text:
|Publication number
|Publication type
|Application number
|Publication date
|Sep 22, 1992
|Filing date
|Jul 23, 1991
|Priority date
|Jul 24, 1990
|Fee status
|Also published as
|Publication number
|Katsunori Watabe, Osamu Motokawa
|Original Assignee
|Shimadzu Corporation
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (12), Referenced by (22), Classifications (23), Legal Events (5)
|External Links: USPTO, USPTO Assignment, Espacenet
The present invention relates to a liquid chromatographic stationary phase having a high chiralrecognition ability for fractionation and analysis of optical isomers.
Liquid chromatography has an excellent resolution power and is applied not only to analysis but also to purification of compounds, resultantly. However, interseparation of compounds identical in general physical and chemical properties and dissimilar only in spatial configuration, such as optical isomers, requires a stationary phase having an ability to specifically discriminate optical activities.
For instance the Pirkle Column is a well-known efficient stationary phase for optical resolution of amino acids, amines, etc. that possesses a chiral center (asymmetric center) having benzoyl derivatives of phenyl glycine, which can be represented by the following typical formula ##STR2## Also, Japanese Kokai Patent Application No. 60-155968 discloses a solid phase having N-carbamoyl-t-leucine as a chiral center.
However, the molecule-recognizing ability of these stationary phases for optical isomers is still insufficient and the advent of a more efficient solid phase for optical resolution liquid chromatography has been earnestly awaited.
The object of the present invention is to provide a chromatographic stationary phase which has a high molecule-recognition ability and is capable of efficient fractionation of optical isomers.
The present invention provides a stationary phase for enantiomeric resolution in chromatography which is characterized by containing a special group, having chiral-recognition as shown by the following formula: ##STR3## [wherein A--CO-- means a chiral moiety, m is an integer of not less than 3, and n is an integer of not less than 5].
Essentially the invention is as follows. By controlling the stereo geometry of the chemically-bonded chiral phase, namely producing enough space for making the interaction between the sample molecule and the chiral moiety in the support efficient, the ability for chiral-recognition can be improved.
FIG. 1 is a schematic diagram showing the manner of fractionation with the stationary phase of the invention.
FIG. 2 is a schematic diagram showing the manner of fractionation with the prior art stationary phase.
FIG. 3 is a schematic diagram showing the molecular structure of the prior art stationary phase.
FIG. 4 is a chromatogram obtained with the stationary phase of the invention.
FIG. 5 is a chromatogram obtained with the corresponding stationary phase without sub-anchors and spacers. The horizontal axis stands for retention time and the vertical axis stands for quantity.
In the stationary phase of the present invention, the chiral moiety: A--CO-- may include a residue of an N-acyl amino acid, an N-carbamoyl amino acid and a N-carbamoyl-α-aromatic alkyl amine. Examples of N-acyl amino acid are N-pivaloyl-L-valine, N-3,5-dinitrobenzoyl-D-phenylglycine and the like. Examples of N-carbamoyl amino acid are N-carbamoyl -leucine, N-carbamoyl-valine and the like. Examples of N-carbamoyl-α-aromatic alkyl amine are N-carbamoyl-α-(1-naphthyl) ethyl amine and the like.
In the stationary phase of the invention, --NH--(CH2)n--CO-- is interposed, as a sub-anchor moiety, between said chiral moiety and an anchor moiety (aminoalkylsilica). The symbol n represents an integer of not less than 5 and preferably 5 to 10. If n is less than 5, the separation ability of the stationary phase will not be as high as desired. While, if n is over 10, the separation ability will not be as high as desired because of increased hydrophobic interaction, unnecessary interaction for chiral recognition, between a sample molecule and a chiral stationary phase and also making easily the interaction between chiral moieties.
The symbol m represents an integer of not less than 3 and preferably 3 to 6. The aminoalkylsilica moiety linking a support to said chiral moiety may be derived from an aminoalkylsilane. The aminoalkylsilane is preferably 6-aminohexylalkoxysilane, 6-aminohexylhalogenosilane, 3-aminopropylalkoxysilane, 3-aminopropyl trihalogenosilane and the like. Suitable examples of 3-aminopropylalkoxysilane and 3-aminopropyltrihalogenosilane are 3-aminopropyl-triethoxysilane and 3-aminopropyl trichlorosilane, respectively.
The support is preferably a silica-containing support such as silica gel or the like and is desirably a finely divided powder with a uniform grain size distribution.
It is further preferable to combine a protective group with a free aminoalkyl group among groups for chiral-recognition on the surface of the support to give "a spacer". The spacer improves a chirality-recognizing ability of the stationary phase for optical isomers. Examples of the protective group are pivaloyl, trifluoroacetyl, acetyl and the like.
Research by the inventors of the present invention revealed that the conventional chromatographic stationary phases are not sufficient in interactivity between the molecule to be separated and the chiral moiety for discriminating the molecule so that the inherently high molecule-discriminating potential of the chiral moiety is not fully exploited.
The following mechanisms may be postulated for the improved resolution power of the stationary phase of the invention over the conventional stationary phases. In the conventional stationary phases for chromatography, a chiral moiety is directly coupled chemically to an aminoalkylsilica. As shown in FIG. 2 by way of example, the molecule-to-molecule interaction between the N-acylamino acid amide type chiral moiety and the amino acid derivative, as the object of optical resolution, results from steric hindrance between the functional groups attached to the two asymmetric carbon atoms and thus optical resolution takes place accordingly. Because of the direct coupling of the chiral moiety and the aminopropylsilica (aminoalkylsilica) in the conventional stationary phase, there is not sufficient space available for such interaction between the molecule as the object of optical resolution and the chiral moiety as shown in FIG. 3.
In contrast, the stationary phase of the present invention has a sub-anchor moiety between the aminopropyl-silica (anchor moiety) and the chiral moiety as shown in FIG. 1 to provide an increased distance therebetween. Moreover, when an aminoalkyl group is protected with a protective group (spacer) such as a pivaloyl group and is provided among the chirality-recognizing groups on the surface of the carrier, there is obtained enough space among adjacent groups for chiral-recognition. When the unreacted aminopropyl(alkyl) group is protected with an appropriate protective group such as pivaloyl, the undesirable interaction between the hydrogen bond and the molecule as the object of optical resolution is precluded.
The method for producing the stationary phase of the invention is now described in detail. In the stationary phase of the invention, the sub-anchor may be introduced by NH2 --(CH2)n--COOH. The chiral moiety is generically represented as A--CO-- for convenience's sake. Prior to joining the chiral moiety to the sub-anchor, the C-terminal of the NH2 --(CH2)n--COOH is first protected in the form of methyl ester as follows. ##STR4##
On the other hand, the free acid portion of the chiral moiety is converted to an active ester by the following reaction. ##STR5##
Then, the sub-anchor of formula [I] is reacted with the chiral moiety of formula [II] in the following manner to provide a chiral moity with sub-anchor of formula [III]. ##STR6##
This chiral moiety with sub-anchor of formula [III] is then treated as follows. ##STR7## The resulting compound of formula [IV] is bound to an aminoalkylsilica (for example, aminopropylsilica) as follows. ##STR8##
A reagent such as pivalic acid is added at the final stage of production of said compound [V] to react the reagent with the free amino groups not joined to a chiral moiety having sub-anchor, on the silica support. Then, the reagent ensures the space among adjacent groups for chiralrecognition and the free amino groups are protected. ##STR9##
The stationary phase obtained as above is washed thoroughly with a solvent such as tetrahydrofuran (THF), methanol, etc. and removing the solvent remained. By the slurry method, the stationary phase prepared is packed into an analytical column for HPLC. Thus, the stationary phase material of the present invention is packed into a chromatographic column and used as a stationary phase for liquid chromatography.
The chromatographic stationary phase of the present invention has a high chiral-recognition ability and, permits efficient resolution of optical isomers.
The following examples are further illustrative of the present invention.
N-Pivaloyl-L-valine and 6-aminohexanoic acid (H2 N(CH2)5 COOH) were used as A--CO--OH and the sub-anchor, respectively.
1 H NMR for the chiral moiety (CDCl3 300 MHz): δ0.97(6H), δ1.23(9H), δ2.25(1H), δ4.60(1H), δ6.30(1H), δ10.80(1H).
To 500 ml of ice-cooled methanol was added 130 ml of thionyl chloride in small portions with constant stirring. Then, at room temperature, 66 g (0.5 mol) of 6-aminohexanoic acid was added and the mixture was stirred for 24 hours.
After completion of the reaction, the solvent was removed and for removal of residual H2 O and HCl, the addition of methanol and subsequent concentration were repeated a few times to give 83.6 g (0.46 mol) of methyl 6-aminohexanoate hydrochloride.
In 1 l of ethyl acetate was dissolved 30 g (0.15 mol) of N-pivaloyl-L-valine and the solution was cooled to -20� C. Then, 37.1 g (0.18 mol) of N,N'-dicyclohexylcarbodiimide and 20.7 g (0.18 mol) of N-hydroxysuccinimide were added and the reaction was conducted overnight. The reaction mixture was then allowed to return to room temperature and the by-product dicyclohexylurea was filtered off. The filtrate was cooled again to -20� C. and 32.7 g (0.18 mol) of methyl 6-aminohexanoate hydrochloride and 40 ml (0.36 mol) of N-methylmorpholine were added. The mixture was stirred with cooling for 48 hours.
The solution was then allowed to return to room temperature and the insoluble matter was filtered off. The ethyl acetate solution was washed successively with H2 O/2% HCl/H2 O/5% NaHCO3 /H2 O to remove the amine and acid components from the solution. The solution was then dehydrated over anhydrous MgSO4 and the solvent was distilled off under reduced pressure to give 44 g (0.134 mol) of methyl N-pivaloyl-L-valine-6-amino-hexanoate.
1 H NMR (CDCl3 300 MHz): δ0.97(6H), δ1.23(9H), δ1.3, δ1.5, δ1.6(6H), δ2.25(1H), δ2.4(2H), δ3.2, δ3.3(2H), δ3.7(3H), δ4.60(1H, δ6.30(1H), δ10.80(1H).
In 500 ml of methanol was dissolved 44 g of methyl N-pivaloyl-L-valine-6-aminohexanoate followed by addition of 150 ml of 1N sodium hydroxide and the mixture was stirred at room temperature for 45 minutes. The ethanol was then evaporated off and 1N HCl and, then, ether were added to the residue. The mixture was shaken to extract the reaction product into the ether. The water layer was removed and the ether layer was dried over magnesium sulfate anhydride and concentrated to dryness under reduced pressure to give 35 g (0.112 mol) of the desired compound.
2.5 g of Aminopropylsilica was added into 3.91 g (0.0125 mol) of N-pivaloyl-L-valine-6-aminohexanoic acid and 1.28 g (0.0125 mol) of pivalic acid disolved in 150 ml of tetrahydrofuran. The mixture was stirred at room temperature for 1 hour. Then, 6.15 g (0.025 mol) of 1-ethoxycarbonyl-2-ethoxy-1,2-dihydro-quinoline (EEDQ) was added and the mixture was further stirred for 48 hours. After completion of the reaction, the silica was recovered by filtration through a 1.0 μm Teflon filter and suspended in methanol, acetone and ether in the order mentioned to remove impurities. The silica was then thoroughly dried and packed into a column in the usual manner.
Coupling rate (%) to aminopiopyl-silica by elemental analysis for C and N: pivaloyl (spacer), 58%; N-pivaloyl-L-valine (sub-anchor), 42%.
The above stationary phase material was packed into an HPLC column (4 mm in. dia.�25 cm long) by the conventional slurry-packing method to provide a liquid chromatographic column. Using this column, a sample was fractionated under the following conditions to evaluate the fractionating power of the column.
Mobile phase: n-Hexane/dichloromethane (99.5/0.5) 1 ml/min
Detector: UV detector (254 nm)
Sample: N-TFA-phenylalanine isopropyl ester
FIG. 1 shows the chromatogram obtained with the stationary phase of the invention of FIG. 2 is the chromatogram obtained with the prior art stationary phase having the same chiral moiety but no sub-anchor moiety. The horizontal axis stands for retention time and the vertical axis stands for quantity. The use of the stationary phase of the invention resulted in a markedly improved resolution of D- and L-isomers. While the peak obtainable by the prior art shows a fair amount of tailing even when alcohol is added to the mobile phase (n-hexane/isopropyl alcohols=99.8/0.2), the present invention promises sharp peaks with good symmetry even in the absence of alcohol, indicating that the interaction takes place efficiently and sufficiently in the present invention.
Resolution coefficient (α): the mobile phase (n-hexane/isopropanol =95:5)
______________________________________ prior art (without sub-anchorSample Example 1 and spacer)______________________________________α-alanine 1.55 1.18α-valine 1.85 1.29α-leucine 2.24 1.44______________________________________
Each sample was converted into N-3,5-dinitrobenzoyl, isopropyl ester derivative for analysis.
A stationary phase was prepared according to the same manner as described in Example 1 except that the chiral moiety and sub-anchor were changed for N-(tert-butylamino-carbonyl) -L-valine and 9-amino nonanoic acid, respectively. The resulting stationary phase for liquid chromatography has a high chirality-recognizing ability as follows.
1 H NMR for chiral moiety (CDCl3 300 MHz): δ0.95(6H), δ1.25(9H), δ2.28(1H, δ4.75(1H), δ9.60(1H), δ10.10(1H), δ11.00(1H).
1 H NMR (CDCl3 300 MHz) for methyl N-(tertbutylamino-carbonyl) -L-valine-9-amino nonanate: δ0.95(6H), δ1.25(9H), δ1.3, δ1.5, δ1.6(6H), δ2.28(1H), δ2.4(2H), δ3.2, δ3.3(2H), δ3.7(3H), δ4.75(1H), δ9.60(1H), δ10.10(1H), δ11.00(1H).
Coupling rate (%) to aminopropyl-silica by elemental analysis for C and N: Pivaloyl (spacer), 62%; N-carbamoyl-L-valine (sub-anchor) 38%.
Resolution coefficient (α):
______________________________________ prior art (without sub-anchorSample Example 2 and spacer)______________________________________α-alanine 1.42 1.12α-valine 1.67 1.34α-leucine 2.98 1.42______________________________________
Each sample was converted into N-acetyl, methyl ester derivotive for analysis.
|Cited Patent
|Filing date
|Publication date
|Feb 25, 1980
|Mar 9, 1982
|Uop Inc.
|Chiral supports for resolution of racemates
|Feb 25, 1980
|Mar 9, 1982
|Uop Inc.
|Chiral supports for resolution of racemates
|Jun 12, 1980
|Mar 30, 1982
|Uop Inc.
|Chiral supports for resolution of racemates
|Jun 12, 1980
|Apr 13, 1982
|Uop Inc.
|Chiral supports for resolution of racemates
|May 18, 1983
|Aug 5, 1986
|Sumitomo Chemical Co., Ltd.
|Packing materials for chromatographic use and a method for analysis of an enantiomer mixture using the same
|Jan 23, 1986
|Dec 29, 1987
|Hoffmann-La Roche Inc.
|Adsorbent for protein purification
|Dec 3, 1987
|May 16, 1989
|Tosoh Corporation
|Packing material for liquid chromatography
|Apr 30, 1986
|Jun 6, 1989
|Varian Associates, Inc.
|Bonded phase chromatographic supports
|Jun 27, 1988
|Aug 8, 1989
|Dow Corning Corporation
|Using liquid chromatography dual zone packing materials
|Sep 19, 1988
|Nov 7, 1989
|Daicel Chemical Industries, Ltd.
|Separation agent comprising acyl- or carbamoyl-substituted polysaccharide
|Dec 9, 1988
|Apr 24, 1990
|The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services
|Liquid chromatographic chiral stationary phase
|Title not available
|Citing Patent
|Filing date
|Publication date
|Jun 23, 1992
|Mar 1, 1994
|Research Corporation Technologies, Inc.
|High performance chiral selector
|Sep 27, 1993
|Jun 6, 1995
|Research Corporation Technologies, Inc.
|High performance chiral selector
|Mar 23, 1994
|Jan 30, 1996
|Research Corporation Technologies, Inc.
|Recognition and separation of carbon clusters
|Sep 11, 1996
|Oct 14, 1997
|Rhone-Poulec Rorer S.A.
|Isoindolinone derivative, preparation thereof and pharmaceutical compositions containing same
|Mar 22, 2000
|Oct 2, 2001
|The United States Of America As Represented By The Secretary Of The Navy
|Metal complexing
|Mar 5, 2002
|Nov 11, 2003
|Dionex Corporation
|Polar silanes and their use on silica supports
|Aug 12, 2003
|Sep 27, 2005
|Dionex Corporation
|Polar silanes and their use on silica supports
|Feb 15, 2005
|Dec 23, 2008
|Dionex Corporation
|Organosilanes and substrates covalently bonded with same and methods for synthesis and use same
|May 25, 2007
|Jul 7, 2009
|Dionex Corporation
|Compositions useful as chromatography stationary phases
|Apr 28, 2008
|May 22, 2012
|Dionex Corporation
|Organosilanes and substrate bonded with same
|May 4, 2012
|Apr 23, 2013
|Dionex Corporation
|Organosilanes and substrate bonded with same
|Sep 10, 2009
|Oct 22, 2013
|Signature R&D Holdings, Llc
|L-Threonine derivatives of high therapeutic index
|Sep 23, 2011
|Jun 7, 2016
|Gelest Technologies, Inc.
|Alkoxysilane derivatives of N-acyl amino acids, N-acyl dipeptides, and N-acyl tripeptides, and particles and stable oil-in-water formulations using the same
|Aug 12, 2003
|Feb 26, 2004
|Xiaodong Liu
|Polar silanes and their use on silica supports
|Jul 3, 2002
|Oct 7, 2004
|Kurt Guenther
|Chromatographic separation of enantiomers of protected amino acids via smb-method
|Feb 15, 2005
|Aug 17, 2006
|Dionex Corporation
|Organosilanes and substrates covalently bonded with same and methods for synthesis and use same
|Apr 28, 2008
|Aug 28, 2008
|Dionex Corporation
|Organosilanes and substrate bonded with same
|May 25, 2007
|Nov 27, 2008
|Dionex Corporation
|Compositions useful as chromatography stationary phases
|Nov 20, 2008
|May 21, 2009
|Dionex Corporation
|Organosilanes and substrates covalently bonded with same and methods for synthesis and use
|Sep 10, 2009
|Jan 7, 2010
|Signature R&D Holdings
|L-threonine derivatives of high therapeutic index
|Sep 10, 2009
|Mar 18, 2010
|Signature R&D Holdings
|L-threonine derivatives of high therapeutic index
|Sep 23, 2011
|Mar 29, 2012
|Gelest Technologies, Inc.
|Alkoxysilane Derivatives of N-Acyl Amino Acids, N-Acyl Dipeptides, and N-Acyl Tripeptides, and Particles and Stable Oil-in-Water Formulations Using the Same
|U.S. Classification
|210/198.2, 502/401, 210/635, 210/502.1, 210/656
|International Classification
|Cooperative Classification
|European Classification
|Mar 5, 1992
Owner name: SHIMADZU CORPORATION, JAPAN
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNORS:WATABE, KATSUNORI;MOTOKAWA, OSAMU;REEL/FRAME:006034/0573
Effective date: 19910704
|Mar 12, 1996
|Fee payment
Year of fee payment: 4
|Apr 18, 2000
|Maintenance fee reminder mailed
|Sep 24, 2000
|Lapse for failure to pay maintenance fees
|Nov 28, 2000
|Expired due to failure to pay maintenance fee
Effective date: 20000922


text:
The girls at the Safe Shelter have had a busy few months, but now school has broken up for the semester: it is the longest extended break of the year. The girls will be off school for two whole months. The two eldest girls Chayya and Sopheak are waiting for their high school diploma results. They have been predicted to pass with good grades and are expected to start University in October. In the meantime they are attending a vocational educational course run by CWDA. They are working on their English and computer skills and also learning how to compose a CV.
The staff at Cambodian Women's Development Agency are working hard to ensure all of the girls have activities arranged to keep them happily occupied over their academic break. We are lucky to have a volunteer, Jenny, from England who is working with CWDA for a couple of months whilst on her university summer break. Each day she teaches the girls English, she makes the lessons very interactive; the girls are learning English songs and games as well as having art and craft sessions.
Jenny says "I really enjoying spending time with the girls, watching their confidence grow as they learn to speak English. They are all really keen to demonstrate what they have learnt, but most of all I enjoy seeing how they all help and encourage one another".
It's not been all work and study during the holidays, thanks to your donations the girls have been able to pick out some new clothes; they are all growing very fast and are very appreciative of being able to choose some new outfits. They have also been on a picnic to the riverside and are still enjoying their weekly yoga sessions. Pohiek has become so accomplished at yoga that she is running daily yoga sessions during her school holidays for all the CWDA staff which is helping to keep us all fit and flexible!
Sokchhouen runs the day-to-day operations of the safe-shelter and is affectionately known by the girls as 'house mother'. She lives on site to ensure all the girls in the safe shelter have consistent full time care and support. As well as her main role as house mother, she is also a trained weaving instructor and teaches the girls weaving in their free time. Under her tutelage some of the girls have weaved scarves that are then sold for a small price in the local market.
Sokchhouen joined CWDA in 1995, and has over 20 years experience working with vulnerable young girls to increase their confidence, self-sufficiency and life-skills. She also prepares the daily meals with the girls at the shelter so that they can develop their cooking skills.
When asked what she enjoys most about her role Sokchhouen said "the organization is like a family to me, all the staff care for, and support each other, and I like to share my knowledge and experience with the girls and give them advice and make them feel calm, happy and comfortable; I think of them as daughters"
Phalla (not her real name), one of the girls at the shelter says that "Sokchhouen looks after us well, she has a lot of responsibility but she is happy and never complains about her job, even when she is up at night looking after us when we are sick".
Thank you so much for donating to the Cambodian Women's Development Agency. Your donation enables us to employ Sokchhouen to live at the Safe Shelter 24/7, this ensures the girls grow up in a caring, stable and loving environment.
Have you seen our new micro-project? We're really excited that we can now raise money to send two of our girls who are in their last year of secondary school to university. This is a really important step in helping young women gain their independence, achieve their full potential and a chance of financial security in the future. The two girls want to study accountancy and management at a Phnom Penh university – something which would have been unimaginable for them had they not been able to access CWDA's Safe Shelter. We're so grateful to our supporters and pleased to say we're over $2000 closer to our target of sending these two young women to further education– incredible!
If you're considering a further donation to CWDA we'd like to encourage you to make use of the bonus matching days which Global Giving have set up – the first is today for the Global Giving US site: make donations today Weds 12th Feb from 9am and an anonymous donor will match 30% until the $75,000 runs out (so get in there early). If you're a UK-based supporter, then there's a whole week beginning March 3rd where 50% of your donation will be matched.
CWDA want to thank again our donors for their generous support - we've raised a total of over $10,000 since our campaign on Global Giving began.

subset: commoncrawl


text:
Squids Odyssey
What parents need to know
Parents Need to Know
Parents need to know that Squids Odyssey is a turn-based tactical role-playing game with an emphasis on action. Combat is cartoonish and completely blood-free. Players control a rotating squad of squids they fling at oozy, inky enemies to deplete their health or push them over the edge of the playing field. The squishy heroes work to save their world from an encroaching evil. They're sympathetic and brave, displaying friendship to the point of self sacrifice.
What kids can learn
- animals
- momentum
Thinking & Reasoning
- strategy
Engagement, Approach, Support
An initial learning hump and middling graphics in the Nintendo 3DS version might put off some kids, but strategy fans who push through this barrier will find a compelling game of turn-based tactics.
The need for strategic play encourages kids to think tactically by planning each move in advance, taking into account map layouts and enemy abilities. Kids will learn from both their successes and mistakes, applying this information in future encounters.
Instructions are provided as needed within the game. The developer has not created a community or forum for players to share and talk about strategies, so most kids will need to work out tactics on their own.
What's it about?
SQUIDS ODYSSEY puts players in command of small groups of squids working to protect their realm from an invading force corrupting the aquatic world. The heroes confront their enemies -- crabs, lobsters, and other creatures covered in black ooze -- by launching themselves at foes. Enemies are defeated when their health bars sink to zero or when they're pushed over the level's edge. They can also be damaged if pushed into hazards, such as pointy sea urchins. Between each of the game's 90-plus missions players can visit a shop to buy more team members or purchase head wear that boosts characters' vital stats. They can also drop by the squids' base to change party members and spend pearls they've collected to improve individual characters.
Is it any good?
Few games are comparable to Squids Odyssey. Its primary play mechanic -- flinging cephalopods across the sea floor and the backs of giant turtles -- is unique and introduces some interesting tactics. The heroes have a limited number of action points each turn, which are used up depending on how hard they're flung. That adds a new level of strategy to the game -- for instance, you can be sneaky, flinging characters in short bursts so they can hit several enemies at once or push an opponent into a hazard. It takes a while to get the hang of the strategy required, but once things start to click it can be a lot of fun -- and surprisingly challenging, too.
It's too bad other parts of the game don't quite live up to the action. Cutscenes between missions are meant to be funny, but are more often just dull. While it's fun to unlock new squad members -- each of whom has their own distinct character -- and buy and outfit your squids with new gear, leveling up characters is anticlimactic. Huge investments of hard-earned pearls often result in small increases to crucial stats, like health. While it's a peculiar game that could have done with a bit more time in the oven, the creative action goes a long way toward recommending it. Turn-based strategy fans who give it a chance will undoubtedly have a fine time.
Families can talk about...
Families can talk about being strategic in daily life. Do you plan ahead? Create contingencies if your plans don't work out? Can you think of any times when you did something impulsively and later wished you'd considered the potential outcomes of your actions?
Discuss the ocean and its curious life forms that are shown in Squids Odyssey, many of which seem almost alien. Squids and octopi are apparently quite intelligent. What do you think cephalopods might think about while swimming in the dark depths of the sea?
Game details
|Nintendo 3DS, Nintendo Wii U
|Pricing structure:
|Available online?
|Available online
|The Game Bakers
|Release date:
|July 8, 2014
|Ocean creatures
|ESRB rating:
|E for Mild Fantasy Violence
About Our Rating System
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text:
FGG Valentine's Day Lite
by: TunaAndAHalf • 572
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by: TunaAndAHalf • 572
Valentine's Day is coming! We have something special for all lovers :)
Give a suprise to one you love !
This Lovely Live Wallpaper with four couples and different backgrounds is perfect for Valentine's Day !
... and there is a kiss when you tap ! :)
Tap twice to enter settings.
Tags: fgg , wallpapers of girls in love , wallpaper dis , valentines day hearts , girl in love wallpaper , julia kiss , valentines day girl , love valentines
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text:
Mission Statement
We proudly serve our community and visitors through safe, efficient and effective delivery of emergency services supported by aggressive fire prevention and public education.
Board Meeting
A training session for the Board of Directors of Siuslaw Valley Fire and Rescue, will be held at the District Office located at 2625 Highway 101 North, Florence, Oregon. The training will take place on July 14th, 2016 at 6:00 p.m. The training will be conducted by SDAO and will focus on Board member communication. The training will be open to the public, however public comment will not be taken.
The next regularly scheduled meeting of the SVFR Board of Directors will be Wednesday July 20th at 6:00 pm.
The agenda will include;policies and procedures and general business of the district. The Board may(if necessary) go in to executive session per ORS 192.660. The meeting location is accessible to persons with disabilities. A request for an interpreter for the hearing impaired or for other accommodations for persons with disabilities should be made at least 48 hours before the meeting.
Location: 2625 Highway 101
Apply for a burn permit
You can now request a back yard burn permit using our online form.
Latest News
New Training/Volunteer Coordinator
Siuslaw Valley Fire and Rescue welcomes Jeff Larson to the position of Training/Volunteer Coordinator.
Board Members Sworn In
New Board members sworn in.
New Firefighters Sworn In
Chief Langborg swears in new firefighters.
Marler and Larson receive EMT-1 Certification
Tyler Marler and Jeff Larson receive their EMT-1 Certificates.
Burn Meter – Extreme
See fire marshals message
A message about the fire danger level
from our Fire Marshal, Sean Barrett
IGA Information
Community Events
- No upcoming events


text:
Albert Kennedy Trust opens housing project for young homeless LGBT people
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Reader comments
Great news. I donate to AKT. I was homeless for a while and its funny how friends and family change when you need them most.
The worst feeling was sitting on a bus with nowhere to go. I suggest every give £10 even if its once a year
I've been homeless too and know the feeling of really not knowing where to go. It's awful and extremely scary.
I donate now too and hope once I'm settled down a bit more (new to the country) also to take on voluntary work with them.
These kids are our future (said the 30yr old lad…), the landscape for them is better but still way too many kids find themselves in these situations. They deserve our help, especially as so few others give it and can relate to our specific experiences.
Problem is the gay agenda has shifted right its everyman for themselves nowadays
Please give us a link on how to donate.
Here's Albert Kennedy Trust's donation link for this project: http://www.akt.org.uk/2/spg356/albert_kennedy_trust_-_helping_young_lgbt_people/can_you_help/give15.aspx
A very worthy endeavour. Of course, no reaching out in brotherly love from the anti-gay religious leaders who've played a role in this appalling problem of young homeless LGBT people.
The combination of the following words, "reaching", "love", "religious leaders", "young" and "people", just made me feel a bit nauseous. I think religious leaders should be kept away from vulnerable young people as a rule. They at the very least have an agenda to preach and convert like missionaries so perhaps it's a silver lining that they refrain from "reaching".
Organisations like this are to be commended and supported.
I dont get it. 76% of the youth on the street is there because of a coming out? Or 76% of all Manchester youth is gay and homeless because of a coming out? The sentense is difficult to understand, the second meaning of course makes no sense, so it is the first one or did I misunderstand completely?
Albert Kennedy Trust's web page gives the full sentence and this quote is about LGBT youth in London, not Manchester:
"… to open the UK's first LGBT specific safe house which is designed for the 76 per cent of the young people coming to AKT in London to escape domestic violence or hate crime as a result of coming out."
AKT are fabulous. Please give them some money to help them continue their work.
These comments are un-moderated and do not necessarily represent the views of PinkNews. If you believe that a comment is inappropriate or libellous, please contact us.
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Tonight's the Night
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Track Listings
|1. Tonight's The Night
|2. Speakin' Out
|3. World On A String
|4. Borrowed Tune
|5. Come On Baby Let's Go Downtown
|6. Mellow My Mind
|7. Roll Another Number (For The Road)
|8. Albuqueque
|9. New Mama
|10. Lookout Joe
|11. Tired Eyes
|12. Tonight's The Night - Part II
Product Description
Product Description
This album acted as a musical expression of grief for Young, who wrote and recorded it in 1973 after the deaths of two close friends who overdosed on heroin. His emotional tone and hoarse voice soar on Tonight's the Night; World on a String; Tired Eyes; Roll Another Number (for the Road); Speakin' Out; Borrowed Tune , and six more.
By 1975 Young had written some of the most enduring anthems in rock history. But from the slow, tension-building piano opening of "Tonight's the Night", he downshifts into darkness and Crazy Horse's folk-country melodies take on a guttural hum that would eventually speak to generations of punk and grunge musicians. Inspired by the overdose deaths of two of Young's friends, roadie Bruce Berry and guitarist Danny Whitten, the title track (and its closing reprise) is a hypnotic cry of "why?" Even the relative party songs, "Come On Baby Let's Go Downtown" and "Roll Another Number", fit the album's bus-to-nowhere resignation. --Steve Knopper
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Customer Reviews
Top Customer Reviews
This album is drunken and emotional, filled to the brim with the drug-fueled decay of the 1970s. The idealism that informed the psychedelic age of the late 60s had given way to death and incoherence just six years later. Suddenly, the excess and the drugs that seemed so hip began to kill people.
By the time Neil Young and his band entered the studio, Hendrix, Joplin and Morrison were dead. No doubt Young felt that these stars' deaths showed the true dangers of excess. He possibly might have felt that these were isolated incidents. After all, drugs expanded and freed the mind, did they not? They didn't kill you in various combinations. Maybe those three just overdid it.
Then Danny Whitten and Bruce Berry also died. Not just one person close to Neil Young, but two. The resulting confusion and grief is everywhere on TONIGHT'S THE NIGHT. This album is a portrait of a man mourning the deaths of others, while struggling to overcome his own addictions. Pretty ironic that Young and company are singing about these deaths, and sound so loaded and wasted at the same time.
The contradiction in TONIGHT'S THE NIGHT is but one of the many facets to Neil Young, who must be considered one of the most complex and gifted artists of the 20th century.
It's safe to say anyone who thinks this album is merely average should probably avoid other "dark nights of the soul" like Exile on Main Street, L.A. Woman, etc. Matter of fact, keep listening to Harvest and CSNY and you should be okay. It's probably not safe to go into the dark.
Seriously, this is Neil's best one by a long shot. He opens up a vein and lets it bleed all over the vinyl, naming names, sounding like he's on the verge of suicide, a drug OD, or both, and it's a beautiful and touching and powerful testament to the bleak era of post-Woodstock, post-Vietnam America. This album is perfectly constructed, remarkably played (dig that Nils Lofgren solo on Speakin' Out....astonishing), and the one record that I can call both beautiful and terrifying. So don't listen to the naysayers. It has less to do with the album's quality and more to do with their middle of the road tastes. This is ESSENTIAL.
Most recent customer reviews
There are two ways to review this album, yielding two completely different results: one is to consider it in the context of Young's life and musical output, as such it provides an... Read morePublished on March 23 2008 by E. Haensel
Released in 1975 (but recorded in 1973), Tonight's The Night represents the darkest period of Neil Young's career. Read morePublished on April 3 2004 by Shotgun Method
The long history of rock and roll is filled with many incongruities. One of the more SEEMING incongruities has already been identified by several reviewers (I didn't read them all,... Read morePublished on Feb. 6 2004 by Rocco Dormarunno
Nineteen seventy five...the Vietnam epoch in its final spasms; Watergate and the resignation of a President...lies, lies lies...and the year I graduated from high school... Read morePublished on Dec 15 2003 by Jeff Rogers
Rarely can music that is this bad be so good. This is what happens when five or six guys decide to throw a wake for a couple of fallen comrades, lock themselves in a studio with a... Read morePublished on Nov. 19 2003 by John Russell
The words "dark," "drunken," and "brooding" appear in so many reviews for Neil Young's "Tonight's The Night" (though it is all of these, and... Read morePublished on Nov. 14 2003 by Arthur D. O'Brien
This album is so perfect! How can you go wrong with an album as beautiful as this? Truly one of his masterpieces and a record I am glad I purchased. Read morePublished on Oct. 6 2003 by doug
This LP has been called an Irish Wake and in many ways it is. Recorded by Young and the remainder of Crazy Horse after the death of guitarist Danny Whitten (heard here on... Read morePublished on Oct. 2 2003 by WILLIE A YOUNG II
I originally owned this...on the good ol' 33 1/3 rpm version..and of course never had a sound system worth a pinch of...well you know... Read morePublished on Aug. 26 2003 by Ross Frisken
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Chamber Orchestra Performances
Great Woods Chamber Orchestra featuring Daniel Bernard RoumainMay 8, 2016Visiting Artist, hip-hop violinist and composer Roumain (DBR) performs his Rosa Parks Symphony with the GWCO as part of the culmination of his yearlong residency at Wheaton. Professor Chase Spruill will perform world premieres of music for violin, written by Wheaton student composers. Winners of Wheaton's Concerto-Aria competition will also perform. Suggested donation $5.. Weber Theatre, Watson Fine Arts, 7:30 p.m.
Great Woods Chamber Orchestra presents Beethoven's FifthDecember 13, 2015 The 50-piece GWCO, under the direction of Associate Professor of Music Delvyn Case, performs Beethoven's epoch-making Fifth Symphony, plus a new work by 2014 Pulitzer prize-winning composer Caroline Shaw, the youngest ever recipient of that award. Kristina Danga, '17, Concerto-Aria Competition winner, will also perform the lyrical Canzonetta from Tchaikovsky's Violin Concerto. Suggested donation $5. Weber Theatre, Watson Fine Arts, 4:00 p.m.
Great Woods Chamber Orchestra, featuring musicians from Community MusicWorksMay 3, 2015 The GWCO presents a varied, multicultural concert in collaboration with musicians from Providence's Community MusicWorks, one of the country's most respected urban music-education programs. The program will include Daniel Bernard Roumain's hip hop-influenced Rosa Parks Symphony, symphonic masterworks presented in conjunction with original films by Wheaton students, and performances by winners of Wheaton's Concerto-Aria Competition. Weber Theatre, Watson Fine Arts, 7:30 p.m.
Great Woods Chamber OrchestraDecember 5, 2014 The Great Woods Chamber Orchestra will perform music by Beethoven and other masters. Winners of the annual Concerto-Aria competition will also be featured. Donations gratefully accepted. Weber Theatre, Watson Fine Arts, 7:30 p.m.


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The DASH Diet (cont.)
Erica Oberg, ND, MPH
Dr. Erica Oberg, ND, MPH, received a BA in anthropology from the University of Colorado, her doctorate of naturopathic medicine (ND) from Bastyr University, and a masters of public health (MPH) in health services research from the University of Washington. She completed her residency at the Bastyr Center for Natural Health in ambulatory primary care and fellowship training at the Health Promotion Research Center at the University of Washington.
Melissa Conrad Stöppler, MD
Melissa Conrad Stöppler, MD, is a U.S. board-certified Anatomic Pathologist with subspecialty training in the fields of Experimental and Molecular Pathology. Dr. Stöppler's educational background includes a BA with Highest Distinction from the University of Virginia and an MD from the University of North Carolina. She completed residency training in Anatomic Pathology at Georgetown University followed by subspecialty fellowship training in molecular diagnostics and experimental pathology.
In this Article
- What is the DASH diet?
- What is the recommended daily allowance of sodium?
- How does the DASH diet lower blood pressure and promote weight loss?
- What foods are allowed in the DASH diet eating plan?
- What foods and drinks should be avoided while following a DASH diet?
- What is a sample DASH diet sample menu?
- What are some DASH diet recipes?
- How can I make the DASH diet tastier?
- What heart-healthy lifestyle interventions are part of the DASH diet?
- Physical activity and high blood pressure
- Stress management and high blood pressure
- Sleep and high blood pressure
- Alcohol use and high blood pressure
- Smoking and high blood pressure
- Weight management and high blood pressure
- Where can I find more information about low sodium foods, diet plans, and low sodium shopping lists?
- Salt FAQs
Stress management and high blood pressure
Stress can raise blood pressure even if you are following a healthy DASH diet plan. Many times, the things that cause stress are outside of our control and we feel we cannot change it (boss at work, family situations, and our health worries). What we can change is how we let stress impact us. By learning to be more stress resilient, we can reduce the impacts of stress, such as high blood pressure and weight gain. Stress management techniques such as courses in meditation (which can be found online or in person) are a good option. Two types of mediation, transcendental meditation and mindfulness-based stress reduction, have been studied and proven to lower blood pressure as well as increase peace of mind and stress resiliency.
Mind and body exercises such as yoga and Tai Chi also may help decrease stress. Check with your health-care professional if one of these is an option for you.
Sleep and high blood pressure
You may not have realized that poor sleep increases blood pressure. For example, people who have sleep apnea have higher blood pressure than those without the condition, and when that is treated (using a device to ease breathing), blood pressure comes down.
Get tips on handling your hypertension.


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Augusta Police Department
Augusta Police Looking for Distracted Drivers
The Augusta Police Department, in partnership with the Bureau of Highway Safety, is going to be conducting patrol activities throughout the city focusing on distracted driving.
Car Burglaries Increasing In Augusta
The Augusta Police Department are urging all residents to lock their car doors after a series of burglaries over the past few days.
Augusta Quick Mart Robbed Sunday Night
The Augusta Police are looking for an armed man who they claim robbed a convenience store Sunday night.
Augusta Police Department is Asking for Your Help
Do you know this man? These are surveillance photos of a man who the Augusta Police Department is looking for. The police are investigating a theft of a cartload of toilet paper from Walgreen's in Augusta.
Woman Murdered In Augusta [UPDATED]
Part Of State Street In Augusta Closed This Morning
The Augusta Police Department are urging drivers to avoid State Street today, a section of the street will be closed as workers install a new monument on the lawn in front of the Kennebec County Courthouse.
Accident on Memorial Bridge in Augusta Briefly Closes Bridge
Last night at 6:03 p.m. a three-vehicle crash on the Memorial Bridge forced the Augusta Police to close the bridge for about 30 minutes.


text: Akamai Last up this week is content delivery network Akamai ( AKAM). At first glance, it looks like Akamai is forming a bearish pattern (the opposite of PETM's setup, in fact). But closer inspection reveals that the setup in Akamai is actually a bullish development; the key is knowing when to buy this name. Right now, Akamai is forming a falling wedge, a setup that looks somewhat similar to a downtrending channel save for one crucial difference: In a falling wedge, the trend lines that form the channel are converging. Like the inverse head-and-shoulders in MRK, this is a statistically significant setup -- one study puts the eventual predictive power of a wedge (falling or rising) at near 90%. To trade a falling wedge, we're looking for a breakout above that downtrending resistance line. It's absolutely essential to wait for that signal before pulling the trigger on this stock. After all, shares could fall significantly further and still remain within the channel. Once we see a breakout in this name, the 200-day moving average looks like an attainable price target. Consider a protective stop just below the 50-day moving average. To see these plays in action, check out the Technical Setups for the Week portfolio on Stockpickr. -- Written by Jonas Elmerraji in Baltimore. RELATED LINKS: >>Profit From These 3 Trading Mistakes >>5 Stocks to Sell Ahead of Earnings >>Screening for Actionable Investment Ideas Follow Stockpickr on Twitter and become a fan on Facebook. Prev 5 of 6 Next


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