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A study in balances, Cader's body of work exists between presence and absence, substance and surface, the part and the whole. Expanse of white on paper or unmarked canvas appear frequently in his work, which almost always rejects the rectangular frame, quietly dissenting with the traditional Western artistic norms. And with this protest Cader not only questions the ownership of the painted landscape but that of the land itself. Reclaiming the practice of landscape painting as a site for identity, Cader imparts a unique personal perspective on what has been largely a rigid artistic tradition. Pushing past the tyranny of a single viewpoint, he moves toward a constellation of perspectives – a kaleidoscopic view that leaves room for interpretation, uncertainty, and a shifting, but ever-present, relationship with the land.
Muhanned Cader
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Friday, August 12, 2011
Don't forget to sign-up for Book Blogger Appreciation Week and nominate your favorite blogs/books!
Welcome to the NEW Book Blogger Hop!
Are you a book blogger? Are you a reader? Then welcome to the place where all of us connect over the weekend and chat about books!
Not sure what a book blogger is and if you are one? Do you have a blog? Do you blog about books? Do you write book reviews on your blog? Do you rave about books and authors on your blog? Is your blog content primarily about books? Then you are most likely considered a book blogger!
How it Works
As long as you meet the qualifications of a book blogger, you may add your book blog link into the linky list below. But before you do that, there are a few requirements. Read up, to save yourself a headache with the linky!
1. Before you add your link, you must post about the Hop on your blog and link directly back to THIS POST (not just my domain, but the direct post for this Hop). The linky is going to review the link that you enter in your submission, looking for a link to this post on your blog. If it doesn't find one, your link will not be approved. This is called back linking and I had to institute it because people were taking advantage of the Hop and getting some free advertising without promoting the Hop themselves. You can read more about this here.
2. While you are creating your post, answer the following question (there's a new prompt each week)!
"Let's talk crazy book titles! Highlight one or two (or as many as you like!) titles in your personal collection that have the most interesting titles! If you can't find any, feel free to find one on the internet!"
I chose another book from my collection.
Until Forever
by Darlene Shortridge (Goodreads Author)
It was something she would never forgive herself for…
It wasn't until lunchtime that Jessi remembered to call home. No answer. She tried calling several times while she ate her lunch. Still no answer. She closed her eyes and rested her arms and head on her desk. She breathed deeply, wishing she had remembered to call earlier.
Until Forever is a story of a young family that is torn apart by the devastating effects of alcoholism. Can healing take place in a relationship when an unforgivable act is committed? Will Jessi's pain and Mark's guilt keep them apart forever, or will unforeseen circumstances bind them together?
Paperback, 270 pages
Published January 25th 2011 by Tate Publishing & Enterprises
15 comments:
THE EARTH, MY BUTT AND OTHER BIG ROUND THINGS BY CAROLYN MACKLER sounds good. Read whole blurb. Very interesting.ReplyDelete
That is a title to grab attention. :)ReplyDelete
have a good weekend
Wow! That is an insanely long title!ReplyDelete
Here's my Friday Hops
Have a GREAT weekend!
Old Follower :)
That is a funny title! Thanks for stopping by my blog!ReplyDelete
Rumana @ Relook the Book
Hey. Thanks for stopping by. I enjoyed checking out your blog as well. The title you found for this weeks question did sound like a fun book. I love wacky titles. See you soon. Keep it shiny!ReplyDelete
That title is hilarious, I hadn't seen it before. Thanks for taking the time to stop by my blog!ReplyDelete
I would so pick up that book just because of the title. I love it. made me LOL. :DReplyDelete
Thanks for visiting my blog. I'm now following you.:D
Lol. That is a great title! Thanks for stopping by!ReplyDelete
That's a great title! Thanks for visiting my blog.ReplyDelete
Best wishes
Haha! Cute title. Thanks for following, following back.ReplyDelete
Hopping through and now following, too! This book was an awesome title and sounds hilarious to boot! :):)ReplyDelete
Take care & happy reading,
Ms. C
Thanks for following me! I'm following you too. That is a strange titleReplyDelete
Thanks for stopping by my blog. Happy reading!ReplyDelete
I enjoyed this book it was on the banned book list so I read it and it was actually very enjoyable. Thanks for stopping by. LisaReplyDelete
Lisa, I had no idea it was every on a banned list. Maybe it was because the author was only fifteen when she wrote it. It may have had adult content and they just waited until she turned legal age. Just guessing. I just thought the title was amusing. Sorry if it has offended anyone. I decided to share another title from my collection ofReplyDelete
to-be-read books.
It's Time To Read Mamaw

subset: commoncrawl


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MARION, Ala. - LaGrange closed out its regular schedule with a split of a non-conference doubleheader with Judson. The Panthers (15-15) rallied to take the first game 5-4 in 8 innings before Judson came back to take the second game 5-3.
Game 1
LC overcame a 3-0 deficit to win the opener. Taylor Long's two-run home run in the fifth cut Judson's lead to 3-2. In the sixth, Sydney Hodorff's two-out RBI single scored pinch-runner Carolyn Harkness with the tying run. The Panthers pushed across two runs in the top of the eighth. Long scored the go-ahead run on Hodorff's sacrifice fly. Haley Coleman's two-out hit plated Brittany Todd to up the lead to 5-3. The Eagles got a run back in its half of the eighth, but Natalie Glass (1-0) retired the last two batters to secure the win. Glass pitched the final 3-2/3 innings, allowing the unearned run on two hits. LC finished with 11 hits as Todd was a perfect 4-for-4 with two doubles.
Game 2
Long led off the game with her second home run of the day to give the Panthers a quick 1-0 lead. Michaela Keel added an RBI single to put LC up 2-0 after an inning. Long drove in McKenzie Brunel with a run-scoring double in the fourth to up the Panthers' lead to 3-0. Judson came back with four runs in its half of the fourth. The Eagles needed only one hit and took advantage of four Panther errors in the inning. Judson added an insurance run in the fifth to make it 5-3. Payton Thomas (6-6) took the loss, allowing four runs, only one earned. Long and Brunel each had two hits, while Kelsey Dietz added a double.
The Panthers play at Huntingdon in the first round of the USA South Tournament. The best of three series begins with a doubleheader Friday, with the if necessary game Saturday.


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It's not just foreign companies that sell goods in China who should seek protection for their intellectual property.
There is a common misconception that if a business manufactures in China without selling goods in China, it doesn't need IP protection in China.
When you place your brand on goods, manufactured in China, you are using your trade mark in China. If you don't register your intellectual property – including trade marks, patents, copyright and domain names – someone else could register your IP first.
There are serious risks for manufacturers who don't register their IP in China:
- you can fall victim to people or companies who register your trade marks in China before you do. They may then be asked you to buy the trade mark back to continue manufacturing
- if another person or company owns your trade mark in China, your manufactured goods can be seized at the border by customs, as suspected counterfeit goods
- you can be sued for infringement by the owner of the trade mark in China
- other people could set up websites in China using your brand, trading or domain name, causing confusion in the market
- this may mean that you may not be able to secure patent protection, and you will lose the opportunity to license your IP and generate revenue.
These problems can have a severe impact on your ability to operate in China and can be very expensive and time-consuming to resolve.
The best thing to do is register your patent, trade mark, copyright and domain in China before you engage with manufactures.


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I hope everyone had a good Patricks day, I went out to a bar with some friends, got drunk, drunker than I expected but it was fun enough. Didn't feel great on sunday though, felt kinda sick. I think my days of drinking without hangovers are coming to an end. First time I felt pretty crappy after drinking. Normally I'm tired but thats it. Seems to be the end of an era. Still I had fun seeing friends and all that. If the hangovers increase in severity I may give up drinking. I don't think it'd be worth it to be quite honest. I suppose I'll worry about that another day.
I'm getting closer to the end of college, two months left. Thats it. Two months and I will have finished my exams (and assuming I pass) I will have a degree. Yay? Hopefully after that I'll be starting a masters degree in Creative Writing. After that year, I have no idea what I'll do. I always said I'd get a hdip, then teach, but I don't know if I want to teach as a stop gap job. I suppose there is no rush or worry there. There's still over a year to go so no use panicking. So much can happen in a few moments, never mind a year.
Speaking of years, it's one month to the one year anniversary of this blog. I'll have to plan something for it. Do something awesome.
Anyway, on with the show!
A Pill A Day.
He counted out the pills, checking and double checking. It was important to get the dosage right. Once he was sure he had exactly twenty, he began taking them. First the five dark blue, then the three red, then the four light blue, two pinks and finally, the last 6 yellows. He washed each grouping down with a gulp of water. Once they were consumed, he began packing away the boxes. It was an annoying daily ritual, but an important one. Once the pills were put away, he took out his vitamins, only three of those at least, grouped together to form massive doses. He didn't have to take them, but he figured it couldn't hurt. It was almost ten years now that he was taking those pills, and every day he counted them out carefully, just to be sure. First individually according to colour, then in total. It hadn't steered him wrong yet. His nieces and nephews, they were more cavalier about the whole thing, their parents gave them their pills. He wondered if, when they were old enough to count them themselves, would they be as careful? The advertisements showcasing the dangers of miscounting, of taking one less or one more had pretty much stopped. Occasionally you would spy a poster, faded and worn from the sun and rain but still clinging to the wall it was glued to. The television didn't show pictures of the deaths, the overdoses, the diseases, not anymore. He never really understood why the order was so important, they were going in on an empty stomach, before breakfast, so surely they would all just jumble up together in his stomach. But it didn't matter that he didn't understand it, it only mattered that he followed it.
With the pills taken and cleared away, he began to make breakfast, just a cereal, drenched in cold milk. He ate slowly, enjoying the food. He liked living alone, the solitude it afforded him. His parents were getting antsy, as were his siblings, he should find someone, settle down. He wasn't worried though, he was still young, only twenty eight. Sure he'd had relationships and enjoyed them, but it was nice, having some time for yourself. His housemates had been moved elsewhere, job relocation so he had the place to himself until new ones moved in, probably only another week or so. Even when the house was full, he enjoyed being alone in his room, it was relaxing. He picked up his bowl and drank the dregs of milk, draining them from the bowl,. His mother always gave out to him for doing it as a child, but it never seemed to stop him. He put the empty bowl in the sink, a benefit of being alone, no one to nag you about the dishes, then began to get ready for work.
He enjoyed working, it was pleasant enough work and there were worse jobs. Though there were better jobs out there, he didn't mind too much, after all, he was a cog and every cog needed to be working or the entire machine could grind to a halt. He knew he wasn't that important, but it could be nice to pretend.
The work day went by pretty fast and he was feeling pleasantly tired when he left for the day. He still had to do his hourly workout, so on the way home, he stopped into the gym, registering his name on the way in and out, logging what exercises he did. He was tired, more tired than normal, but he pushed himself harder to complete the run. He preferred running outside, but they were putting a stop to that now. Apparently people had been lying about their exercise times, about how much they did. When people checked into the gym they couldn't lie. He still ran outside occasionally, but he didn't need to log it, it went into his extra activity file.
His life was mundane, but he enjoyed it. He never wanted to travel or see the world. He was happy with his family and friends. Why would he need to travel? Exotic foods were interesting distractions, but he did not need to leave the country to sample them, everything was available here for him. He met many interesting and different people all the time, he was constantly exposed to other cultures. Everything he could ever want was at his finger tips and he was happy. Sure there were bad days, but everyone had those. Days where things were dull and boring and pointless, but they faded away, they always did. The truth was he was happy and so was everyone else.
When he got home, he was too tired to do much of anything so he decided to go to bed. He wanted to sleep, but felt a little guilty for it, so instead, he dozed and watched the television. It was nice, peaceful, the gentle lull of sounds in the background, the warm, comfortable bed.
He jerked awake, the TV was suddenly louder, it was dark outside, the room was bathed in red light from the TV screen. An urgent bulletin. The music was loud, too loud. It made his head hurt, the light made his eyes ache. He picked up the remote and tried to turn it off. Nothing. He looked at the clock, its blue numbers glowing faintly. It was half nine. This wasn't the news. He felt faint stirrings of panic rising. Something big must have happened. Another terrorist attack? That was usually the case, though he could only recall one other urgent bulletin. He had been seven, five nearby towns had been bombed, they had been warned to stay indoors but he and his family went outside to look anyway and all around them they could see thick plumes of smoke. People they had known and cared about, killed while working, while shopping, while visiting relatives. The music reached it's crescendo, then the screen switched to a reporter. She was pretty, maybe twenty five, her eyes were wide and shining with fear. Her long black hair framed her face, pouring down over her shoulders. She was wearing make up but it couldn't hide how pale she looked. He sat up in bed, fighting with the duvet to get it off him, he was too hot. She began to speak, he squinted at the screen, there was no sound, someone had cut it off. Someone must have said something to her off screen, she looked to her left, then shook her head Writing started scrolling across the bottom. He tried to make it out, his eyes were tired, sore.
Words jumped out at him, pills, poison, sabotage. It took a few moments for his brain to kick in, to sort out the jumble. They were saying the pills had been sabotaged. That they had been poisoned. Her voice clicked in suddenly, filling the room, making him jump, "-Terrorists have issued a statement, alleging that they have sabotaged shipments of Health Pills. The statement is unconfirmed but state health agencies are encouraging people to dispose of their pills at the nearest Centre for Health and collect new dosages. Again, they are asking people not to panic at this unconfirmed statement. They have made no demands." His heart was thudding heavily, she was frightened, so was he, no one knew much about the terrorists, only that they wanted to destroy the new way of life.
He tried to calm himself but it wasn't working, urgent bulletins were only used in dire situations. He had been sheltered from most of them, his parents told him when they were children were was usually one at least once a week. He threw his legs over the side of the bed, he was sore all over. He stood, then fall back into bed, his legs cramping uncontrollably. He grit his teeth, face screwing up, trying not to scream in agony. Somewhere he could hear a phone ringing. Sweat poured down his face, soaking his pyjamas, his sheets. The cramps eventually subsided, leaving him lying on the bed, gasping for breath. The phone was ringing again, he looked at it, it seemed so far away. Cramps wracked his body again, he gave in and begun to scream.


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Research Proves Brides-To-Be Are Overspending On This One Thing
If you've ever watched "The Wedding Planner" or anything on TLC, then you know weddings are infamously expensive to organize. There are unforeseen costs everywhere from the place settings to the flower arrangements to the matching miniature bowties (or is that just dog weddings?).
While no one expects a fabulous wedding to come cheap, there is one thing brides are paying way too much for. According to research conducted by Edited, the most overpriced wedding item is one that many also consider to be the most important: the wedding dress.
As Business Insider points out, retailers -- like the "Say Yes To the Dress" mega store, Kleinfeld Bridal -- charge brides-to-be about 3.9 times as much for wedding gowns as they would for similar white dresses. That's a huge markup for a dress that you'll likely only wear for one day.
But the markup madness doesn't stop there. Oh no... Bridesmaids' dresses are sold for nearly twice the price of similarly ugly dresses. Yikes.
So what's the lesson to be learned here? Don't let retailers trick you into spending way more than you want to. Better yet, avoid saying the word "wedding" altogether. Buy a regular dress, a regular cake and a regular ring and you may be surprised by how much money you save.
Citations: This Is How Much Wedding-Dress Prices Are Marked Up By Retailers (Refinery29)


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Phencyclidine (PCP) and ketamine are dissociative anesthetics capable of inducing analgesia, psychomimetic behavior, and a catatonic state of unconsciousness. Despite broad similarities, there are notable differences between the clinical actions of ketamine and PCP. Ketamine has a lower incidence of adverse effects and generally produces greater CNS depression than PCP. Both noncompetitively inhibit NMDA receptors, yet there is little evidence that these drugs affect GABAA receptors, the primary target of most anesthetics. α6β2/3δ receptors are subtypes of the GABAA receptor family and are abundantly expressed in granular neurons within the adult cerebellum. Here, using an oocyte expression system, we show that at anesthetically relevant concentrations, ketamine, but not PCP, modulates α6β2δ and α6β3δ receptors. Additionally, at higher concentrations, ketamine directly activates these GABAA receptors. Comparatively, dizocilpine (MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate]), a potent noncompetitive antagonist of NMDA receptors that is structurally unrelated to PCP, did not produce any effect on α6β2δ receptors. Of the recombinant GABAA receptor subtypes examined (α1β2, α1β2γ2, α1β2δ, α4β2γ2, α4β2δ, α6β2γ2, α6β2δ, and α6β3δ), the actions of ketamine were unique to α6β2δ and α6β3δ receptors. In dissociated granule neurons and cerebellar slice recordings, ketamine potentiated the GABAergic conductance arising from α6-containing GABAA receptors, whereas PCP showed no effect. Furthermore, ketamine potentiation was absent in cerebellar granule neurons from transgenic functionally null α6−/− and δ−/−mice. These findings suggest that the higher CNS depressant level achieved by ketamine may be the result of its selective actions on α6β2/3δ receptors.
- ketamine
- α6β2/3δ GABAA receptors
- granule neurons
- slice recording
- cerebellum
- transgenic mice
- tonic conductance
Ketamine and phencyclidine (PCP) are chemical congeners belonging to a class of pharmacological agents known as dissociative anesthetics. These drugs produce similar clinical actions, although the impact of ketamine on CNS functioning differs from that of PCP and its analogues (Greifenstein et al., 1958; Johnstone et al., 1959; Collins et al., 1960; Chen, 1965; Domino et al., 1965; Corssen and Domino, 1966). Ketamine has a lower potency, a shorter duration of action, a faster rate of induction, results in a lower incidence of adverse emergence reactions, and is an effective anesthetic across different animal species (PCP shows species selectivity). Furthermore, ketamine lacks the convulsive side effects that PCP produces at higher doses. Collectively, these studies suggest that ketamine possesses a higher CNS depressant activity and produces a better quality of anesthesia than PCP (McCarthy et al., 1965).
It has been established that dissociative anesthetics are noncompetitive inhibitors of NMDA excitatory ligand-gated ion channels (Lodge and Anis, 1982; Anis et al., 1983; MacDonald et al., 1987, 1991; ffrench-Mullen and Rogawski, 1989; Rogawski and Wenk, 2003). These drugs also modulate the activity of nicotinic acetylcholine, muscarinic, and opioid receptors, and voltage-gated ion channels, but at significantly higher concentrations than needed to block NMDA receptors (Finck and Ngai, 1982; Ramoa et al., 1990; Hustveit et al., 1995; Hirota and Lambert, 1996; Scheller et al., 1996; Brau et al., 1997; Furuya et al., 1999; Flood and Krasowski, 2000; Yamakura et al., 2000; Schnoebel et al., 2005). Studies conducted at low doses of ketamine suggest that the inhibition of NMDA receptors results in its psychomimetic and analgesic properties (Tricklebank et al., 1987; Klepstad et al., 1990; Oye et al., 1992). However, the mechanism by which ketamine produces a higher CNS depression than PCP at high doses has remained an enigma (Kress, 1997).
GABAA receptors are the prime target for the hypnotic class of anesthetic compounds (Franks and Lieb, 1994; Macdonald and Olsen, 1994). A number of studies also implicated GABAA receptors in ketamine anesthesia (Scholfield, 1980; Gage and Robertson, 1985; Bennett et al., 1988; Irifune et al., 1992, 2000; Lin et al., 1992; Wakasugi et al., 1999), although these provided either indirect evidence for the action of ketamine on GABAA receptors, or the concentration of ketamine used was significantly higher than the anesthetically relevant concentration.
The GABAA receptor subtypes α6β2/3δ are expressed at high levels exclusively within mature cerebellar granule neurons (Laurie et al., 1992; Wisden et al., 1996) and show high sensitivity to GABA (Saxena and Macdonald, 1996; Storustovu and Ebert, 2006; Hadley and Amin, 2007).
We investigated the effects of ketamine, PCP, and MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate] (a potent noncompetitive inhibitor of NMDA receptor) on α6- and δ-containing GABAA receptors. We show that ketamine, but not PCP or MK-801, within an anesthetically relevant concentration range, potentiated the GABA current arising from α6- and δ-containing GABAA receptors in oocytes, dissociated granule neurons, and cerebellar slices isolated from rodents. The potential role of GABAA α6β2/3δ receptors in ketamine anesthesia is discussed.
Materials and Methods
cRNA quantitation and oocyte injection.
Xenopus laevis frogs were anesthetized by bathing in a solution containing 0.1% MS-222 (tricaine methane sulfonate; Sigma-Aldrich). Before ovariectomy, the toe of the frog was pinched to assess the state of anesthesia. After surgery, the frog was killed by decapitation according to the protocol approved by the Institutional Animal Care and Use Committee. Oocyte preparation, in vitro transcription of complementary rat RNA (cRNA), and the drug perfusion system have been described previously (Walters et al., 2000). The quality of cRNA was determined by electrophoresis of the cRNA on a 1% formaldehyde-containing agarose gel and then quantified spectrophotometrically. Two to four preparations of cRNAs were tested for each subunit. The cRNA mixture (in diethylpyrocarbonate-treated water) was injected into Xenopus laevis oocytes using a Picospritzer II (General Valve Corporation). The ratio of the coinjected subunits α:β:γ/δ was1:1:1.8 except for expression of α6β2δ receptors in the low-affinity state where the amount of β2 was relatively decreased to one-tenth (1:0.1:1.8) (Hadley and Amin, 2007). Five to ten nanograms of α6, β2, and δ cRNA mixture per oocyte was used for the ketamine studies.
Oocytes electrophysiology.
Recording microelectrodes were fabricated with a Narishige PP-83 puller filled with 3 m KCl, and had input resistances of 0.7–1.6 MΩ. A Turbo TEC-05 (NPI Electronic) two-electrode voltage-clamp amplifier (Adams and List) was used to record the currents. In all oocyte recordings, membrane potential was clamped to −70 mV. Data were visualized on a Gould TA-240 chart recorder during the experiments and stored online using Pulse Fit (HEKA).
Cerebellar preparation.
Sprague Dawley rats, C57BL/6 mice, δ−/−mice (provided by G. Homanics, University of Pittsburgh, Pittsburgh, PA) (Mihalek et al., 1999), and α6−/−mice [provided by W. Wisden (University of Aberdeen, Aberdeen, UK) and E. Korpi (University of Turku, Turku, Finland)] (Jones et al., 1997) were reared in the central animal facilities of the University of Mainz and the University of Leipzig and transferred to the local adaptation facilities several days before experiments. All procedures followed the German guidelines for animal care. Male animals between postnatal day 20 (P20) and P48 were decapitated and their brains rapidly removed into ice-cold carboxygenated (5% CO2/95% O2) cutting solution (see below, Solutions and drugs). The cerebellar vermis was trimmed and then glued to the stage of an IntegraSlice 7550MM (cyanoacrylate glue; Campden Instruments). Sagittal slices of ∼200 or ∼500 μm thickness were prepared and maintained in a continuously carboxygenated perfusion chamber at room temperature (21°C) containing artificial CSF (ACSF) (see below, Solutions and drugs) for 1 h. Single slices (∼200 μm) were transferred to a recording chamber (RC-26GLP; Warner Instruments), placed under an upright fixed stage microscope (Axioskop FS; Zeiss), and perfused at ∼4 ml/min with carboxygenated ACSF. Using Nomarski optics and an enhanced infrared video system (Luigs and Neumann), whole-cell patch-clamp recordings of individual cells within the second or third layer of the inner granule cell area were obtained. To account for possible regional differences in the expression of the α6-subunit (Mellor et al., 1998), we restricted slice studies to lobes VIII to X of the cerebellar cortex.
Preparation of dissociated granule neurons.
To obtain dissociated cells, slices of ∼500 μm thickness were transferred to preheated cutting solution (35°C, bubbled with carbogen) supplemented with 0.5–1 mg/ml pronase. After 20–40 min, slices were transferred to ice-cold HEPES-buffered cutting solution and carefully triturated with fire-polished glass pipettes of decreasing tip diameter. An aliquot (∼ 20 μl) of dissociated-cell suspension was plated onto poly-l-lysine-coated coverslips and allowed to settle in ACSF for ∼20 min before recordings.
Granule neurons electrophysiology.
Whole-cell recordings were obtained with thick-walled borosilicate electrodes (1.5 mm outer diameter, 0.5 mm inner diameter; 8–12 MΩ resistances; Vitrex 11394; Science Products) using standard procedures (Hamill et al., 1981). Recordings were routinely filtered at 1 kHz, amplified and recorded on a personal computer using an EPC-9 amplifier and Pulse 8 software (HEKA). Current responses were recorded under voltage-clamp conditions at a holding potential of −60 mV and series resistances within 20–35 MΩ were compensated (70–80%; Pulse software; HEKA). Adequate clamp conditions (error <5 mV) (Rossi et al., 1994) were verified by the fast activation of routinely recorded voltage-gated Na+ currents (300 μs time to peak).
Solutions and drugs.
For oocyte recording, the extracellular oocyte ringer (OR2) solution contained (in mm) 83.5 NaCl, 2.5 KCl, 10 HEPES, 1 CaCl2, and 1 MgCl2, pH 7.5. For cerebellar recording, the ACSF was bubbled with carbogen and contained (in mm) 135 NaCl, 5 KCl, 2 CaCl2, 1 MgCl2, 10 glucose, 30 Na2HCO3, and 1.5 NaHPO4, pH 7.4. For tissue preparation and cutting, the solution contained (in mm) 60 NaCl, 140 sucrose, 5 KCl, 0.3 CaCl2, 6 MgCl2, 10 glucose, 30 Na2HCO3, and 1.5 NaHPO4, pH 7.4. For cell dissociation, Na2HCO3 and NaHPO4 were replaced by HEPES. For dissociated granule neurons or slice recordings, drugs were diluted in (in mm) 150 NaCl, 5 KCl, 2 CaCl2, 1 MgCl2, 10 glucose, and 10 HEPES, with pH 7.4 (NaOH). All solutions were adjusted to ∼305 mOsmol with sucrose or H2O. Patch electrodes were filled with (in mm) 125 CsCl, 2 MgCl2, 10 EGTA, 10 tetra-ethyl-ammonium chloride (TEA), 4–5 Na2-ATP, 0.5 Na-GTP, and 10 HEPES, pH 7.3 (CsOH), adjusted to ∼295 mOsmol with sucrose or H2O.
All solutions were made from analytical grade salts. TEA, picrotoxinin, furosemide, ketamine, and bicuculline were purchased from Sigma-Aldrich. For some experiments, a premade ketamine solution (ketalar, 100 mg/ml) was used without noticeable differences. GABA was diluted from a 100 mm fresh or frozen stock solution to the final concentrations, furosemide from a 100 mm stock solution in 200 mm NaOH, picrotoxinin from a 10 mm stock solution in ethanol, bicucculine from a 100 mm in DMSO, and ketamine from a 100 mm in water. DMSO or ethanol at their highest concentrations used (0.1 and 0.5%, respectively, for oocytes) did not alter the responses. For oocyte recordings, stock solutions were diluted in the recording OR2 solution.
For slice recordings, drugs were applied focally using a gravity-fed Y-tube system described previously (Hevers and Luddens, 2002). In short, a 5-mm-long fused-silica tube (MicroFil; World Precision Instruments) was inserted into a sharply bent Teflon tube connected on one side to a vacuum source and on the other to the drug reservoirs. Focal drug application was initiated by interrupting the vacuum line with the tip, positioned in close proximity (<50 μm) to the cell, allowing a solution exchange within ∼150 ms. For dissociated cells, a parallel three-barrel system was used in which the middle barrel contained buffer and the outside barrels contained different drugs. The middle barrel outlet was positioned in close proximity to the cells and switched to one of the drug lines with a stepping motor (Warner SF-77B; Warner Instruments) or a piezo translator (Burleigh LSS-3200; NPI Electronic).
Data analysis.
We estimated the EC50 value for GABA and ketamine direct action by fitting the data from concentration–response relationships to the logistic equation according to the following formula (Sigmaplot 2000 or origin 6.0; OriginLab): I = Imax/(1+ (EC50/[A])n).
The data for the GABA concentration response relationship of α6β2δ receptors was fitted with a sum of two logistic equations: I = Imax1/(1+ (EC501/[A])n1 + Imax2/(1+ (EC502/[A])n2), where I is the peak current at a given concentration of agonist A, Imax, Imax1 and Imax2 are the maximum currents, EC50, EC501, and EC502 are the concentrations of agonist yielding the half maximal currents, and n, n1, and n2 are the Hill coefficients of the curves.
Determinations of the statistical significant were performed either using the student t test or ANOVA as appropriate, requiring a p value of <0.05 for statistical significance. All statistical calculations are presented as means ± SE.
α6β2δ receptors show high sensitivity to ketamine
The degree a drug inhibits or potentiates the activity of a GABAA receptor depends markedly on the level of receptor channel activation by GABA (Morris et al., 1999; Walters et al., 2000). To test the modulatory activity of ketamine on α6β2δ receptors, we determined the GABA concentration–response relationship for α6β2δ receptors to establish the concentrations eliciting 1, 3, 8, and 16% of the maximal current (EC1,GABA EC3,GABA, EC8,GABA, and EC16,GABA, respectively). Three to four days after cRNA injection, GABA-activated currents were recorded (Fig. 1 A,B). The GABA data for α6β2δ receptors were fitted with a logistic equation (see Materials and Methods) and the extrapolated EC values were tested and adjusted empirically. These experiments revealed both a high-affinity and a low-affinity state of the α6β2δ receptors [the detailed characterization of GABA concentration–response relationship for these receptors has recently been described further (Hadley and Amin, 2007)]. A significant level of spontaneous channel activity accompanies the high-affinity state.
The sensitivity of α6β2δ receptors to ketamine was examined next at the presence of EC1,GABA EC3,GABA, EC8,GABA, and EC16,GABA values (Fig. 1C,D). Ketamine at 10 μm increased the EC1,GABA current by 46 ± 8%, whereas at 20, 50, and 100 μm the increases in GABA currents by ketamine were 100 ± 14%, 261 ± 30%, and 540 ± 60%, respectively. Ketamine at 10 to 100 μm augmented the EC3,GABA currents from ∼30–260% (Fig. 1). At EC8,GABA and EC16,GABA, ketamine produced a moderate increase in the GABA currents; i.e., for 10 and 100 μm ketamine, the increase of the EC16,GABA currents ranged from 10 to 91%, respectively. After ketamine application, the subsequent GABA currents were similar in magnitude to the preceding GABA control. Therefore ketamine exhibited little to no residual effects (data not shown).
The high sensitivity of ketamine is unique to α6β2δ receptors
We compared the sensitivity of ketamine to α1β2γ2, α6β2γ2, α1β2δ, α4β2δ, α4β2γ2, α1β2, and α6β2δ GABAA receptors at their respective EC3,GABA value (Fig. 2). Ketamine produced diminutive effects on α1β2γ2, α4β2γ2, and α6β2γ2 receptors. Ketamine (100 μm) increased the respective EC3,GABA currents between 22 and 39%, the values being significantly below those induced by 20 μm ketamine on α6β2δ receptors. The increases by 50 and 100 μm ketamine for α4β2δ receptors were 37 ± 6% and 66 ± 10%, respectively, whereas the corresponding values for α1β2δ receptors were 39 ± 7% and 74 ± 9%. Thus, ketamine produced a modest potentiation at the EC3,GABA currents for α1β2δ and α4β2δ receptors. The α1β2 GABA current (EC3) increased by 46 ± 5% and 81 ± 7% at 50 and 100 μm ketamine, respectively.
In summary, the presence of the γ2 subunit within GABAA receptors reduced the effects of ketamine, whereas those receptors containing the δ subunits (or α1β2 alone) exhibited relatively higher sensitivity to ketamine. However, both α6 and δ subunits were needed to confer the highest sensitivity to ketamine. Thus, among the tested GABAA receptor subtypes, the high sensitivity to ketamine is unique to α6β2δ receptors.
Ketamine directly activates α6β2δ and α6β3δ receptors
Intravenous anesthetics such as pentobarbital modulate and directly activate most, if not all, GABAA receptor subtypes. To examine whether ketamine can also act as an agonist, we bath applied ketamine in concentrations ranging from 5 to 5000 μm on oocytes expressing α6β2δ receptors (Fig. 3A). Ketamine directly activated α6β2δ receptors at concentrations as low as 50 μm, with an EC50 of 577 ± 63 μm and a Hill slope of 1.20 ± 0.09 (n = 4). When higher concentrations of ketamine were removed, the residual current increased before returning to the baseline, suggesting that ketamine possessed a low-affinity blocking action (Fig. 3A). This apparent block by ketamine at higher concentrations resembled the direct action of pentobarbital on GABAA receptors.
For α6β2δ receptors, the relative maximal current of ketamine (1.8 mm) to GABA (50 μm) was 0.51 ± 0.06 (n = 10), indicating that ketamine is a partial agonist on α6β2δ receptors. In contrast, ketamine did not directly activate α1β2δ, α6β2γ2, α4β2δ, and α4β2γ2 receptors, with the relative efficacies ranging from 0.01 to 0.02 for ketamine (1.8 mm) to GABA (1.2 mm).
In addition to the β2 subunit, the β3 subunit is abundantly expressed in adult cerebellar granule neurons. Thus, we examined the modulatory and direct actions of ketamine on α6β3δ receptors as well (Fig. 3B). At 10, 20, 50, and 100 μm ketamine potentiated the EC3,GABA by 43 ± 6%, 72 ± 16%, 177 ± 35%, and 416 ± 128%, respectively, similar to those of α6β2δ receptors. Ketamine also directly activated α6β3δ receptors with an EC50 of 245 ± 26 μm and slope of 1.9 ± 0.1 (n = 11). Thus, ketamine at low concentrations (10–20 μm) significantly potentiated the GABA current of α6β3δ receptors and at higher concentration directly activated these receptors.
In summary, ketamine directly activated α6β2δ and α6β3δ receptors. The direct and modulatory actions of ketamine resemble those of the classical intravenous anesthetic pentobarbital. However, direct activation of ketamine appeared to be selective to α6β2/3δ receptors, whereas pentobarbital directly activates most GABAA receptors, including α1β2/3γ2 receptors.
MK-801 or PCP do not modulate α6β2/3δ receptors
PCP blocks NMDA receptors by an order of magnitude higher than that of ketamine. MK-801, a dissociative anesthetic chemically unrelated to PCP, possesses an even greater affinity to, and inhibits NMDA receptors with higher potency than PCP (Wong et al., 1986; Huettner and Bean, 1988; MacDonald and Nowak, 1990; MacDonald et al., 1991). Furthermore, the blocking action of MK-801 on the NMDA receptor is less dependent on the membrane potential than ketamine or PCP (Halliwell et al., 1989; Dravid et al., 2007). We examined whether the sensitivity of α6β2δ and α6β3δ receptors to ketamine extends to PCP or MK-801. First, the modulatory effect of PCP at the EC3,GABA value for α6β2δ and α6β3δ receptors was examined (Fig. 4A,B). PCP produced no significant potentiation of the GABA current arising from α6β2δ receptors even at 50 μm, a concentration significantly higher than the anesthetically relevant concentrations. Second, the effect of MK-801 up to 50 μm was tested on α6β2δ receptors (Fig. 4C). As with PCP, MK-801 did not affect the EC3,GABA currents arising from α6β2δ receptors. Thus, among the three dissociative anesthetics tested, α6β2δ receptors are uniquely sensitive to ketamine.
Action of ketamine on the α6β2δ receptors within a low- or high-affinity state
The affinity state of the α6β2δ receptors toward GABA expressed in Xenopus oocytes can be controlled by (1) the expression level and (2) the alteration of the ratio of β2 to α6 and δ subunits (Hadley and Amin, 2007). The ketamine data for α6β2δ receptors shown up to here was obtained using a cRNA injection ratio for α6:β2:δ of 1:1:1.8 (5–10 ng of cRNA per injection), where both the high- and low-affinity states of the receptor coexist. The high-affinity state exhibits constitutive activity. Previous studies have shown that injection using a lower ratio of β subunit cRNA, i.e., 1:0.1:1.8, results in a preponderance of α6β2δ receptors in the low-affinity state (Hadley and Amin, 2007). To investigate the sensitivity of α6β2δ receptors to ketamine in the high- versus low-affinity state, we injected oocytes with either the standard ratio of 1:1:1.8 with 10–15 ng of cRNA per injection (see Materials and Methods) or with a low β2 subunit ratio of 1:0.1:1.8 to express the α6β2δ receptors in predominantly the high- or low-affinity state, respectively. For the α6β2δ receptor in the low-affinity state, the percentage increases of the GABA current at EC3,GABA by 50 and 100 μm ketamine were 106 ± 5% and 356 ± 11%, respectively (Fig. 5), compared with the α6β2δ receptor in the high-affinity state, whereas the increase was 79 ± 1% and 173 ± 8% for 50 and 100 μm ketamine, respectively. Furthermore, ketamine on its own showed low efficacy (Imax ketamine/Imax GABA ∼ 0.1) for α6β2δ receptors in the low-affinity state. Collectively, ketamine can significantly potentiate the GABA currents arising from α6β2δ receptors in either the low or the high-affinity states yet the direct activation by ketamine appears to be selective for α6β2δ receptors in the high-affinity state.
Action of ketamine on cerebellar granule neurons
We investigated the action of ketamine on granule neurons in rat cerebellar slices from P20–P48 when the expression of α6 and δ subunit reaches high levels (Laurie et al., 1992). Individual granule neurons from the inner granule layer were voltage clamped (−60 mV) in whole-cell recording configurations using equimolar Cl− concentrations. In these recordings, granule neurons showed a tonic current that could be blocked by adding the GABAA receptor antagonist bicuculline (20 μm), or the specific α6-containing GABAA receptor antagonist furosemide (300 μm) (Korpi et al., 1995; Korpi and Luddens, 1997) (Fig. 6A,B). Ketamine (1 mm) evoked currents that ranged in amplitude from 15 to over 100 pA (58.5 ± 8.6 pA; n = 11). Bicuculline (20 μm) and furosemide (300 μm) blocked the ketamine-induced currents within the granule neurons, indicating that these currents arose from α6-containing GABAA receptors (Fig. 6C).
We next examined the potentiation of the tonic current by 10, 30, 100, 300, and 1000 μm ketamine (Fig. 7). The level of bicuculline-dependent block of the tonic current was used as the denominator to determine the ketamine potentiation. Ketamine, at a concentration as low as 30 μm, produced a significant increase in the tonic current, resulting in 20 ± 15% potentiation (p = 0.0003; n = 10). Furthermore, 100, 300, and 1000 μm ketamine increased the tonic current by 50, 130, and 280%, respectively. Thus, ketamine at clinically relevant concentrations (see Discussion) of 30 or 100 μm can increase the tonic current significantly.
Ketamine does not induce currents in α6−/−or δ−/− transgenic mice
To further elucidate the involvement of α6 and test whether δ subunits play a role in the ketamine-induced currents recorded in cerebellar slices, we used mice in which the functional expression of α6- and δ- (α6−/−) or δ-subunits (δ−/−) alone was abolished (Jones et al., 1997). The GABAergic tonic background conductance was found to be absent or nearly absent within the cerebellar slice recordings from granule neurons of α6−/− or δ−/−mice, respectively (Fig. 8). In contrast to experiments from wild-type animals, ketamine (1 mm) did not induce a current in granule cells from either α6−/− or δ−/−mice. These experiments demonstrate that the δ subunit and, likely, the α6 subunit are needed to confer ketamine sensitivity to cerebellar granule neurons.
Ketamine's modulation of dissociated granule neurons
The tonic activation of extrasynaptically localized α6β2/3δ receptors may indicate the omnipresence of low concentrations of GABA at these receptor sites. To differentiate the modulatory effects in the presence of GABA versus a direct effect of ketamine on granule neurons, we developed a preparation of dissociated granule neurons from mice and rats up to an age of P28. In this procedure, neurons resembled granule neurons with small globular shape with several offshoots and dendrites (Fig. 9A). The cell capacitance was not significantly (p = 0.29) altered a few hours after dissociation (2.76 ± 0.27 pF; n = 6) when compared with granule neurons within the slice (2.89 ± 0.16 pF; n = 15). We verified presence of α6- and δ-containing GABAA receptors within the dissociated neuron using furosemide, 3-carbomethoxy-4-ethyl-6,7-dimethoxy-β-carboline (DMCM), and 4,5,6,7-tetrahydrois-oxazolo[5,4-c]-pyridin-3-ol (THIP). Furosemide inhibited, whereas DMCM potentiated, the GABA-induced current in these cells (Fig. 9B). Furthermore, 1 μm THIP, a concentration that can selectively activate α6- and δ-containing GABAA receptors (Storustovu and Ebert, 2006; Saarelainen et al., 2008), evoked 37.5 ± 4.8 pA compared with 38.3 ± 5.2 pA (n = 11) of current for 1 μm GABA within these dissociated granule neurons. These data suggest the presence of α6- and δ-containing GABAA receptors within the dissociated granule neurons. Ketamine produced a marked potentiation of the GABA current (1 μm), whereas, in contrast to slice recordings, bicuculline did not change the control current (Fig. 9C).
We tested the ketamine concentration response relationship in the presence of a low concentration of GABA (1 μm) for the dissociated granule neurons isolated from rats or mice (Fig. 9D,E). The half maximal potentiation was ∼300 μm for the two species (mice: 260 ± 16 μm, maximal potentiation 310 ± 50%; for rats: 198 ± 32 μm, maximal potentiation 240 ± 80%). Within these experiments, 100 μm ketamine induced a significant potentiation of the GABA current (Fig. 9F). In the presence of 3 μm GABA, 100 μm ketamine produced a 140 ± 5% potentiation (n = 26, rats and mice pooled because there were little species-dependent difference between the mice and rats in terms of ketamine modulation). Under equivalent conditions, PCP at 1 and 3 mm was ineffective in modulating the GABA current (Fig. 9F) (1 mm PCP, 106 ± 2.7%, n = 8, p = 0.78; 3 mm PCP, 112 ± 3.5%, n = 8, p = 0.67). Thus, similar to the oocyte experiments, ketamine, but not PCP, modulated the α6- and δ-containing GABAA receptors.
Ketamine evoked a relatively small current on its own with a mean value of 4.2 pA (Fig. 9C), which could be blocked by bicuculline (data not shown). These experiments suggest that α6β2/3δ receptors may be present predominately in a low-affinity state and the α6β2/3δ receptors in the high-affinity state could constitute a small fraction of the total receptor population in these dissociated granule neurons from preadolescent p28 or younger animals.
The effect of increasing concentrations of GABA on the ketamine response (1 mm) was also examined within wild-type and α6−/− or δ−/−mice dissociated granule cells (Fig. 10). For wild-type mice, the effect of ketamine was most pronounced at concentrations of GABA <100 μm with an EC50 of 57 ± 18 μm (slope = 0.98; n = 6). In contrast, ketamine potentiation was absent in the mutant α6−/− or δ−/−mice regardless of the GABA concentration, indicating the importance of α6 or δ subunits in the action of ketamine.
Collectively, these data support the findings from the oocyte and slice recording experiments, demonstrating the unique action of ketamine on the α6- and δ-containing GABAA receptors, whereas PCP had no effect.
We demonstrated that ketamine selectively modulates rat α6β2/3δ GABAA receptors within the oocyte expression system. These receptors were highly sensitive to ketamine, but showed no response to PCP or MK-801. Ketamine-induced currents were observed in the recordings of cerebellar granule neurons from rodents, where they were confirmed to arise from α6- and δ-containing GABAA receptors. Furthermore, the ketamine-evoked currents were absent within cerebellar granule neurons of transgenic functionally null α6−/− or δ−/−mice.
The cerebellum has a primary function in motor control and learning. Previous anatomical, neuroimaging, and pyschological studies suggest that the cerebellum may also participate in higher cognitive functions. Patients with physical-induced lesions of the cerebellum exhibit both motor and cognitive disabilities. Cerebellum anomalies have been noted in patients suffering from schizophrenia, dyslexia, and autism (Martin and Albers, 1995; Timmann and Daum, 2007). Furthermore, neuroimaging recordings of volunteers performing cognitive tasks suggest that the cerebellum is involved in memory, learning, language and attention (Bellebaum and Daum, 2007; Haarmeier and Thier, 2007; Sultan and Glickstein, 2007; Thach, 2007; Timmann and Daum, 2007). Collectively, the cerebellum appears to coordinate not only motor, but also cognitive activity.
Cerebellar granule cells are the most abundant neurons in the CNS and play a pivotal role in storing motor commands (Tyrrell and Willshaw, 1992). A key characteristic of these neurons is the postnatal development of a tonic chloride current, known as tonic inhibition, which arises from GABAA receptors containing α6 subunits (Kaneda et al., 1995; Brickley et al., 1996; Tia et al., 1996; Wall and Usowicz, 1997; Hamann et al., 2002). The tonic inhibition plays an important role in tuning the indirect transmission of information from mossy fibers to the Purkinje neurons (via granule neurons) by reducing the overall gain of information transmitted through the cerebellar cortex. It is calculated that at the adult stage, contribution of the tonic inhibition to overall inhibitory conductance is at least threefold larger than phasic inhibition. Moreover, >90% of the tonic inhibition of granule neurons is mediated by α6- and δ-containing GABAA receptors (Hamann et al., 2002). Thus, the high sensitivity of α6β2/3δ receptors to ketamine has the potential to impact the informational transfer from mossy fibers to the Purkinje neurons. Ketamine/xylazine anesthesia has been used to study cerebellar circuitry in vivo. In these studies, ketamine/xylazine significantly suppresses the activity within the parallel fiber synapses, and the states of the membrane potential of the Purkinje neurons are significantly affected as well (Schonewille et al., 2006; Bengtsson and Jorntell, 2007). In addition to the α6β2/3δ GABAA receptors, there are also NMDA and AMPA receptors expressed within the granule neurons (Garthwaite and Brodbelt, 1990). Compared with the action of ketamine on the α6β2/3δ GABAA receptors, however, block of these receptors by ketamine occurs at markedly higher concentrations (Arenz et al., 2006). Given the relatively higher sensitivity of α6β2/3δ GABAA receptors to ketamine and the abundance of these receptors at the adult stage, the ketamine potentiation of the tonic current arising from α6β2/3δ GABAA receptors may have a profoundly greater impact on the overall suppression of the parallel fiber synapses than the blocking action of ketamine on the excitatory pathway during ketamine anesthesia.
The action of ketamine on cerebellar α6β2/3δ receptors occurred at anesthetically relevant concentrations. The steady-state ketamine concentration in the plasma of anesthetized rats is ∼100 μm after the distribution phase. In the brain, the ketamine concentration has been shown to exceed 300 μm (Cohen and Trevor, 1974). Here, we demonstrate that 10–100 μm ketamine significantly potentiated GABA currents arising from α6β2/3δ receptors. Thus, the concentrations of ketamine effective at α6β2/3δ receptors are within the realm of anesthetically relevant concentrations.
The anesthetic efficacies of ketamine, PCP, and MK-801 measured by CNS depressive action do not show a strong correlation to their actions on NMDA receptors. Binding and electrophysiological studies have demonstrated that PCP and MK-801 are superior noncompetitive inhibitors of, and have markedly higher affinity for, NMDA receptors than ketamine (Chen et al., 1959; Johnstone et al., 1959; Chen, 1965; McCarthy et al., 1965; Wong et al., 1986; MacDonald et al., 1991; Rogawski and Wenk, 2003). In addition, MK-801 block can occur across different membrane potentials, whereas PCP and ketamine inhibit NMDA receptors predominately at depolarized potentials (Halliwell et al., 1989; Dravid et al., 2007). However, a number of studies have shown that PCP and MK-801 are not effective anesthetics in rats, mice or pigeons, even at near lethal doses (Chen et al., 1959; Koek et al., 1987a,b, 1988; Kelland et al., 1993; Irifune et al., 2007). Therefore, contrary to the order of their impact on NMDA receptors, ketamine is a more effective anesthetic across different animal species and appears to possess a higher CNS depressant activity than PCP and MK-801 (Chen et al., 1959; Johnstone et al., 1959; Chen, 1965; Domino et al., 1965; McCarthy et al., 1965).
In human studies, a number of patients placed under catatonic state using PCP are arousable (Johnstone et al., 1959), indicating suboptimal CNS depression, whereas patients under ketamine anesthesia do not respond to verbal commands. Furthermore, with increasing doses, PCP can induce surgically unrelated excitation (Greifenstein et al., 1958), an adverse effect absent with ketamine administration. Ketamine also produces a lower rate and a shorter duration of emergence reactions, such as vivid dreams and hallucinations, when compared with PCP.
Collectively, these observations have led to the withdrawal of PCP from further clinical trails and veterinary practice despite the higher potency of PCP in producing dissociation and having a significantly higher affinity to NMDA receptors. Although MK-801 has been extensively characterized for two decades and possesses a nearly 1000 times greater affinity for the NMDA receptors than ketamine, MK-801 has not been approved for clinical or veterinary practice. Our findings suggest the distinguishing factor is the alternative action of ketamine on the inhibitory pathway via GABAA α6β2/3δ receptors.
We have shown that ketamine, but not PCP, can increase the activity of GABAA receptors containing α6 and δ subunits within an anesthetically relevant concentration range. This is the first demonstration of two anesthetics, highly analogous in chemical structure, molecular action, and clinical effect, in which each exhibits differentiating all or none action on cerebellar α6β2/3δ GABAA receptors. The actions of ketamine are disproportionate regarding their impact on excitatory (NMDA) versus inhibitory (GABAA) pathways, with the former showing higher potency. These findings have the potential to lead to the development of PCP analogues that exhibit more balanced actions on the inhibitory versus excitatory pathways. Such anesthetics would offer a broader spectrum for desired effects, lower the incidence of adverse effects, and provide a higher margin of safety.
This work was supported by grants from the German Science Foundation (Deutsche Forschungsgemeinschaft Lu 319/2–1) (H.L.), the MAIFOR program of the University of Mainz (W.H.), and American Heart Established Investigator Awards (J.A.). We thank Blake Singletary for help with editing, Stacey Kolar for help with Figures, and Ingo Bohme for genotyping the mouse lines.
- Correspondence should be addressed to Jahanshah Amin, Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL 33612. Jamin{at}health.usf.edu


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General Fishing Report October 21, 2019
General Fishing Report for October 21. 2019
Greetings Anglers! You've got 10 days left of the regular trout season! Are you ready? With some more rain in the forecast and decent daytime temperatures for the next 10 days, it looks to be shaping up for a wonderful end of the regular season. With the last dump of rain, the fishing seemed to get better (at least for me) as the water levels dropped, and the weekend went on. Nymphs that got looks this weekend included stoneflies, worms, rainbow warriors, Caddis and Walt's worms. Streamers got some looks from some better than average fish for me on Friday as well. I was throwing some 3-5 inch olive colored streamers (Butte Rats) which showed up rather well in the stained water. Because of favorable water temps, fish are still happily eating, mainly just off the current seams as they take advantage before the lean winter months come. As we move forward, with rain tomorrow, the middle to end of the week could be good, depending of course on how much rain we get. If you do fish the dirtier water, remember to give the fish a fly that gives a good silouhette (bigger nymphs and streamers), and as the water clears, then make the switch to smaller and more natural looking flies. I'm still seeing tan Caddis out there, which when paired with a girdle bug, produced some fish for me on Sunday. At this time of year and especially with the off-colored water, 9 times out of 10 I'm going to go for the girdle bug, with the tenth time being probably a jigged bugger fished like a nymph. Focus on getting a good drift with the nymphs, and good action with your streamers.
The Otter is high and not advisable to wade fish right now, but with some luck it will come down, as it is one of the best and closest options for trout fishing after the season closes. Remember it is open after the 31st all the way to Danby, which is a ton of water. Please check the regulations for all open water after the 31st!
Also, as mentioned previous, be on the lookout for pre-spawn or spawning trout! I've heard several reports of fish staging on redds, so watch the steps. If you are lucky enough, you might even be able to scan the water and spot these fish; a cool sight. Most literature does advise to not target these fish, as they are making future trout for us all to enjoy.
This will probably be the last report before the season closes, but I will keep updating as conditions warrant. Thanks to all of you that have sent notes and questions throughout the year. And please, keep them coming, email@example.com. I hope you all get a chance to go out in the last few days of the season; good luck, be safe and have fun. Cheers,
Previous Reports
Greetings out there anglers! Trout fishing continues to be mostly weather dependent, with cooler mornings and after rain events getting the most action. Who knows, we may have left the majority of the heat and humidity behind us with this last bout storms that rolled through. At least for this coming week, the nighttime lows are looking good, so it is a possibility that some more water could be fishable in the mornings. Please do take temperatures before you start fishing. It seems that most folks are still pickling up fish on nymphs, mostly in sizes 14-16 and of the mayfly variety.


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DENR apprehends P31 M worth of illegal forest products, 5 persons charged in court
By Herzon F. Gallego
Butuan City— The DENR has apprehend about P31,937,964.90 worth of illegal lumbers and other forest products in the 7-day relentless operations against illegal logging in Caraga Region. Five other persons were arrested and face criminal charges in court.
Reports reaching the DENR 13 OperationCenter indicated that the 21 teams which were simultaneously sent to investigate the wood processing factories in the four provinces of the region have so far apprehended about 6,892.24 cubic meters of logs and veneer products and 217,275.34 bd.ft. lumber,flitches and sticks during the first wave of operations.
There were 21 unregistered WPP and lumber dealers that were uncovered in places in Buenavista, Kitacharao, Jabonga, Cabadbaran and Nasipit in Agusan del Norte , Butuan City, and in Bayugan, Talacogon, San Franz and Bunawan in Agusan del Sur
The operation which was ordered by DENR Secretary Roy A. Cimatu following a directive from the President Rodrigo R. Duterte seeks to end all means of illegal logging and illegal mining activities in Mindanao.
It is backed up by two brigades of the Philippine Army troops under the 4th Infantry Division Commanding General Major Gen. Rogelio Villanueva , the Philippine National Police , the DOJ-National Bureau of Investigation and the Criminal Investigation and Detection Group ( CIDG).
DENR 13 Regional Executive Director Atty. Felix S. ALicer said the all-out war against illegal logging in Caraga Region which is also participated by the DENR personnel from regional offices in Region 11, 10 and 13 was considered fruitful since it was launched on Saturday , April 14,2018 and has been sustained . The operations was focused on the 106 WPPs established in the region and 72 of these wood factories are dormant and have not operated since the DENR cancelled their permits.
The 21 teams engaged in in the operation havee thoroughly examined the documents of the Wood Processing Plants to determine the legal source of their log supplies. Most of the illegal trading of processed lumbers take place during night time to evade detection. The report also indicated most the CCTVs installed by most operators of the wood factors are mal functioning or not operating.
In 35 incidence of apprehensions made by the operatives 10 WPPs were found to have operated with expired permit and its source of log suppliers are questionable. They included furniture shops and several stores of lumber materials along the roads and highways in Bayugan, Agusan del Sur, Buenavista in Agusan del Norte , Butuan City . Most of these establishments have no valid permits.
The biggest haul of illegal forest products was made at a furniture shop in Barangay Sumilihon in Butuan City which had continue to buy illegally-cut logs from unknown suppliers in spite of an with an expired permit.
The report said only about 24 WPP of the existing WPPs that were visited by the operatives were have documents in order and clean except for the 10 wood factories which were closed and padlocked by the DENR after the operatives found them have flagrantly violated the environmental law closed
The operatives also dismantled 45 sawmill facilities including band saw, table planer, moulding machine, jointer, kiln dryer, electric motor, ply-wheel with block, saw blade, circular saw and chainsaw .
Meanwhile, the group of DENR lawyers have filed criminal cases at the Fiscal Office and the Regional Environmental Courts against the violators of laws, policies, rules and regulation of Environmental and Natural Resources.
, " This illegal cuttings and harvest of trees in the forest will continue for as long as there are available markets that cater to the undocumented-cut logs from timber poachers and smugglers ' Director Alicer said . " We hope to deny the illegal outlets of undocumented forest products so that timber poaching and smuggling would be stopped ", he said.
Environment Secretary Roy A. Cimatu on Tuesday (April 24) said the existing Boracay Master Plan will be reviewed and updated during the six-month closure to incorporate developments that would also cover nearby islands to boost tourism revenues in the Northern Aklan region.
Updating the old Boracay Master Plan is part of the 'first aid' measures the DENR is implementing to solve the woes of the world-famous island destination.
"We intend to revisit the Boracay Master plan to incorporate it into a more comprehensive Northern Aklan master plan which will hasten the development of Caticlan, Malay, and Carabao island and radiate it to the nearby areas possibly including Romblon," Cimatu said during the launch of 'Tayo ang Kalikasan' People's Stewardship movement in Laoag City, Ilocos Norte.
Boracay Island will be closed for six months beginning April 26 to give way to rehabilitation activities, including the demolition of structures situated in the wetlands.
"Within that period, we intend to put in place what we might call the 'First aid' solution to Boracay's problems: among others, putting the sewage and solid waste systems in place; demolish illegal structures, whether big or small – in the foreshore, on wetlands, in forest lands or even within road easements; set up rules and regulations to keep Boracay safe, including the use of jetty ports, vehicles and other means of transport, the entry and exit of people and the like. And of course, the governance of the place," Cimatu said.
During the island's closure, the Environment chief also said a thorough review of the tourism program of Boracay Island will also be reviewed by the inter-agency task force who will also lock heads in the formulation of new attractions. This will include cultural shows and historical tours in the island and neighboring towns or cities with rich cultural heritage.
Careful consideration for the island's original inhabitants, the Atis, will also be implemented during the rehabilitation phase so they will not feel out of place even as developments in their beloved island are set in place.
Cimatu assured everyone that a cleaner and livelier Boracay Island will unfold once the work has been completed. He said 'healing' Boracay from the grudges of unbridled tourism is a must so future generations will still be able to experience its beauty.
"Boracay Island was left with the problem of sewage, solid waste and other pollutive activities to the tender mercies. They let greed and neglect, as President Duterte so emphatically noted, turn this jewel into a 'cesspool'. So now, we have to rehabilitate it to let it breathe and to let it live," Cimatu said. ###
DENR to highlight Boracay rehab in State of the Environment Address
The ongoing rehabilitation efforts in the pollution-challenged Boracay will be among the highlights of the State of the Environment Address to be delivered by Environment Secretary Roy A. Cimatu during Philippine Earth Day celebrations on April 22.
Cimatu is also expected to discuss the achievements and plans of the Department of Environment and Natural Resources (DENR) under various programs, with focus on strict enforcement of laws and regulations on clean air, clean water and solid waste management.
Philippine Earth Day celebrations will be held at the Cultural Center of the Philippines Complex in Pasay City. This year's theme is "Green the Cities, Green the Oceans."
The event comes four days before the start of the temporary shutdown of Boracay to pave the way for its rehabilitation that could last for at least six months.
The Earth Day 2018 theme supports the international goal to end plastic pollution in the oceans through proper solid waste management in households, institutions and organizations. It focuses on reducing wastes from single-use plastics and to end plastic pollution.
According to the 2015 report of the Ocean Conservancy and McKinsey Center for Business and Environment, the Philippines ranks third among the highest source of plastic pollution in global waters, next to China and Indonesia.
The exponential use of plastic has led to plastic pollution which is poisoning and injuring marine life. It is also negatively affects human health, litter beaches and landscapes, and clog waterways.
Earth Day activities will begin with a "bike parade" from Quezon City to the CCP Complex. This will be followed by welcome remarks from Manila Mayor Joseph Estrada, a message from Earth Day Network Philippines president and country coordinator Isagani Serrano and the address of Secretary Cimatu.
Stakeholders will then sign the "Commitment to Green the Cities," and musical performances and advocacy presentations will cap the celebrations.
Other activities leading to Earth Day include the roundtable discussion dubbed "Plastic Pollution in Oceans and Possible Solutions" held on March 21; coastal cleanup at the Las Piñas-Parañaque Critical Habitat and Ecotourism Area (LPPCHEA) on April 7; and the holding of "Isang Diwa sa Pagdiriwang ng Kalikasan" or SANDIWANG Festival for the Philippine Forests held April 15.at the Arroceros Forest Park in Manila.
Earth Day Jam, a free concert featuring live performances from various Filipino artists, will be held at the Quezon Memorial Circle on April 28.
The Philippines first celebrated Earth Day in 1990 by virtue of Presidential Proclamation No. 553.
In 2008, Proclamation 1481 declared April 22 of every year as the Philippine Earth Day. It enjoined all government agencies, local government units, and the private sector to conduct environmental activities to campaign for a clean and sustainable environment. ###
DENR gives biz owners 30 days to remove illegal structures in Coron, warns them of "DENR" impostors
The Department of Environment and Natural Resources (DENR) is giving 75 business owners 30 days to remove and self-demolish their structures built on the waters and within the easement zones of Coron, Palawan.
The directive is cited in the Notices to Vacate served by Task Force Coron on Thursday to erring establishments located in four barangays, namely Tagumpay, Poblacion 1, Poblacion 3, and Poblacion 5. These establishments include hotels, restaurants, dive shops, laundry shops, and lodging and boarding houses.
The Notice to Vacate specified provisions of the Water Code of the Philippines which prohibit occupation of river banks, sea shores and lakes within a zone of three meters in urban areas and 40 meters in forest areas. Barangay Tagumpay is classified as timberland, the rest as urban areas.
The Notice also cited the Civil Code of the Philippines which defines shores "and others of similar character" as property of public dominion. The Civil Code also declares as nuisance "establishment, business or condition of property, or anything else which obstructs or interferes with the free passage of any body of water."
"Malinaw po sa batas na wala dapat nakatayong mga istruktura sa mga ganitong lugar. Ipinapatupad lang po namin kung ano ang nasa batas para maprotektahan at mapanatiling malinis, maayos, at maganda ang bayan ng Coron," Engineer Roman Legaspi, head of Task Force Coron said.
Coron is famous for its pristine island beaches and breathtaking landscapes. It receives an increasing number of tourists every year, with an estimate of 178,000 tourists recorded in 2016. The influx of tourists prompted proliferation of business establishments, some of which do not only encroached easement zones, but were also found to have contributed to water pollution by discharging untreated wastewater directly into Coron Bay.
This aggravated Coron's water problem, which is mainly attributed to the town's lack of a centralized wastewater treatment facility.
"Kaya hindi lang encroachment ang tinitingnan natin. Sinisiguro rin natin na sumusunod ang mga business establishments sa mga batas ukol sa tamang paraan ng pagtatapon ng basura at maruming tubig, at iba pang batas na nagpoprotekta sa ating kalikasan," Legaspi expressed.
DENR MIMAROPA (Mindoro, Marinduque, Romblon, and Palawan) created Task Force Coron on February 26, 2018 in response to a marching order of DENR Secretary Roy A. Cimatu to ensure enforcement of environmental laws in the country's prime beach destinations. Task Force Coron is composed of representatives from DENR and Environmental Management Bureau and coordinates with the local government of Coron and other agencies, such as Palawan Council for Sustainable Development, Department of the Tourism, Department of the Interior and Local Government, Philippine Navy, and Philippine Coast Guard.
In a related development, DENR MIMAROPA cautions establishment owners affected by the cleanup drive in Coron and elsewhere in the region not to deal with impostors posing as DENR officials.
"We urge you not to deal with people who obviously want to extort from business owners," says DENR MIMAROPA Regional Director Natividad Bernardino.
"The DENR does not authorize anyone to deal with business owners other than members of the Task Forces, which were tasked to lead the cleanup and rehabilitation of beaches in Coron, El Nido, and Puerto Galera," she adds.
The warning came about following reports that DENR field officials in Oriental Mindoro and Palawan were receiving calls and text messages from unknown persons identifying themselves as Secretary Cimatu, and seeking copies of establishments which were issued Notices.
The Office of Secretary Cimatu has been informed about the incident, which then advised DENR MIMAROPA to take appropriate security measures. ###
Latest News
- 12 million Seedlings at NGP sites in Agusan del Norte hang on dry months
- Top star-studded military generals witness mayors ink commitment on clean river in Surigao del Sur
- DENR secures nesting ground of Giant Sea Turtle in Agusan Norte
- DENR notes zero smuggling of illegal lumbers at Nasipit Port
- RED's Mindanao Cluster gives priority on watershed and clean river
- Two seasoned PENRO placed in timber poaching "hot spots"
- 2019 Arbor Day Celebration
- DENR 13 top exec eyes regular visit of NGP sites
- Cimatu urges youth to join efforts to prevent biodiversity loss
- Cimatu orders a stop to all quarry operations in eight regions, relieves MGB-7 officials
- Cimatu warns against keeping wild animals as pets
- Gov't to declare more mineral reservation areas soon—DENR
- ASEAN moves towards poverty eradication and localizing global goals
- Cimatu urges public to be vigilant for landslides, floods
Mga Bag-ong Balita
- Agila ginganlan ug Sakura
- DENR – pag-isyu sa emission permit para sa mga bag-ong sakyanan anaa na online
- DENR nag-implementa sa pagkunserbar sa threatened species sa nasud
- DENR gipakusgan ang paggamit sa hinlo nga krudo sa mga sakyanan


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Barbara do Amaral
Certified Since September 2017
Barbara do Amaral
Barbara lives in Bozeman Montana. As a business owner, and currently working on her doctorate in Adult & Higher Education, at Montana State University, she perpetually sets goals for herself. She discovered the ChiRunning technique back in 2013, and continues to practice it as a life-long endeavor. Barbara speaks of her life transforming running experience with deep conviction. She became a firm believer of ChiRunning and ChiWalking, and the fitness benefits of fully engaging in its practice, quite early on. This is evident in her teaching style; patient, gentle, and focused. She loves to share her knowledge, and guide her students on how to run efficiently, and injury free; while building up their confidence in the process.


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Dee's Bunnies
Based in Kent
Back to Dee Millen.co.uk
Back to Bunnies looking for homes
To Email us click here
Terms and Conditions for re-homing/buying a Rabbit/s.
We will provided you with a top quality hand tame pedigree rabbit, that is fully weaned, treated against hay mite, lice & thread worm, we will advise you on the most suitable breed for your needs and also advise you on the correct housing for the breed of rabbit/s you are homing and show you accessories from Dee's shop that will aid you in having a happy healthy well behaved pet bunny.
We will spend time with you when you select your pet, should you decided to opt for our full package option- you will receive on collection a fully "bunny workshop" on training and interaction, were we will show you how to handle, train and interact with your chosen rabbit/s.
If you are still at the not sure stage -we do offer a " Bunny workshop" at an hourly pre-paid rate- (this is to pay for the time we spend with you.) This is then refund should you decide to go ahead and book bunny/s and full kit within a month of your workshop.
So who are we? We are hobbyist show rabbit breeder. Dee has been a member of the British Rabbit Council for over 30 years and a member of the Rabbit Welfare Association for over 10 years. We keep and breed three types of rabbits these are: Mini Lops, Lionheads, Netherland Dwarfs.
We will take the time to make sure you understand what is involved with keeping and caring for rabbits. we will show you how to approach and handle your chosen rabbit.
Dee offer's a 10% discount on the Malling Deluxe hutch range, when purchased and collected with our bunnies, plus a 10% discounts on indoor housing packages, feed & bedding packs plus more.
If we feel that what you have is unsuitable, we reserve the right to refuse the homing of the rabbit/s until correct housing is available. We will not home any rabbit/s to live in unsuitable housing.
There are two ways in which you can pay a deposit on your chosen bunny:
We are happy to offer advice.
Neutering Service
We offer a neutering and re-bonding service for rabbits leaving here. If you have a single bunny already or one that has just lost its partner and are looking for a companion, we can advise you on which of our available bunnies would be best suited, we can arrange their neuter but can not bonded them for you, however we are happy to guide you in the bonding of the rabbits.
Please note.*
Your pet is guaranteed for 72 hours providing the guide lines that you are given are followed and that the rabbit has not been dropped or injured in any way or put under any stress. If you should experience any problems with your new pet, you must consult us first and we will help if we can. If you choose to seek veterinarian consultation without first consulting us, you will be liable for any fees incurred. We regret that, as non-profit-making hobbyists show breeder, we cannot give refunds or reimburse any vet bills.
After the 72 hours we cannot be held responsible for your pet in anyway.


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Train from Sapporo to Niseko
Although a little complex, it's possible to catch trains to Niseko from the airport or Sapporo City. From New Chitose airport a rapid train takes about 35 minutes to Sapporo. A train from Sapporo to Otaru takes from 32 to 50 minutes, and then a train to Kutchan takes between 1 hour and 1:20 hours. Niseko station is a further 15-20 minutes on from Kutchan. For train timetables and fares check out Hyperdia.
Kutchan is the best train station for those staying in Hirafu or Hanazono, whilst Niseko station is closer for those staying in Niseko Village (Higashiyama) or Annupuri. Buses are available from Kutchan train station, and taxis available from both train stations, or some lodgings provide a pick up service. A taxi between Kutchan station and Hirafu costs about ¥2,500 and takes about 15 minutes.
Trains from Honshu to Niseko
A tunnel runs between Honshu (the main island of Japan) and Hokkaido, and trains between Shin-Aomori (at the northern tip of Honshu) and Kutchan take as little as 4.5 hours as the first part of the trip is a bullet train. It's about 3 hours from Tokyo to Shin-Aomori by bullet train. See Hyperdia for train timetables and fares.
Another option for getting to Niseko is to rent a car at the New Chitose Airport or in Sapporo. This provides the flexibility to do day trips to other ski resorts near Niseko or to do some sightseeing (e.g. to Otaru or Lake Toya) on down days.
You can rent a car with an English GPS, you plug in the phone number of where you want to go, and the GPS shows you how to get there. Super easy! It's also reasonably easy to self navigate because many of the road signs are in English. You don't need to put chains on, because the rental cars have snow tyres.
The telephone number for Hirafu Niseko for GPS navigation is 0136-22-0109.
Please note that it is mandatory that you have an international drivers license to rent and drive a vehicle in Japan. If you turn up without one, the rental company will not rent you a vehicle.
You may want to rent a car for a day or a few days so that you can readily visit other ski areas near Niseko.
Moiwa (aka Niseko Moiwa) is 12km southwest of Hirafu Niseko and 2.5km west of Annupuri Niseko. Moiwa is well known for its off-piste and steep side-country runs, and there's a slightly better chance of scoring freshies than at Niseko. Moiwa is interconnected with Niseko United via the slopes (when the backcountry gates are open), or you can catch a free bus from Hirafu to Moiwa. You can head there on a guided day tour with WhiteRoom Tours.
Rusutsu is 28km southwest of Hirafu which is about a half hour drive by car. Rusutsu is bliss for powder hounds and another good opportunity to get away from the Niseko crowds. A guided tour can help you get the most out of Rusutsu and BDTs often go to Rusutsu on the PowderHunter trips or you can head there with WhiteRoom Tours.
Kiroro is 51km northeast of Hirafu, about an hour away by car or 100 minutes by bus. Otherwise Kiroro is sometimes included on the guided Powder Hunter day tours or head there on a guided day tour. Or Sky Station provide private transfers between Niseko and Kiroro (click on the drop down items).
Other nearby ski resorts that may be visited on guided day Niseko ski tours include Sapporo Teine and Sapporo Kokusai.
Niseko United Shuttle
The Niseko United shuttle buses link the bases of Hirafu, Hanazono, Niseko Village, and An'nupuri. This bus is free if you have a Niseko United lift ticket. Otherwise it costs about 200-500 yen depending on the distance travelled. The Niseko United shuttle doesn't operate after about 9:30pm.
Niseko Village Bus
This is a handy shuttle bus for those staying in Niseko Village. The free hotel bus goes from about 9am to the wee hours of the morning and travels between the Hilton, a few locations within Niseko Village, the Hirafu Crossing, Hirafu Welcome Center, and Kutchan Station. Timetables are available at the Hilton or Niseko Village accommodations.
Grand Hirafu Shuttle Bus
The Hirafu village bus has a few different routes and offers a very frequent service. The bus operates from 8:30am - 9:00pm and is useful for getting around the Hirafu village and Hanazono.
Niseko Town Shuttle
This shuttle only runs about four times a day between JR Niseko Station, Niseko Village, the Higashiyama area (Niseko Village) and the Annupuri Konbu area.
Hotel Shuttles
There are lots of Niseko accommodation providers, particularly some of the big hotels, that offer shuttle services around Niseko. Some provide shuttles to the lifts or evening transport around Hirafu or even into Kutchan.
Other Buses
You might want to venture to the nearby town of Kutchan for a change of scenery or for groceries, ski shops, or restaurants. There are various different buses that go to Kutchan including the Night Go bus. See the tourist maps for more information. Similarly there are various buses that travel around to some of the onsens including those in the Annupuri and Konbu Onsen area.
Taxis are readily available, particularly in Hirafu, and can be hailed on major streets. Many taxis have roof racks but they may have to be a little creative when fitting in large ski or board bags. Prices are reasonable but more expensive than many other parts of Japan.


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Download & Install Gurzil Kodi on Latest Version Kodi 17.5:
Install Gurzil Kodi: Hello Friends, in this article, we are going to see How to Download and Install Gurzil Kodi Addon on Kodi 17.5 and Kodi 17 series and also on Kodi Jarvis 16.1. In the recent days, Gurzil Kodi is doing Great and it should be noted that it is a Fork of Exodus Kodi Addon which was one of the Best Kodi Addons once and which is currently down. Currently, Gurzil Kodi Addon holds a place in the list of Best Kodi Addons. This Tutorial will help you to install Gurzil Kodi Addon on Kodi Player using step by step Image Reference method.
Table of Contents:
- Different methods to get Gurzil Kodi
- Install Gurzil Addon on Kodi Krypton 17.5 & 17
- How to install Gurzil Kodi on Kodi Jarvis 16.1
- How to Download Gurzil Kodi- Video Tutorial
- The Conclusion of the Article
Different Methods to Install this Addon on Kodi Player:
There are different methods available to Download this addon on your Kodi Player. This article explains How to install Gurzil Kodi using Smash Repo on Kodi Krypton as well as Kodi Jarvis.
Install Latest Gurzil Kodi Addon on Kodi using Smash Repo [Kodi Krypton]:
This is the simplest method to get this addon.
- Open Kodi Krypton 17.
- Go to Addons section that is available on the Left side of the Home screen.
- Then Choose Addons icon(Package Installer) which is there in the Top Left of the screen.
- Proceed with Install from Zip file.
- Navigate to the Smash Repo(Download the Repo from http://mediarepos.org/kodistuff/) and Install it.
- Kindly wait for Addon enabled notification of Smash Repo.
- Choose Install from Repository of Addons.
- Open Smash Repo.
- Choose Video Addons.
- Search and Locate Guzil Kodi Addon from the list.
- Choose Install.
- Kindly wait for Addon Enabled Notification of Gurzil Kodi Addon.
- Once you get the Addon Enabled Notification of Guzil Addon then it is ready for use on your Latest Version Kodi 17.5 and other Kodi 17 series.
How to Install Gurzil Kodi Addon on Kodi Jarvis 16.1:
Here, we will see How to Install Kodi Addon on Kodi Jarvis 16.1 using File Manager method.
- Open Kodi Player.
- Choose Settings.
- Select File Manager.
- Now choose Add source.
- Add file source pop up will appear now. Choose None.
- Enter the Path as "http://mediarepos.org/kodistuff/".
- Enter the Media name as "Smash Repo".
- Finally, Click OK.
- Go to Install from Zip file option.
- Choose Smash Repo that you have created in the above step.
- Now Gurzil Kodi Addon can be installed using the Video Addons of Smash Repo.
How to Download Gurzil Kodi Addon- Video Tutorial:
The conclusion of the Article:
This article provides all the information about How to Download Gurzil Kodi Addon on Latest Kodi Player 17.5 and other Kodi 17 series and also on Kodi Jarvis 16.1. If you have any Query or if you face any problem in following the above article then Kindly Comment Us and we will revert with a solution soon. Have a Nice Day.
Gurzil Kodi Article Review
This article Provides good info about Gurzil Kodi and Hence it deserves a score of 4.3 out of 5.0. For more info, you may visit Kodi Info Park


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Does sex sell? In a red light district it most certainly does. And when it comes to raunchy magazines, it definitely does. Eric Prydz has shown us that people will buy any old tat if it's promoted with busty beauties.
So right on cue with her single to promote, Lisa's due to "show curves in her sexy undies" in 'The Sun' later today, complete with one of their fantastically original article titles, which we've stolen for this update. The mind boggles.


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Fundraising Made Easy and Fun
Dell Lanes has many great Fundraising ideas and events for lots of groups. Many local school groups have raised money to help their sports teams, music departments and much more. Bowling is a great fundraiser for churches, charities and other organizations too!
/lane (up to 6 people)
We require a reservation of a minimum of 10 lanes and a non refundable deposit of 50% two weeks prior to the fundraisers date.
Our Recommendations
Sell each ticket for $20
$20 X 6 People= $120 per lane ($120-$70 = $50 profit per lane)
We also have a Fundraiser option where you sell our bowling memberships for $30 each and get $5.00 per membership you sell, contact us for details.
Why should you host your fundraiser at our center?
- Bowling Is Fun
- Families Can Do It Together
- Almost Everyone Can Bowl
- It's Inside – Weather Is Never a Factor
- We can accommodate many guests
- Great Audio System To Make Announcements and use a MC or a DJ
- Groups Keep a Large Portion of ALL Money Raised
- Our staff will be there to help assist you and organize the event
Each Fundraiser has different elements and options that can be customized for your group. The different types of fundraiser also have a very different level of volunteers and time line, it is best to talk to us while planning your event to see what program will work best for your organization.
Dell Lanes has helped area groups and organizations raise over $100,000 here are just a few of them:
* Big Brothers/Sisters
* Make A Wish Foundation
* CP Center
Plus…many more!