Climbing and Gnawing.
Male ICR mice (4 weeks old) were individually allowed at least 1 h to acclimate to the wire-mesh cage (length × width × height: 130 × 180 × 250 mm). APO is a D2/D1 receptor agonist that is known to induce stereotyped behaviors such as oral stereotypy (gnawing, licking, and biting) at higher doses than those that induce climbing. APO was used at 2 mg/kg in the present study because this dosage has been shown to be the minimum effective dose that induces stable climbing behavior without consequent oral stereotypy.
Each compound or vehicle was injected 20 min before APO was injected, and 20 min after injection of APO (2 mg/kg s.c.), duration of climbing behavior was measured for 2 min. Holding four paws against the wall was counted as climbing behavior. Gnawing was assessed by scoring, with a score of 0 for 0 to 9 times, 1 for 10 to 19 times, and 2 for more than 20 instances of gnawing in 2 min. As reference drugs, atypical antipsychotics, olanzapine, risperidone, and amisulpride, were also examined.
Methamphetamine-Induced Hyperlocomotion Test.
In the MAP-induced hyperlocomotion test, male ICR mice (4–5 weeks old) were used. Individual mice were placed in experimental cages (length × width × height: 300 × 350 × 175 mm) for an acclimatization period before 60 min of MAP injection. All compounds were administered 30 min before MAP injection, and locomotor activity were measured immediately after injection of saline or MAP (1 mg/kg s.c.). Locomotor activity was measured for 30 min by using SUPERMEX (Muromachi Kikai Co., Ltd., Tokyo, Japan). Data were analyzed by using CompAct AMS version 3.51 (Muromachi Kikai Co., Ltd.). As reference drugs, olanzapine and risperidone were also examined.
Spontaneous Locomotor Test.
Male ICR mice (4–5 weeks old) were injected with drugs or vehicle (intraperitoneally) and returned to their home cage. Thirty minutes later, mice were placed in experimental cages (length × width × height : 300 × 350 × 175 mm), and locomotor activity was recorded for 30 min by using SUPERMEX.
Reserpine-Induced Hypothermia.
Male ICR mice (7–8 weeks old) were placed in gray (two sides and top cover) and transparent (two sides) individual plastic cages (length × width × height: 120 × 180 × 170 mm) with ALPHA-dri chip bedding (LSG Corporation). Measurement of body temperature was performed 0, 4, and 7 h after starting the experiment, using an intrarectum probe (Physitemp Instruments Inc., Clifton, NJ). Reserpine (3 mg/kg s.c.) was administered at 0 h (experiment initiation), and mice were subsequently injected with drug 4 h after reserpine treatment. Body temperature change was measured 3 h after drug treatment.
Forced-Swim Test.
Antidepressant-like effect was evaluated for norZTP, ZTP, olanzapine, and risperidone in the forced-swim test with the doses used in the MAP-induced hyperlocomotion test. The conventional antidepressants desipramine and paroxetine were examined as reference compounds. DBA/2N male mice (13–14 weeks old) were administered either vehicle or test compounds intraperitoneally 30 min before testing, except for paroxetine that was administered orally 60 min before testing.
The forced-swim test was performed in a pool (cylinder diameter: 140 mm) at a water depth of 130 mm and water temperature of 23 to 24°C. Animals were tested in an automated forced-swim apparatus (MV-20LAN; MELQUEST Ltd., Toyama, Japan). Immobility time was calculated from activity time as (total) − (active) time by using analysis software of the apparatus. Cumulative immobility time was scored for 6 min during the test.
Catalepsy Test.
Male ICR mice (5 weeks old) were used. Catalepsy was measured 30 min after intraperitoneal injection of ZTP, norZTP, antipsychotics, or vehicle. The forepaws of the mice were placed on a horizontal steel bar (diameter 3 mm) elevated 3 cm above the tabletop. If duration of catalepsy reached 30 s, catalepsy was scored as positive. Incidence of catalepsy was expressed as the number of mice scored as positive versus the total number of mice evaluated in a group.
Statistical Analysis.
Behavioral data were reported as means ± S.E.M., and all statistical analyses were conducted by using SAS version 8.2 (SAS Institute, Cary, NC). Dunnett's multiple comparison test was used to evaluate multiple groups including vehicle and test compounds in all tests except for the catalepsy test, in which vehicle-treated and drug-treated groups were compared by using Steel's test. Student's t test for unpaired data was used to compare MAP- or APO-treated group data with control group data. For all tests, a value of p < 0.05 was considered statistically significant. ED50 values were calculated by using linear regression.
Receptor Binding Affinities.
ZTP and norZTP were subjected to multitarget binding screening against G protein-coupled receptors, ion channels, a neurotransmitter transporters, and enzymes (Table 1). Both compounds showed weak or low binding affinity (<50% inhibition at 1 μM) for human dopamine transporter and the targets shown in Table 1, including adenosine A1, β-adrenergic receptor, GABAA and GABAB, and histamine H2 and H3 receptors. Ki values were determined for compounds exhibiting more than 50% inhibition in the initial test at 1 μM.
As shown in Table 2, ZTP and norZTP demonstrated high affinity (Ki <10 nM) for D2, 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, α1A, and H1 receptors; moderate affinity (Ki = 10–100 nM) for α2A and D1 receptors; and low affinity (Ki = 100-1000 nM) for 5-HT1A and M1 receptors. Affinity of norZTP for D2, M1, and H1 receptors was more than 3-fold less potent than that of ZTP (Table 2).
Functional Assay for Norepinephrine and Serotonin Transporter in Vitro.
In HEK293 cells transiently expressing mouse NET, ZTP demonstrated norepinephrine reuptake inhibition comparable with the conventional tricyclic antidepressant imipramine (ZTP IC50 71 ± 23 nM; Table 3). Norepinephrine reuptake inhibition by norZTP was also potent (IC50 11 ± 1.4 nM), more so than ZTP (Table 3). The antidepressant desipramine also showed a similar potency to inhibit mouse NET (IC50 9.4 ± 5.8 nM; Table 3). (+)-(S,S)-reboxetine showed potent inhibition for NET (Table 3) (IC50 2.7 ± 1.1 nM), findings that have been previously reported as well (Zeng et al., 2009). In HEK293 cells transiently expressing human NET, norZTP showed 16-fold more potent inhibition of NET activity than did ZTP, with IC50 values of 4.2 ± 1.8 nM (norZTP) and 69 ± 14 nM (ZTP).
Although both ZTP and norZTP showed weak or minimal inhibition of human and mouse SERT (IC50 > 5000 nM), this effect was more than 100-fold less potent than their inhibition of NET (Table 3). In the present study, paroxetine showed potent inhibition on mouse SERT (IC50 4.7 ± 0.1 nM). Neither desipramine nor (+)-(S,S)-reboxetine showed inhibitory activity for SERT.
Histamine H1 Receptor Binding and Functional Assay.
Although norZTP demonstrated affinity for the human H1 receptor (Ki 1.6 ± 0.03 nM), ZTP's affinity was three times more potent (Ki 0.47 ± 0.02 nM; Table 2), and both compounds showed negligible affinities (less than 50% inhibition at 1 μM) for the histamine H2 and H3 receptors (Table 1). In functional assays, both norZTP and ZTP showed antagonistic activity to the H1 receptor, although ZTP's activity was four times more potent [corrected IC50 8.0 ± 1.8 nM (ZTP) versus 38 ± 1.1 nM (norZTP); norZTP corrected IC50 value comparable with risperidone (26 ± 0.9 nM)] (Table 4). In the functional assay, olanzapine showed 8- and 38-fold more potent antagonistic activity (1.1 ± 0.3 nM) than did ZTP and norZTP, respectively, whereas neither ziprasidone nor haloperidol showed any significant antagonistic activity (>300 nM) (Table 4).
Pharmacokinetic Study.
After administration of ZTP (3.2 mg/kg i.p.) in mice, ZTP was detected in plasma and brain (Fig. 2); however, the concentration of norZTP in these tissues was under the detection limit (20 ng/ml). After administration of norZTP in mice (3.2 mg/kg i.p.), norZTP was detected in both plasma and brain (Fig. 2). Both ZTP and norZTP showed good brain permeability, and their brain-to-plasma concentration ratios (Kp) were 22 and 24, respectively, at 30 min after individual injection. Brain Cmax (mean ± S.E.M.) values were 918 ± 18 ng/g tissue (ZTP) and 639 ± 209 ng/g tissue (norZTP). Brain area under the curve (0–4 h; mean ± S.E.M.) of ZTP was 2-fold higher than that of norZTP (ZTP: 2645 ± 195 ng·h/g; norZTP: 1018 ± 243 ng·h/g; n = 3). Based on these pharmacokinetic data, an intraperitonial injection route for norZTP and ZTP for subsequent in vivo studies was selected, because ZTP was not metabolized to norZTP with this route in mice, which would presumably allow us to interpret the in vivo data of norZTP and ZTP as pharmacological actions of each individual compounds unlike in human cases.
Apomorphine-Induced Climbing Test and Gnawing Behavior.
On average, APO-injected control mice (2 mg/kg s.c.) climbed for more than 110 s during the 120-s observation period, in contrast to the vehicle-treated mice, which climbed for less than 10 s during observation. As shown in Table 5, both ZTP (0.3–3 mg/kg i.p.) and norZTP (1–10 mg/kg i.p.) dose-dependently inhibited climbing behavior. In particular, ZTP significantly reduced climbing time at 1 and 3 mg/kg (p < 0.05 and 0.001, respectively), compared with vehicle-treated animals. In contrast, norZTP had no effect on climbing at 1 and 3 mg/kg, and significant reduction was observed only at 10 mg/kg i.p. ZTP showed 5-fold more potent activity than norZTP, with ED50 values of 0.73 and 3.9 mg/kg, respectively (Table 5). Olanzapine and risperidone showed climbing inhibition, and their ED50 values were comparable with previously reported values (Corbett et al., 1995). Treatment with norZTP (3 mg/kg i.p.) and amisulpride (10 and 30 mg/kg i.p.) after APO administration (2 mg/kg s.c.) significantly induced gnawing behavior (Table 5).
Methamphetamine-Induced Hyperlocomotion.
Antipsychotic activity of ZTP and norZTP was assessed by using MAP (1 mg/kg s.c.)-induced hyperlocomotion, with olanzapine and risperidone included as reference compounds. All compounds showed dose-dependent inhibition of MAP-induced hyperlocomotion (Table 6). Specifically, ZTP (1 and 3 mg/kg i.p.) and norZTP (1, 3, and 10 mg/kg i. p.) significantly inhibited MAP-induced hyperlocomotion, with comparable ED50 values (0.27 and 0.33 mg/kg, respectively) (Table 6).
Spontaneous Locomotor Activity.
Effects of ZTP, norZTP, and antipsychotics on spontaneous locomotor activity of mice were investigated without MAP administration. Both ZTP and norZTP showed sedative effects at doses exceeding 3 mg/kg i.p., and ED50 values between the two were comparable (3.3 and 3.1 mg/kg, respectively) (Table 7). Other compounds significantly reduced spontaneous locomotor activity at relatively high doses, and those ED50 values were higher than those observed for the MAP-induced hyperlocomotion test (Table 6).
norZTP did not induce catalepsy in mice when administered at dosages up to 10 mg/kg. In contrast, zotepine (10 mg/kg i.p.), olanzapine (1–3 mg/kg i.p.), and risperidone (0.3 mg/kg i.p.) showed significant catalepsy induction (Table 7), with catalepsy-inducing ED50 values comparable with spontaneous activity inhibitory doses.
Reserpine-Induced Hypothermia.
The reserpine-induced hypothermia test is commonly used when developing pharmacological profiles for antidepressants in vivo, as norephinephrine reuptake inhibitors reverse the hypothermia induced by reserpine treatment (Wong et al., 2000). In the present study, desipramine (0.3–3 mg/kg i.p.) showed dose-dependent inhibition of reserpine-induced hypothermia (ED50 0.46 mg/kg) (Fig. 3), confirming that this compound does indeed have norepinephrine uptake inhibition activity in vivo. norZTP (0.1–1 mg/kg i.p.) also demonstrated dose-dependent inhibition of hypothermia (ED50 0.23 mg/kg), with a statistically significant change observed at a dosage of 1 mg/kg (p < 0.001), the same dose level that produced antipsychotic-like effects in the MAP-induced hyperlocomotion test (Fig. 3 and Table 6). At 0.3 mg/kg, norZTP showed 58% inhibition, a value not statistically significant, whereas ZTP showed 45% inhibition at 3 mg/kg and 56% inhibition at 10 mg/kg, values that were also not statistically significant. Neither olanzapine, risperidone, nor paroxetine attenuated the hypothermia at any of the dose levels that induced antipsychotic-like effects.
Forced-Swim Test.
In the forced-swim test, mice became immobile when placed in a water bath. The duration of immobility relative to vehicle-treated mice was significantly reduced with treatment with norZTP at 1 and 3 mg/kg i.p. (p < 0.05 and < 0.001, respectively), doses that were comparable with the effective doses observed in MAP-induced hyperlocomotion test (Fig. 4 and Table 6). Although ZTP induced a 29% reduction in immobility time at 3 mg/kg, this change was not statistically significant, and the effect was reversed at 10 mg/kg (data not shown). Paroxetine (3, 10, and 30 mg/kg p.o.) and desipramine (10 and 20 mg/kg i.p.) showed dose-dependent reduction in immobility time (Fig. 4), as reported previously (Lucki et al., 2001; Ghasemi et al., 2009). Neither olanzapine nor risperidone showed any effects in the forced-swim test at the doses used.
Investigations regarding drug metabolites often lead to novel findings providing biological background information for clinical effects or unexpected side effects of mother compounds. For example, active metabolites of clozapine (Burstein et al., 2005) and quetiapine (Jensen et al., 2008; Winter et al., 2008) have been reported to have unique profiles differing from that of their mother compounds. A recent report showed that a metabolite of quetiapine (N-desalkylquetiapine) is capable of inhibiting norepinephrine uptake, suggesting that the antidepressant effect of quetiapine in bipolar depression is at least partially mediated by the potent antidepressant activity of N-desalkylquetiapine (Jensen et al., 2008). In this regard, clinical reports demonstrating that N-desmethyl zotepine, norZTP, is a main metabolite of zotepine observed after oral administration of ZTP in humans have prompted us to investigate the pharmacological profiles of norZTP.
The initial aim of the present study, therefore, was to compare in vitro pharmacological properties of norZTP with those of ZTP. Thorough in vitro panel screening of ZTP and norZTP with regard to affinity for the number of neurotransmitter receptors showed that both compounds had relatively similarly potent affinities for D2, 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, α1A, H1, and D1 receptors at therapeutically relevant concentrations and had similar affinities to 5-HT1A, α2A, and M1 receptors at high concentrations. These observations suggest that norZTP has an overall binding profile similar to that of ZTP for important neurotransmitter receptors known to be responsible for ZTP's antipsychotic activity.
The major finding of the present in vitro study was that norZTP potently inhibits norepinephrine reuptake. Although ZTP is structurally similar to tricyclic antidepressants and has been reported to show norepinephrine transporter binding affinity (Leysen et al., 1993; Prakash and Lamb, 1998; Tatsumi et al., 1999), we demonstrated for the first time in the present study the more potent norepinephrine reuptake inhibitory activity of norZTP by using cell-based functional assay, closely comparable with that of conventional antidepressants. These results suggest that NET inhibitory activity of norZTP may contribute to the clinical effects of ZTP, at least in part.
In the present study, both ZTP and norZTP inhibited MAP-induced hyperlocomotion and APO-induced climbing behavior, indicating that norZTP itself exerts antipsychotic-like effects similar to those of ZTP and other antipsychotics. The ratio of norZTP and ZTP ED50 values for inhibition of APO-induced climbing (3.9 mg/kg versus 0.73 mg/kg) corresponded to their ratio of Ki values of D2 receptor binding (6.5 versus 2.3 nM), suggesting again that norZTP exerts antipsychotic activity similar to ZTP, presumably involving D2 receptor blockade. However, the ED50 value of norZTP required for inhibition of MAP-induced hyperlocomotion was actually comparable with that of ZTP. Because MAP increases concentrations of several neurotransmitters in extracellular fluid (Gough et al., 2002), antagonisms of 5-HT and H1 receptors and a number of other mechanisms have been suggested to be involved in the inhibitory activities of antipsychotics on such MAP-induced behaviors. As such, the present findings suggestive of norZTP's D2-blocking activity do not fully explain the inhibitory activity of norZTP on MAP hyperlocomotion, indicating that other mechanisms may be involved in this activity.
The forced-swim test is standard for assessing antidepressant-like activity (Porsolt et al., 1978) and existing antidepressants (tricyclics, selective norepinephrine and serotonin reuptake inhibitors, and monoamine oxidase inhibitors) are active in this test. In the present study, norZTP demonstrated antidepressant-like effects at doses that also showed antipsychotic-like effects, whereas ZTP showed no significant antidepressant-like effects at comparable doses. Although there is the possibility that ZTP may exhibit antidepressant-like effect at higher doses, these potential effects may not be detected because of ZTP's sedative effect seen at doses exceeding 3 mg/kg, and we actually observed the reversal of the activity toward the baseline at 10 mg/kg (data not shown). Mice with genetically altered serotonin 5-HT1A, 5-HT2A, α2A, and 5-HT7 receptors exhibited depression or antidepressant-related phenotype, and agonists or antagonists of these receptors have been reported to induce antidepressant-like effects in the forced-swim test (Cryan et al., 2002). Jensen et al. (2008) suggested that the antidepressant activity of quetiapine is at least partially mediated by the NET inhibitory activity and partial 5-HT1A agonistic and 5-HT7 antagonistic activity of N-desalkylquetiapine. A recent report has indicated that amisulpride has high affinity for the 5-HT7A receptor and the compound's antidepressant-like effects disappeared in knockout mice lacking the 5-HT7 receptor, suggesting that 5-HT7A antagonism is important for amisulpride to exert its antidepressant-like activity (Abbas et al., 2009). ZTP is known to have high affinity for 5-HT7 receptor (Roth et al., 1994), and the present study revealed that not only ZTP but also norZTP shows similar high affinity for 5-HT7 receptor (Ki 4.6 and 3.7 nM, respectively). However, although risperidone was shown to have high affinity for the 5-HT7 receptor (Roth et al., 1994), we observed no antidepressant-like effects here. These findings suggest that NET inhibitory activity may play a major role in norZTP's antidepressant-like effect, whereas additional receptors (such as 5-HT1A, 5-HT2A, α2A, and 5-HT7) may also be involved and merit further exploration.
Although NET inhibition by norZTP is assuredly the mechanism most likely involved in the compound's antidepressant effect, this inhibition may also be involved in norZTP's low induction of EPS and weight gain and the potentiation of antipsychotic action of the parent compound. Reboxetine, a norepinephrine reuptake inhibitor (NRI) introduced relatively recently, reportedly enhances the antipsychotic-like activity of the D2 blocker raclopride in rat conditioned avoidance and potentiates D2 blocker-induced dopamine release in the medial prefrontal cortex in rats (Linnér et al., 2002). Furthermore, a clinical report has indicated that reboxetine attenuates appetite and weight gain in olanzapine-treated schizophrenia patients (Poyurovsky et al., 2007). However, the effects of NET inhibition on antipsychotic-induced catalepsy have not been well investigated and still warrant further investigations. Pretreatment with reboxetine has been reported to have no effect on racropride-induced catalepsy in rats (Linnér et al., 2002). However, in our preliminary study, (+)-(S,S)-reboxetine, an NRI with greater selectivity for NET than reboxetine (Wong et al., 2000; Zeng et al., 2009), significantly attenuated haloperidol-induced catalepsy with concomitant injection (unpublished observation). Taken together, these findings suggest that NET inhibition may contribute to catalepsy attenuation, and the NET inhibitory activity of norZTP may be involved in the unique in vivo profile demonstrated in the present study. Further studies are nevertheless required to clarify the detailed mechanisms behind the reduced propensity of EPS associated with NET inhibition.
norZTP and amisulpride both significantly potentiated APO-induced gnawing at doses similar to those found to inhibit climbing behavior. Similar observations were reported on amitriptyline, imipramine, and clozapine (Hedley and Wallach, 1983). These results may suggest that direct or indirect dopamine receptor potentiation and blocking were occurring simultaneously. Studies have shown that NET reuptakes not only norephinephrine but also dopamine (Carboni et al., 2006). In vivo microdialysis study showed that ZTP increases dopamine and norepinephrine release from the rat frontal cortex (Rowley et al., 2000; Nakamura et al., 2005), and therefore norZTP may increase extracellular dopamine and stimulate dopamine neurons indirectly through NET inhibition. Although further studies are still needed to investigate the possible relationship between NET inhibition and gnawing potentiation, these data may indicate that NRIs indirectly stimulate dopamine receptors and induce potentiation of the striatal function.
In addition to its inhibitory activity on NET, norZTP showed affinity for other receptors differing from that observed with ZTP. In particular, norZTP's affinity for 5-HT1A, H1, and M1 receptors was less potent than that of ZTP. H1 receptor affinity has been reported to be positively correlated with the side effect of body weight gain (Kroeze et al., 2003). Indeed, olanzapine and clozapine, which show high affinity for the H1 receptor, are the two antipsychotics known to have the greatest propensity to induce weight gain (Nasrallah, 2008). Although ZTP and norZTP both showed affinity for H1 receptors in the binding assay, on evaluating the H1 receptor antagonistic activity of these compounds in functional assay, we observed that ZTP was less potent than olanzapine, whereas norZTP was less potent than even ZTP. Although the ability of ZTP to induce weight gain has not been extensively documented, several clinical reports have shown that ZTP use in schizophrenia patients is associated with weight gain to an extent comparable with other atypical antipsychotics such as risperidone or quetiapine, albeit not as significantly as olanzapine and clozapine (Baptista et al., 2002). Although norZTP showed weaker affinity to the histamine H1 receptor than ZTP in the present study, subsequently suggesting lower weight gain-inducing ability than ZTP, further clinical data regarding the relationship between plasma concentrations of ZTP and norZTP and weight gain in patients is required to better understand the contribution of norZTP to this side effect of ZTP.
In conclusion, the present study demonstrated norZTP's potent in vitro and in vivo activity to inhibit NET, a target molecule of existing antidepressants, and additionally showed that norZTP has antidepressant-like activity in preclinical animal models. Taken together, these findings suggest that norZTP may contribute to the unique clinical profiles of its mother compound, ZTP.
We thank Drs. Kiyohiro Samizu, Takahiko Tobe, Ryo Naito, Megumi Irie, Masahiko Morita, and Minoru Iijima for assistance throughout the present study and valuable input in preparing the manuscript.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
- zotepine
- norZTP
- norzotepine
- apomorphine hydrochloride
- extrapyramidal symptoms
- serotonin
- methamphetamine hydrochloride
- norepinephrine transporter
- norepinephrine reuptake inhibiter
- serotonin transporter
- human embryonic kidney
- high-performance liquid chromatography.
- Received January 24, 2010.
- Accepted March 10, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
- Abbas et al., 2009.↵
- Amann et al., 2005.↵
- Baptista et al., 2002.↵
- Burstein et al., 2005.↵
- Carboni et al., 2006.↵
- Chou et al., 2005.↵
- Cooper et al., 2000.↵
- Corbett et al., 1995.↵
- Cryan et al., 2002.↵
- Davis et al., 2003.↵
- Fleischhacker et al., 1989.↵
- Ghasemi et al., 2009.↵
- Gough et al., 2002.↵
- Heal and Needham, 1996.↵
- Hedley and Wallach, 1983.↵
- Jensen et al., 2008.↵
- Kondo et al., 1993.↵
- Kroeze et al., 2003.↵
- Leysen et al., 1993.↵
- Linnér et al., 2002.↵
- Lucki et al., 2001.↵
- Meltzer et al., 1989a.↵
- Meltzer et al., 1989b.↵
- Nakamura et al., 2005.↵
- Nasrallah, 2008.↵
- Ohki et al., 1999.↵
- Petit et al., 1996.↵
- Porsolt et al., 1978.↵
- Poyurovsky et al., 2007.↵
- Prakash and Lamb, 1998.↵
- Roth et al., 1994.↵
- Rowley et al., 2000.↵
- Schotte et al., 1996.↵
- Shiraga et al., 1999.↵
- Stockmeier et al., 1993.↵
- Tatsumi et al., 1999.↵
- Velagapudi et al., 1997.↵
- Winter et al., 2008.↵
- Wong et al., 2000.↵
- Zeng et al., 2009.↵


text: well, i've searched around google and i can't seem to find what i need, wich is more simple than a mail form. i have a tv show site and would like to put a Report link at the bottom of the posts that would mail me the URL of the post, so i know the link is dead and replace it. i know it's nothing fancy. it wouldn't even need another page to open, just ppl to press the Report link and it would silently send me the mail containing the link of the page where it was pressed. maybe echoing one line saying report sent or something only. If somebody can help me with this i'm willing to contribute to your paypal account!


text:
Happy 100th Birthday, Emma!
Healthy Aging: It's not the years in our lives, but the life in our years!
This is Emma, celebrating her 99th birthday last year. She'd rather talk politics than weather and she loves to play harmonica. She'll be playing for friends and an extensive family this Saturday (1/25/14), when they come together to celebrate Birthday Number 100. How did Emma get to become a centenarian?
Her parents lived on an acreage on the edge of Fond du Lac, Wisconsin, when Emma was born in 1914. She was raised during a time when nearly half of the U.S. population lived in rural areas (49% in 1920). Gardens were "free food" for anyone with a yard. Growing your own food, hunting, fishing, and foraging were common activities. Emma got plenty of exercise, ate mostly organic food, and drank raw milk.
Organic food is what gardeners and farmers raised before pesticides became big business in the mid-1940s. A few cows ensured your family plenty of milk. Everyone drank the full fat version, thinking that the bluish cast of skimmed milk made that fine for baby calves and piglets, but not so much the family. People knew how to churn butter. Farmers nurtured animals mainly for eggs, milk, and cash; they limited eating them.
Emma has a positive outlook (which, statistically, contributes to longevity), and yes, she has great genes for health and longevity.
I grew up on a farm, too, raising pigs, then turkeys, then pigs again, and growing fruit, vegetable, and flower gardens. A great cucumber crop meant picking and pickling in August, no matter how hot and buggy the weather. Milking a small herd of cows before school and in the evenings taught my siblings and me discipline, earned us cash, and provided fresh milk, butter, and the occasional ice cream. We lived on what we raised, fished, trapped, and foraged, keeping the grocery store bills to a minimum. But I moved to the city and I like this life. With my genes, I don't think I'll reach 100, but I'd like to stay active, and maybe even pain-free, until the end.
So this isn't a New Year's Resolution, but more of a reminder from research* on how long-lived populations get to be long-lived:
- Being active is a regular part of daily routines
- Eating to "not-quite-full" (in Okinawa they say: hara hachi bu—stop eating when you are about 80% full)
- Eating more beans, nuts, vegetables, whole grains, and fruits and less meat and processed foods
- Drinking red wine in moderation
- Having a plan for living and a reason to get up in the morning
- Making time to relieve stress
- Being an active part of a spiritual community
- Upholding rituals and traditions and making family a priority
- Surrounding yourself with people who share long-life values—pick buddies who will support (not sabotage) your good intentions!
So here's to my friend Margaret, who is making activity an integral part of her daily life, and to her mom: Happy 100th Birthday, Emma!
*The nine point summary comes from research conducted by Dan Buettner and published in the book, The Blue Zones: Lessons for living longer from the people who have lived the longest. Washington, D.C.: National Geographic Society, 2008.


text:
We are storyboard artists in animation. During the course of production millions of sketches are produced. Some are used but most are not. These are the ones that "got away" and scribbly scribbles deemed not worthy for prime time.
Tuesday, February 23, 2010
Late P.M doodle
Guy on a plane...must still have tonight's episode of Lost in my head...give me some answers Abrams!
Posted by Spooky at 2/23/2010 11:55:00 PM
3 comments:
- Jeff said...
Why were you looking down at him?? Did he mind??
- 1:48 PM, February 26, 2010
- Sam said...
I like this :)
- 7:23 PM, June 14, 2010
- amauryons said...
What to say about your drawings. They are so cool very expressive.
Download The Vampire Diaries Episodes
- 7:54 PM, September 03, 2011
Subscribe to: Post Comments (Atom)


text:
I recently found that using FMOD_INIT_SYNCMIXERWITHUPDATE would nicely help me with my application. But as said in the documentation it is only supported by the following platforms: Win32/Wii/PS3/Xbox/Xbox 360
Is that the horrible truth ? Won't it support Mac or Linux ?
If that is, why is there such a limitation ?
- ronan.fmod asked 10 years ago
this leads to another question:
When I apply a parameter on a DSP, when is it applied ? I mean taken into account in the audio process callback
does it also means that the mixer may process buffer length different than mixer buffer size on these platforms ?
- ronan.fmod answered 10 years ago
If you apply a parameter to a DSP it will take effect in the system right away, but you won't actually hear the change until that mix is played.
For systems like that on Linux, Mac the hardware requests a certain number of samples and we deliver through a callback, this will mean you get the lowest latency between change and hearing it.
Other platforms buffer up a certain amount of data to account for the fact they are polled manually. You can tweak the amount of buffering done for all platforms with setDSPBufferSize.
Certain output modes work by polling our mixer thread regularily to keep their buffer of cached audio full, this adds latency. Other output modes like on Linux, Mac and Vista, have the hardware tell us when and how much data it needs, so we mix it on demand, resulting in lower latency.
Due to this difference FMOD_INIT_SYNCMIXERWITHUPDATE doesn't work on all platforms (since we don't control when the mix happens, the hardware does). It may be possible for us to expose this feature to more output modes in the future (which would result in higher latencies), but I don't want to set a date on something like that at present.
Please login first to submit.


text:
LEGEND SHIRTLong sleeve hooded shirt
Details https://www.animal.co.uk/outlet-boys-clothing/legend_shirt-CL7WL658.html
Item# CL7WL658
£44.99 £31.40
Find wild this winter with the Legend long sleeve hooded shirt. Yarn dyed check in darkest navy gets a worn-well feel and textured cord detail for backcountry days. Super-soft sherpa lining brings solid winter-weight warmth for cold weather adventurers out with their crew.
Additional Information
Animal boys' Legend long sleeve hooded shirt - Product code CL7WL658
- Cord facing yard dyed check
- Sherpa lined body & hood
- Chest pockets
- Appliqué elbow patches
- Cotton with cord facing
- Silicone softener wash
- Press stud fastening front & cuffs
- Scooped hem
- Woven badge branding
- Fabric Composition
- 100% cotton
- Care Advice
- Wash at 40 degrees
- Do not bleach
- Do not tumble dry
- Cool iron
- Do not dry clean
- FREE delivery to selected Animal stores
- FREE standard delivery on all orders
- FREE Collectplus delivery on all orders
- Next working day delivery £5.00 - order before 2pm
- Saturday delivery £8.00 – order before 2pm
- Take a look at the Delivery Information for estimated timings and costs
- Returns are simple and hassle-free. View our Returns Information


text:
One of the first emails is from a gal writing for a woman's magazine: They are doing a piece on how women can have the best orgasms/sex life possible from "experts." I get right to it. The last question is: "What is your own go-to trick when it comes to reaching an orgasm in your own sex/masturbation life?"
Well, I answer, it not a "trick" it's actually a skill.
First I want privacy! Phones turned off, a towel placed on the bed and my Magic Wand vibrator has been fully charged. I chose a favorite dildo and place a bottle of Almond oil next to me. I begin with a vulva massage while scanning my sexual fantasy repertoire. Once I choose one, I begin with the vibe near but not on my clitoris. Next I do slow, very slow penetration matching my fantasy as I bring the vibe closer to my clitoris. Today it's a modified rape fantasy. A way too big penis slowly pushing into my way too tight little virginal vagina. Finally I will be fully penetrated by my beloved which can be "Daddy" or "Big Brother" or "Prince Charming" depending upon my mood.
My current favorite dildo has weight. I lay the oiled knob of this Obsidian 10 inch phallus just at my vaginal opening. As the vibe grazes my clitoris I squeeze and release my PC muscle allowing the weight of my dildo to press in just a tiny bit before I pull the muscle in tight again, pushing the knob out while moving the vibe closer to my clitoris again and again. Until I can no longer hold back and the dildo plunges in all the way up to the hilt.
Once full arousal is reached, I allow myself to get close to coming, but pull back and breathe deep, dropping back down. I repeat this pattern called "edging" for up to 30 minutes while remaining in fantasy mode. After several passes, I can no longer hold back. Finally letting go, I release all my sexual tension into a full body orgasm; laughing and howling and at times, even sobbing with ecstasy.
I ended by telling the writer that I really didn't expect the powers that be to approve of my personal masturbation technique. It's too subversive and threatening to Patriarchal as well as Matriarchal controls to maintain absolute power for the 1%. The writer promised to push for it's inclusion.
Following that, I was turned on and did what I had just written about. It was even better than usual except for a cramp in my left leg that caused me to orgasm sooner than I desired. Note to me: "OK Dodson, there's the motivation you've needed to leave your little slice of heaven and hit the street, park or Health Club, if you want to continue edging orgasms for at least thirty minutes. An hour or more would be even better."
Orgasm is the sudden discharge of accumulated sexual tension resulting in rhythmic muscular contractions in the pelvic region that produce intensely pleasurable sensations followed by rapid relaxation. Write Cheap Essay For Me Orgasm is also in part a psychological experience of pleasure and abandon, when the mind is focused solely on the personal experience. It is sometimes called climaxing or coming.
Here i am share a home page in this type of platform file explorer windows 10 you can learnd lots of things on the basis of new latest window explorer here you know everything that you can operate the browser easily.


text:
Photographer Takes Pictures at the Port of Los Angeles and Has Two FBI Agents Show Up at His House Asking Questions
Forums – iStockphoto Discussion – Two FBI agents just showed up at my door… (I think I'm being investigated) | iStockphoto.com
File this under more irrational reactionary police action against photographers. One of my Flickr friends, Hal Bergman, emailed me today to tell me about a recent run in he had with the FBI after photographing the Port of Los Angeles.
According to Bergman, he and a buddy were taking photos at the Port of Los Angeles when they were confronted by a security guard who told them that they could not take photographs of a Valero plant even from the public street. You can see some of the shots that they got that day on Flickr here.
Bergman didn't push the issue at the time and left his shoot. After leaving his shoot he was followed by a man in a pick up truck for a while.
Fast forward to this morning when Bergman says two men with badges show up at his door:
"So, I go to talk to them. The first one informs me he needs to ask me some questions about what I was doing in the port complex two weeks ago. The other one demands to see my driver's license. I politely decline, and he informs me that he already has all the information on it (I look, and sure enough, there is a photo of me on his clipboard along with god knows what else). He makes a crack about "wow, you're younger than you look in this photo" when he comments on my birthdate (gee, thanks). I decide to give him my ID.
We exchange cards. I give him my business card that says "Photographer" as well as my iStock card (for legitimacy), and he gives me his card that says "Detective, FBI Joint Terrorism Task Force". Yikes."
Personally it troubles me that the FBI would think that their best use of time would be to harass photographers out shooting industrial stuff. It would also seem that at a minimum the FBI used DMV records to track down Bergman and pulled his personal information for the crime of photography. Stuff like this worries me and makes me wonder if the FBI now isn't keeping some sort of file on Bergman that could impact him in other ways down the road.
I had a similar run in a few years back when Sheriffs in Oakland stopped me and a few friends while we were shooting in an industrial area of Oakland and demanded our drivers licenses and ran what I felt were illegal background checks on us.
Photographers who are documenting the American landscape should not be subjected to this kind of harassment.
Photography is not a crime.


text:
gigas is a valid word in this word list. For a definition, see the external dictionary links below.
The word "gigas" uses 5 letters: A G G I S.
No direct anagrams for gigas found in this word list.
Words formed by adding one letter before or after gigas (in bold), or to aggis in any order:
e - aggies h - haggis n - agings
Shorter words found within gigas:
ag ai ais as gag gags gas gig giga gigs is sag si
List shorter words within gigas, sorted by length
Words formed from any letters in gigas, plus an optional blank or existing letter
Try a search for gigas in these online resources (some words may not be found):
Wiktionary - OneLook Dictionaries - Merriam-Webster - Google Search
Each search will normally open in a new window.
List all words starting with gigas, words containing gigas or words ending with gigas
All words formed from gigas by changing one letter
Other words with the same letter pairs: gi ig ga as
Browse words starting with gigas by next letter
Previous word in list: gigantisms
Next word in list: gigaton
Some random words: bhakta wulfenite lesbian irk wyandotte ohed wrack
This is not a dictionary, it's a word game wordfinder.
- Help and FAQ - Examples - Home
Privacy and Cookies Policy - Share - © Copyright 2004-2018 Morewords.com - 22.444mS


text:
Titus-Will Toyota in Tacoma, Washington, has its own finance team that works with a network of lenders to find the best rate for the dealership's customers. TitusWillToyota.com also features a 30-second credit application tool on its finance page.
In addition to helping customers find car loans to finance their new or pre-owned vehicle purchases, Titus-Will Toyota offers customers a range of Toyota leasing programs. Leasing allows customers to drive a superior model for a lower monthly installment than they would pay for a loan and to upgrade to a new car more frequently, as leasing agreement terms are generally shorter.


text: So was anyone else bothered by the fact that now all of a sudden we will have to purchase At Bat again next season? This was not disclosed in the original description of At Bat - at least to my knowledge. Ever since the Playoffs update, we now have been notified that we will have have to purchase the App again next season! This to me sounds like false advertising since the original description never said that the app would only work for the 2008 season. Eric


text:
- gpiglet
- 4 years ago
- Wedding: October 2014
So we decided to hit vegas in August, ideally we would like to stay close to strip and have nice pool to chill.
Any one can recommend one for us?? I'm so excited!!!
So we decided to hit vegas in August, ideally we would like to stay close to strip and have nice pool to chill.
Any one can recommend one for us?? I'm so excited!!!
The Palms or the Wynn hotel are perfect!
Depends what your looking for. If you want cheap and cheerful on the strip you can't go wrong with the Luxor and New York new York both are great for what you pay.
If your looking for something a bit more high end the ceasers, bellagio or the Wynn are your best bets.
Enjoy vegas is amazing!!!
Palms is not on the strip.
I would stay at Cosmopolitan, Planet Hollywood, Venetian, or aria. I always feel that the Wynn is geared towards an older crowd but I never stayed there so I could be wrong.
I'd say Venetian, Cosmopolitan, Mandarin, or Vdara. It really depends what you're looking for in amenities. Some pools are more quiet than others since some have major pool parties. Also, would you want a casino in the hotel? Depending if you smoke or not, that may be an issue. If there is a casino the smell of smoke is a bit nauseating.
gpiglet: I usually stay at Monte Carlo. I like it bc it's affordable, nice, and in the middle of the strip
Whenever my friends and I go to Vegas, we almost always stay at the Marriott Grand Chateau. It's technically off the strip, but the strip is like a 2 minute walk away. There's no casino at the hotel, but you're directly across from the Planet Hollywood hotel and the City Center (Cosmopolitan, Aria, Vdara) is about a 10 minute walk. You can get a suite (it's pretty much a 2 bedroom apartment complete with a kitchen and dining area) for a great price.
The topic 'Vegas hotel for my stag!!! any recommendation?' is closed to new replies.


text:
Results: 6
Clamp-It is an adjustable craft tool holder designed for use by individuals with use of only one hand, arthritis, or fine motor or physical disabilities. Clamp-It is mounted on four suction cups, and can be used vertically or horizontally to hold an item in a fixed position. The clamp size can be changed by turning two wing nuts. DIMENSIONS: Maximum holding width is one inch.
--- "DO IT YOURSELF" ENTRY ------- PURPOSE: Device to hold thread and maintain tension on it to allow a person with use of one arm to crochet. Describes a wood stand with a box to hold the yarn or thread, and a system of buffers and levers to maintain tension on it and position the work in process; tension is released with a foot operated pedal. Includes photograph. COMMENTS: Designed by Bob Loughlin. For further information contact: Technical Aid to the Disabled, 227 Morrison Road, PO Box 108,
--- "DO IT YOURSELF" ENTRY ------- PURPOSE: Aid developed to allow a below-elbow amputee using a prosthetic hook to crochet. Device constructed from a plastic (Polyform) strip 32 by 2 cm bent in half at right angles with one half bent into an oval; and a strip of velcro. Describes how the device and the prosthetic hook used together anchor the thread and provide tension to facilitate crocheting. Includes photograph and drawings. COMMENTS: Author affiliated with Loma Linda University Medical Cent
Crochet Grips are crocheting aids that help control motion and provide a better grip for weak hands. The form-fitted grip, My-Grip, is applied to the crochet hook, heated, and molded to the fingers of individual users. SIZES: Large (11317) fits hook sizes I - L; Small (11318) fits hook sizes B - H and steel hooks 00 - 14.
The Kroh's Crochet Aid is a crocheting aid designed for use by individuals with multiple sclerosis, arthritis, or neurological or other disabilities which limit upper extremity strength, dexterity, or range of motion. This device consists of a Velcro band that wraps around the user's wrist or hand and can be adjusted for the proper amount of yarn tension. A ring attached to the band has a small slit for the yarn to pass through, keeping the yarn from slipping through the side. A second ring, whi
--- "DO IT YOURSELF" ENTRY ------- PURPOSE: Holder enables those with use of one hand to knit or crochet. Knitting needle or crochet hook is inserted into hardwood holder. Holder is held in place on table or other surface with suction feet. Includes photograph. SKILLS REQUIRED: Assembly. AUTHOR: New York University Bellevue Medical Center Institute of Physical Medicine and Rehabilitation TITLE: Self-Help Devices for Rehabilitation REF: Dubuque, Iowa: Wm C Brown: p 272 NARIC CALL NUMBER: R3360 PA
print close directions


text:
Do you know what Chromatic Browser is?
Today, there is no shortage of browser imitators trying to pass on as somewhat more enhanced and error-free versions of the original. Chromatic Browser is one such program that you should remove, because it is a cheap rip off of Google Chrome, one of the best web browsers used in every corner of the globe. Yet for some reason the developers think users should go in favor of Chromatic Browser. While, we at Spyware-techie.com recommend that you use your old browser, whichever it might be.
Chromatic Browser has a promotional website, but during testing we found that it cannot be downloaded from it. If you click the download button a "Coming soon!" message appears. However, the browser can be downloaded from other sources. It comes bundled with malicious software , such as MySafeProxy, SpeedChecker, and a few others. It must also be said that Chromatic Browser is very similar to BoBrowser and CrossBrowser. The developer of Chromatic Browser is a mystery as the browser's information section refers to the developers as Chromatic Authors. The browser itself is based on the Chromium open source project and other open source software. It actually looks the same as Google Chrome. So why not remove this mysterious browser and use Google Chrome instead? After all there is no substitute for the real thing.Chromatic Browser screenshot
Scroll down for full removal instructions
The strange thing about this browser is that it is supposed to be a better alternative to Chrome without its shortcomings. But it is actually based on the browser that the developers deem flawed in terms of privacy. And the website Chromatic.rocks is full of contradictions. In one instance claiming that Chrome is secure. Apart from the shortcut color scheme you could not tell Chromatic from Chrome apart. After installation the browsing history is copied from Chrome to Chromatic. The browser uses Re.search-webresults.com as its default search engine, but it redirects you to Search.yahoo.com when you search from something.
All in all, we are of the opinion that Chromatic Browser is not an alternative to Chrome. It is unreliable, since there is not information about its developers, and it comes bundled with malicious software. Its search engine is also unreliable since the Search.yahoo.com has been modified. Therefore, we recommend that you remove Chromatic Browser and use Chrome instead, since the problems that plague Chrome will surely be found on Chromatic as well.
Remove Chromatic Browser from your computer
Windows 8 and 8.1
- Open the Charm bar.
- Click Search, type uninstall program and open it.
- Find Chromatic Browser, and right-click on it.
- Click Uninstall.
Windows 7 and Vista
- Open the Start menu.
- Select Control Panel, and go to Uninstall a program.
- Find Chromatic Browser, and right-click on it.
- Click Uninstall.
Windows XP
- Click Start, go to the Control Panel.
- Open Add or remove programs.
- Find Chromatic Browser, and click Remove.
In non-techie terms:
Chromatic Browser is a potentially unwanted program that you can remove without any hesitation. It is based on the Chromium open source project. It is claimed that Chromatic Browser is a better alternative to Google Chrome, but the developers of this "gem" remain a mystery. Furthermore, Chromatic Browser comes bundled with malicious programs, so we do not recommend installing or using this browser.


text:
STEVEN CANYON SPECIAL EDITION DVD REVIEW IS UP!0 Comments Published November 4th, 2012 in At The Movies, Current News and Events
Very pleased to announce a new review of a project by independent producer John R. Ellis: The Steve Canyon Special Edition DVD! This 1958 television show starred the talented Dean Fredericks as the title character, and you can get some background on this terrific series HERE.
No Responses to "STEVEN CANYON SPECIAL EDITION DVD REVIEW IS UP!"
- No Comments
Posting Your Comment
Please Wait
Please Wait


text: Is there a tool that goes to a URL every 10 seconds. You may think this is autorefresh every 10 seconds, but that's not what I'm talking about. I am looking for a firefox addon or a tool that goes to a website every 10 seconds, like going to a youtube video every 10 seconds. I am not asking for autorefresh, because let's pretend I get redirected to a different page, then it would be refreshing the different page, not my youtube video. So to combat that problem, I am looking for a tool that juts directs to the youtube video. ya.


text: The largest adult personals network in The Marches is available for Free with absolutely no charge ever required. Personals Society is a free website which takes under a minute to join. Click a city within The Marches from the directory below or search profiles directly from the left side of your screen.


text:
George W. Bush sends Alabama kicker encouraging letter after loss to Auburn
Alabama kicker Cade Foster has received a lot of hate since missing three field goal attempts in his team's stunning loss to Auburn, but he has at least one fan: former President George W. Bush.
The 43rd president reportedly sent Foster a personalized letter encouraging him to press on through life's challenges.
"Dear Cade (#43), life has its setbacks. I know! However, you will be a stronger human with time. I wish you all the best. Sincerely, another 43, George Bush," the letter reads.
Foster posted a picture of the letter to his Twitter account Wednesday.
Foster was inundated with hate messages on the social media site missing two field goal attempts and having a third blocked in the Crimson Tide's Iron Bowl loss, which took away their shot at the national championship.
Fans reacted angrily to Foster on his Twitter account in the game's aftermath,with one telling him to "drink bleach" and another saying "Cade foster I'm gonna kill you and your family just FYI."
However, Foster also received support from his teammates and thousands of other fans. Alabama quarterback AJ McCarron posted on Twitter that "we win & lose as a team. If u blame this on 1 guy U aren't a true fan!"
Linebacker C.J. Mosley was even more emphatic with a tweet urging "fake" and "spoiled" fans to "stop sending threats to my teammates."
The Associated Press contributed to this report


text:
Makeup bag must-haves
Makeup bag must-haves
Most makeup bags are a mishmash of old favourites and one or two never-wear mistakes. However, updating and refreshing your look largely depends upon how well your basics are chosen. Many women are reluctant to spend money on makeup tools, but these can make or break your makeup application, and are as important as your cosmetics to get a refined and foolproof look. Most makeup now has a best-before date, so don't hang on to old products that won't do their job properly anymore. Anything that looks or smells "odd" should be thrown away immediately, as the contents have deteriorated. Look for a box with drawers to keep everything on hand and organized.
Your foundation is designed to even out your skin tone, rather than give colour. A perfectly matched foundation is the canvas for the rest of your makeup. Cream and liquid foundations are available.
It's a good idea to have two or three blushes in your basic makeup kit. At least one should be a neutral, cream blush for daytime wear, while the others can be more lively shades for evenings and dramatic makeup looks.
Every makeup bag should contain at least a couple of concealers. A green-based one will neutralize redness, while light-reflective concealers bounce away dark undereye circles. A concealer stick will cover blemishes and an olive pan-stick will help to mask shadows.
Sponge applicator
While many women are happy just using their fingers to blend in their base, using a wedge-shaped, soft sponge or latex applicator will give a better, more even finish. These can be bought in packs at any drugstore. Keep them scrupulously clean by washing in mild soap, or simply throw away after a week. Synthetic and natural sea sponges are available.
Blush brush
A soft, fat blush brush gives a pop of colour to the cheeks in a very natural-looking way that is hard to replicate with fingers. It can also be used to sweep powder over the face, but ensure you have tapped away any residual blush first.
Face powder is available in a wide range of shades and textures. However, a light, translucent powder, applied sparingly just to give a matte finish and prevent your foundation from streaking or running, is usually all that is required for a fresh "unclogged" look.
Page 1 of 2
Excerpted from 101 Beauty Tips: The Modern Woman's Complete Guide to Looking and Feeling Great by Jane Cunningham. Copyright 2007 Quantum Publishing Ltd. Published in North America by Firefly Books. All rights reserved. No part of this excerpt may be reproduced except with permission in writing from the publisher.
Tinted moisturizer
Part hydrating treatment, part cosmetic, a tinted moisturizer is perfect for a natural, luminous look. Lighter than full foundation, it gently tints the skin and moisturizes at the same time. Perfect for hot days or when skin is dry and dull.
Eye shadow palette
The joy of a colour palette is that it stops your makeup bag from getting filled up with lots of separate little single-colour containers. A well-chosen palette gives you a choice of colours to work with. Look out for refillable palettes so if one shade is used more than the others you can top it up. Eye shadow pencils, liquid eye shadows and cream shadows are also available.
Two mascaras: one black and one brown, and preferably waterproof for daytime or evening lashes. Block mascaras and liquid wand mascaras are available.
Eyeliners give the eyes definition. Depending upon your choice of eye shadow palette, a coordinating liner will liven up your eyes. Kohl eyeliners will give a bold look.
Lip balm
A lip balm is probably the most versatile item in your makeup bag. It can be used to soothe chapped lips, smooth unruly eyebrows or give sheen highlighting to the cheeks.
Lip gloss
A range of lip glosses in your favourite shades gives versatility and flexibility to your look. Pick two or three to have as staples.
More matte in consistency than glosses, lipsticks have more staying power and colour pigmentation. If you have a lip colour you love, buy more than one as lipsticks have a habit of being discontinued.
Eye shadow brush
An eye shadow brush should be blunt at the tip, soft and full. This helps with blending and even application. Choose natural fibres where possible.
Other equipment
A mid-brown brow liner will define your brows and help you create a perfect arch. Sparkling body gel may be used on your face, but not around the eyes. Block mascara must be dampened before use. Eyedrops can be used to make eyes sparkle. Tweezers are useful for plucking eyebrows. False eyelashes are fun accessories. Eyelash curlers can create beautifully upturned lashes. A small brush can be used to style eyebrows, and an eyebrow pencil will be needed if you need to draw these on. Lip brushes can be used for more intricate application of colour than a lipstick. A thin lip pencil is used for outlining and a thick lip pencil for filling in. Tissues are useful for blotting.
Page 2 of 2
Excerpted from 101 Beauty Tips: The Modern Woman's Complete Guide to Looking and Feeling Great by Jane Cunningham. Copyright 2007 Quantum Publishing Ltd. Published in North America by Firefly Books. All rights reserved. No part of this excerpt may be reproduced except with permission in writing from the publisher.


text:
'Middle-class families shouldn't pay higher taxes than millionaires and billionaires. That's pretty straightforward."
That's what President Barack Obama said in his White House speech Monday on deficit reduction. It was even more straightforward than he seemed to think. Not only should middle-class families pay less than millionaires and billionaires, but in fact they already do pay less than millionaires and billionaires. Much less.
Obama tried to blunt anticipated criticism of his remarks with a parenthetical: "This is not class warfare. It's math." But the actual math tells a very different story.
In 2009, about 237,000 individual income tax filers reported adjusted gross income of $1 million or more. Taken together, these filers — families and small businesses — made a grand total of $722 billion, and paid $178 billion of that in income taxes.
Their effective federal income tax rate was 24.6 percent, between three and four times the effective rate on middle-income families that pull in $50,000 to $75,000 per year.
This million-plus crowd — which makes up less than 0.2 percent of all taxpayers — made 10.6 percent of all income in 2009 and paid 20.5 percent of all individual income taxes.
To be sure, the wealthy can and should pay more in taxes than the poor. The point here is that they already do pay more — a lot more. So when we discuss tax increases on the wealthy, we aren't really talking about whether we should be letting "millionaires and billionaires" slide on their obligations to society.
We are really talking about how large their share of the tax burden has to become before liberals finally decide it's "fair."
For politicians, the answer to that question is based on what they decide to spend. "The rich" — and that means everyone making over $200,000 per year — will always be failing to pull their weight until they are covering the spread between what government takes in and what politicians dish out.
Unfortunately, America's top earners can never hope to keep up with politicians like Obama, who has just proposed an additional $447 billion in deficit spending.
In 2009, the earners Obama is targeting had $1.5 trillion in income after paying their federal income taxes and before paying taxes to states and municipalities.
Were Obama to seize every dime of that money, it would just barely cover the $1.3 trillion deficit he just ran in the fiscal year that ends next week. And of course, even a smaller seizure would have a crushing effect on the jobs that these earners create through directly through their small businesses or indirectly through their investments.
In order to make the tax hike more palatable, Obama referred to it as "tax reform." But the term "tax reform" was never meant as a euphemism for tax increases.
Tax reform is needed because lobbyists have successfully inserted hundreds of incentives into the tax code that lead individuals and corporations to engage in economy-stunting and otherwise irrational behavior.
Tax reform is needed because 58 percent of American tax filers (81 million) had to use paid preparers to do their individual income taxes in 2008, and 75 million had to consult the IRS itself.
If Obama was serious about tax reform, he would present a reform plan that isn't just a tax hike in disguise. And if he was serious about reducing the deficit, he would at least avoid presenting his tax hikes alongside massive new deficit spending proposals.
Columnist David Freddoso is The Washington Examiner online opinion editor.


text:
C025/4599 Rights Managed
530 pixels on longest edge, unwatermarked
Request/Download high-res file
Uncompressed file size: 36.0MB
Downloadable file size: 4.7MB
Please login to use the price calculator
Credit: GIRAND/BSIP/SCIENCE PHOTO LIBRARY
Release details: Model release not required. Property release not available.
Keywords: adult, close-up, crowded, dermatologic, dermatological, dermatology, dermatoses, dermatosis, detail, european, female, finger, fingers, hand, hands, human, many, medical, medicinal, medicine, one person, person, skin, skin condition, skin conditions, skin disease, skin diseases, verruca, wart, warts, woman
Licence fees: A licence fee will be charged for any media (low or high resolution) used in your project.


text:
Find a free baby turtle by looking in ponds or near the edge of lakes for young turtles that live there. Alternatively, adopt a baby turtle from someone who raises them. Beware, it is illegal in the U.S. to sell small turtles or give them away with a purchase.
According to the Humane Society, all turtles carry salmonella bacteria, which is dangerous for humans and can be deadly for small children and the elderly. For this reason, they do not recommend keeping turtles as pets, even those obtained from a pet shop. It is this risk that led to the 1975 ban on selling turtles in the U.S.
There are some animal adoption facilities that adopt out turtles that cannot be released into the wild, and there are some individuals who may want to give away their pet turtles. Allpaws.com is a site that matches adoptive pets such as turtles, cats, dogs and other animals with loving new owners. Tortoise.com features information about caring for turtles, and it offers a link to a list of places that offer turtles for adoption.
Baby turtles may be adorable, but they carry health risks to humans and require specialized care. Turtles can live for decades, so unless you are prepared to offer the time and care they need, you may want to consider a different pet or enjoy visiting the turtles at the local zoo.


text:
Glow-in-the-Dark Games
Date: January 19, 2018
Time: 7:30 pm - 8:30 pm
Kirk Family YMCA
Phone: 540-342-9622
Join us for this new series of fun and interactive programs that give you an opportunity to connect with other adults. Every six weeks we will offer a new program for you to enjoy!
Glow-in-the Dark Games
Unwind and start your weekend at the Y! Glow-in-the dark games are intense and active, get your adrenaline pumping and will bring some of your favorite games to a whole new level. Games will include dodgeball, volleyball and SPUD.
WHO: Adults ages 21 - 40
WHEN: January 12 - February 16
Fridays from 7:30 - 8:30 pm
COST: Members: FREE, Non-members: $3


text:
Meal Type
Featured Videos
Featured Content
Featured Brand Sites
Featured Brand Sites
Product By Category
Tools & Info
Cooking Tips
Healthy Living
Your Kids
Recipe Ideas
food&family Magazine
8 servings
Read MoreRead Less
Tap or click steps to mark as complete
Serve with your favorite steamed vegetable.
Substitute a serrano chile or canned chipotle pepper in adobo sauce for the jalapeño pepper.
Substitute a 12-cup fluted tube pan for the casserole dish. Spoon prepared Dinner mixture into prepared pan. Do not add remaining crumb topping. Bake as directed. Let stand 10 min. Unmold onto plate; sprinkle with crumb topping.
* Nutrition information is estimated based on the ingredients and cooking instructions as described in each recipe and is intended to be used for informational purposes only. Please note that nutrition details may vary based on methods of preparation, origin and freshness of ingredients used.


text: Digital Who Will Rescue the Chilean Miners from Super Junior? By David Cohen|October 15, 2010Share By David Cohen|October 15, 2010Share The rescued Chilean miners may have prompted huge usage upticks for media outlets like CNN.com, msnbc.com, and Univision Interactive Media, but the thrilling tale was only good for second place on the Top 10 Most Tweeted Brands list, created by AdAge.com and social-media trend-analytics service What the Trend, as the miners were topped by South Korean boy band Super Junior. How does the Top 10 Most Tweeted Brands list work? From the Notes section at the bottom of the AdAge.com post: We broadly define "brands" to include major marketers (e.g., Apple) and branded products (e.g., iPad), as well as celebrity and entertainment brands (e.g., Lady Gaga, American Idol). Ad Age works with WTT to consolidate multiple threads of brand chatter (e.g., Apple, iPad, iTampon, Apple Tablet) into one position on the chart when it's clear that related Twitter conversations are basically all about the same topic, even if they use different keywords. The rest of the list, following Super Junior and the Chilean minors: Nobel Prize, Twitter, David Arquette-Courtney Cox, NFL, BET Hip Hop Awards, MLB, X-Factor, and The Simpsons. Share http://adweek.it/2kAAtxn copy Adweek Adweek


text:
Philip was discharged from King Edward VII Hospital in central London yesterday after spending five days there having treatment for a bladder infection.
A spokesman for Buckingham Palace would only say that he would be spending the day ''privately''.
He said yesterday: ''The Duke of Edinburgh continues to make a good recovery and he will continue his convalescence at home.''
The Duke, who is usually known for being fighting fit for his age, previously suffered a health scare over Christmas when he received treatment for a blocked coronary artery.
Then the Duke was back carrying out engagements within a matter of weeks and in his grandson Prince Harry said the operation had given him ''a new spurt of life''.
Yesterday he was already showing signs of his acerbic wit by answering one reporter who asked him if he was feeling better: ''Well, I wouldn't be coming out if I wasn't.''
Philip received a number of visitors during his hospital stay, including his grandsons, the Duke of Cambridge and Prince Harry who paid a short, private visit on Friday.
William visited his grandfather while on leave from his RAF Search and Rescue duties.
Harry, meanwhile, was spending the week since the Diamond Jubilee celebrations on pre-deployment training at Wattisham in Suffolk.
The Queen, the Duke of York, the Earl and Countess of Wessex and their children, Louise and James also went to see him during his stay.
Philip has been planning to celebrate his birthday privately and is not due to attend his next scheduled engagement until Tuesday, when the Queen hosts a garden party at the Sandringham Estate to mark her Diamond Jubilee.
It is hoped her husband will be by her side at her Norfolk retreat if he is feeling strong enough following his discharge from hospital.
It is also hoped he will be able to accompany her to the East Midlands on Wednesday for a two-day visit as part of the Queen's Jubilee tour of the UK.
Philip's admission to hospital meant he was forced to miss some of the Jubilee celebrations this week.
He spent Sunday braving the elements for the Thames River Pageant, which doctors suggested might have exacerbated his condition if he did not make enough visits to the toilet.
The King's Troop Royal Horse Artillery will fire a salute in London's Hyde Park to mark Philip's birthday.
The salute is fired every year to herald the occasion and the event is open to the public but not customarily attended by members of the Royal Family.
Two gun salutes will be fired tomorrow to mark the Duke's birthday.
The King's Troop's 41-gun salute in Hyde Park will be accompanied by a 62-gun tribute by the Honourable Artillery Company at the Tower of London, both at midday.


text:
Okay so I've decided that the month of September is going to be the first month I complete a financial challenge. Today marks the start of the 'No Take-Out Challenge'.
I've got some good reasons for this, one being a financial one of course. Take-out for us can range anywhere from $20 at a fast food joint to $60+ at a chain restaurant. And that's not with apps or drinks or anything – just a meal and soda or juice.
For $50 I can get steaks, potatoes, veggies, a loaf of fresh bread, dessert, and still have money left over. And we don't eat like that every day (hardly ever, actually).
We're definitely a meat and potatoes kind of family, and my daughter is kind of strangely addicted to asparagus. Chicken and asparagus is her favorite meal. (She loves hummus too – my 4 year old connoisseur!)
So in an attempt to not only save money, but help expand her palate, teach her how to cook, and eat healthier in this house – we're fasting from take-out (actually, eating out entirely – in restaurant or not) for the month.
Only one tiny exception: I'm on a work trip for a few days and without a kitchen (or being with the family), not eating out is going to be pretty much impossible. But it's a work trip, so that's kind of different.
Anyway… I'd love to have you join my challenge, and let me know how you're doing. I'll be posting recipes we try, and keeping you up to date on how much I spent on food for the three of us at the grocery store that week. Menus and all.
My GOAL is to spend less than $500 at the grocery store for the month, and with the exception of my work trip, not eating out at all.
Are you in?