Mr. Muhammad Amir Rana was a founder member of PIPS when it was launched in January 2006. He has previously worked as a journalist with various Urdu and English daily newspapers from 1996 until 2004. He has also been affiliated with the Institute of Defence and Strategic Studies, Singapore as a visiting fellow. He has also given lectures at several universities and security institutes in Pakistan and abroad. He has worked extensively on issues related to counter-terrorism, counter-extremism, and internal and regional security and politics. He has published widely in national and international journals, professional publications and magazines. He writes regularly for Dawn, Pakistan's leading English newspaper. He has also been invited to appear as an expert on the electronic media, including CNN, BBC World, Al Jazeera English, Voice of America, Al-Arabia and other Pakistani and international news channels. He is also the editor of Pakistan Annual Security Report, PIPS' English research journal 'Conflict and Peace Studies' and Urdu monthly magazine Tajziat.
Prof. Dr. Tara Prasad Sapkota isa former dean at Faculty of Law, Tribhuvan University .He is a graduate from the very same university and also bears a degree of MA in Political Science (TU), LLM and Ph.D. from Japan.
Dr. Khadga K.C. is Associate Professor and Program Coordinator of Masters in International Relations and Diplomacy, Faculty of Humanities and Social Sciences, Tribhuvan University. He did Masters` and PhD from the Nagasaki University, Japan 2009. His PhD Dissertations was on, "Foreign Aid and Democratization in Nepal". His postdoctoral research was also on International Role in Democratization in Nepal. Dr. K.C. is a visiting SUSI short term scholar at US Foreign Policy at the University of Florida, Harvard, The Chicago University and the MIT. He was also Japan Foundation Fellow at Graduate School of Asian and African Area Studies, Kyoto University, Japan (May, 2012- March 2013). His areas of interests are modernization and democratic theories, democratization, security discourses, foreign policy, international relations, global governance, Japanese affairs among others.
Dr. Atindra Dahal is currently working in the capacity of Associate Professor at Kathmandu School of law and has done PhD on Issues of Nation Building as continuous effort in pursuing higher education after earning M. Phil. in English Literature & Philosophy, M.A. in English Literature and Philosophy and M. A. in political science respectively. Dahal has capaciously produced research based academic writings. As of now, 30 of his academic research papers are published in various prestigious journals from nation and abroad. Quite regularly, he delivers guest classes in different areas of political psychology and communication paradigms to academic and corporate practitioners and associates as well. He is also the Editor of Kathmandu School of Law Review.


Hi folks, I know it's been a while since I've written a new post. Life has been busy, and this just got pushed to the back burner. This post is here to let you know what's new with my business and what resources are available. There's a real post (with pictures and everything) coming right after this, I promise.
Thank you for your interest in learning how to restore your health through improving your body's alignment. It's an honor to help you reach your goals and live an active, pain free life. I've started two new methods of communication: a newsletter & an Anthology Wellness Facebook Page. This is an effort to stay better connected with you and provide you with more options, so you can choose what works best for YOU.
Perhaps you are wondering how the newsletter & Facebook page will be different than this blog. The blog tends to be mostly educational material. My intention for the newsletter is to highlight current classes, workshops & events, as they are constantly changing. The newsletter will also include links to online classes and other tools to help you in your quest for better alignment. The Facebook page will share helpful tips, quick facts, and relevant articles from myself, other Restorative Exercise™ Specialists, katysays.com, and other health professionals.
I hope this helps you find the tools YOU need to help you on your alignment journey. You can use the links below to subscribe to the newsletter, read the most recent one or find me on Facebook.
Next postStay Healthy This Cold & Flu Season, Move Your Lymph.


Judge Strenkoski presides on the 1st and 3rd Tuesday of each month at 6:00 p.m.
Judge Angela Stamm Philipps presides on the 2nd and 4th Tuesday of each month at 6:00 p.m.
If there happens to be a 5th Tuesday in the month, no court is scheduled.
Proper dress is required for all court hearings.
What forms of payment are acceptable? Can I make a payment by phone or online?
What are the hours to pay my Traffic Ticket?
How do I file a Small Claim in Wheatfield Court?


Thanks to our friends at Audi South Burlington, VT for this great infographic on 7 tips to improve driving posture! Check it out and see if you need to make any changes to feel better while driving. It's so great that local businesses are starting to think about how they can impact the health and wellness of their customers and community!


Discussion in 'Permanent Shelters' started by Hick Industries, Mar 11, 2019.
Son of liberty asked me to talk about building my new house.
My idea of a perfect retirement, was to buy a rough piece of land, and build a ranch from scratch. If you were to guess that entails a hell of a lot of work, your right.
My wife and I wanted a nice log house with a basement. The land we bought has a lot of slope to it, so I choose a site where we could build a walk out basement, and have access to all sides. I was very carefully to choose a place where surface runoff runs away from the house. So far, so good.
We started in early June, by digging a hole. A big hole. Big enough for the basement and a two car garage. The basement walls are made from insulated concrete forms. This produces a very strong, very tight, well insulated building. On top the ICF walls, we built a cedar log home, purchased as a kit. Actually, a framing crew assembled the walls, and the roof for me, but I did write them a nice check.
Once the house was dried in, I began installing the extra insulation to the outer walls, the power and water lines, and the vinyl flooring. My primary heat is a soap stone wood stove (https://www.hearthstonestoves.com/en/wood) and my water storage is a 3,000 gal tank located on the hill side above the house.
I still have a couple of systems left to install before I move in. I'm having a 3 ton mini split heat pump installed, with wall units for the basement, main floor, and the loft. My water tested hard with considerable sulfate and calcium/magnesium carbonate, so I'm installing a whole house filter/softener. Finally, I will be putting in a septic tank and a 500 gal propane tank.
lalakai, randyt, Morgan101 and 5 others like this.
Liberty Guy asked me to talk about building my new house.
Once the house was dried in, I began installing the extra insulation to the outer walls, the power and water lines, and the vinyl flooring. My primary heat is a soap stone wood stove, and my water storage is a 3,000 gal tank located on the hill side above the house.
Not water efficient then, pitty. How about electricity, off grid?
I believe you live in a dry area, perhaps Austrailia? I lived in the Mojave desert for 32 yrs so I know what it takes to find and store enough water, when it only rains a couple days per yr.
So when I retired I sold my house in the California desert, and moved to eastern Oklahoma. It rains an average of 46" per yr, I have four springs on the property, and a small creek runs through my lower pasture. Far more concerned with draining flood waters, than conserving water.
I have a couple of solar panels powering lights, and my shallow well pump. But since this is a real ranch, I have the deep well pump, and all my shop tools hooked up to line power. Not trying to go off grid, but we have ice storms that close the roads and damage the power lines.
Morgan101, TMT Tactical, poltiregist and 1 other person like this.
Do you have well water or is it piped in from some municipality? Well water is not always pure or clean. Lotta folk must treat their well water.
Good thing that you have a wood stove. I'd not heard of soap stone wood stoves. I've heard of huge masonry stoves like those of Scandinavian countries. So, I've just now found some online info about these soap stone stoves -- sound neat so far. Thanx for bringing up the topic.
I think that it would be neat having an escape tunnel leading away from a survival house. I'm from an area of the South that was anti-slavery / pro-Republican during this country's first Civil War. A good-sized mansion about a half-mile from where I used to live had tunnels leading away from it and opening out in the woods. The place was one of the many safe-houses on the "underground railroad", a term meaning escape routes to the North. So, if that mansion had been the target of a Southern raid, the run-away slaves could head out of the house underground to the far end opening in the surrounding forest. What with today's durable piping, a tunnel could be made rather safe.
Great question about well water quality. We have two deepwells, and one shallow well. We pulled a sample and sent it to National Testing Labs. Report indicate no bacteria, nitrates, or heavy metals. But it is alkaline and contains sulfates, calcium, magesium carbonate. We purchased a good whole house filter and water softener unit.
Hick, how hard is your water and what softener system did you go with? Here in PA where we are our water tested 25 grains hardness. We put in a Culligan system but we seemed to have swapped hard white calcium on everything to hard white salt as the unit requires so much to drop the hardness. I'm thinking about changing it to something else if I can find a better or different unit that doesn't trade one for the other. I really wish I would have went with a Kinetico though I think it;s the same salt for calcium ion replacement technology. Thanks for all the info.
Well, good for you and yours. Municipal supplies will go intermittently or go off, period. This is why most folk need storage barrels. I live where there are streams and rivers all about.
If getting water out streams, one must filter first with ceramic then with charcoal. Even after those treatments, one should still boil the water. Viruses must be killed. The number one killer of kids on our planet is dysentery.
Welcome, your house looks and sounds great. We built an ICF home back in 2006, we're about 10 degrees of latitude north of you and incorporated passive solar heating into the design. The sun and a lower level wood stove are our primary heat sources and we use less wood a year than many homes half the size of ours. First ICF home I ever lived in, and can't envision not living in one now. They have many survival advantages beyond energy efficiency too. Like you we wrote a check for the construction and did many updates ourselves afterwards. Modern homes just aren't well designed for griddown/offgrid living, the builders' solution to everything is to throw more kilowatts and BTUs at any problem until it's solved. If you want it done right you need to design it yourself.
You did the digging yourself? Did you rent a backhoe or something? How hard is ICF to work with? Can you ballpark me on the cost to build the house and basement? Is it significantly cheaper than just building an all metal building?
Icf is not difficult once you have seen it done once or twice. I would not suggest learning on your own home. Either work for a crew for a year, or hire it done.
I bought myself a 65hp ag tractor with a backhoe when I first retired and moved here. I prepared the building site and trenched all the utilities, but hired the basement excavation, and concrete work.
I built a 24x40 post frame metal building for $3400.
Add another $ 2000 to insulate the ceiling and walls, and pour a slab.
My icf basement cost $44/sqft and that just supports the log home above.
Duncan, watcherchris, Sonofliberty and 2 others like this.
sounds nice. it will be interesting to follow as you live and refine the operation. Definitely a great source of highly useful info. thanks.


text:
Vaccination yes or no? That's why SPD co-chair Esken expects a long debate
Home » News » Vaccination yes or no? That's why SPD co-chair Esken expects a long debate
Debate about compulsory vaccination against the corona virus: Saskia Esken from the SPD does not expect a decision until March at the earliest.
Bonn – Before a possible vaccination against the Coronavirus comes in Germany, he has to Bundestag debate about it. The co-chair of SPD, Saskia Esken (60), assumes that a decision will be made in March at the earliest.
Saskia Esken (60) is co-chair of the SPD party. © Bernd von Jutrczenka/dpa
"In any case, we want to come to a decision in the first quarter, ideally at the beginning of March," says Esken im phoenix-Interview this Saturday.
Until then, the parliament in the Bundestag will have enough time to intensively discuss the pros and cons of compulsory vaccination for all citizens in Germany.
"We are now in mid-January, we would then have half of January and the whole of February for the debate, which also takes place when we don't have session weeks. We have all the time to debate the topic in depth," said the SPD -Politician.
The current vaccination rate of 75 percent is not sufficient to stop the pandemic.
The politician said about this fact: "We have had to realize that we cannot achieve the vaccination rate we need through pure persuasion and that we obviously need vaccination."
The SPD politician spoke out in favor of "compulsory vaccination from the age of 18". In the SPD, she expects a high level of approval for the obligation: "I assume that the SPD will agree in large numbers."

redpajama_set_name: RedPajamaCommonCrawl


Wondering where to go for a family holiday during this year's school holidays? The biggest dilemma regarding planning a family holiday is to choose a destination that has attractions and activities to keep your kids intrigued and interested in the whole duration of your vacation. Malaysia is an impressive Asian destination that offers loads of attractions and entertainment for family holidaymakers. Planning for such a vacation can seem daunting and the main question that looms in your mind is where to go to Malaysia to please everyone in your family, right from the youngest to the oldest member. Take a look at these Malaysian points of interests that are best suited for all age groups.
The lively city of Kuala Lumpur feels like an over-hyped metropolitan with a business-like attitude. However, peek into the depths and you will find fascinating Malaysian tourist spots ideal for a family outing. Start with the majestic vistas of Petronas Twin Towers which are the tallest standing structure in Malaysia. The Kuala Lumpur City Center (KLCC) also offers plentiful attractions that can be enjoyed by kids and grownups alike. Visit Petrosains Discovery Center and KidZania Kuala Lumpur where little visitors can have a delightful time getting introduced to new experiences in Malaysia. Take a 15-minute drive away from KLCC and you can enjoy the rest of the day with your family amid nature's beauteous splendors. The Perdana Botanical Garden is set at the outskirts of the city which works as an idyllic nature escape from the city life. A visit to the park is a great way to reconnect with nature without leaving the city behind. Here, you and your dear ones can marvel at an amazing array of floral blooms at Orchid & Hibiscus Gardens.
Johor Bahru is often ignored as a Malaysian holiday destination, but if you are travelling with kids, then you should include this destination in your Malaysia family vacation. This is one place in Malaysia that offers numerous exhilarating attractions to keep kids thrilled all day long.Set on the southern tip of the Malay Peninsula, Johor Bahru is a charming town close to Singapore and is the main entry point from Malaysia to Singapore. This is one of the reasons why Johor Bahru is popular amid family visitors as they could easily club Singapore to their Malaysia family vacation. This way they can enjoy best of kid-friendly attractions offered by both the nations. Johor Bahru is home to world-renowned theme parks such asLegoland Malaysia and Angry Birds Theme Park. If you are visiting with toddlers, take them to Thomas Town and Sanrio Hello Kitty Town which has rides and activities specially designed for them. Grownups can join in on the fun at Austin Heights Water & Adventure Park and Zenxin Organic Park. Don't forget to explore this quaint township on your visit as it offers some of the most breathtaking sceneries in Malaysia. Overall, Johor Bahru is a destination that offers wholesome fun for family visitors.
Need a pinch of outdoorsy adventure in your Malaysia family vacation? If you want to vary a bit from theme parks and usual Malaysia sightseeing and attractions, then head to Bukit Gasing for a nature adventure. Located in Petaling Jaya, around 30 minutes away from Kuala Lumpur, Bukit Gasing offers numerous charming nature trails that meander through verdant wilderness. Hiking through these trails is easy and kids can effortlessly trek without any stress. Only challenging sections are the suspension bridges and steep and rugged climbs at certain parts of the trails. However, the experience in nature is a memory they will cherish for a lifetime.
One of the most prominent places to visit in Malaysia is Batu Caves.Approximately 30 minutes away from Kuala Lumpur City Center, a sprawling forested limestone terrain guarded by a colossal statue of Hindu God Murugan enthralls your sight. Dedicated as a Hindu shrine, Batu Caves hold spiritual significance to the Hindu community of Malaysia. However, exploring the network of limestone caves and the panoramic view of Malaysia once you reach the top is definitely 'not to be missed' experiences. The tranquil ambiance and gorgeous lush nature accentuated by sculptures and murals of deities offer a soul-stirring experience for its visitors. Batu Caves is a great idea if you wish to take a break from Kuala Lumpur and venture to an outdoorsy spot. Though the flight of stairs and journey can seem tiresome, Batu Cave offers young visitors an insight into the refreshing essence of nature and into Malaysia's multi-ethnic elements.
Malaysia is a fantastic destination to take a break from routine life and have some family-bonding time together. Also, planning a family trip to Malaysia certainly not difficult. All you need to know about is how to get Malaysia tourist visa, when to travel and where to go and you are all sorted for a memorable Malaysian family holiday.
It's a great country to visit from the cameron highlands to georgetown and KL of course. I still prefer Thailand but this country has a lot to offer. It's a non drinking country note!


1. Candidate must have a direct familial relationship to the sponsor.
3. The candidate will be a full time student (Min. 12 credit hours per semester) enrolled in a university or junior college working toward a degree.
4. The candidate will be required to complete the attached application. The application must be completed in its entirety in order to receive consideration.
5. A current or recent grade transcript (Official or Unofficial) is required by Sophomores, Juniors, and Seniors. Incoming freshman will be required to furnish a schedule upon registration.


text:
10 Great Richard E. Grant roles
February 20, 2019 flawintheiris
The undisputed media star of this year's Academy Awards season—coming to a conclusion with the ceremony on Sunday, February 24—is the Swaziland-born veteran actor Richard E. Grant.
Those of us deeply embedded in the cult of his first feature film, Withnail and I, are especially enjoying the various articles about Grant's enthusiasm, and his deft social media presence. Through his 32-year career in cinema, Grant has shone in supporting parts and leads, in indies and Hollywood prestige pictures, as comfortable in blockbusters as in quirky British fare.
Though Can You Ever Forgive Me? only played for a few weeks in the fall and didn't reopen in cinemas locally with the Oscar nominations—for Best Actress, Melissa McCarthy, Best Supporting Actor, Grant, and Best Adapted Screenplay, Nicole Holofcener and Jeff Whitty—it will be available this week on iTunes.
The film is an examination of forgery and loneliness, not necessarily in that order, with McCarthy as Lee Israel, a down-on-her-luck writer in early-90s New York City who finds a sideline, then mainline, as a forger of literary letters. Grant plays her friend and sometime partner-in-crime, Jack Hock. It's a delightful, moving performance. One can't help but see the shadow of Withnail here, though Jack isn't anywhere near as pathologically selfish as Grant's debut feature character.
For those who don't know, Withnail and I is an independent comedy drama written and directed by Bruce Robinson. Robinson started as an actor and a quite successful one, but eventually turned to screenwriting, penning the script for The Killing Fields and earning an Oscar nod.
The unnamed character "I" (or Marwood, as he was called in the script), played by Paul McGann, is Robinson's proxy, and the story is based on his years in the 1960s as a struggling actor in London. The two friends, concerned about their health and needing to break the cycle of drinking and drugs, pay a visit to Withnail's flamboyantly gay Uncle Monty (Richard Griffiths). From him they're able to secure the keys to a ramshackle cottage in the Lake District. They take off in a banged-up Jaguar out of decaying London, but soon start to feel as though they've gone on holiday by mistake.
Grant is absolutely hilarious. His Withnail is cowardly, egocentric and absolutely charming. You kind of hate him and you kind of want to be him, or at least as witty as him. But you feel for McGann's character, who is at the mercy of Withnail's whims.
It's a script crammed with classic bits of dialogue. When Withnail returns from a failed audition for a cigar commercial, he says, "a gang of cheroot vendors thought a haircut beyond my ability." Even the throw-away lines are brilliant. It is the kind of movie that improves with multiple viewings, with a kind of grit common in the work of Mike Leigh or Stephen Frears… but generally a lot funnier.
I can't think of a film that's as melancholy as this, but also so incredibly humorous. It's a film that must've been stitched together budget-wise with spare string and bubblegum, but the script and key performances, by Grant, McGann, Ralph Brown, and the late, great Griffiths, are all wonderful. I saw it at age 16 in London at a Baker Street cinema, and I've seen it a dozen times since. It simply never ages.
I've even got the Ralph Steadman poster up on my wall.
How To Get Ahead in Advertising, also starring Grant, another comedy from Robinson's fervid imagination, but an even blacker one. A satire on marketing, it's the story of Denis Bagley, an ad man trying to come up with a campaign for pimple cream, who then develops a terrible, talking boil on his neck. It's utterly unhinged. An little bit of trivia: Grant's co-star in this film, Rachel Ward, is directing a feature now called Palm Beach, and Grant will star.
Thanks to these performances, Hollywood took notice. Grant's next role was in a low-budget fantasy called Warlock, with Julian Sands as a 17th Century warlock, and Grant as a witch-hunter looking to stop him from reassembling the Grand Grimoire, a very evil book.
The warlock finds a way to travel through time to present-day Los Angeles, with Grant's Redferne hot on his heels. There they run into Lori Singer's Kassandra-with-a-K, and Redferne and Kassandra chase the warlock across the countryside toward Boston. The effects haven't aged too well, but the movie is actually a lot of fun, with the script mining the fish-out-of-water humour between's Grant's man-out-of-time and Singer's California girl as they travel together, like a weird take on Midnight Run.
Warlock doesn't take itself too seriously, given dialogue like the following—Redferne revealing his plan of "thwarting a vile beast of a man who shall not rest until God himself is thrown down, and all of creation becomes Satan's black hell-besmeared farting hole!"
From here on, Grant becomes a frequent and reliable ensemble and supporting player for the world's best filmmakers.
He's worked with Bob Rafelson (Mountains of the Moon), Robert Altman (The Player, Prêt-a-Porter, and Gosford Park), Jane Campion (The Portrait Of A Lady), Martin Scorcese (The Age Of Innocence), and Pablo Larrain (Jackie). These are all notable films—and most of them are terrific—with Grant's performance in each making them better for his presence. Of his supporting work in large casts, I'd direct the curious toward two in particular:
He is Hugo in Henry & June, Philip Kaufman's look at the intersecting lives of Anaïs Nin (Maria De Medeiros), Henry Miller (Fred Ward), and Miller's wife, June (Uma Thurman), in the early 1930s in Paris. It's a film deeply concerned with sensuality, and Grant has one of the toughest roles, playing Nin's repressed husband. On first impression Hugo seems so dull in comparison to the explosive sexuality in the three leads, but eventually experiences an awakening of his own.
Also check out Dr Jack Seward in Bram Stoker's Dracula. Francis Ford Coppola's gothic drama. The starry cast—including Gary Oldman, Winona Ryder, Anthony Hopkins, Keanu Reeves, Billy Campbell, Sadie Frost, and Tom Waits—doesn't leave Grant a lot of room to shine, but he still makes an impression with his character's nobility and courage in the face of the undead horror.
In the midst of his first brush with Hollywood, Grant starred in one famously disastrous action picture, and another much-adored cult comedy.
The turkey was Hudson Hawk from 1991, a Bruce Willis vehicle that failed to soar at the box office. It actually has plenty of entertainment value as any film with a cast including Willis in his prime, Danny Aiello, Andie MacDowell, James Coburn, David Caruso, Frank Stallone, and in a killer double-act, Grant and Sandra Bernhard as the villainous Mayflower siblings, who blackmail Willis' ex-con cat burglar to steal a Da Vinci. Grant has never gone bigger than this, and it's a delight whenever he and Bernhard are on screen together. Willis is at his most self-satisfied, which doesn't do the movie any favours.
Grant wrote a wildly entertaining book about his first few years in Hollywood, entitled With Nails, saving his juiciest revelations about working on the set of Hudson Hawk. It's essential reading for anyone interested in a balcony view look at Tinseltown from an outsider's perspective.
The cult comedy was LA Story, written by and starring Steve Martin. Though it's a cliche to say a film is a love-letter to something, this is a picture that absolutely adores Los Angeles, while also being very clear-eyed about its flakey contradictions. Martin is Harris K. Telemacher, a weatherman before they called them meteorologists, who's mired in an awful relationship with Trudi (Marilu Henner). Then along comes English journalist Sara (Victoria Tennant), and to the soothing sounds of Enya, Harris and Sara fall in love. Grant is Roland, Sara's ex-husband, who she may want to get back together with. Grant underplays Roland, making him an altogether likeable fellow, if slightly piteous. Rounding out the cast is Sarah Jessica Parker as the delightful SanDeE*, who enjoys colonic irrigation and spinning on the beach, and keep your eyes open for a wonderful Patrick Stewart cameo. The film is at once surreal, riotous, and surprisingly heartwarming for a romantic comedy that also features a sentient digital highway sign.
I have to admit, a browse of Grant's IMDB profile reveals much more of his work in the past two decades or so unseen than seen by me, which has a lot to do with his having done so many films in the UK—Grant has referred to "the inert corpse of my American career"—while his European films never opened in North America, or else are barely available.
His 1995 romantic drama Jack & Sarah is available to be seen on YouTube, but others are harder to track down. like the George Orwell adaptation Keep The Aspidistras Flying aka A Merry War, also starring Helena Bonham Carter. Grant is one of the few reasons to watch the Spice Girls' movie Spice World—though he credits it for having landed a gig on Lena Dunham's Girls, as she is a fan of the movie—while his work in films such as Monsieur N. and Bright Young Things is very much still on my list to see.
In 2005, Grant wrote and directed Wah-Wah, an autobiographical tale of life at the end of the British colonial era in Swaziland, starring Gabriel Byrne, Miranda Richardson, Emily Watson, and Nicholas Hoult. Grant directs with a light touch despite a fairly bleak tale of alcoholism and family strife—this is far from the comedy it might look like on the surface.
It's also an affecting coming-of-age tale, and you can feel the actor slip easily into the role of filmmaker when the material is so close to his heart, even casting his daughter, Olivia, in a supporting role. It's available now on Amazon Prime.
Dom Hemingway maybe was a bit of a stretch for Jude Law, a charming performer playing someone so free of charm, a violent and unpleasant ex-con. I had some issues with the film, but Grant shines as Hemingway's wonderfully droll buddy Dickie Black, a role with some real style and swagger.
I have a feeling we'll be seeing a lot more of Grant in Hollywood in the coming years, his role in Can You Ever Forgive Me? having reminded those directors and casting agents of his broad talent. He's got a part in the upcoming Star Wars film, and you know he's sure to be a First Order baddie of some sort. If this is the stage of his career where we see him more often as the villain, the kind of part Mark Strong has been playing for a decade, that works, too. He deftly filled that part in Logan, as Dr Rice, the malevolent scientist who experiments on young mutants.
I want to wish all the best for Richard E. Grant at the Academy Awards on Sunday, and the career kick that will likely come from it. Grant says he's not writing a speech because he's sure Mahershala Ali will win for his role in Green Book. I'm sure he'll have a blast either way.
Andie MacDowellAnthony HopkinsBilly CampbellBob RafelsonBruce RobinsonBruce WillisDanny AielloDavid CarusoEmily WatsonEnyaFrancis Ford CoppolaFrank StalloneFred WardGabriel ByrneGary OldmanGeorge OrwellHelena Bonham CarterJames CoburnJane CampionJude LawJulian SandsKeanu ReevesLena DunhamLori SingerMaria De MedeirosMarilu HennerMartin ScorceseMelissa McCarthyMiranda RichardsonNicholas HoultPablo LarrainPatrick StewartPaul McGannPhilip KaufmanRalph SteadmanRichard E. GrantRichard GriffithsRobert AltmanSadie FrostSandra BernhardSarah Jessica ParkerSteve MartinTom WaitsUma ThurmanVictoria TennantWinona Ryder
Previous PostAlita: Battle Angel review — High production value can't save wet script
Next PostArctic review — Brilliant, brutal ice-bound thriller


text:
Q: Validate header rows different from database column names with Laravel Excel I'm using the following package https://laravel-excel.com/ to import excel files but have run into a problem while validating the rows.
The header row names might be different from the column names in the database. So my question is how can I validate the header rows with a different name? For example the database column name is first_name but the header row name can be either first_name or voornaam.
I was also wondering why the :message isn't using the localization :attribute from the language files. For example the attribute first_name is translated in lang/nl/validation.php as voornaam the error message still returns first_name.
The import function:
public function model( array $row )
{
        return new Participant([
            'salutation' => $row['salutation'] ?? $row['aanhef'] ?? null,
            'first_name' => $row['first_name'] ?? $row['voornaam'] ?? $row['voorletters'] ?? $row['voorletter'],
            'last_name' => $row['last_name'] ?? $row['achternaam']
     ]);
}

The validation rules:
public function rules(): array
{
        return [
            'salutation' => 'nullable|string',
            'first_name' => 'required|string',
            'last_name' => 'required|string',
       ]
}

I have tried to use the customValidationAttributes but that doesn't work. Also made a issue about it but so far no response.
public function customValidationAttributes()
{
    return [
        'salutation' => 'salutation',
        'aanhef' => 'salutation',
        'first_name' => 'first_name',
        'voornaam' => 'first_name',
        'last_name' => 'last_name',
        'achternaam' => 'last_name'
     ]
 }

redpajama_set_name: RedPajamaStackExchange


text:
A 3440 Stampfer (ideiglenes jelöléssel 1950 DD) a Naprendszer kisbolygóövében található aszteroida. Karl Wilhelm Reinmuth fedezte fel 1950. február 17-én.

Kapcsolódó szócikkek
 Kisbolygók listája (3001–3500)

Jegyzetek

A Naprendszer kisbolygói

redpajama_set_name: RedPajamaWikipedia


text:
WcoAnimedub: Where to Watch Free Anime Online
By Erika Noise Last updated Sep 12, 2022
The website wcoanimedub should be well-known to anime fans. It is a website that offers anime, cartoons, and ova series in both dubbed and subtitled versions. You may also download the files for later viewing on the site, which is entirely free. You may watch anime without registering or paying anything, unlike kissanime. It offers more than 300,000 episodes, many of which are from the most well-known brands.
Providing dubbed content
The most popular version is free
The WcoAnimedub you can download
This is a popular site for watching anime
The previous streaming information can be found here
Wcoanimedub has a good reputation
Simple and functional user interface
This website is a great resource for watching anime for free. It offers dubbed content as well as the option to download the videos for offline viewing. The website streams anime in a downloadable format using HTML5 and Flash technology. The website also has an integrated subtitler that lets you choose the language and subtitle you desire. You can locate the book you desire on the site because many of the titles are offered in various languages.
WcoAnimeDub.com, which also offers a free version of the majority of popular series, is another excellent source for anime. On this website, users can reserve seats and download the episodes they're watching. The website supports Firefox and Chrome and provides a download option in the video player's lower half. The only thing to bear in mind is that wcoanimedub, which is the major reason it's so popular, is not available in every nation.
WcoAnimeDub is another free anime website. This website provides a list of well-liked anime programmes. To reserve seats to watch currently airing anime, simply search for the shows you're interested in. Along with a list of top titles, this website also features a search function. If you're not happy with the quality, you can download a free version of wcoanimedub.
Try alternative websites for free anime if you're not a fan of wcoanimedub. You may reserve your seats on Animetoz, a famous website for watching anime. WcoAnimeDub provides dubbed and subbed anime in addition to the free version, allowing you to watch it without any restrictions. WcoAnimeDub is free to use, and you can even sign up for a monthly subscription.
If you enjoy anime, wcoanimedub is a great place to stream it. Episodes can also be downloaded. The languages available on wcoanimedub can be chosen based on your preferences. On your PC, you can use it to view anime. Videos and TV programmes are available for free download. Downloading a series that interests you is also free. You will have a large selection of titles to choose from because this website features a wide range of anime.
In contrast to kissanimedub, wcoanimedub features a vast selection of well-known anime and lets you reserve seats. Both subtitled and dubbed content is available on the website, which is compatible with Chrome and Firefox browsers. Additionally, logging in and reserving seats is simple. Funimation is a country-focused anime choice with a number of websites. It provides a huge selection of well-known series in both dubbed and English versions.
You can choose from a variety of anime series on the wcoanimedub website, including wcoanimedub.com. Although it has a user interface similar to fmovies, it provides access to more than simply anime. You could even reserve some seats. You can also browse and save your past streaming data on this website. Also on the website is a download icon.
Since it has been operating for a while, wcoanimedub.com has earned a solid reputation as the most comprehensive anime website on the Internet. This website includes a wide selection of movies and TV shows in addition to being a wonderful place to find anime. Finding and watching movies and anime is its primary objective. WcoAnimeDub is only one of many additional websites.
WcoAnimeDub is a fantastic option if you like cartoons. Its user design is straightforward and practical, and compared to other anime websites, it has fewer advertising. You may download and register for free, and you can watch anime with subtitles. While wcoanimedub is more practical than adblocking websites, you can watch anime online without creating an account. If you enjoy cartoons, wcoanimedubli.com will offer a wide variety of your favourite programmes.
Read Also: Minato Namikaze Parents, Wiki, Clan, Spoilers, Facts, And More
Anime is one of the most popular genres of entertainment worldwide, and for good reason. With story lines that are both exciting and engaging, anime has a way of drawing in viewers from all walks of life. However, with so many anime shows available to watch online, it can be hard to decide which show to start watching first. That's where WcoAnimedub comes in! We have compiled a list of the best free anime streaming sites so that you can find your next favorite show without any hassle. So what are you waiting for? Start watching some great anime today!
Lucy Letby Evidence, Motivation, How Eight Babies Died?
Jesy Nelson Biography, Wiki, Age, Ethnicity, Parents, Boyfriend, Career, Net Worth, And More
The Zoe Chip | Is It Legal Or A Scam?
Life On The Flower Road Of The Grand Duchess Spoilers
Koichi Hair Evolution – Koichi Hirose
Is The Orville Season 4 Renewed Or Not? Here The Update


Not seeking for anything sexual from you, well unless you have some sort of idea haha. My overall attiude is be the great you can be and keep moving forward in your personal Matude and relationship, I'am a very focused person who believes in working hard and taking care of my love ones. Cool confident company. Friend had Mature long island luck with this.
Find hundreds of single New York mature females already online finding love and friendship in Long Matre Sign up in 30 seconds and meet someone.
Long Island Single Mature Women. My name is sherry and I am 64 years old.
I am divorced and I am a plus size woman. I am looking for a friend and companion And see where it goes.
I am looking for someone that knows what Skip to Job PostingsSearch Close. Upload your Matufe Sign in. Full-time 28 Part-time 17 Commission 6 Temporary 3.
Entry Level 25 Mid Level Upload your resume - Let employers find you. Life Coaching Mentor Job Path 15 reviews. Matureself-motivated, Mature long island, have a strong sense of responsibility, and sound judgment.
Be sensitive to the special needs and interests of children and We are looking for matureresponsible individuals Mature long island provide services to adults with developmental disabilities in residential settings How are the working hours?
Do they follow through with the random drug testing protocol?
Responsible for the Adult English Class Curriculum. Ensure all adults are taken care Matre during program times with care Sign up in 30 seconds and meet someone.
Long Island Mature Mature long island. Mature Dating in Staten Island Richie My name is sherry and I am 64 years old. I am divorced and Mature long island am a plus size woman.


A seed is planted in the ground. The darkness is a difficult place to be. In the darkness you are alone, isolated. In the darkness, none of the things that used to work, that used to bring light into your world, will work any more. In the darkness none of your strategies will bring the light, none of your efforts make any difference, none of your talents or knowledge or experience have any impact. Even everything we thought we knew about God is useless in the darkness. You are helpless and cannot find the light, much less be a light. It the darkness it just won't work.
Sometimes the darkness descends on us individually. Other times the darkness descends on us collectively. Maybe you are living in the dark today. Our whole world can seem dark sometimes. Some feel that this is the experience of LCM, that darkness has descended on us as a congregation. Many things that used to bring life is working. Some of our efforts seem to be failing. We keep trying different things to recapture life and light, and yet the darkness doesn't lift. We desperately look to what we know and what we trust to get us out of the darkness.
We fix worship styles and music styles, but there is no new life.
We seek to reinstate a dead Sunday School institution because it used to work, but there are few kids.
We want to start new programs, correct our doctrine, get the new members to bring life and energy. But the darkness isn't lifted.
We cling to memories of the magical days of the 1960s, or 70s, or 80s, or whenever, wondering why those days seemed so bright and today seems so dark.
We tweak and we work and we struggle in the dark. We argue and we look for someone to blame and we defend what we love, and the darkness still permeates.
When you are in the darkness, nothing you do or know or try has any effect. You can die in the darkness.
So it makes sense that we would cling to anything, to everything that we think can give us life. We cling with desperation to the things that made sense before the darkness descended. We even cling to our former notions about God and call that faith. But the more we cling, the deeper the darkness.
Eventually, in the darkness everything will be stripped away. All our notions and preconceptions. Our pride, our justifications, our desperation, our knowledge, our certainties. Even what we know–or thought we knew–about God will all die in the darkness.
And then can new life emerge.
Some Greeks came up to Philip and wanted to see Jesus. Jesus replies, "Unless a grain of wheat falls into the earth and dies, it remains just a single grain; but if it dies, it bears much fruit." If you want to see Jesus, it will involve darkness. "Those who love their life lose it, and those who hate their life in this world will keep it for eternal life." To see Jesus, to follow Jesus, to live in Jesus means a journey into the darkness. Like a seed being planted in the darkness of the ground.
A seed can cling to anything in its former life as a seed. Sunshine, birds flying by, life hanging out on a branch or a stalk. But clinging to that won't bring it life. A seed has to be buried in the darkness of the earth in order to spring forth in its new life, a life bearing fruit.
The very core, the very breath, the very heartbeat of Christianity is that there is a God who brings life out of death, light out of darkness.
Like a seed growing up from the darkness of the ground.
Like a crucified body rising up to life from the darkness of a tomb.
Are you in the dark? Is the world around us in the dark? Is LCM in the dark? What is being stripped away in the darkness? What is being opened up, made new, given new life in the darkness? What is emerging from the darkness that will bear much fruit?
What is dying in the darkness so that something new and fruitful and alive can be brought forth? This is what God does. This is what we say we believe. This is the heartbeat of our faith: God brings life from death. God brings light from darkness.
We have a God of light who is with us in the darkness. And new life comes.
What is Jesus so mad about? Are the temple moneychangers cheating people or being dishonest? No.
Is this whole setup of exchanging money that declares Caesar as Lord for money that declares God as Lord not working? No.
Is this temple system ineffective? No, it's working quite well, actually.
Is it dishonoring God? No, not really.
So why is he so angry?
The whole temple system, which operates quite well and efficiently, isn't empowering people with God's love, forgiveness, and generosity. It's not pointing people to Jesus, who brings that into the world.
The fact that it works isn't what counts. The fact that sincere, God-loving people like it isn't what counts. The fact that it's been around for centuries isn't what counts. The fact that it's good religious practice isn't what counts.
The temple system of sacrifice, even though it functions well, doesn't reveal what God is doing. It doesn't bring people into forgiving others, loving others, being generous to others. It doesn't allow for Reign of God, the Heart of God coming in Jesus. It's a system of religious practice that functions in a cul-de-sac all by itself. But it's not connecting with God and God's mission of forgiveness, love, and generosity happening in Jesus.
Jesus comes into the temple and is dismantling the system, taking it apart. Any system that bears God's name but isn't about God's work—isn't empowering, even compelling, people into forgiving, loving, being generous ought to be dismantled.
That's all well and good. But here's where this gets hard. God's doing it again. A religious system that operates well and that lots of God-fearing people like is being dismantled. Church as we know it is being taken apart—by God, I believe. For similar reasons. The church we are familiar with isn't set up to reveal the fullness of God's will as revealed in Jesus. Christianity as an institutional church is more about self-perpetuation than forgiveness. It's more about numerical growth than unconditional love. We care more about fellow Christians than we do about atheists, Jews, Muslims, or non-religious people. We, the Christian Church, are a well-functioning, religious, well established cul-de-sac that functions far too often separately from God and God's mission. And we are being dismantled. Look around at all the countries that we used to call "Christian." Every one of the traditional Christian countries is losing members hand over fist.
What if that is by the leading of the Holy Spirit? What if Jesus has come into our temples and is turning over our systems of practicing religion because they aren't joining people to what God is doing? What if the people leaving our churches in droves are being led by God to something else?
Sure, some of those who participated in the temple system in Jesus' day were moved to greater love and forgiveness. And sure, some people who participate in the church today are authentically moved to greater mercy and generosity. But it seems the system of church itself isn't accomplishing that.
Because I don't know what it's going to look like. If God would show us what she's doing with the church, perhaps we could help with it. But that doesn't seem to be the case. We don't know, and that makes us uncomfortable at best, terrified at worst. Or else we just ignore it and keep offering our temple sacrifices despite Jesus turning over the tables.
If this is happening, what do we do?
Vs. 22, "After he was raised from the dead, his disciples remembered that he has said this; and they believed the scripture and the word that Jesus had spoken." I guess we cling to Jesus. I guess we trust God. I guess we follow the Holy Spirit's movement as we can. What else can we do? God is going to do what God is going to do. Love, forgiveness, and generosity—those things of God—will be the signs of Jesus' disciples. Why not run full speed to Jesus? Run headlong to forgiveness, love, and generosity. The tables of the church are being overturned. Let's see what Jesus is up to. And let us follow him.


text:
CCR Focus
Heterogeneity and Targeting of Pancreatic Cancer Stem Cells
Vesselin R. Penchev, Zeshaan A. Rasheed, Anirban Maitra and William Matsui
Vesselin R. Penchev
Authors' Affiliations: Departments of 1Oncology and 2Pathology, 3The Sol Goldman Pancreatic Cancer Research Center, The Sidney Kimmel Comprehensive Cancer, Johns Hopkins University School of Medicine, Baltimore, Maryland
Zeshaan A. Rasheed
Authors' Affiliations: Departments of 1Oncology and 2Pathology, 3The Sol Goldman Pancreatic Cancer Research Center, The Sidney Kimmel Comprehensive Cancer, Johns Hopkins University School of Medicine, Baltimore, MarylandAuthors' Affiliations: Departments of 1Oncology and 2Pathology, 3The Sol Goldman Pancreatic Cancer Research Center, The Sidney Kimmel Comprehensive Cancer, Johns Hopkins University School of Medicine, Baltimore, Maryland
William Matsui
DOI: 10.1158/1078-0432.CCR-11-3112 Published August 2012
Cancer stem cells (CSC) have been identified in an ever-increasing number of human malignancies on the basis of their ability to recapitulate tumors in the ectopic setting and maintain long-term tumorigenic potential. In addition, in pancreatic adenocarcinoma, CSCs may display additional properties, such as relative drug resistance and enhanced invasive and migratory potential that implicate a role in disease pathogenesis spanning initial tumor formation to metastatic disease progression. Importantly, these findings also indicate that the development of novel therapeutic strategies capable of inhibiting or eliminating CSCs will improve clinical outcomes. Preclinical studies have already described a wide array of potential approaches that target CSC-specific surface antigens and cellular pathways involved in cell survival, adhesion, self-renewal, and differentiation. Further, progress in this area should continue to move forward as the unique biology of CSCs is better understood. All preclinical studies to date have focused on targeting specific and phenotypically defined CSCs, but multiple cell populations with the ability to form tumors and self-renew have been identified in pancreatic carcinoma. As the clinical efficacy of CSC-directed therapies will depend on the inhibition of all sources of tumor self-renewal, better understanding of how specific CSC populations are related to one another and whether each possesses specific functional properties will be critical. In this CCR Focus article, we discuss the potential relationships between different pancreatic CSC populations and strategies to identify novel targeting approaches. Clin Cancer Res; 18(16); 4277–84. ©2012 AACR.
Pancreatic ductal adenocarcinoma (PDAC) carries one of the worst prognoses of any malignancy and is the fourth leading cause of cancer-related deaths in the United States (1). Despite advances in understanding of the basic biology of PDAC, survival rates have not significantly improved over the past 30 years, and less than 5% of patients are alive 5 years after diagnosis. Therefore, new treatments are needed for PDAC, and cancer stem cells (CSC) have emerged as potential therapeutic targets.
CSCs represent phenotypically distinct cells that possess enhanced tumor-initiating potential, self-renewal, and the ability to recapitulate the cellular heterogeneity of the original tumor (2). Following these initial findings, additional features, including their rarity, relative chemoresistance, and metastatic potential have been described, and these properties have allowed them to be referred to by more precise terms, such as tumor-initiating cells. However, due to the heterogeneous properties exhibited by CSCs, it has been difficult to provide a label capable of encompassing all of these attributes. Therefore, we refer to these specialized cell populations by the general term "CSC" throughout this review. Although the identification of CSCs was limited to myeloid leukemias in the 1990s (3, 4), they have been described in an increasing number of solid tumors over the past decade, including multiple reports in PDAC (5–7). Several aspects of the CSC hypothesis have been hotly debated (8–10), but their clinical significance is the aspect that is most relevant. In PDAC, early data have indicated that the identification of CSCs in primary tumors is associated with shorter overall survival (6), and it is likely that additional functional properties, including relative resistance to the standard cytotoxic agent gemcitabine and enhanced metastatic potential are, in part, responsible for these findings (7, 11).
The identification and characterization of CSCs has generated novel hypotheses with regard to the mechanisms involved in PDAC growth and dissemination, but several critical questions remain. We initially review studies identifying pancreatic CSCs and hypothesize how these distinct cell populations may be related to one another. Thereafter, we discuss potential strategies to target pancreatic CSCs.
Identification of pancreatic CSCs
At the most basic level, the CSC hypothesis links phenotypically defined tumor cells with specific functional properties, and CSCs have been stringently defined by their ability to differentiate and self-renew (12). The differentiation of CSCs gives rise to the full range of malignant cell types and histologic recapitulation of the original tumor, whereas self-renewal is responsible for maintaining long-term growth potential. In most diseases, the ability of putative CSCs to form tumors has been evaluated using immunodeficient mice (e.g., NOD/SCID and NSG) followed by histologic examination and serial transplantation to show self-renewal (13). Although these mouse models remain the gold standard to evaluate CSCs, in vitro assays have been developed to assess the clonogenic potential of CSCs, including colony formation in semi-solid media or tumor sphere formation in liquid culture. Moreover, these in vitro assays may quantify the number of cells with self-renewal and long-term growth potential through serial rounds of plating.
Candidate CSC markers have largely consisted of differentially expressed cell-surface antigens or drug-resistance pathways. One approach to identify novel CSC populations has been the use of surface antigens expressed by normal stem cells in the tissue of origin, such as CD34 in myeloid leukemias (3, 14). Alternatively, antigens or enzymes capable of identifying normal stem cells in multiple tissues, such as CD133 and aldehyde dehydrogenase (ALDH), have been used to isolate CSCs in several diseases (15–19). Finally, specific antigens associated with poor prognosis, such as CD44 or c-Met, have served as CSC markers (5, 20–22).
The initial identification of pancreatic CSCs extended ground-breaking work in breast cancer and investigated the expression of CD44, CD24, and epithelial-specific antigen (ESA; Table 1; ref.5). Relative to unsorted cells, CD44+CD24+ESA+ cells isolated from low-passage PDAC xenografts were highly tumorigenic and recapitulated the histology and cellular heterogeneity of the original tumor. Further, the functional differences between CD44+CD24+ESA+ and CD44−CD24−ESA− cells were maintained following subcutaneous or orthotopic injection, indicating that tumorigenic potential was cell autonomous and independent of local environmental factors. A second report showed that CD133 could also identify pancreatic CSCs (7). In addition to being highly tumorigenic, CD133+ pancreatic cancer cells were found to be relatively resistant to gemcitabine treatment compared with CD133− cells.
Phenotype and functional properties of pancreatic CSC populations
In addition, cellular markers associated with drug resistance have been used to identify CSCs. ALDH, specifically ALDH1A1, is required for the synthesis of all-trans-retinoic acid, and high enzyme activity marks normal mouse pancreatic progenitor cells and normal human stem cells in several organ systems (23, 24). Moreover, ALDH may play a role in drug resistance as it can metabolize and neutralize cytotoxic alkylators, such as cyclophosphamide. We studied ALDH in PDAC and found that ALDH+ cells are highly tumorigenic compared with bulk tumor cells (6, 25). Moreover, ALDH+ cells appear to be relatively resistant to gemcitabine in vivo and have increased invasive potential, indicating a role in disease progression (6, 11).
Despite the importance of CD44, CD133, and ALDH in identifying pancreatic CSCs, it is unclear whether these antigens are involved in regulating CSC function or merely serve as phenotypic markers. However, other pancreatic CSC markers have been identified that may be functionally relevant. For example, CXCR4 serves as the chemokine receptor for stromal cell-derived factor-1 (SDF-1, CXCL12) and is expressed by a subset of CD133+ CSCs that have enhanced metastatic capacity (7). In addition, recent studies have shown that c-Met can identify and regulate pancreatic CSCs in a manner similar to findings in glioblastoma (22, 26). Thus, several strategies have been used to identify pancreatic CSCs, and some of these may provide insights into regulatory factors and potential targeting strategies.
The relationship between distinct pancreatic CSC populations
In most normal organ systems, such as the blood, central nervous system (CNS), and skin, cells are functionally and phenotypically organized according to a strict cellular hierarchy in which self-renewing stem cells give rise to short-lived progenitors and then terminally differentiated effector cells. The earliest studies in acute myeloid leukemia (AML) showed that tumor cells resembling normal hematopoietic stem cells can self-renew and give rise to relatively differentiated and nontumorigenic blasts (4). Therefore, it has been generally assumed that cancers are organized in a hierarchical manner similar to normal tissues. However, several CSC populations have been identified in PDAC, and it is not clear how each of these populations fits into a specific hierarchy or how they are related to one another. One possibility is that all of the current markers recognize the same cell, but the vast majority of ALDH+ pancreatic tumor cells appear to lack CD44 and CD133. Therefore, it is likely that these antigens identify at least 2, or even 3, unique cell populations (6, 27). Alternatively, because each putative CSC marker enriches for cells with increased tumorigenic potential but fails to isolate pure populations of CSCs (i.e., every cell expressing a specific marker is not tumorigenic), it is possible that combining antigens will greatly increase the purity of CSCs. However, this does not appear to be the case as the tumor–initiating-cell frequency of rare PDAC cells coexpressing CD44, CD24, and ALDH is not significantly greater than that of either ALDH+ or CD44+CD24+ cells (25). Moreover, c-Met is expressed, albeit at variable levels, on CD44+, CD133+, or ALDH+ cells, but increased tumorigenic potential is limited to CD44+c-Methigh cells (22).
The significance of the various pancreatic CSC markers and the cells they identify clearly requires further clarification. If multiple CSC populations actually exist, an understanding of how they are related to one another will be important because clinically effective targeting possibly requires the elimination of all self-renewing cells within the tumor. One possibility is that PDAC cells are organized in a hierarchical and linear manner with a single, phenotypically distinct CSC at the apex giving rise to the other CSC populations and ultimately nonclonogenic mature tumor cells (Fig. 1). In addition, it is possible that each phenotypically distinct CSC population represents a specific cellular state of the same clonogenic cell that gives rise to mature tumor cells. Another possibility is that each CSC population is unrelated to another and parallel lines of mature tumor cell production exist. Finally, it is conceivable that a rigid hierarchy of unidirectional differentiation does not exist, but that the system is plastic with nonclonogenic cells giving rise to tumorigenic CSCs displaying a variety of phenotypes. To better understand how different CSCs are related to one another, studies examining the overlap between putative CSC populations and the cell types that arise from each specific CSC are needed.
Potential relationships between CSCs and mature tumor cells. A, a linear organization with a single phenotypically distinct CSC giving rise to the other CSC populations and ultimately nonclonogenic mature cells. B, each phenotypic CSC represents a distinct state of the same clonogenic cell that gives rise to the mature tumor cell. C, each CSC population is unrelated to another and parallel lines of mature tumor cell production exist. D, a plastic system in which nonclonogenic mature cells give rise to CSC displaying a variety of phenotypes.
Beyond the organization of phenotypically defined CSC populations, it is also unclear whether the various CSCs are functionally similar or distinct. Although tumor formation, histologic recapitulation, and self-renewal define CSCs, other properties, including relative drug resistance, invasion, migration, and metastatic potential have been ascribed to CSCs and may contribute to their clinical impact (28). It is possible that certain CSC populations could be primarily responsible for tumor initiation and maintenance at the primary site of disease, whereas others could be responsible for tumor dissemination and growth at metastatic sites, such as the subpopulation of CD133+ CSCs expressing CXCR4 (7). In addition, it is possible that different organs, such as the liver and lung, harbor different microenvironments with distinct endothelial or stromal cell types or extracellular matrix components that promote or inhibit tumor growth (Fig. 2; ref. 29). Therefore, if metastatic dissemination depends on the interaction of CSCs with a particular niche, then different niches might call for unique CSCs. An evaluation of the tumor-forming potential of specific CSCs at orthotropic and different metastatic sites may determine whether certain populations are better suited to grow within particular locations.
Potential functional relationships between CSCs. A, distinct CSCs may give rise to macroscopic tumors in distinct anatomic locations. Each population is responsible for tumor growth and resistance to therapy in different organs. B, a primary CSC population is responsible for tumor initiation and growth at the primary site. Additional populations are responsible for initiation and maintenance at metastatic sites and for resistance to chemotherapy.
Moreover, it is possible that the phenotypes exhibited by CSCs are dictated by the external microenvironment. For example, pancreatic tumors are characterized by desmoplasia and dense fibrosis that may expose cells to relative hypoxia, and the hypoxic state has been found to alter the expression of the CSC marker CD133 in brain tumors (30). In addition, several markers used to identify CSCs, such as ALDH and the side population assay, are indicative of drug-resistance mechanisms, and it is possible that their expression is induced in response to cellular damage. Finally, it is possible that the adaptive metabolic changes undertaken by tumor cells also modify the expression of CSC makers, although such findings have yet to be reported (31).
Recent studies have shown a clear link between CSCs and the epithelial-to-mesenchymal transition (EMT) in solid tumors. Therefore, it is possible that CSCs represent a specific cellular state expressing multiple phenotypes. Reports using breast cancer models have shown that the induction of EMT by TGF-β or the modulation of specific gene expression (e.g., induction of Twist or repression of E-cadherin) results in increased expression of CD44 and tumorigenic potential (32, 33). In pancreatic cancer, ALDH+ cells appear to have a gene expression profile consistent with EMT and increased invasive and migratory potential as compared with bulk tumor cells and CD44+CD24+ cells (6). Moreover, studies examining ZEB1, an inducer of EMT, in pancreatic cancer cells have identified a direct link among EMT, increased tumorigenicity, and drug resistance (34). Therefore, it is possible that a more "epithelial" or "mesenchymal" state is important in determining the functional properties of CSCs. The specific functional properties of different pancreatic CSCs are unclear, and the quantification of tumor formation, metastatic potential, and drug resistance is needed.
Inter- and intrapatient diversity of pancreatic CSCs
Interpatient heterogeneity may contribute to the existence of multiple pancreatic CSCs. Recurrent genetic alterations are a hallmark of cancer, and mutations in KRas are present in the vast majority of PDACs (35, 36). On the other hand, mutations in other genes, such as p53 and Smad4/DPC4, can be identified in some, but not all tumors (37, 38). Therefore, pancreatic cancers are not genetically homogeneous but rather vary from patient to patient (39). If alterations in specific genes are prognostic and CSCs truly dictate the natural history of PDACs, given their potential roles in tumor formation, drug resistance, and metastatic progression, then, it is likely that specific mutations influence both the phenotype and function of CSCs. Currently, it is unclear whether phenotypically identical CSCs from different patients have the same functional attributes and contribute to disease progression in similar ways. However, such a finding would imply that personalized and individualized CSC-targeting therapies are needed. To examine inter-patient diversity, the functional properties of different CSCs derived from human tumors with distinct genotypes will need to be determined. In addition, the examination of CSC phenotypes and functional properties in tumors derived from transgenic animal models of pancreatic cancer may be particularly helpful because specific genetic lesions can be modulated in these systems (40).
To further complicate matters, increasing evidence indicates that human cancers can be genetically heterogeneous within the same individual (41–44). Therefore, intrapatient genetic heterogeneity may also drive the phenotypic and functional diversification of CSCs. In many cancers, including PDAC, specific genetic alternations may accumulate in an orderly fashion during disease progression (45, 46); thus, it is possible that different CSCs are responsible for relapse and progression over the course of the disease. In PDAC, metastatic lesions may be genetically distinct from one another and the primary tumor (47). Moreover, primary tumors are composed of geographically and genetically distinct subclones. The role of genetic evolution and diversification in the emergence of distinct CSCs, or conversely, the impact of CSCs on the clonal composition of an individual tumor is not entirely clear, but it is likely that these 2 processes interact at some level. A systematic investigation of genetic lesions within CSCs, their phenotypes, and functional properties, such as tumorigenic potential, metastasis, and drug resistance, within primary tumors and metastatic lesions derived from the same patient may address this possibility.
Targeting of pancreatic CSCs
The self-renewal potential and resistance to traditional cytotoxic agents indicate that successful CSC-targeting strategies will improve clinical outcomes. One potential approach is targeting the cell-surface antigens that characterize pancreatic CSCs using monoclonal antibodies. For example, a bispecific antibody recognizing both ESA and CD3 has been found to eliminate pancreatic CSCs by redirecting cytotoxic T lymphocytes (48). CD44 is another surface protein expressed by CSCs in multiple diseases (49), and a specific monoclonal antibody against CD44 can eliminate AML stem cells by inducing terminal differentiation (50). In addition, the functional activities of specific pancreatic CSC markers may serve as potential targets (Table 2). The hepatocyte growth factor (HGF) receptor c-Met identifies highly tumorigenic CSCs in combination with CD44, and the pharmacologic inhibition of its activity has been found to inhibit tumor growth and metastasis (22). Another functionally relevant marker is CXCR4, which plays an important role in the homing of hematopoietic stem cells to the bone marrow. CXCR4 has been identified on a subset of CD133+ pancreatic CSCs with enhanced metastatic capacity, and CXCR4 antagonists may prevent tumor dissemination (7). Another potential cell-surface target is the Death receptor 5 (DR5), which induces apoptosis following binding to TRAIL. A recent study found that ALDH+ and CD44+CD24+ pancreatic CSCs express relatively increased levels of DR5, and receptor engagement using an agonistic monoclonal antibody markedly reduced CSC frequency and tumor growth in vivo (51).
Pancreatic CSC-specific targeting strategies and agents
Several cellular signaling pathways have been identified that regulate the self-renewal of normal stem cells and may serve as targets against CSCs. These include pathways required for normal embryonic development, and the Hedgehog (Hh), Notch, and Nodal/Activin pathways may be active in pancreatic CSCs. Nodal and Activin are ligands of the TGF-β superfamily, and a recent study showed that these ligands and their receptor ALK4 are overexpressed in pancreatic CSCs (52). The pharmacologic inhibition or knockdown of ALK4 abrogated self-renewal and tumorigenicity and also sensitized CSCs to gemcitabine. Another series of studies has examined the Hh signaling pathway in pancreatic CSCs and found that pharmacologic pathway inhibition reduced the frequency of CSCs and decreased tumor formation and metastasis (11, 53, 54). Notably, a recent phase II clinical trial compared gemcitabine alone or in combination with the novel Hh inhibitor saridegib (IPI-926) in patients with metastatic pancreatic cancer on the basis of preclinical data showing enhanced responses to cytotoxic chemotherapy (55). A higher rate of progressive disease was observed at an interim analysis in patients receiving saridegib (56). Although the precise reasons for these results are unclear, it is possible that the Hh pathway regulates the development, rather than maintenance, of metastatic lesions, and other ongoing trials of Hh inhibitors in the neoadjuvant setting may provide a better scenario to detect these potential anti-CSC effects. Finally, the inhibition of Notch signaling has been found to inhibit EMT and cellular invasion as well as to decrease the frequency of ALDH+ CSCs (57). Thus, cellular pathways involved in regulating the self-renewal of normal stem cells may represent pancreatic CSC targets.
In addition, the association of EMT and CSCs may form the basis for identifying novel targeting agents. High-throughput strategies to screen for novel anti-CSC compounds have been difficult to carry out because of the lack of pure CSC populations and the complex nature of the assays used to assess their functions, but several methods may induce EMT and increase the frequency of CSCs. This approach was ingeniously used by Gupta and colleagues, who genetically engineered human breast cancer cell lines to induce EMT and screened for compounds that could induce cell death (32). The ionophore salinomycin was identified as a potential CSC targeting agent and then subsequently found to block tumor formation and metastasis in vivo. Shortly thereafter, salinomycin was shown to inhibit the growth of pancreatic CSCs, indicating that it may represent a potential CSC-targeting agent in multiple malignancies (58). Therefore, similar strategies based on EMT may identify novel agents that inhibit pancreatic CSCs.
The CSC hypothesis may provide novel insights into the pathogenesis of PDAC and the mechanisms that regulate clinical chemoresistance and the propensity to develop metastatic disease. Moreover, it may lead to a better understanding of self-renewal that allows tumors to persist over time and to the development of novel therapeutic strategies targeting the regulatory pathways involved. With the increased recognition of cellular heterogeneity in PDAC and identification of tumor cells with enhanced tumorigenic potential and self-renewal, questions have emerged regarding the diversity of pancreatic CSCs and their relationships to one another that will need to be addressed. However, these findings are likely to provide a framework to better understand advancements in many of the other fields that are the subjects of this CCR Focus section, including alterations in genetics, tumor metabolism, and the microenvironment. Ultimately, merging these distinct aspects of PDAC biology may provide the basis for truly novel and effective therapies with a positive impact clinical outcomes.
No potential conflicts of interest have been disclosed.
Conception and design: V.R. Penchev, Z.A. Rasheed, A. Maitra, W. Matsui
Writing, review, and/or revision of the manuscript: V.R. Penchev, Z. A. Rasheed, A. Maitra, W. Matsui
This study was financially supported by research grants from the NIH (R01 CA150142, R01 CA113669, R01 CA134767, P01CA134292) and the Lustgarten Foundation. Z.A. Rasheed is a recipient of the Pancreatic Cancer Action Network-AACR Career Development Award.
Revision received May 17, 2012.
Accepted June 5, 2012.
Siegel R,
Naishadham D,
Jemal A
. Cancer statistics, 2012. CA Cancer J Clin 2012;62:10–29.
Reya T,
Morrison SJ,
Clarke MF,
Weissman IL
. Stem cells, cancer, and cancer stem cells. Nature 2001;414:105–11.
Bonnet D,
Dick JE
. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997;3:730–7.
Lapidot T,
Sirard C,
Vormoor J,
Murdoch B,
Hoang T,
Caceres-Cortes J,
A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 1994;367:645–8.
Li C,
Heidt DG,
Dalerba P,
Burant CF,
Zhang L,
Adsay V,
Identification of pancreatic cancer stem cells. Cancer Res 2007;67:1030–7.
Yang J,
Wang Q,
Kowalski J,
Freed I,
Murter C,
Prognostic significance of tumorigenic cells with mesenchymal features in pancreatic adenocarcinoma. J Natl Cancer Inst 2010;102:340–51.
Hermann PC,
Huber SL,
Herrler T,
Aicher A,
Ellwart JW,
Guba M,
Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 2007;1:313–23.
Kern SE,
Shibata D
. The fuzzy math of solid tumor stem cells: a perspective. Cancer Res 2007;67:8985–8.
Adams JM,
Strasser A
. Is tumor growth sustained by rare cancer stem cells or dominant clones? Cancer Res 2008;68:4018–21.
Tomasson MH
. Cancer stem cells: a guide for skeptics. J Cell Biochem 2009;106:745–9.
Feldmann G,
Suárez-Gauthier A,
Rasheed Z,
Solomon A,
Zou G-M,
A direct pancreatic cancer xenograft model as a platform for cancer stem cell therapeutic development. Mol Cancer Ther 2009;8:310–4.
Dick JE,
Dirks PB,
Eaves CJ,
Jamieson CHM,
Jones DL,
Cancer stem cells–perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res 2006;66:9339–44.
Brennan S,
Matsui W
. Cancer stem cells: controversies in multiple myeloma. J Mol Med 2009;87:1079–85.
Fajerman Y,
Kollet O
. Immune-deficient SCID and NOD/SCID mice models as functional assays for studying normal and malignant human hematopoiesis. J Mol Med 1997;75:664–73.
Singh SK,
Hawkins C,
Clarke ID,
Squire JA,
Bayani J,
Hide T,
Identification of human brain tumour initiating cells. Nature 2004;432:396–401.
O'Brien CA,
Pollett A,
Gallinger S,
. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 2007;445:106–10.
Matsui W,
Barber JP,
Smith BD,
Borrello I,
Clonogenic multiple myeloma progenitors, stem cell properties, and drug resistance. Cancer Res 2008;68:190–7.
Ginestier C,
Hur MH,
Charafe-Jauffret E,
Monville F,
Dutcher J,
Brown M,
ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 2007;1:555–67.
Jones RJ,
Gocke CD,
Kasamon YL,
Miller CB,
Perkins B,
Circulating clonotypic B cells in classic Hodgkin lymphoma. Blood 2009;113:5920–6.
Al-Hajj M,
Wicha MS,
Benito-Hernandez A,
Clarke MF
. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 2003;100:3983–8.
Dylla SJ,
Park I-K,
Liu R,
Wang X,
Cho RW,
Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci U S A 2007;104:10158–63.
Wu JÄ,
Hynes M,
Dosch J,
Sarkar B,
Welling TH,
c-Met Is a marker of pancreatic cancer stem cells and therapeutic target. Gastroenterology 2011;141:2218–27.e5.
Emadi A,
Brodsky RA
. Cyclophosphamide and cancer: golden anniversary. Nat Rev Clin Oncol 2009;6:638–47.
Rovira M,
Scott S-G,
Liss AS,
Jensen J,
Thayer SP,
Leach SD
. Isolation and characterization of centroacinar/terminal ductal progenitor cells in adult mouse pancreas. Proc Natl Acad Sci U S A 2010;107:75–80.
Ishizawa K,
Karisch R,
Susky E,
Tumor-initiating cells are rare in many human tumors. Cell Stem Cell 2010;7:279–82.
Li A,
Glas M,
Lal B,
Ying M,
Sang Y,
c-Met signaling induces a reprogramming network and supports the glioblastoma stem-like phenotype. Proc Natl Acad Sci U S A 2011;108:9951–6.
Kim MP,
Fleming JB,
Wang H,
Abbruzzese JL,
Choi W,
Kopetz S,
ALDH activity selectively defines an enhanced tumor-initiating cell population relative to CD133 expression in human pancreatic adenocarcinoma. PloS One 2011;6:e20636.
. Concise review: emerging concepts in clinical targeting of cancer stem cells. Stem Cells 2011;29:883–7.
Feig C,
Gopinathan A,
Neesse A,
Chan DS,
Cook N,
Tuveson DA
. The pancreas cancer microenvironment. Clin Cancer Res 2012;18:4266–76.
Bar EE,
Lin A,
Mahairaki V,
Eberhart CG
. Hypoxia increases the expression of stem-cell markers and promotes clonogenicity in glioblastoma neurospheres. Am J Pathol 2010;177:1491–502.
Le A,
Maitra A,
Dang CV
. Conceptual framework for cutting the pancreatic cancer fuel supply. Clin Cancer Res 2012;18:4285–90.
Gupta PB,
Onder TT,
Jiang G,
Tao K,
Kuperwasser C,
Weinberg RA,
Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell 2009;138:645–59.
Mani S,
Evans K,
Hollier B,
Guo W,
Weinberg R
. Generation of stem-like cells via EMT: a new twist in cancer initiation and progression. AACR Education Book; 2009:173.
Wellner U,
Schubert J,
Burk UC,
Schmalhofer O,
Zhu F,
Sonntag A,
The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nat Cell Biol 2009;11:1487–95.
Adsay NV,
Argani P,
De MA,
Cameron JL,
Multicomponent analysis of the pancreatic adenocarcinoma progression model using a pancreatic intraepithelial neoplasia tissue microarray. Mod Pathol 2003;16:902–12.
van Mansfeld AD,
Offerhaus GJ,
van Weering DH,
Allison DC,
Goodman SN,
K-ras oncogene activation in adenocarcinoma of the human pancreas. A study of 82 carcinomas using a combination of mutant-enriched polymerase chain reaction analysis and allele-specific oligonucleotide hybridization. Am J Pathol 1993;143:545–54.
Redston MS,
Caldas C,
Seymour AB,
da Costa L,
Yeo CJ,
p53 Mutations in pancreatic carcinoma and evidence of common involvement of homocopolymer tracts in DNA microdeletions. Cancer Res 1994;54:3025–33.
Hahn SA,
Schutte M,
Hoque ATMS,
Moskaluk CA,
da Costa LT,
Rozenblum E,
DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 1996;271:350–3.
Lin JC-H,
Tuveson DA,
Hingorani SR
. Ductal pancreatic cancer in humans and mice. Cold Spring Harbor Symp Quant Biol 2005;70:65–72.
Anderson K,
Lutz C,
van Delft FW,
Bateman CM,
Guo Y,
Colman SM,
Genetic variegation of clonal architecture and propagating cells in leukaemia. Nature 2011;469:356–61.
Notta F,
Mullighan CG,
Wang JCY,
Poeppl A,
Doulatov S,
Phillips LA,
Evolution of human BCR-ABL1 lymphoblastic leukaemia-initiating cells. Nature 2011;469:362–7.
Yachida S,
Bozic I,
Antal T,
Leary R,
Fu B,
Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 2010;467:1114–7.
Gerlinger M,
Rowan AJ,
Horswell S,
Larkin J,
Endesfelder D,
Gronroos E,
Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. New Engl J Med 2012;366:883–92.
Hruban RH
. Molecular pathogenesis of pancreatic cancer. Best Pract Res Clin Gastroenterol 2006;20:211–26.
Greaves M,
Maley CC
. Clonal evolution in cancer. Nature 2012;481:306–13.
Iacobuzio-Donahue CA,
Velculescu VE,
Wolfgang CL,
. Genetic basis of pancreas cancer development and progression: insights from whole-exome and whole-genome sequencing. Clin Cancer Res 2012;18:4257–65.
Cioffi M,
Dorado J,
Baeuerle PA,
Heeschen C
. EpCAM/CD3-bispecific T-cell engaging antibody MT110 eliminates primary human pancreatic cancer stem cells. Clin Cancer Res 2012;18:465–74.
. Cancer stem cells: models and concepts. Annu Rev Med 2007;58:267–84.
Jin L,
Hope KJ,
Zhai Q,
Smadja-Joffe F,
. Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat Med 2006;12:1167–74.
Lopez-Rios F,
Lonardo E,
Mueller M-T,
Huber S,
Balic A,
Miranda-Lorenzo I,
Nodal/Activin signaling drives self-renewal and tumorigenicity of pancreatic cancer stem cells and provides a target for combined drug therapy. Cell Stem Cell 2011;9:433–46.
Fendrich V,
McGovern K,
Bedja D,
Bisht S,
Alvarez H,
An orally bioavailable small-molecule inhibitor of Hedgehog signaling inhibits tumor initiation and metastasis in pancreatic cancer. Mol Cancer Ther 2008;7:2725–35.
Dhara S,
Beaty R,
Mullendore M,
Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: a new paradigm for combination therapy in solid cancers. Cancer Res 2007;67:2187–96.
Olive KP,
Jacobetz MA,
Davidson CJ,
McIntyre D,
Honess D,
Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 2009;324:1457–61.
Infinity stops phase 2 trials of saridegib in chondrosarcoma and myelofibrosis. [cited 2012 May 17]. Available from:http://www.reuters.com/article/2012/06/18/idUS87102+18-Jun-2012+BW20120618.
Mullendore ME,
Koorstra J-B,
Li Y-M,
Fan X,
Henderson CM,
Ligand-dependent Notch signaling is involved in tumor initiation and tumor maintenance in pancreatic cancer. Clin Cancer Res 2009;15:2291–301.
Zhang G-N,
Zhou L-J,
Chen S-P,
Chen G,
Zhang T-P,
Combination of salinomycin and gemcitabine eliminates pancreatic cancer cells. Cancer Lett 2011;313:137–44.
You are going to email the following Heterogeneity and Targeting of Pancreatic Cancer Stem Cells
Clin Cancer Res August 15 2012 (18) (16) 4277-4284; DOI: 10.1158/1078-0432.CCR-11-3112
Endpoints for Immuno-oncology Trials
Limitations and Challenges in Immuno-oncology Trials
Developing Early-Phase Combination Immunotherapy Trials
Show more CCR Focus


text:
Parallel surfaces
Revision as of 17:22, 7 February 2011 by 127.0.0.1 (talk) (Importing text file)
Diffeomorphic equi-oriented surfaces and having parallel tangent planes at corresponding points and such that the distance between corresponding points of and is constant and equal to that between the corresponding tangent planes. The position vectors and of two parallel surfaces and are connected by a relation , where is a unit normal vector that is the same for at and at .
Thus, one can define a one-parameter family of surfaces parallel to a given , where is regular for sufficiently small values of for which
To the values of the roots and of the equation there correspond two surfaces and that are evolutes of , so that parallel surfaces have a common evolute (cf. Evolute (surface)). The mean curvature and the Gaussian curvature of a surface parallel to are connected with the corresponding quantities and of by the relations
lines of curvature of parallel surfaces correspond to each other, so that between them there is a Combescour correspondence, which is a special case of a Peterson correspondence.
For a linear family of closed convex parallel surfaces (depending linearly on a parameter ) the Steiner formula holds: The volume of the point set bounded by them is a polynomial of degree 3 in . An analogous result holds for arbitrary dimensions. The Steiner formula is a special case of formulas for general polynomials in Minkowski's theory of mixed volumes, and, even more general, in the theory of valuations.
For references see Parallel lines.
Parallel surfaces. Encyclopedia of Mathematics. URL: http://encyclopediaofmath.org/index.php?title=Parallel_surfaces&oldid=17715
This article was adapted from an original article by I.Kh. Sabitov (originator), which appeared in Encyclopedia of Mathematics - ISBN 1402006098. See original article
Retrieved from "https://encyclopediaofmath.org/index.php?title=Parallel_surfaces&oldid=17715"


Quite possibly our favorite new product of the season! Elena, one of our pro seamstresses, makes the patterns for her clothing herself and has such an eye for color. You'll love the details she chooses that a special Peruvian touch to the outer lining of the pockets and drawstrings of this sweatshirt. Made with a soft cotton flannel for maximum comfort and coziness all winter long!
Please contact us directly if you'd like to order the size S. It's backordered already due to popularity!


This Spring, treat your senses to an escape on the Central Coast, NSW Australia. Just one hour's drive north of Sydney, you will find yourself in a destination that has a distinctive change of place and pace, perfect for a short break or a longer escape.
Beaches, wildlife and wilderness - all the natural elements come together on the Central Coast. At the essence of the region is a world of beautiful coastlines,golden beaches, alluring lakes and pristine National Parks. These treasured natural assets stretch across the six regions of the Central Coast, each with their own unique qualities, energy and style.
The Central Coast has a wide variety of accommodation including motels, apartments and luxury hotels.
Buccaneer Motel Long Jetty Budget hotel motel accommodation in Long Jetty, in the scenic NSW Central Coast - affordable beach holiday accommodation.
Beachcomber Hotel Toukley 3.5 star hotel with magnificent water views, perfect for the business traveller & leisure guest Located on Lake Budgewoi.


Published 04/20/2019 04:11:30 am at 04/20/2019 04:11:30 am in Eave Fascia Board.
eave fascia board eaves soffits and fascia trim 4 rake trim boards 5 roof shingles 6 roof flashing and roof boots 7 chimney 8 chimney crown soffit fascia board.
eave fascia board,roof eave fascia board,soffit fascia board,replace eave fascia boards,eave fascia boards,eave fascia trim board, different types of fascias and soffits vinyl aluminium and wood fasciasoffitboardscost, soffit and fascia installation trim bender aluminum fascia with hip roof, eaves board new home review , how to repair rotted eaves steps with pictures wikihow image titled repair rotted eaves step , installing vinyl siding on soffits and trim biytodaycom build insert the soffit panels into the ftrim on both sides.


Tinnitus Remedy Blog | Cure Yor Tinnitus Now!!!
Are you hearing voices in your ears that are not there? Is there ringing in your head (brain) or ears that is not present physically? Then you could be suffering from Tinnitus. Tinnitus is a condition, not a disease. The condition is in itself evidence of some other underlying issues that need to be solved.
The noises and ringing in your head and ears, when there is physically no evidence of the same, is a sign that your hearing (auditory) system has some fault. The voices you hear are from the body, they are not external. You need a Tinnitus miracle but first, which are the sounds that you hear when you have been affected by Tinnitus?
In his Tinnitus Miracle Book, Thomas Coleman explains in detail the causes of Tinnitus. Offering his Tinnitus Miracle solution, Thomas Coleman analyses both the common and the rare causes of this condition. Let us explore some of them.
The causes of Tinnitus are wide and varied but the most common is a hearing loss as result of noise. When you listen to music etc using earphones that have been inserted deep into the ears, increasing the volume beyond temperate levels can cause Tinnitus. This is especially so because there is nothing to absorb or deflect the sound as it reaches the ear canal. While natural hearing loss causes Tinnitus in the aged, it is mostly caused by excessive noise in the young people.
Anemia: when blood becomes thinner as a result of red blood cells decrease. This causes the blood to circulate at high speed producing a noise.
Thomas Coleman does not just give you the causes, he also shows you how to get rid of tinnitus altogether. Numerous tinnitus miracle reviews have been documented. People who once suffered from tinnitus now permanently cured. Tinnitus miracle book gives about 60 days within which a patient should see results after closely following the step by step.
The best way of knowing whether a product or service is good is by asking those who have used it. Read any tinnitus miracle review and you will find a pattern; they had a problem, tinnitus miracle solved it. As the process is entirely natural (no chemical treatments, surgery etc), tinnitus miracle book is a must have for all those with this condition.
If you are suffering from tinnitus, consider tinnitus miracle. And once you have followed the guide in the tinnitus miracle book, be sure to post your tinnitus miracle review once you see results.


text:
Movies|Once More Unto the Galactic Void
https://nyti.ms/NjMsKQ
Movies | Movie Review
Once More Unto the Galactic Void
Review: 'Prometheus,' by Ridley Scott, With Noomi Rapace
Directed by Ridley Scott
Adventure, Mystery, Sci-Fi
By A. O. SCOTT JUNE 7, 2012
Michael Fassbender in "Prometheus." Credit Kerry Brown/20th Century Fox
If you grew up in the 1970s, you may have a dim memory of "Chariots of the Gods," an international best seller by Erich von Däniken full of dubious speculation about extraterrestrial influences on ancient earthling civilizations. The book, a kind of space age "Da Vinci Code," inspired a goofy German documentary and, if memory serves, some earnest, anxious debates among sixth-grade protogeeks who shall remain nameless.
Ridley Scott's "Alien," which arrived at the decade's end, had a far more durable impact. If you saw it in a theater at an impressionable age you may still be seized by irrational, mortal fear every time you experience a touch of indigestion. A powerful, perfect blend of the space-travel and horror genres, "Alien" tapped into a deep, claustrophobic anxiety and an equally primal sense of adventure, the simultaneous thrill and terror of the unknown. The sinewy resilience of Sigourney Weaver's Ripley and the designs of the Swiss graphic artist H. R. Giger — including various horrible manifestations of the alien itself — have been etched into the pop-cultural DNA ever since.
In his new film, "Prometheus," Mr. Scott, returning to science fiction after a 30-year post-"Blade Runner" absence, entwines the visceral, creatural dread of "Alien" with some of the quasi-mythic grandiosity of "Chariots." Once again a vessel lumbers through the galactic void, and a diverse crew must contend with menacing weirdness outside the ship and growing paranoia within it. The Giger alien may still be out there. Something wicked lurks in subterranean tunnels, their walls etched in freaky runes. And hovering over all the scary stuff are some big, metaphysical questions about the origin and ultimate fate of humanity.
A lot of the pleasure of "Prometheus" is in that hovering. Once the themes touch down and the arc of the story becomes clear, some disappointment sets in. But Mr. Scott's sense of visual scale, which has often produced hectic, hectoring grandiosity (are you not entertained?), achieves, especially in the first hour, something like genuine grandeur. Twinned opening scenes — the first involving a giant, alabaster-skinned biped sacrificing himself to propagate life on Earth, and the second, thousands of years later, devoted to scientists' finding traces of his presences — impart a palpable sense of awe. The music, by Marc Streitenfeld, soars and rumbles toward cosmic significance. And the shudders of sublimity only grow more intense as Mr. Scott elegantly lays out a series of overlapping conceits.
You might also call them science-fiction clichés, but the amazing thing is that, at least for a while, they don't feel that way. The visual scheme is sufficiently captivating, and most of the performances are subtle enough that whatever skepticism you may arrive with quickly turns into happy disorientation. The 3-D is unusually graceful — your gaze is absorbed rather than assaulted — and you are pulled into a world of lovely and disconcerting strangeness with plenty of time to puzzle over the behavior of its inhabitants.
Noomi Rapace in "Prometheus." Credit 20th Century Fox
These include David, an android played with silken wit by Michael Fassbender. The sentient, sensitive, possibly treacherous robot is hardly a novelty in this kind of movie, and David is partly a collage of cinematic allusions. His name and his air of innocence recall the mechanical boy hero of Steven Spielberg's "A. I.," but David also has a clear kinship with HAL 9000 from "2001: A Space Odyssey" and the existentially wounded replicants in "Blade Runner." His chosen role model, however, is Peter O'Toole in "Lawrence of Arabia," whose mannerisms and worldview inform David's idea of what it is to be human.
The actual humans in his company are the usual motley bunch. The captain of the Prometheus is Idris Elba, who smokes cigarillos and owns an ancient squeezebox and a bewildering accent. His boss, representing obscure but undoubtedly sinister corporate interests, is Charlize Theron, who is doing everything she can (in this movie and in "Snow White & the Huntsman") to make this an icy June at the movies.
Like John Ford and Shakespeare, Mr. Scott likes to throw a few clownish, expendable rustics into his ensembles, though in this case the designated buffoons are bickering scientists played by Rafe Spall and Sean Harris. Tradition dictates that there also be, among all this compromised, agenda-driven humanity, a paragon of decency and idealism under duress. This would be Elizabeth Shaw — Dr. Who fans take note: Your bases have been covered too — a researcher played by Noomi Rapace. Along with her husband, Charlie Holloway (Logan Marshall-Green), Shaw regards the voyage of the Prometheus as a spiritual quest. The child of missionaries (glimpsed in flashback), she wears a cross and speaks sincerely and literally about going to meet her maker.
Ms. Rapace, the girl with the dragon tattoo in the Swedish film adaptations of the Stieg Larsson trilogy, is a fine heroine, vulnerable and determined. Her physique and features suggest a Hello Kitty version of Ms. Weaver's Ripley, though, as in the "Dragon Tattoo" movies, her pixieishness is accompanied by superhuman endurance. This is evident, above all, in a scene of self-inflicted surgery capable of reducing a packed, rowdy theater to stunned, appalled, almost reverent silence.
But the virtuosity on display makes the weakness of the story — the screenplay is by Jon Spaihts and Damon Lindelof — all the more frustrating. I'll avoid spoilers here, but "Prometheus" kind of spoils itself with twists and reversals that pull the movie away from its lofty, mind-blowing potential. Geeks and dreamers will hold onto scraps of splendor and wish for more. There are no revelations, only what are called, in the cynical jargon of commercial storytelling, "reveals," bits of momentarily surprising information bereft of meaning or resonance. For example: A sequel is coming.
"Prometheus" is rated R (Under 17 requires accompanying parent or adult guardian). Some gory sights and salty talk.
Director Ridley Scott
Writers Jon Spaihts, Damon Lindelof
Stars Noomi Rapace, Logan Marshall-Green, Michael Fassbender, Charlize Theron
Rating R
Running Time 2h 4m
Genres Adventure, Mystery, Sci-Fi
Movie data powered by IMDb.com
Last updated: Nov 2, 2017
A version of this review appears in print on June 8, 2012, on Page C1 of the New York edition with the headline: Once More Unto the Galactic Void. Order Reprints| Today's Paper|Subscribe
The Design of 'Prometheus' JUNE 7, 2012
'Prometheus' Returns Ridley Scott to Outer Space
Noomi Rapace Arrives in Hollywood


Safe Place for Youth's mission is to inspire, nurture and empower the resilient human spirit of homeless youth by providing immediate and lasting solutions, one young person at a time. S.P.Y. has a closet that needs to be replenished each day. The So-Cal team sorted through bags of clothing, categorized what they sorted and restocked the "closet" so the youth at the center on that day could go "shopping" for a fresh outfit. Each day, youth are allowed to choose a clean outfit and a pair of shoes.


Why not simply use default scope with ordering? I believe it would be equivalent.
And using default_scope. I think using default_scope might mess with the situation when default_scope is already being used for some other purpose (other than default_scope is already referred as a bit dangerous play in long run).
Also it's to have an exact functionality, then a work-around using some function intended for different purposes.
i.e. the default scope ordering is always included and any additional order clauses are appended. You'd have to remember to call reorder() or unscoped() instead.
Why not to use simple scope?
This is what we do currently.
The problem isn't that it's impossible to scope a relation so that first/last return the first/last created records. It's that there is an inconsistency in behaviour when using non-incremental primary keys, which can lead to confusion and catch people out.
Unfortunately calling first/last without an ordered scope has become part of the muscle memory of the Rails community precisely because the methods default to ordering by primary key, which has acted as a proxy for creation order. This change would make it possible to configure models with uuids as their primary key so that first/last return something closer to what people expect.
If I use first/last in my code, I tend to also use an 'ordered' scope as my criteria for order varies from case to case, although I generally use created_at as that criteria. I prefer my code to be more explicit about it's ordering when I'm looking at it anyway.
Does anyone have any thoughts as to whether this change is likely to be accepted? I'm more than happy to work up a PR.
> Does anyone have any thoughts as to whether this change is likely to be accepted? I'm more than happy to work up a PR.
> You received this message because you are subscribed to the Google Groups "Ruby on Rails: Core" group.
> Visit this group at https://groups.google.com/group/rubyonrails-core.
Covered this in a previous response. See below.