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text:
Minnesota people! Watch out for 651-815-48...
651-815 651-815-48 CT (UTC -06:00)
Norman Dodge Carlton Kandiyohi Pine
361-337-1983 Texas 267-242-4150 Pennsylvania 780-455-1004 Alberta 780-904-8531 Alberta 605-505-2322 South Dakota 908-631-1235 New Jersey 662-985-9791 Mississippi 719-380-6036 Colorado 908-252-6026 New Jersey 479-226-9654 Arkansas 920-931-9759 Wisconsin 385-257-8908 Utah 562-965-1081 California 440-882-6798 Ohio 305-629-7125 Florida 321-696-8260 Florida 630-546-5116 Illinois 204-869-4876 Manitoba
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The subsidiary T-Systems Business Services GmbH and the landline division maintain large real estate holdings in the town of Heusenstamm. Offices to sell insurance policies or accept payment for electricity, landline telephone, or gas bills. Until the 1990s, post offices would collect fees. School in Hoveton. In addition to the usual terrestrial TV and telephone landline services, the following communication services are available in Horning:. Benefits are seen in underdeveloped countries. For instance, cabling for landline telephone service is expensive and requires a lot of time to complete, . From any UK landline to charge any telephone calls made to the cardholder's BT home telephone account, at no cost to the owner of the landline the card was. Bells' former parent ATT Corporation and took on the ATT name, and CenturyLink acquired Qwest in 2011 and later became Lumen Technologies. Courtney. Pipe Dreams. Landline. Australian Broadcasting Corporationhttp://www. abc. net. au/tv/programs/landline/old-site/content/2010/s2888078. Dialling code for Dromore, like the rest of Northern Ireland, is 028. Local landline numbers typically appear in the format 028 9269 xxxx. The town's local. The Great Orme telegraph station was converted to electric telegraph. Landlines and submarine cables connected the Orme to Liverpool and Holyhead. At. Cellular phones has grown enormously, surpassing that for standard telephones in 2003, the overall ratio of phones per capita had, by 2004. Operates the operation center for SR, internal external communications, landlines, IT services. Training School – Training and Development. Initial training. Faster than landline use, new area codes typically have a disproportionately large fraction of mobile and nomadic numbers, although landline and other services. 2019-02-28. Courtney, Pip. Deniliquin taps into 'Ute fever'. Landline. ABC. Archived from the original on 2002-06-18. 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redpajama_set_name: RedPajamaCommonCrawl


text:
Q: devtool clones the wrong repository for recipe development I am using krogoth and recently I have been observing that everytime I do the following:

*

*Add a recipe
devtool add buttonflux https://github.com/shantanoo-desai/buttonflux/archive/v1.0.tar.gz

I get the a previous recipe which I worked up.
here is the recipe-tool generated recipe of the above repository:
# Recipe created by recipetool
# This is the basis of a recipe and may need further editing in order to be fully functional.
# (Feel free to remove these comments when editing.)
#
# WARNING: the following LICENSE and LIC_FILES_CHKSUM values are best guesses - it is
# your responsibility to verify that the values are complete and correct.
LICENSE = "MIT"
LIC_FILES_CHKSUM = "file://LICENSE;md5=7e8b8d2e60aca564edd8578b5f1f4951"

HOMEPAGE = "https://github.com/shantanoo-desai/bnoflux"
SUMMARY = "Extract IMU Values from BNO055 and store them in InfluxDB via UDP"

SRC_URI = "https://github.com/shantanoo-desai/buttonflux/archive/v${PV}.tar.gz"
SRC_URI[md5sum] = "1c897adf29ed058315d23d3a79f9c532"
SRC_URI[sha256sum] = "1c5611a579ee169a611fc5b401eb1aa6ad8cb4c168722df0dba7d61bb8fd2d2b"

S = "${WORKDIR}/bnoflux-${PV}"

inherit setuptools

# WARNING: the following rdepends are from setuptools install_requires. These
# upstream names may not correspond exactly to bitbake package names.
RDEPENDS_${PN} += "python-influxdb"

# WARNING: the following rdepends are determined through basic analysis of the
# python sources, and might not be 100% accurate.
RDEPENDS_${PN} += "python-argparse python-core python-logging"

# WARNING: We were unable to map the following python package/module
# dependencies to the bitbake packages which include them:
#    influxdb.client
#    smbus

It is worth noting the the HOMEPAGE is false and so are the SRC_URI hashes. (I want to use buttonflux and not bnoflux which was my previously worked upon recipe)
I tried reseting the recipes but this problem is still persistent.
my workspace clones also the wrong repository:
workspace/
├── appends
│   └── buttonflux_1.0.bbappend
├── attic
├── conf
│   └── layer.conf
├── README
├── recipes
│   └── buttonflux
│       └── buttonflux_1.0.bb
└── sources
    └── buttonflux
        ├── bin
        │   ├── bnoflux
        │   └── calibrate
        ├── bnoflux
        │   ├── BNO055.py
        │   ├── bnoflux.py
        │   ├── calibrate.py
        │   └── __init__.py
        ├── LICENSE
        ├── MANIFEST.in
        ├── README.md
        └── setup.py

even though the source is called buttonflux the code within it belongs to bnoflux repository.
I do not understand why this is happening.

redpajama_set_name: RedPajamaStackExchange


As we see in the new year, I extend heartfelt greetings to all the people and service personnel and wish that homes across the country will brim with affection, hope and happiness.
My warm new year greetings go also to the compatriots in the south and abroad who shared our will in writing a new history of reconciliation, unity, peace and prosperity of the nation.
I wish success to the work of the Heads of State and other foreign friends who are making efforts for social progress and development and global peace and justice.
The year 2018 was a historic year in which remarkable changes took place in the internal and external situations and our socialist construction entered a new stage thanks to our Party's line of independence and strategic decision.
Thanks to our proactive and positive efforts a peace-orientated current was created on the Korean Peninsula and the international prestige of our Republic continued to be raised, and in the midst of this we celebrated the 70th anniversary of the founding of the glorious DPRK in splendour with great dignity and self-confidence.
Through the celebratory events held in September, the might of the DPRK which achieved the ideological oneness of the whole society and the single-hearted unity of the Party and the people and which possesses a reliable self-supporting economy and self-reliant defence capabilities, and the ardent will of the heroic Korean people to fight to the end for the victory of the socialist cause were fully demonstrated in front of the eyes of the whole world.
This year we are faced with the task of expanding the country's capability of independent development to open up bright prospects for taking a step forward towards socialist construction.
We have the strength and foundations to bring forward a brighter future of socialism by our own efforts, and we have also developed our own strategy and creative methods to this end. When we strive hard with an indefatigable spirit on the principle of self-reliance by adhering to the Party's new strategic line, our country's strength will redouble and our people's dreams and ideals will come true.
"Let us open a new road of advance for socialist construction under the uplifted banner of self-reliance!" - this is the slogan we should uphold. We should bring about a revolutionary upsurge on all fronts of socialist construction by regarding self-reliance as a treasured sword for prosperity, a spirit which has always been a banner of struggle and driving force for a leap forward in the whole course of the Korean revolution.
We should properly plan and thoroughly implement the national operations aimed at maintaining, reinforcing and re-energising the national economy as a whole.
It is necessary to unite the broad sections of the masses solidly around the Party by thoroughly applying the Juche-orientated view on the people, a people orientated philosophy, in the Party ans State activities.
We should accelerate the building of (a) socialist civilization.
The munitions industry should, on the one hand steadily raise the national defence capacity to that of the world's advanced countries by stepping up the effort for making the defence industry Juche-based and modern, therefore guaranteeing the peace on the Korean Peninsula by force of arms, and, on the other (hand) should actively support economic construction.
In order to successfully carry out the militant tasks facing us this year, officials, leading members of the revolution should make redoubled efforts and struggle with determination and courage.
Today, young people should play a large part in promoting socialist construction.
It is needed to increase the role of Party organisations.
Last year was a stirring year which witnessed a dramatic change unprecedented in the history of national division spanning 70 years.
It is unprecedented that three rounds of inter-Korean summit meetings and talks were held in a year amid great expectations and interest of peoples at home and abroad and this clearly showed that north-south relations entered into a completely different stage.
All the nationals should hold high the slogan "Let us usher in a heyday of peace, prosperity and reunification of the Korean Peninsula by thoroughly implementing the historic North-South declarations!"
Inter-Korean co-operation and exchanges should be expanded and developed in an all-round way so that national reconciliation and unity can be consolidated and all the fellow countrymen can practically benefit from improved north-south relations.
For the present, we are willing to resume the Kaesong Industrial Park and Mt. Kumgang tourism without any precondition and in return for nothing, in consideration of the hard conditions of business-persons of the south side who had advanced into the Kaesong Industrial Park and the desire of the southern compratiots who are eager to visit the nation's celebrated mountain.
Last year our Party and the government of our Republic exerted responsible efforts to safeguard the peace and security of the world and expand and strengthen friendship with different countries.
The historic, first ever DPRK-US summit meeting and talks brought about a dramatic turn in the bilateral relationship which was the most hostile on the earth and made a great contribution to ensuring peace and security of the Korean Peninsula and the region.


Anyone will lose weight on 500 kcal per day--HCG or no HCG!
The lose-weight-fast market is largely fad-driven, and often fraud-driven. The FDA (Food and Drug Administration) and the FTC (Federal Trade Commission) has warned manufacturers of weight-loss products containing human chorionic gonadotropin (HCG) that these are illegal. The FDA has posted a short video on the dangers these products pose to dieters.
PositiveTip: Beware of miracle weight-loss products. A balanced, healthful diet combined with physical activity will yield beneficial results.


South Lincolnshire Wildfowlers Club was formed in 1952 and offers its members true coastal wildfowling around the western edge of the Wash.
Wildfowling is not for the faint hearted, it is often a solitary pursuit of a quarry in an environment in which both time and tide are against you. Successful wildfowlers need true fieldcraft as well as an intimate knowledge of their surroundings.
Most wildfowling is on muddy or sandy estuaries. The higher parts will be green marsh or saltings with plants such as grasses and samphire. The lower parts or foreshore will be mud or sand.
The sea and seashores of estuaries are rich in plant and animal life and support large numbers of birds, many roost and feed on the Wash e.g. waders and some duck, others such as geese roost here and feed mostly inland.


text:
La morte mi attende è un film statunitense diretto da Vincent Sherman nel 1941 e distribuito in Italia nel 1953.

Trama
Un insegnante di filosofia ha solo sei mesi di vita perché affetto da un aneurisma ed elabora una teoria secondo cui, con l'intento di rendersi utile alla società, si trasforma in un giustiziere uccidendo una donna che ha rovinato la famiglia di un pittore suo amico. Confessa il suo delitto, viene processato e condannato alla sedia elettrica ma vorrebbe fuggire per non essere giustiziato. Quando viene a sapere che il suo esempio ha indotto un altro giovane a farsi giustizia da sé, decide però di subire la condanna e scrive una lettera per chiedere perdono e rinnegare la sua teoria.

Note

Collegamenti esterni

Film drammatici

redpajama_set_name: RedPajamaWikipedia


text:
Toy drone disrupts aircraft fighting California wildfire
A private drone trying to film a wildfire that has charred nearly six square miles in Northern California briefly disrupted firefighting efforts, although workers had gained the upper hand against the blaze, officials said on Monday.
Fire officials spotted the drone over the so-called Sand Fire on Sunday and immediately called police to find the drone's owner and have the toy grounded to avoid a possible mid-air collision, a California fire official said.
"That drone was flying within our air space and was a hazard for our aircraft," said California Department of Forestry and Fire Protection spokesman Kevin Lucero. "It essentially inhibited some of our operations going on."
The El Dorado County Sheriff's Office told the Sacramento Bee newspaper that it was investigating the incident. It said the drone's owner was a hobbyist trying to film the blaze.
Check out more information at news.msn.com
Thailand robot search and rescue in building collapse
Last night, BART LAB Rescue Robotics Team performed in a real search and rescue situation in the northern part of Bangkok where an under construction 6-story building has collapsed in the late afternoon.
Origami Robot Could Be Used In Search And Rescue Missions
Researchers developed a robot that employs a self-folding method inspired by the ancient art of origami.
The researchers found a way to coax flat sheets of composite materials to self-fold into robots with complex mobility, the American Association for the Advancement of Science reported. The findings were published in the August 8 edition of Science.
The new robots formed themselves through paper and shape memory polymers; these materials responded to heat above 100 degrees Celsius. The flat composite proved to be able to transform itself into a functional machine in only about four minutes; the final product can crawl at a speed of two inches per second. The new approach allows researchers to produce complex robots that can be scaled to different sizes and are strong for their weight.
Check out more information at hngn.com
China earthquake: Drone on-site plus other ways robots can help.
[youtube]https://www.youtube.com/watch?v=-PpKtrll7Gg[/youtube] The death toll continues to rise in China's Yunnan Province earthquake and our thoughts and prayers are with the victims, families, and responders. The Chinese Army is already using drones to provide responders (as well as geologists and hydrologists) with assessment of damage in the remote, rural areas. In general, ground robots are not terribly useful in earthquakes unless there are significant building collapses where canines can smell survivors but robots are needed to crawl in spaces that responders and canines can't get in. Unmanned marine vehicles can be useful in help inspecting the underwater portion of bridges and rapidly determining river channels are open so that ships can bring in supplies. So while robots are unlikely to directly save lives, they fulfill their goal of helping the responders help the survivors!


Flex in specs: a license to innovate?
Military specifications are designed to prevent problems or defects that occurred in past procurements and to ensure that goods are of high quality. They can become a hindrance, however, when they prevent new solutions to problems that call for obsolete technology. Specifications and standards do show signs of becoming more flexible. One aim is to minimize their use in the early phase of military system development, allowing program managers and contractors to make basic decisions between different system designs before the details become solidified. Another aim is to tailor the specifications and standards to a particular system. Each branch of the military has instituted programs to streamline the creation and use of military specs. The US Air Force is considered the leader with a program that trades standardization for quality and performance goals. Efforts are also being made to increase and standards.
Douglas Aircraft's DC-3, based on its predecessor DC-2, is an example of the successful redesign of an existing aircraft. Certain constraints distinguish a redesign from ordinary design changes. Existing tooling may have to be utilized for the new design. Redesigns are divided into two categories: fixes and updates. Fixes correct problems that were not expected in the original product. Updates are usually planned developments of a product's life cycle.
Product information, Product life cycle, Design, MD, Aircraft, Douglas Aircraft Co.


text:
KAWS painting sets artist record at $14.8 million
'THE KAWS ALBUM', KAWS. Courtesy Sotheby's.
By Katherine Keener Published on 8 April 2019 at 17 h 54 min
On April 1st, an artwork by the notorious street artist cum fine arts craze Brain Donnelly, better known as KAWS, set an artist record when his work THE KAWS ALBUM (2005) sold for HK$115.9 million ($14.8 million) and it was no April Fool's joke. The artwork was one of 33 lots sold at Sotheby's Hong Kong during their 'NIGOLDENEYE® Vol. 1' sale. The white glove auction consisted solely of artworks by KAWS, BAPE (the brand created by the seller), Futura, and Stash from the private collection of Tomoaki Nagao, a Japanese entrepreneur, DJ, designer, and record producer best known by the name NIGO. NIGO has collaborated with a number of artists including KAWS (as seen in the auction), Kanye West, and Pharrell Williams. 'NIGOLDENEYE® Vol. 1' was NIGO's third sale with Sotheby's following his 2014 'NIGO Only Live Twice' and a 2015 auction of rare Star Wars figurines.
'THE KAWS ALBUM', KAWS. Courtesy Sotheby's.
THE KAWS ALBUM takes parody to a new level. In 1998, the animated TV show The Simpsons released an album of original songs recorded over the prior years. The second album made by the famous yellow characters, though, had a somewhat less original album cover. Featuring a slew of characters from the show, they recreated the Beatles' 1967 album cover for Sgt. Pepper's Lonely Hearts Club Band retrofitting the renowned cover art with details from The Simpsons. The 2005 parody of a parody keeps the iconic characters from The Simpsons, but replaces their eyes with KAWS' hallmark X's and their mouths with more skull-like jaw. At the bottom, where the original picture read 'The Beatles' and The Simpsons' The Yellow Album read 'The Simpsons', one finds instead 'Kimpsons' the name KAWS has given his characters.
NIGO met KAWS in 1996 when visiting KAWS studio. NIGO told Sotheby's that he was 'fascinated' by KAWS' process and that piqued NIGO's interest in collaborating with the then-street artist. NIGO commissioned THE KAWS ALBUM directly from KAWS. The work featured in a 2016 retrospective for KAWS at the Modern Art Museum of Fort Worth, which was subsequently shown at Shanghai's Yuz Museum.
'Holiday', KAWS in Hong Kong's Victoria Harbour during Art Basel Hong Kong. Courtesy Flickr Commons.
The record-breaking sale for KAWS shows just how popular the artist has become in a relatively short period of time. Prior to the April 1st auction, KAWS' previous record sat at $2.7 million from the sale of Untitled (Fatal Group), which sold last year at Phillips London. By the end of 2018, KAWS had become so sought after that his top 20 auction prices were set all in that year. Even the presale estimate for THE KAWS ALBUM was only $1 million. KAWS' large-scale cartoon figure titled Holiday was a huge hit at Art Basel Hong Kong. The 115-foot-long inflated installation floated in the the city's Victoria Harbour attracting large numbers of visitors.
In addition to THE KAWS ALBUM, his 2003 paintings UNTITLED (KIMPSONS) and UNTITLED (KIMPSONS #3) sold at the auction for $2.7 million and $2.6 million, respectively, setting records for KAWS as his third and fourth most expensive artworks sold. Overall, 'NIGOLDENEYE® Vol. 1' generated HK$216.9 million ($27.6 million) over the course of the night.
'NIGOLDENEYE® Vol. 1' 'THE KAWS ALBUM' artist record BAPE Brain Donnelly Futura KAWS NIGO Sgt. Pepper's. The Simpsons Sotheby's Stash The Beatles The Yellow Album Tomoaki Nagao
Marketplace - Deals
MSCHF sells off 1000 copies of Andy Warhol's 'Fairies'
Brandon Lorimer 1 November 2021
Marketplace - Trafficking
David Bowie Painting 'DHead XLVI' discovered in donation centre
Brandon Lorimer 14 June 2021


Remember to take your Kawasaki ATV repair manual whenever you ride. It will easily fit in your gearbag, toolbox, or glove box.
But really now, your Kawasaki repair manual is cheap insurance against the dreaded Ride Day Demons, that show up unexpectedly.


text:
Counsel Jobs > Inhouse News > Drug Companies and
Inhouse News
Drug Companies and
In-House News:
Drug Companies and "Off-Label" Marketing
By Anique Gonzalez
Recently, pharmaceutical companies have come under fire for allegedly employing a practice known as "off-labeling," whereby they persuade physicians to prescribe drugs for reasons other than the drugs' developed purposes. As a result, Congress has launched an investigation into the practice, class-action suits have been filed, and large settlements have been reached.
It is important to note that doctors, in most cases, are not breaking the law when they prescribe medicine off-label. The legal implications present themselves when drug companies begin marketing these drugs for purposes other than their original intended uses.
Plaintiffs' attorneys claim that drug companies will often conduct research to discover additional uses for a specific drug and then present the information to doctors in hopes that the number of prescriptions for that drug will increase. While many may not consider this ethical, it is legal. A fine line has developed, however, between drug companies providing information about possible off-label uses and drug companies promoting use in a manner not sanctioned by the Food and Drug Administration (FDA).
In several of the lawsuits filed thus far, plaintiffs include not only individuals who claim they were injured by inappropriately prescribed drugs but also insurance companies who are contesting the off-label prescriptions they were forced to cover.
Such suits include a 7,000-member multidistrict Florida case that was filed against AstraZeneca. The plaintiffs allege that the drug company not only encouraged off-label use of the drug Seroquel but also suppressed information about the drug's side effects. Welfare Fund of Teamsters Local 863 v. Pfizer Inc. is a New Jersey case that involves the drug company Pfizer and its cholesterol drug, Lipitor.
Various insurance companies and unions allege that they lost billions of dollars as a result of being forced to cover drugs that were prescribed off-label. Insurance carriers in Massachusetts filed a similar suit against Pfizer, claiming that many of the prescriptions written for the drug Neurontin were off-label prescriptions.
Many of the plaintiffs' lawyers argue that off-labeling has padded pharmaceutical companies' bottom lines and is responsible for large portions of their revenues. Insurance companies are now watching for drugs that have high levels of sales but whose uses, as defined by the FDA, are extremely limited. Consequently, insurance companies are starting to file suit in instances where they believe the majority of prescriptions were off-label.
Such lawsuits can yield extensive monetary damages for the drug companies involved, even when the suits do not go to trial. In the past two years, for instance, the United States Department of Justice has negotiated settlements that have now reached more than $1 billion.
Other large settlements have included those of Schering Plough and Serono, both of which were accused of marketing their drugs off-label. In 2005, Serono settled a lawsuit for $704 million, and in 2006, Schering Plough agreed to pay $435 million after it, too, negotiated a settlement.
According to a study entitled "Off-Label Prescribing Among Office-Based Physicians" published in the Archives of Internal Medicine, off-label prescriptions accounted for 21% of drugs prescribed in 2001. In addition to insurance carriers and individual drug users, this recent surge in off-labeling has also interested Congress, which recently announced that it was investigating three drug companies as a result of claims that they were marketing anti-psychotic and narcotic drugs for off-label purposes.
However, Congress is not the only arm of government taking action. The United States Attorney's Office in Philadelphia and Connecticut's attorney general are both examining claims that Cephalon, Inc.'s drug Actiq was primarily used by individuals who were suffering from back pain and migraines instead of being used by cancer patients as it was originally intended.
On the Net
archinte.ama-assn.org/cgi/content/abstract/166/9/1021
www.fda.gov
www.pfizer.com
Article Title: Drug Companies and


text:
I'm Looking Through You
In addition to a game, The Beatles: Rock Band aspires to be a shrine to the fab four and a role-playing exercise for people wishing to participate in the retelling of cultural myths. The game's story is a stylized presentation of the band's career. From the Cavern Club in 1963 to the psychedelic strawberry fields of the late 60s to the final rooftop concert at 3 Savile Row in 1969, the game enables to player to participate in the retelling of a cultural legend.
But what kind of legend is this? As I play the game, I grow continually more interested in the narrative and its relationship to historical events. More than once, I found myself thinking of one of my favorite films, which also deals with the line between truth and myth: The Man Who Shot Liberty Valance.
The Man Who Shot Liberty Valance is a Western that explores the utility of cultural myths and the morality of a noble lie. Ransom Stoddard, played by Jimmy Stewart, is an idealistic Eastern tenderfoot who comes to a town terrorized by a bandit named Liberty Valance. Tom Doniphon , played by John Wayne, is the only one who can stand up to Valance and repeatedly tries to prove to Stoddard that justice is better upheld by guns than by laws.
Stoddard eventually gives in to this logic and confronts Valance. Miraculously, he out-shoots Valance, becoming an instant hero.
Stoddard's feat propels him into a career as a politician and he uses this support to transform his life and improve the lives of others through public policy. He transforms the bleak Western wilderness into a garden.
However, this reputation was built on a lie:
The Beatles: Rock Band possesses a similar ethos to that of The Man Who Shot Liberty Valance. While the game is less about lies than it is about omitting certain facts, the final product is devoted to the legend of The Beatles, rather than The Beatles themselves.
The Rock Band version of The Beatles exist in a strange universe that is divorced from both historical and personal context. The four Beatles journey across a temporal dream-scape, creating music as they go, existing as a unit of pure imaginative energy. There are no digital versions of people like Yoko Ono, Brian Epstein, and Phil Spector. Their contributions, both positive and negative, are edited out of the game and the legend it helps us create.
The band's personal and musical transformation reflects the turbulence of the 1960s, but The Rock Band Beatles exist outside of history and its events. Playing the game is to venture into a world without Vietnam, a world in which "Helter Skelter" is scrubbed of its murderous associations, and where psychedelic art and creative experimentation are never aided by drugs. We can find "Day Tripper," in the game, but we cannot find the faintest whiff of pot or the tiniest tab of acid. Perhaps real-world Paul is bogarting it all?
In many ways, The Beatles: Rock Band evokes the squeaky-clean "kid-friendly" incarnation of the band that shows up in so many kids' albums. The digital Beatles we play are always a happy, smiling family, unencumbered by legal and creative differences. As the digital Beatles play "Come Together" we can recreate a scene of band unity that never happened: by the time the real Beatles sang "Come Together," they were already miles apart.
The game's story offers no hints at either the bloodshed or the bad blood that would plague the former band-mates after their breakup. Even after John Lennon's murder in 1980, the surviving members had not resolved their differences. In 1988, The Beatles were inducted into the Rock and Roll Hall of fame. Paul declined to make an appearance, stating:
"After 20 years, the Beatles still have some business differences which I had hoped would have been settled by now. Unfortunately, they haven't been, so I would feel like a complete hypocrite waving and smiling with them at a fake reunion."
At the end of The Man Who Shot Liberty Valance, Stoddard tells the truth about the duel with Liberty to a newspaper editor, knowing full well that his confession undermines his all of his life's achievements. The editor recognizes this as well, and burns the notes that his young reporter was taking. Stoddard expresses his surprise, confusion, and amusement that they are not going to run with the story. The editor replies that "When the legend becomes fact, print the legend."
In making The Beatles: Rock Band, I imagine Harmonix felt a bit like that newspaper editor. Of course, the task of obtaining permission from the various owners and estates of The Beatles is Herculean by itself. It is understandable that both the surviving members, their families, and the record companies are invested in recreating the Beatles in the most flattering (and profitable) way possible. But on top of that, there is the legend's sanctity to consider: How does one go about tearing down myths that define a culture?
Harmonix, like the newspaper editor, simply chooses not to. The ending cinematic is a perfect metaphor for the game: it is a testament to the reverent isolationism we impose on legends:
The very world around them is transformed into a wonderful fantasy, disconnected from the flow of time, and beyond human blemishes. It is a world where their creativity overpowers the dreariness of our world, a world that exists to inspire us with its ideals, rather than its veracity. It is a world in which Ransom Stoddard shot Liberty Valance, a world whose artificially constructed existence helps improve our own.
Labels: culture, features, game design
Tesh February 3, 2010 at 3:56 PM
Myths have a long and storied history in human culture. If they were mere recitations of facts and dates, they would be as dry as that lame high school history class.
There is a place for objective and absolute truth. Likewise, there is a place for myth and fiction. The trouble is confusing one for the other. *shrug*
leandrodubost February 14, 2010 at 3:40 PM
You're mixing things up. Badly.
It's a Beatles game. A musical Beatles game. It's not a history class to teach us what they meant, what was happening in the world at their time, why were they successfull and how did they managed to be so important.
It's a musical game where you play music and have fun. That's it!
To expect anything else from this game and it's so called 'storyline' is useless!
Watch The Beatles Anthology instead...
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By now, you've probably heard of Marie Kondo and her organizational methods. They involve getting rid of anything that, when you hold it, doesn't "spark joy." It's about cherishing what you have and letting go of what doesn't make you feel good.
She's written four books and just launched a Netflix series called "Tidying Up With Marie Kondo" that is surprisingly touching and sweet. And memes abound.
I watched it thinking I'd learn how to fold my clothes better and create more space on my bookshelves (I mean, the online bourgeoisie just about broke the internet from ire after she suggested giving up books, so I was preparing my bibliophile self emotionally).
I started taking note of the things I have that I need not, like books that collect more dust than curious eyes, and clothes I haven't worn in, well, sometimes ever.
Three can openers? Two of those certainly aren't sparking joy (or opening cans), so thank you, but goodbye.
The ends of wrapping paper rolls that aren't big enough to cover a present? You take up space in my garage, but not in my heart, so I hope your recycled life brings you incredible meaning.
To the half bowl of cereal in the box: You're disrespecting my bowl. Gracias. And ta-ta.
I started with that horrendous sound people make when eating a banana. (I can't even believe they're allowed in public) and then added superfluous or impossible-to-open packaging (why are scissors always so far away?).
Endless threads of unnecessary reply-all emails (UNSUBSCRIBE).
People walking backward in crowded places (don't let my toes be the undeserving recipients of your lack of direction).
Kids' toys that don't have volume control (dang it, bud, Mommy accidentally hit that with a hammer — thrice).
That person who, despite your blinker and three-minute wait, zips in and takes your parking spot (they're in your capable hands now, Karma).
The narrow constraints of professional attire (increased discomfort = decreased performance, fools!).
The requirement that ads for pharmaceuticals have to list ANY AND ALL potential side effects (pro tip: "May cause death" is not a strong selling point).
My heart was racing and the ideas were flowing. I could barely keep up. And then everything seemed to escalate. We were far beyond unread books and banana eating now.
What about that bill in the Legislature that would deny people the right to change their gender marker on their birth certificate (why do the rest of us get to have our documents reflect our true selves?).
Or, even bigger, that women of the world lack any autonomy (kindly remove your unwanted parts and policy from invading our bodies).
And the lawmakers who act like marionettes controlled by the strings of their religious faith.
Or that Utah still allows conversion therapy, a devastatingly flawed practice that is literally killing our young people.
The list went on (and included more and perhaps spicier items than I could include here), but ended with: a president whose ego is only outsized by his inability, and whose disregard for truth and goodness will — without intervention — be among the most detrimental to the stability of life on Earth.
Um, Marie Kondo, I'm not sure I'm I doing this right?


text:
\section{Introduction}
\label{sec:intro}

The development of epifluorescence microscopy techniques in combination with single-molecule methods such as molecular combing has had an enormous impact on the study of DNA replication [see Refs.~\cite{Humana_chapter_Herrick, Herrick:2008p883, Herrick:1999p1088} for reviews].  Earlier approaches such as autoradiography~\cite{Cairns:1963p208} and 2D gel electrophoresis~\cite{Bell:1983p527} were not only slow but also provided only limited and localized information about the replication process.  The advent of reliable, high-throughput methods such as molecular combing led to genome-wide studies of DNA replication kinetics.  Moreover, the possibility of genome-level observations made possible complex experiments such as a study of the checkpoint regulation of DNA replication~\cite{Marheineke:2004p1086} and one of the relation between replication fork movement and origin spacing~\cite{Conti:2007p1424}.

Molecular-combing measurements provide information about the DNA replication kinetics at a given time during the S phase~\cite{Bensimon:1994p1633}.  These snapshots of the replication process can be used to improve our knowledge about the location of replication origins, along with their activation time~\cite{Marheineke:2004p1086,Conti:2007p1424,Norio:2001p1594,Norio:2004p1566,Norio:2005p1567,Courbet:2008p1429,Katsuno:2009p1565, Pasero:2002p1639,Patel:2008p1640,Patel:2006p1634,Anglana:2003p1641, Herrick:2000p1396, Hyrien:2003p193,Herrick:2002p200}.  Such an analysis of the origin-firing program can, at least qualitatively, be based on a simple interpretation of combing measurements.  For example, even when studying cell cycles that are completely asynchronous, we can  infer from a series of combing measurements the relative replication times of different regions of the molecule.  This is of biological importance when considering both local and global changes in replication patterns that occur during normal cell differentiation, oncogenesis and oncogene-induced senescence~\cite{DiMicco:2007p154,DiMicco:2006p198},  Pluripotent embryonic stem cells, for example, rely on smaller replicon sizes that allow for diversification into distinct somatic cell lineages~\cite{Gondor:2009p1643}.  Knowledge of how replication patterns change during differentiation can give insight about underlying regulatory mechanisms and have contributed to our understanding of the impact of chromatin structure on technologies such as cloning~\cite{Lemaitre:2005p1644}.  Experiments based on synchronized cell populations can shed even more light on the origin positions and firing times, providing a detailed description of the space-time initiation program of DNA replication.

In order to fully exploit the large data sets obtained from molecular-combing experiments, we must rely on computer-modeling techniques.  An approach commonly used to interpret combing results is to perform Monte Carlo simulations of hypothetical replication scenarios~\cite{Blow:2009p1454,Goldar:2008p982,Lygeros:2008p978, deMoura:2010p1630,Spiesser:2009p1631}.  In such cases, the models are not designed to reproduce all the biological details of DNA replication but rather are focused on the kinetic aspects of the process (i.e., the rate at which origins are activated or the speed at which DNA is duplicated by replication forks).  Nevertheless, fundamental biological features relating to the effect of chromatin modulations on replication patterns can be readily investigated.  Therefore, these simulations allow one to test hypotheses about the overall replication scenario and to quantify the kinetic parameters of a given scenario.  However, such simulations can be computationally intensive and therefore too slow to explore a series of scenarios (e.g., when performing a fit).  The numerical modeling approach we present here addresses this issue by allowing us to study the average replication kinetics without having to do simulations.  More precisely, our calculation technique gives the average replication rates and forks densities one would measure if an infinite number of replication cycles were observed or simulated.  The speed gain from using our method compared to simulations makes it possible to explore a variety of kinetic parameters and to fit experimental data.  This will facilitate automation of sample analysis that is of potential clinical and diagnostic interest because many genetic diseases such as cancer involve altered cell cycle and DNA replication kinetics~\cite{Kaufmann:2010p1604}.

In the following sections, we will present our calculation technique and show how it can be used to study a given replication scenario.  Our modeling approach is flexible enough to accommodate inhomogeneous DNA replication kinetics, which are  scenarios in which the initiation rate and replication fork speed can change with position (and time) along the molecule.  Indeed, the methods presented here were motivated by single-molecule data that show clearly that the initiation of DNA replication in mammalian cells can occur in zones and that these zones are under developmental control~\cite{Norio:2005p1567}.  In addition, large-scale spatial variation of initiation rates and developmental control of such rates has been seen in many microarray-based experiments that give information about local, population-averaged replication rates [for example, \cite{Hiratani:2010p1642}].  Different chromatin environments, for example, correspond to regions with significantly different replication kinetics. The type of analysis discussed here can facilitate experiments addressing questions as to which chromatin factors (acetylation, methylation, phosphorylation) are involved in determining, on a concept specific basis, fork rates and origin efficiencies over extensive genomic regions.

In the Materials Section, we will describe the type of combing data considered in the examples presented in this article.  The Methods Section will present the details of our calculation, as well as a comparison with simulated data.  This section will also show how our model can be adapted to study asynchronously replicating cells and how we can infer information about the replication program by fitting simulated combing data.  Finally, in the Notes Section, we will briefly discuss how a global analysis of all the replication kinetic parameters could be performed.  We will also discuss how the effects of fork blocks (or pause sites) can be included into our model.  This is also of potential clinical interest when examining the effects of a drug on DNA replication kinetics.  Recently, for example, it has been shown that sister replisomes decouple when they encounter damaged DNA~\cite{Doksani:2009p1515}.  Therefore, the number of unidirectional forks might be an indicator of the number of blocked replication forks in a normal cell cycle.  Such forks can be used as a marker to quantify and monitor transient DNA damage and DNA repair efficiencies on a genome-wide basis~\cite{Conti:2007p1475}.  This is just one example among many potential applications of this type of modeling.

\section{Materials and Methods}
\label{sec:materials}

\subsection{Kinetic description of DNA replication}
The experimental situation we consider in this article is sketched in Fig.~\ref{fig:schema}.  Part (a) is a space-time illustration of the DNA replication kinetics during one cell cycle.  In this representation, replication can be initiated at various positions $x$ along the genome and at different times $t$ since the beginning of S phase (see the circles in Fig.~\ref{fig:schema}(a)).  A pair of oppositely moving replication forks emerges from each initiation site, and each fork starts to duplicate DNA at a speed $v(x, t)$. The dependence on $x$ and $t$ means that $v$ can change with both the location along the genome and the time during S phase.  For simplicity, the fork velocity used in this article is assumed constant throughout both space and time, as illustrated in Fig.~\ref{fig:schema}.  The forks progress until they reach one end of the molecule or until they coalesce with an oppositely moving fork (diamond symbol in Fig.~\ref{fig:schema}(a)).

\begin{widetext}

\begin{figure}
\begin{center}
\includegraphics[width=12.0cm]{schema2}
\caption{(a) Schematic of the space-time progression of replication forks (triangles).  S phase starts at $t_0$.  Circles at times $t_1$ and $t_2$ show origins of replication, while the diamond indicates the termination site where forks from two origins coalesce at time $t_4$.  Replication forks move at  constant speed until they coalesce or reach the ends of the molecule of length $L$ (around $t_5$ and $t_6$).  Gray solid lines represent the original DNA molecule, while newly synthesized DNA is shown in black.  (b) Examples of labeled molecules collected during a combing experiment studying the replication kinetics presented in (a).  Gray stars indicate fluorescently labeled regions, while thick black lines correspond to label-free sections of the molecules.  Each molecule represents the labeling pattern one would observe if the nucleotides used for the DNA synthesis were replaced by fluorescent nucleotides at time $t_i$.  (c) Space-time replication fraction $f(x, t)$ of the replication cycle presented in (a).  White and black areas represent unreplicated and replicated DNA, respectively.         }
\label{fig:schema}
\end{center}
\end{figure}

\end{widetext}

\subsection{Molecular labeling}
The labeling procedure consists in supplementing the regular nucleotides used for the DNA synthesis with nucleotide analogs
that can be detected by immunofluorescence microscopy.  If the cell cycles are synchronized, the nucleotide analogs can be introduced at a precise time $t_i$ after the beginning of S phase.  Figure~\ref{fig:schema}(b) shows examples of fluorescently labeled molecules that might be collected given the replication cycle presented in Fig.~\ref{fig:schema}(a).  Each example, from bottom to top, illustrates the labeled molecule obtained if the analogs were added at times $t_0$, $t_1$, $t_2$, $t_3$, $t_4$, $t_5$ or $t_6$.  Basically, this procedure labels the DNA that is replicated after the specific time $t_i$.  In an actual experiment, a second type of nucleotide analog would be used to map the rest of the molecule and hence obtain a fully labeled molecule.  In the simulations presented in this article, a second label is unnecessary, since there is no ambiguity about the molecule alignment or stretching.  The results we will present here focus on the \textit{replication fraction} of a molecule, $f(x,t)$, which is the probability that the section of the molecule located at the position $x$ along the genome is replicated by a given time $t$ during S phase.

\subsection{Data collection}
\label{ss:data_collection}
In order to calculate the replication fraction $f(x, t)$, we must ensure that the experimentally collected labeled molecules meet the following conditions:
\begin{itemize}
\item the precise time when nucleotides were added must be known;
\item the molecules must be combed and stretched to identify the location of the labeled regions;
\item the molecules must be oriented (which can be achieved using hybridization probes).
\end{itemize}
Once these requirements are fulfilled, as in Fig.~\ref{fig:schema}(b), we can compute the replication fraction profile $f(x)$ of each labeled molecule by assigning the value $f=1$ (replicated at time $t$) to the non-labeled regions of the molecule and $f=0$ (unreplicated at $t$) to the labeled ones.  Figure~\ref{fig:schema}(c) presents the complete space-time replication profile resulting from our labeling procedure for the replication cycle example shown in Fig.~\ref{fig:schema}(a).  The labeling sequence can also be used to locate the positions and directions of replication forks as a function of time.  Although it is possible to analyze fork data, too, we focus here on the replication fraction [see Ref.~\cite{gauthier_submitted} for more on analyzing fork-density data].

In the following sections, we will compare calculated replication fractions to simulated ones.  Our simulated data sets mimic the data one could experimentally collect, in the sense that we simulate each step of a similar combing experiment.  On the other hand, our simulated data sets are ``better" in some ways than their experimental counterparts:
\begin{itemize}
\item the simulated cell cycles are perfectly synchronized;
\item the time when nucleotide analogs are introduced is known exactly (and once added, labels are instantly used for sequencing);
\item the positions along the simulated molecules are clearly defined (simulated results represent molecules that are perfectly stretched, aligned, and oriented).
\end{itemize}
Such ideal simulated data allow us to obtain precise statistics about the kinetics of replication itself, independent of experimental noise.  (We could also simulate the noise processes, but that would complicate the presentation here.)  As we will see below, these simulations can be used to test our numerical calculations.

\subsection{Monte Carlo simulations of combing experiments}
\label{ss:mcsim}
As mentioned above, we need to generate simulated data in order to test our numerical model of DNA replication.  The simulations we carried out follow the requirements listed in Section~\ref{ss:data_collection}.  For each simulated labeled molecule used in this article, we performed a Monte Carlo simulation of the replication dynamics as presented in Fig.~\ref{fig:schema}(a).  The numerical-simulation procedure we followed is presented in detail in Ref.~\cite{Jun:2005p149} and can be summarized as follows:
\begin{enumerate}
\item Define a simulation time step $\delta t$.
\item Begin a cell-cycle simulation with an unreplicated molecule of size $L$ at time $t=0$, which marks the beginning of S phase.
\item Simulate the initiation of replication origins (circles in Fig.~\ref{fig:schema}(a)) between $t$ and $t+\delta t$ using a pre-defined initiation rate $I(x, t)$.  This rate is defined as the number of initiations per time per length of unreplicated DNA.
\item Allocate to each origin that fires a pair of oppositely moving replication forks (triangles in Fig.~\ref{fig:schema}(a)).
\item Calculate the displacement of all existing replication forks during the time step $\delta t$ using the fork velocity profile $v(x, t)$.  Fork movement corresponds to DNA replication.
\item Delete forks that coalesce with oppositely moving forks (diamond in Fig.~\ref{fig:schema}(a)) or that reach the end of the molecule.
\item Repeat from Step 3 until the replication of the molecule is completed.
\item Define the time when the fluorescent nucleotides were introduced and deduce the corresponding labeled molecule pattern (as illustrated in Fig.~\ref{fig:schema}(b) for various label addition times).  As discussed below, this step is the one when we distinguish between synchronously and asynchronously replicating cells.
\item Repeat from Step 2 to collect more molecules.
\end{enumerate}

The simulation steps described above are valid if all cell cycles are perfectly synchronous.  For asynchronously replicating cells, we need to estimate the distribution of S phase start times (for example, using a Gaussian probability function).  Then, cell cycles themselves can be simulated following Steps 1--7 above.  However, the time when fluorescent nucleotides are added must be corrected relative to the S-phase start-time distribution.  In other words, we must keep track of the \textit{laboratory clock} compared to the \textit{cell-cycle clock}.

\subsection{Rate-equation approach}
\label{ss:req}
Our approach for calculating replication kinetics is based on a set of three coupled rate equations that describe the average space-time evolution of replication variables such as the replication fraction, $f(x, t)$, or the replication fork density, $\rho(x, t)$ (defined as the average number of forks per length at location $x$ and time $t$).  As we will see, the equations can be numerically solved in order to obtain the mean-field replication kinetics of a given replication scenario.

The first equation of our set describes the rate of change of the probability that a given position along the genome is replicated as a function of time,
\begin{equation}
	\frac{\partial f}{\partial t} = (v_{-} \,\rho_{-}) + (v_{+} \,\rho_{+}) \,,
	\label{e:dfdt}
\end{equation}
where the $\pm$ subscripts indicate the fork propagation direction (for right- and left-moving forks, respectively). Note that Table~\ref{tab:1} presents  the definition and units of all symbols used in this article.  Equation~\ref{e:dfdt} simply states that the rate of change of the replication fraction is given by the product of the local fork densities times the rate at which each fork replicates.  Note that the velocity of left- and right-moving forks can be different in our formalism, although here they are kept equal.

The second and third equations of our set express the space-time rate of change of the right- and left-moving fork densities as
\begin{equation}
	\label{e:drhodt_r}
	\frac{\partial\rho_{+}}{\partial t}  + \frac{\partial (v_{+} \rho_{+})}{\partial x} = I (1-f) - \frac{(v_{-}+v_{+}) \rho_{-} \rho_{+}}{1-f}  \,,
\end{equation}
and
\begin{equation}
	\label{e:drhodt_l}
	\frac{\partial\rho_{-}}{\partial t}  - \frac{\partial (v_{-} \rho_{-})}{\partial x} = I (1-f) - \frac{(v_{-}+v_{+}) \rho_{-} \rho_{+}}{1-f}  \,,
\end{equation}
respectively.  The left-hand sides of these equations describe the change of fork densities due to their displacement along the genome.  The right-hand sides present the contributions associated with initiations and coalescences of forks.  The first term is simply given by the product of the local initiation rate, $I(x, t)$, normalized by the probability that the genome is not already replicated at position $x$ .  The second term gives the frequency at which converging replication forks meet at $x$ and $t$.  This coalescence rate is proportional to the local densities of both types of forks and their relative speed when they merge.  This rate must also be normalized by the probability that the local DNA is not already replicated, $1-f(x, t)$.  For clarity, we did not explicitly specify in Eqs.~\ref{e:dfdt}--\ref{e:drhodt_l} that $f(x, t)$, $\rho_\pm(x, t)$, $v_\pm(x, t)$ and $I(x, t)$ can all change with both the position along the genome, $x$,  and the time elapsed from the beginning of S phase, $t$.

Given a replication scenario for the initiation rate, $I(x, t)$, and the fork propagation speed, $v_\pm(x, t)$, Eqs.~\ref{e:dfdt}--\ref{e:drhodt_l} can be numerically solved for $f(x, t)$ and $\rho_\pm(x,t)$.  The initial conditions must be set to $f(x, 0)=0$ and $\rho_\pm(x,0)=0$ for all positions along the molecule.  Such a numerical analysis can be carried out using various approaches.  We developed and ran our own numerical code using IGOR~Pro~\cite{igor}.  In the code, we discretize the modeled space-time region and approximate the partial derivatives in the equations describing the replication kinetics by finite differences.  Knowing the initial conditions for all positions at time $t=0$, one can then numerically integrate the system as a function of time [details about such numerical methods can be found in Ref.~\cite{nr2007}, for example].  The results presented in this article were obtained using the single-step explicit Euler method.  We used $dx=0.002$~Mb and $dt=0.0 \bar{1}$~hr (note that we must have $dx/dt \geq v$ in order to solve the system).  For simulating or fitting to larger regions of the genome, the added efficiency of a more sophisticated numerical method for integrating the partial differential equations could be worth the extra effort to implement.

\subsection{Boundaries and finite-size fragments}
\label{ss:boundary}
When modeling a whole genome using our calculation technique, one must specify the boundary conditions.  The modeling we have described so far applies to linear DNA where replications forks vanish when they reach the ends of the molecule.  Our simulation algorithm and calculation method can easily be adapted for the modeling of circular DNA molecules by using \emph{Periodic Boundary Conditions} (PBCs).  This simply means that any fork that reaches one end of our modeled domain (i.e., $x=0$ or $x=L$) is re-inserted at the other end.  In terms of our rate-equation system, using PBCs means imposing the conditions that $\rho_\pm(0, t)=\rho_\pm(L, t)$ at all times $t$.

Molecular-combing experiments are often designed to extract DNA fragments from a particular region of the genome [e.g. \cite{Norio:2005p1567,Lebofsky:2006p1627}].  In order to model such fragments, we have two options:
\begin{enumerate}
\item We can model the whole chromosome and extract the information about the region that represents the experimentally observed fragment.
\item We can model only the fragment of interest, adding boundary terms to include replication by forks that initiate outside the fragment and then enter it during S phase.
\end{enumerate}
The first option is a straightforward application of the model presented in Section~\ref{ss:req} and has been applied, for example, to the study of Chromosome VI in yeast (\textit{S. cerevisiae})~\cite{Czajkowsky:2008p152}.  However, if the chromosome is much longer than the fragment of interest, as is usually the case, it will be experimentally and computationally inefficient to study and model the whole molecule.  In such a case, the second option can be an excellent approach, as long as we can model the effective flux of incoming forks at the modeled domain boundaries.  The simplest situation is that no forks from outside the domain cross the boundaries.  However, such a situation is realistic only when the ``outside origins," if they exist, are far from the fragment's boundaries.  More generally, we can include the contribution of origins near the fragment region in our model by replacing the periodic boundary conditions with time-dependent functions at either side that represent the flux of forks coming from outside the domain.  The fork densities at the fragment boundaries are then~\cite{gauthier_submitted}
\begin{eqnarray}
	\rho_+ &= \beta_{+}(t)\,[1-f_+]  \quad \text{(left edge)}
	\,, \nonumber \\[3pt]
	\rho_- &= \beta_{-}(t)\,[1-f_-]  \quad \text{(right edge)} \,,
\label{e:rho_boundaries}
\end{eqnarray}
where $\rho_+ = \rho(x=0,t)$, $f_+ = f(x=0,t)$, $\rho_- = \rho(x=L,t)$, and $f_- = f(x=L,t)$.  The functions $\beta_\pm(t)$ characterize the injection of right- and left-moving forks at $x=0$ and $x=L$, respectively.  For example, if the initiation rate outside the left and right edges is constant ($I_\pm$, respectively) in the semi-infinite region beyond the analyzed fragment, and if the fork velocity is constant as well, then $\beta_\pm(t) = I_\pm \, t$~\cite{gauthier_submitted}.  However, the real advantage in focusing on the fork fluxes $\rho_\pm$ is that we do not need to have a detailed scenario of replication outside the region where data are collected but we only need to find a form for the time dependence of $\rho_\pm$ that fits the data well.  If it turns out that $\rho_\pm = I_\pm t(1-f_\pm)$ fits the data well, then we can assert that origin initiation outside the region, insofar as it affects the region under study, is equivalent to a zone of constant intitiation rate.  In practice, we have found that the functional form $\rho_\pm = I_\pm t(1-f_\pm)$, with $I_\pm$ as fit parameters, works well, because the closest origin or origin cluster to the boundary tends to dominate.

\subsection{Post-treatment of the rate-equation solution}
Once the solution of our rate-equation system is obtained for a given replication scenario [$I(x,t)$, $v(x,t)$, boundary conditions, ...], we can use it to calculate the space-time distributions of initiations and coalescences.  These probability profiles tell us where and when such events are more likely to occur, deepening our knowledge about the replication kinetics.

The initiation density function is given by
\begin{equation}
\label{e:phi_i}
	\phi_i = \frac{I(1-f)}{N_i} \,,
\end{equation}
where
\begin{equation}
\label{e:N_i}
	N_i=\int_0^\infty\int_0^LI(1-f)\,dx\,dt \,,
\end{equation}
is the average number of initiations per replication cycle between $x=0$ and $x=L$.  The initiation density function is thus simply a normalized version of the initiation term in Eqs.~\ref{e:drhodt_r} and~\ref{e:drhodt_l}.  Similarly, we can normalize the coalescence term to obtain the space-time probability density of observing a coalescence as
\begin{equation}
	\label{e:phi_c}
	\phi_c =\frac{(v_{-}+v_{+}) \rho_{-} \rho_{+}}{N_c(1-f)} 	\,,
\end{equation}
with the average number of coalescences per cycle given by
\begin{equation}
	N_{c}=\int_0^\infty\int_0^L\frac{(v_{-}+v_{+}) \rho_{-} \rho_{+}}{(1-f)} \,dx\,dt \,.
\label{e:N_c}
\end{equation}
Other useful replication-related information can be derived from our rate-equation solution.  For example, we can use $f(x, t)$ and $\rho_\pm(x, t)$ to derive the distributions of the first initiation or the last coalescence times [see Ref.~\cite{gauthier_submitted} for more details].

\section{Results and Discussion}
\subsection{Model validation}
We now compare our rate-equation solution to simulation results.  The origin-initiation scenario we chose is presented in Fig.~\ref{fig:init_rate}(a).  It consists of a Gaussian-shaped initiation zone at the center of a 1~Mb fragment.  We used the boundary conditions derived at the end of Section~\ref{ss:boundary}, i.e., a constant level of initiation outside the fragment region [parameters for $I(x,t)$ are presented in caption of Fig.~\ref{fig:init_rate}].  In order to simplify the interpretation of the results, we assumed that the initiation profile of Fig.~\ref{fig:init_rate}(a) does not change with time, although our modeling formalism allows such variation.  Similarly, we used a constant fork velocity ($v=0.15$~Mb/hr $= 2.5$~kb/min).  Again, our formalism also works equally well if the fork velocity depends on space and/or time.

\begin{figure}
\begin{center}
\includegraphics[width=9cm]{init_rate_w_fit.pdf}
\caption{(a) Initiation profile $I(x)$ used in the simulations and calculations presented here.  The solid line represents the number of initiations per unreplicated length of DNA per unit time as a function of the position along the genome.  The curve itself is defined as a $I(x)=I_0 e^{-(x-\mu)^2/2\sigma^2}/\sqrt{2\pi\sigma^2}$, with $I_0=0.3$~hr$^{-1}$, $\mu=0.5$~Mb and $\sigma=0.05$~Mb.  The arrows at $x=0$ and $x=L$ indicate the level of initiation outside the modeled region (shaded in light gray), $I_+=0$~Mb$^{-1}$hr$^{-1}$ and $I_-=1.5$~Mb$^{-1}$hr$^{-1}$ (see Section~\ref{ss:boundary}).
(b) Fit (dashed line and arrow) of the eight simulated replication profiles for synchronous cells presented in Fig.~\ref{fig:sync_vs_async}(a).  The fit is compared to the original initiation scenario from part (a), which is shown in light gray.  The parameters obtained from the fit are $I_0=0.301$~hr$^{-1}$, $\mu=0.499$~Mb, $\sigma=0.0464$~Mb and $I_-=1.57$~Mb$^{-1}$hr$^{-1}$
}
\label{fig:init_rate}
\end{center}
\end{figure}

Figure~\ref{fig:sim2REQ} compares the calculated replication fraction and the initiation and the coalescence probability densities with simulation data.  Part (I) of that figure helps to understand the physical meaning of our rate-equation solution.  The figure illustrates that the calculated replication profile corresponds to the average profile we would get were we able to perform an infinite number of simulation iterations (the mean-field solution).  Figure~\ref{fig:sim2REQ} shows that our calculated initiation and coalescence probability density functions agree with simulation results as well.  More specifically, we used Eqs.~\ref{e:N_i} and~\ref{e:N_c} to calculate the average numbers of initiations and coalescences observed within the modeled domain per replication cycle (we obtained $N_i=0.91$ and $N_c=0.84$).  These calculated values agree, within statistical fluctuations, with the simulation averages of $N_i=0.91\pm0.04$ and $N_c=0.82\pm0.04$, based on 500 simulated replication cycles.

Finally, note that although the number of simulated replication cycles is large, the average profiles presented in part (b) are still relatively noisy.  Using rate equations gives us access to the exact average replication kinetics, whereas a simulation always gives a noisy approximation.  Reducing the noise to usable levels can take a large number of simulations.   On the other hand, simulations are good for understanding the level of statistical noise in a given experiment (by simulating the exact number of molecular fragments collected, etc.) and can also give information about more subtle features, such as correlations in the fluctuations of different measurements.

\begin{figure}
\begin{center}
\includegraphics[width=8.0cm]{sim_to_REQ_Mbh.pdf}
\caption{Simulated replication cycles (a, b) compared to our rate-equation solution (c).  In part (I), the shading indicates the value of the replication fraction, $f(x, t)$, from 0 (white) to 1 (black).  The dashed lines in (b-I) and (c-I) represent 1\%, 40\%, 70\% and 90\% contour curves (from bottom to top).  Contour curves show the time when the genomic locations reach a given probability of being replicated.   Parts (II) and (III) indicate the likelihood of initiations and coalescences, respectively.  Part (a) shows individual initiations and coalescences from one cycle, while parts (b) and (c) give the normalized probability density functions of observing such events as a function of space and time, $\phi_i(x, t)$ and $\phi_{c}(x, t)$.  The gray scales go from 0 (white) to $3.6$/Mb/hr (black) for initiations and from 0 (white) to $1.8$/Mb/hr (black) for coalescences.  Both the simulation and the calculation were done using the initiation function $I(x)$ presented in Fig.~\ref{fig:init_rate}(a) (constant throughout time).  The fork velocity was set to $v(x, t)= 0.15$~Mb/hr.
  }
\label{fig:sim2REQ}
\end{center}
\end{figure}

\subsection{Modeling a synchronous combing experiment}
As described in Section~\ref{ss:mcsim}, our Monte Carlo algorithm can mimic a simple combing experiment of synchronously replicating cells.  The gray bands in Fig.~\ref{fig:sync_vs_async}(a) present simulated combing results obtained using the replication scenario described in Fig.~\ref{fig:init_rate}(a).  These bands represent the average simulated combing profiles for various incorporation times of the nucleotide analogs (from 1 to 8~hrs).  For each band, 500 combed molecules were simulated; the gray bands shown in Fig.~\ref{fig:sync_vs_async}(a) are the average replication profiles $\pm$ the standard error of the means.

These simulation results can be directly compared to the calculated mean-field replication fraction, $f(x,t_{i})$, where $t_i$ is the analogs supplementing time.  The calculated combing profiles are presented as solid lines in Fig.~\ref{fig:sync_vs_async}(a) and agree with the simulated ones within statistical limits.

\begin{figure}
\begin{center}
\includegraphics[width=8.0cm]{sync_vs_async.pdf}
\caption{(a) Average combing profile (or replication fraction) at a series of time points (from bottom to top: 1, 2, 3, 4, 5, 6, 7 and 8~hrs) for synchronous replication cycles.  The shaded areas represent the confidence intervals of the average simulated combing profiles (the average value $\pm$ the standard error of the mean, obtained from 500 iterations).  The solid lines show the rate-equation solution for $f(x)$ at the corresponding times (the same solution presented in Fig.~\ref{fig:sim2REQ}(c-I)).  (b) Similar data for asynchronous replication cycles.  The start-time distribution was the same as in Fig.~\ref{fig:sync2async}).  The simulated data were collected as in part (a) except that the start times of the cycles were randomly chosen.  The rate-equation solution was modified to account for the start-time asynchrony (see text and Fig.~\ref{fig:sync2async} for details).      }
\label{fig:sync_vs_async}
\end{center}
\end{figure}

\subsection{Correction for cell-cycle asynchrony}
In the previous section, we demonstrated that our rate-equation approach is consistent with averaged combing results when all cell cycles are perfectly synchronous.  We now show how our calculated replication fraction $f(x, t)$ can be modified in order to take into account the asynchrony of S phase start times in the population of measured cells.  We consider two cases: (1) the distribution of start times is known, and (2) cell cycles are completely asynchronous.

\subsubsection{S phase start-time distribution}
Let $t$ refer to the laboratory clock and let $\phi_{\mathrm{start}}(t)$ be the S phase start-time probability density function.  If $\phi_{\mathrm{start}}(t)$ is known (or assumed), we can convolute $\phi_{\mathrm{start}}(t)$ with our rate-equation solution for $f(x, t)$ to find the asynchronous replication curve:
\begin{align}
	f_{\mathrm{async}}(x, t) &= \phi_{\mathrm{start}}(t) *f(x, t) \nonumber \\
	&\equiv  \int_{-\infty}^{\infty} \phi_{\mathrm{start}}(t^\prime) f(x, t-t^\prime)dt^\prime \,,
	\label{e:fasync}
\end{align}
where $f_{\mathrm{async}}(x, t)$ is the average observed replication function.  The convolution operation is illustrated in Fig.~\ref{fig:sync2async} for our replication scenario solution example of Fig.~\ref{fig:sim2REQ}(c-I) and a Gaussian distribution for the cell-cycle start times.  The situation depicted here could correspond to an experiment where cells are imperfectly synchronized by drug treatment [see Ref~\cite{Herrick:2002p200} for an example].  In such a case, Eq.~\ref{e:fasync} can be used to correct our calculation.

The impact of an asynchronous start-time distribution on combing measurements is presented in Fig.~\ref{fig:sync_vs_async}(b).  For this figure, the same simulation procedure as in part (a) was followed except that a Gaussian distribution with a standard deviation of 1.5~hr was used to adjust the cell-cycle clock with respect to the laboratory time.  Again, the gray bands represent the average and standard error of the mean obtained from 500 simulations, while the solid lines represent calculated profiles, $f_{\mathrm{async}}(x, t_i)$.

\begin{figure}
\begin{center}
\includegraphics[width=9cm]{sync_to_async_Mbh.pdf}
\caption{The rate-equation solution for $f(x,t)$ can be convoluted with the replication start-time distribution to obtain the average replication profile of asynchronously replicating cells.  Left:  Representation of the same solution as shown in Fig.~\ref{fig:sim2REQ}(c-I) with an extended time axis.  Middle: Probability density function of the start time of S phase for asynchronized cells.  The distribution is Gaussian, with standard deviation $\sigma_{\mathrm{start}}=1.5$~hr).  Right:  Transformed replication fraction profile, $f_{\mathrm{async}}(x, t)$ (see Eq.~\ref{e:fasync}).  As in Fig.~\ref{fig:sim2REQ}, the dashed lines indicate the 1\%, 40\%, 70\% and 90\% contour curves.    }
\label{fig:sync2async}
\end{center}
\end{figure}

\subsubsection{Perfectly asynchronous cells}
Equation~\ref{e:fasync} allows us to study a great number of partially synchronous cases but must be modified when the spread of start times becomes wider than the typical replication time.
An extreme case is the limit of perfect asynchrony, where molecular fragments are collected at any time during the cell cycle, with a uniform probability distribution.
In this limit, $f_{\rm asynch}(x,t) $ is constant for all $x$ and $t$ and no useful information about the replication kinetics can be inferred.
Norio~\textit{et~al.} introduced another way to analyze data obtained for this case of perfect asynchrony~\cite{Norio:2001p1594}.  The method uses only information from fragments that show evidence of active replication (i.e., that have at least one replication fork).  The main difficulty is that the length of S phase---the time between the first initiation and the last coalescence---is different for each cell because initiations are stochastic and vary from cell to cell.  Although the analysis is more involved and beyond the scope of this paper, it is still possible to extract replication parameters (initiation rates, fork velocities, etc.).  See Ref.~\cite{gauthier_submitted} for details.

\subsection{Fitting data}
\label{ss:inference}
An analytical formalism such as that presented in this article makes fast predictions of statistical profiles from a given replication scenario.  Using this mathematical approach, we can infer replication parameters from experimental data more quickly and precisely than using simulation-based fitting methods.

To illustrate these possibilities, we performed a simple fit of the synchronous simulation data presented in Fig.~\ref{fig:sync_vs_async}(a) using the initiation profile as a fitting variable.  More precisely, we fitted for the three parameters, \{$I_0$, $\mu$, $\sigma$\}, used to describe the Gaussian initiation peak of Fig.~\ref{fig:init_rate}(a) and for the outside contribution, $I_-$, as well (the left side contribution, $I_+$, was set to zero since a free fit gave a value consistent with zero).  The eight experimental curves of Fig.~\ref{fig:sync_vs_async}(a) were simultaneously fit using a standard routine~\cite{igor}.  The best-fit initiation profile is presented and compared to the original one in Fig.~\ref{fig:init_rate}(b).  Adding parameters, we can also infer the fork velocity, $v$, and the standard deviation of S phase start times, $\sigma_{\mathrm{start}}$ (for asynchronous data).  Note the need to account for correlations in the noise fluctuations to evaluate correctly the statistical errors of the fit parameters [see Section~\ref{ss:fork} and Ref.~\cite{gauthier_submitted} for details].

\subsection{Fork density profiles}
\label{ss:fork}
DNA replication patterns, which depend on chromatin context, origin efficiencies and replication fork rates, are highly inhomogeneous both within the genome and across different tissue types.  Knowledge of these patterns and how they evolve is crucial to understanding regulation of the cell cycle in both normal and diseased cells.  As we discussed above, molecular-combing measurements provide replication fractions, $f(x)$, at a given time $t$ during S phase, and we have shown here that such profiles can be reproduced using our calculation technique.  In addition to the replication state of the molecule, combing experiments also indicate the location of replication forks, and hence their density, at the time of nucleotide-analog incorporation.  This additional information about fork densities can also be compared with our rate-equation solution.  Thus, we could improve the inference technique presented in Section~\ref{ss:inference} by simultaneously fitting the replication fractions and the two fork density functions using a common set of parameters.  However, such ``global fits" are not trivial.  The correlations between fluctuations in different parts of the data---for example, how replication fractions correlate with fork densities---must be taken into account~\cite{gauthier_submitted}.

\subsection{Fork arrest and DNA damage}
Tumor cells are characterized by extensive karyotype alterations and aberrant DNA replication kinetics associated with deletions and amplifications.  The altered kinetics has been found to depend on amplicon structure~\cite{Conti:2007p1475, Griffiths:1991p1535}, and recently a Werner syndrome cell line was shown to exhibit altered rDNA patterns and elevated densities of unidirectional replication forks.  The relationship between genetic structure and replication kinetics is poorly understood, but repeat-rich sequences in heterochromatin and elsewhere in the genome have an important impact on replication kinetics and genome stability~\cite{Rodriguez:2002p30}.  Our rate-equation techniques can be easily adapted to study the impact of stochastic fork arrests on the replication kinetics.  Using the model presented in this article, we can model the effect of a change in speed of the replication forks as they move along the genome, via the velocity profile $v(x, t)$.  Such an approach could be used to model zones where forks slow (for example, the replication slow zones discussed in~\cite{Cha:2002p1432}).  The same approach can also be used to model a local or global change in fork velocity due to a checkpoint response.  On the other hand, phenomena such as fork blocks due to DNA damage~\cite{Vilenchik:2003p1523}, where the fork velocity is different in each cell, need to be modeled differently.  Our model can be adapted to such situations.  For example, we have considered cases where forks stall at randomly located DNA lesions and may eventually restart after repair~\cite{gauthier_submitted,Gauthier:2010p1614}.  The main modification needed is to introduce two new fork densities, $\rho_\pm^\prime(x, t)$, which represent the densities of left- and right-moving forks that have stalled.  The rate of change of these new densities is governed by the stall rate of regular forks and the repair frequency of stalled forks.  The replication kinetics would then be described using five differential equations instead of three.  Two extra terms must also be added to the right-hand sides of Eqs.~\ref{e:drhodt_r} and~\ref{e:drhodt_l}, to represent the stall and repair rates.

\section{Conclusions}
In this paper, we presented a simple and versatile simulation technique to model inhomogeneous DNA replication kinetics. We demonstrated that our modeling approach can be used to analyze or simulate molecular combing data as well as microarray-based results. We showed that our model can also be used to infer information about the replication kinetics from fitting typical experimental measurements.

\section*{Acknowledgments}
This work was supported by a Discovery Grant from the Natural Sciences and Engineering Research Council of Canada and by the Human Frontier Science Program.  We thank Paolo Norio, whose experimental results and cheerful collaboration pushed us to develop many of the results presented here.

redpajama_set_name: RedPajamaArXiv


The devastated friends of a popular Matson man killed on Sunday night have launched a fundraising appeal to support his family.
Kirk Lane died after a crash in Painswick Road, he was 31-years-old.
He had been cycling along the road when he was hit by a car, investigations into the incident have now entered a third day .
She said: "I'm totally shocked I only saw him the other week. He was a really good friend of the family and we made a nickname up for him 'Toffee' and it stuck with him.
"Everyone who knew him knew him as Toffee, he will be sadly missed but a lot of people, I set the GoFundMe page up as I know funerals cost a lot and wanted to help his family anyway I could."
She added: "He was well known by a lot of people so caring and kind hearted, he would do anything for anyone."
Kirk's brother Shane Beard said he would miss him dearly.
He said: "Now you're gone and laid to rest our memories we hold are only the best no matter where you gone or what you shall do I know I will always have them special thought of you please shine bright my brother going to miss you every day love you always."
Police want anyone who saw the collision, and particularly anyone who caught any of it on dashcam , to make themselves known as they may be able to help.
A full collision investigation is now under way and anyone who witnessed the collision or has any relevant footage is being urged to call 101 and quote incident 362 of October 1.


Hassan Rouhani, the new Iranian president, went to the UN summit to meet with the US President Obama and offer the US some forms of collaboration between the two states.
While the US and Israel have repeatedly referred to Iran's nuclear weapons program, the leaders of Iran have consistently maintained that their nuclear program is for civilian purposes only.
(1) The US is the only state that has used atomic bombs (during WWII).
(2) According to the foreign press, Israel possesses at least 200 tactical atomic bombs.
(3) If Iran were an ally of the US, like Pakistan, the US would not object to its possession of nuclear weapons.
Thus the issue is not the right of a state to develop weapons of mass destruction, but whether the state in question is perceived as an ally of the US.
In this sense, Israel's fear is that Iran and the US will negotiate some forms of collaboration which will end Israel monopoly over the nuclear weapons in the region. Israel wants to be the only state in the Middle East which possesses nuclear weapons in order to retain its unsure position as a strategic asset of the West in the region.
The fact that Obama wants to come to some form of an agreement with Tehran indicates the decline of the importance of Israel for the Western imperialist states. If the war of 1967 made Israel the darling of the West, Israel has subsequently gone down hill, at least from 2000, when it was forced to flee Lebanon. Since then, it has lost yet a second war in Lebanon in 2006, as well as the Gaza war against Hamas in 2012.
Thus the possible new relations being established between the US and Iran indicate the growing isolation of Israel, not only among the general population even in Europe, but among its traditional supporters in the other Western imperialist states.
These developments are also an indicator of the declining power of American imperialism and the growing influence of Russian and Chinese imperialism with whom Iran is allied in support of the Assad regime in Syria.
The US would like to pry Iran away from the Russian and the Chinese imperialists; Iran, from its side, wants to end the Western economic sanctions against her and open markets in the US and Europe to trade with her.
Today what all the imperialist powers, both Western and Eastern, have in common is their determination to derail the Arab revolution. Only by doing so can they prevent it from developing in the direction of a completed democratic revolution, one that can only be won as a worker-led revolution.
It is not very likely that Iran will break with Russia and China and become a full ally of the US. However, it is possible that the level of tension between the US and Iran will decrease. This thawing of US-Iranian relations infuriates the Israeli ruling class since the latter has no power to do much to ruin the party, except for some more covert sabotage of Iranian installations and additional targeted killings of Iranian nuclear and computer experts.
We can not be certain, but it is more than likely that Israel is behind the killing of Mojtaba Ahmadi, who served as commander of Iran's Cyber War Headquarters. Ahmadi was found dead this past weekend in a wooded area near the town of Karaj, north-west of the capital, Tehran.
Defend Iran against the imperialist Aggression of the U.S. and Israel! Long Live the Iranian Revolution against the Mullah Regime!
At the same time ISL and the RCIT call the workers, peasants and urban poor in Iran to organize for the revolutionary struggle against the reactionary regime in Teheran. The only way forward is to overthrow of the capitalist ruling class of Iran and to build a workers' and peasants' republic! Such a secular republic would immediately guarantees full democratic rights for women as well as religious minorities and the right for national self-determination – including separation – for the Kurdish, Azeri and other oppressed nations! For a Socialist Federation of the people in the Middle East!


text:
Home Exclusives Covid-19: Israeli Health Minister Dashes Hope of Easing Lockdown Anytime Soon
Covid-19: Israeli Health Minister Dashes Hope of Easing Lockdown Anytime Soon
The Israeli Health Minister, Yuli Edelstein has dashed the hope of nationals who looked
forward to the easing of lockdown in the country.
The health minister stated on Tuesday that there was "no way" the country's second nationwide coronavirus lockdown would be lifted after three weeks as it was originally scheduled.
"There's no way that in 10 days we'll be lifting all the restrictions and saying it's all over, everything is fine," he said.
"There might be some changes for the better, but this time, as part of the learning process from what happened in April, we'll exit (the lockdown) gradually, responsibly," Edelstein explained.
In his words, "The opening of the economy and our lives will be gradual and slow."
It should be recalled that Isreal started its second lockdown on September 18 after the coronavirus infection rate increased. It was originally scheduled to come to an end on October 10.
Places affected by lockdown include: schools, cultural events, majority of workplaces, markets and places of worship.
Benjamin Netanyahu has earlier admitted "mistakes" in the reopening of Israel's educational system and economy after the first lockdown this year.
It was gathered that Israel has recorded more than 233,000 infections and 1,507 deaths in a population of nine million.
The military intelligence disclosed that not only does Israel have the world's highest weekly infection rate per capita, it has also surpassed the United States, which is the world's hardest-hit country in terms of daily death rate per capita.
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The Importance of Being Earnest by the master of comedy Oscar Wilde, makes a welcome return to Guildford society in this wonderfully witty, deliciously decadent and classic revival from The Original Theatre Company.
Jack wishes to marry Algernon's cousin the beautiful Gwendolen but first he must convince her mother, the fearsome Lady Bracknell, of the respectability of his parents and his past. For Jack, however, this is not as easy as it sounds, having started life abandoned in a handbag at Victoria station.
Starring national treasure Gwen Taylor (Coronation Street, Duty Free and Barbara) as the formidable Lady Bracknell, the delightful Susan Penhaligon (Upstairs Downstairs and Bergerac) as the hapless Miss Prism, Downton Abbey favourite Thomas Howes as Algernon and with Broadway and West End star Kerry Ellis as Gwendolen.They will be joined by Geoff Aymer, Louise Coulthard, Peter Sandys-Clarke and Simon Shackleton.


Peter and his team were very professional in designing and installing their pad and walkway design. They were provided more value for money when compared to other estimates and their recommended materials exceeded the specs of their comparables. Overall very satisfied with their work.
Thank you for placing this review, Danny. Enjoy your new landscape and parking on your new parking pad.


text:
Q: mod_wsgi: Unable to stat Python home and ImportError: No module named 'encodings'  I am trying to construct a web site on Apache 2.4 using Django and mod_wsgi on Python 3.5.2. But when apache daemon httpd is started, following error message is output on /var/log/httpd/error_log.

[Fri Sep 16 17:44:57.145900 2016] [wsgi:warn] [pid 20593] (13)Permission denied: mod_wsgi (pid=20593): Unable to stat Python home /home/ec2-user/.pyenv/versions/3.5.2. Python interpreter may not be able to be initialized correctly. Verify the supplied path and access permissions for whole of the path.
  Fatal Python error: Py_Initialize: Unable to get the locale encoding
  ImportError: No module named 'encodings'

 So, I explored some articles about similar problems, e.g.

*

*Django + Apache + mod_wsgi permission denied

*mod_wsgi: ImportError: No module named 'encodings'
but the causes of error message above are not yet resolved.
 Please indicate some points to be checked or documents to read and so on.
My development environments are as follows.
(1) Host and OS

*

*Hosting Service: Amazon AWS EC2

*OS: Amazon Linux AMI release 2016.03

(2) Django Project
 I made Django project named testprj in the directory /home/ec2-user/django-sites  with user account of ec2-user.
[ec2-user@MyEC2 django-sites]$ pwd
/home/ec2-user/django-sites
[ec2-user@MyEC2 django-sites]$ ls -l
total 4
drwxrwxr-x 3 ec2-user ec2-user 4096 Sep 16 14:50 testprj

Database which the testprj uses is already set up. So, development server provided in Django is successfully started with no error as bellow.
[ec2-user@MyEC2 testprj]$ python manage.py runserver
Performing system checks...

System check identified no issues (0 silenced).
September 16, 2016 - 14:23:47
Django version 1.10.1, using settings 'testprj.settings'
Starting development server at http://127.0.0.1:8000/
Quit the server with CONTROL-C.

(3) Environments of Python
 I installed Python 3.5.2 by pyenv install 3.5.2. And then I set
pyenv virtualenv 3.5.2 django-sites.
And I set local of /home/ec2-user/django-sites to env django-sites as bellow.
[ec2-user@MyEC2 django-sites]$ pwd
/home/ec2-user/django-sites
[ec2-user@MyEC2 django-sites]$ pyenv versions
  system
  3.5.2
  3.5.2/envs/django-sites
* django-sites (set by /home/ec2-user/django-sites/.python-version)
[ec2-user@MyEC2 django-sites]$ python -V
Python 3.5.2

 And I installed following modules through pip command.
[ec2-user@MyEC2 django-sites]$ pwd
 /home/ec2-user/django-sites
[ec2-user@MyEC2 django-sites]$ pip list
configparser (3.5.0)
Django (1.10.1)
mod-wsgi (4.5.7)
pip (8.1.2)
PyMySQL (0.7.9)
setuptools (27.2.0)

(4) Web server
 Web server which I use is Apache 2.4 as bellow.
[ec2-user@MyEC2 ~]$ httpd -v
Server version: Apache/2.4.23 (Amazon)
Server built:   Jul 29 2016 21:42:17

 User and Group of executing Apache are both apache as next lines in /etc/httpd/conf/httpd.conf.
User apache
Group apache

(5) Additinal conf file for the Django project testprj
 I intend to configure such that the URL
http://[MyEC2 domain]/testprj/

can access a top page of Django project located at /home/ec2-user/django-sites/testprj.
 [MyEC2 domain] above is like
ec2-XX-XX-XX-XX.us-west-2.compute.amazonaws.com

So, I wrote testprj.conf in  /etc/httpd/conf.d as bellow.
[ec2-user@MyEC2 conf.d]$ pwd
/etc/httpd/conf.d
[ec2-user@MyEC2 conf.d]$ cat -n testprj.conf

 1  LoadModule wsgi_module /home/ec2-user/.pyenv/versions/django-sites/lib/python3.5/site-packages/mod_wsgi/server/mod_wsgi-py35.cpython-35m-x86_64-linux-gnu.so
 2
 3  WSGIPythonHome /home/ec2-user/.pyenv/versions/3.5.2
 4  WSGIScriptReloading On
 5  WSGIScriptAlias  /testprj/ /home/ec2-user/django-sites/testprj/testprj/wsgi.py
 6  WSGIPythonPath /home/ec2-user/django-sites/testprj:/home/ec2-user/.pyenv/versions/django-sites/lib/python3.5/site-packages
 7
 8  <VirtualHost *:80>
 9
10    ServerName http://ec2-XX-XX-XX-XX.us-west-2.compute.amazonaws.com
11    SuexecUserGroup apache apache
12
13    <Directory /home/ec2-user/django-sites/testprj/testprj>
14      <Files wsgi.py>
15      Require all granted
16      </Files>
17    </Directory>
18
19    Alias /static/ "/home/ec2-user/django-sites/testprj/static/"
20
21    <Directory /home/ec2-user/django-sites/testprj/static>
22      <Files *>
23      Require all granted
24      </Files>
25    </Directory>
26
27  </VirtualHost>
28

[ec2-user@MyEC2 conf.d]$

Best regards.

A: A couple of things to check.

*

*The pyenv tool doesn't install Python with a shared library by default. That could result in problems as mod_wsgi wants a shared library. You need to explicitly tell pyenv to build Python with a shared library.

*A home directory on many Linux systems is not readable to other users. When mod_wsgi is being initialised, it is running as the Apache user and will not be able to see inside of the home directory. There isn't an issue when the mod_wsgi module is loaded by Apache as Apache is running as root at that point.
There are other issues with your configuration where don't follow best practices, but the above, especially the second item is likely the cause of your problem.