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dict | score
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01:35
Fucking Her Doggystyle and Cum in Her Hair 946 0%
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Busty MILF - Hot soccer mom outdoors with her big tits out and exposed - busty milf.
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xxx
...x
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Some instant observations from the Texas Orange-White Scrimmage, which answered a lot of questions and brought up a few more for the Longhorns.
Top offensive performer
Johnathan Gray did what seniors should be allowed to do in the spring game -- take a couple of snaps and then relax. This created an opportunity for a number of Texas' young backs to get touches, and D'Onta Foreman took advantage. The rising sophomore from Texas City is known as a bruiser, but he displayed quickness in space and a wrecking-ball like downhill running ability. Foreman totaled 12 rushes for 75 yards and a touchdown. His longest tote of the day went for 28 yards, and he also showed toughness on the goal line to punch the ball in on fourth down. He won't start in 2015, but Foreman showed he is more than capable of helping Gray shoulder the load.
Top defensive performer
There are a lot of options here -- John Booney, Bryson Echols and Bryce Cottrell each had huge games -- but no one looked better than freshman linebacker Malik Jefferson. The former five-star recruit arrived on campus four months ago, but he still looked spectacular Saturday. He was asked to play different roles for Texas, and excelled at each. Jefferson created havoc when he rushed the passer and displayed his elite speed defending in the flat. Most impressively, he caught one of Texas' fastest players, Daje Johnson, from behind and forced a fumble after a monster hit. Edwin Freeman picked up the ball and sprinted for an easy defensive touchdown, points where much of the credit should go to Jefferson. He was the No. 1 player in the state for a reason in the 2015 class, and he looks like he might be one Texas' best on the field next season.
Reason to feel optimistic
A young and inexperienced Texas secondary looked very good, especially the first-team defense. Bryson Echols was forced into a starting role for the spring game due to injuries to Sheroid Evans and Duke Thomas, and he played really well. He's always been fast, but Echols showed great ball skills, especially on an interception of Jerrod Heard. He wasn't the only defensive back who flashed, either. John Bonney made a number of big tackles. The secondary got beat from time to time, but for the most part, it won almost every time over an equally inexperienced group of wide outs.
Also, in a bonus dose of optimism, Texas' new up-tempo attack looked good. It wasn't perfect, but it really looked like it fit the team's personnel. There were no major hiccups and the Longhorns moved the ball well and almost always snapped the ball in 20 seconds or less.
Reason to be Pessimistic
Speaking of the wide receivers, they had a pretty tough day. All the talk leading into the spring game was about how the quarterbacks would play -- more on Tyrone Swoopes and Heard later -- but the players on the outside didn't do the signal callers many favors. Armanti Foreman and Jacorey Warrick looked pretty solid inside and on quick outs, but Texas' other wide receivers had issues. Dorrian Lenoard got a lot of hype this spring, but managed just 3 catches for 22 yards. He also had three drops, one of which would have been a touchdown, and an unsportsmanlike penalty. Johnson was finally supposed to break out, but he fumbled twice. There are four freshman wide outs coming to campus this summer, and expect them to get a chance to contribute right away. The Longhorns need help with John Harris and Jaxon Shipley no longer on the Forty Acres.
Tweet of the Day
Charlie Strong says go say your sorry:
Tyrone Swoopes threw a ball away into the stands. Looks like he hit a kid. Strong sent Swoopes over to say sorry to the kid. — Max Olson (@max_olson) April 18, 2015
Modest proposal
Playing time in the a spring game is at a premium, everyone has to get some, so it's not a huge surprise some players didn't touch the ball too much. But one player that should moving forward is Warrick. The rising junior is the type of playmaker in space Texas needs, and a talent who could help Texas' new offensive tempo keep up the speed. There are plenty of options on the roster to do so, but Warrick made a positive contribution nearly every time he touched the ball Saturday.
Vines
Jefferson is making plays early in his Texas spring game debut:
His contribution didn't stop there, though. He lays the wood here:
That's not the end of that sequence; the fumble ended up resulting in a defensive touchdown:
Not a Vine, but still a heck of a play from Dillon Boldt.
El walkon Dillon Boldt intercepta a Swoopes, pero queda anulado por una falta defensiva #hookem #TexasSpringGame pic.twitter.com/d5s6KTDLi9 — Cuarenta Acres (@CuarentaAcres) April 18, 2015
Biggest question moving into the summer
Well, the obvious was saved for last. Of course we have to talk about the quarterbacks. Both Swoopes and Heard flashed Saturday, but neither shined. Swoopes looked pretty good in the pocket. He showed nice touch on deep balls, was solid on the move and displayed his big arm. But he was far from the difference maker Texas needs at the position. Some of Swoopes' throws still floated, and he missed some easy passes to the flat. Heard looked like what he is -- a very talented freshman. He displayed the speed that he did so many times at Denton Guyer and also, at times, made Texas' new up-tempo offense appear lethal. But he also made some poor throws into double coverage and his lack of elite arm strength was evident.
Here's a look at the stats from both QBs from Saturday:
Tyrone Swoopes -- Passing: 13-of-24, 112 yards; Rushing: 6 rushes, 16 yards, 1 TD
Jerrod Heard -- Passing: 20-of-29, 177 yards, 1 INT; Rushing: 12 rushes, 15 yards, 1 TD
Both quarterbacks have their pluses, but it's too close to call right now as to who will start come Texas' season opener against Notre Dame on Sept. 5. Don't be surprised if Swoopes and Heard each play quite a bit in 2015.
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Baghdad Phototreat | iStock/360 | Getty Images
Baghdad signed into law one of its largest-ever spending packages last week after months of gridlock. At $111.8 billion, the 2019 budget is a nearly 45 percent increase on the previous year's, featuring the highest deficit and second-highest spending volume in Iraq's history since the fall of Saddam Hussein in 2003. But despite desperate need for reconstruction funding after its devastating three-year war with the Islamic State, and with a crippled business sector beset by government corruption, Iraqi experts say the spending plan still fails to address the country's most urgent problems. "The amount of waste and wrongly allocated money is outrageous," Abbas Kadhim, director of the Atlantic Council's Iraq Initiative, told CNBC on Tuesday. "Despite being a very large spending plan, Iraq's new budget still suffers from the same problems. Too much of the budget goes to salaries… In the meantime, necessary spending on new infrastructure and reconstruction is not adequate." Nearly half of the budget — $52 billion — will go to public sector salaries, pensions, and social security for government employees, a 15 percent spike from 2018. $27.8 billion will go to investments, with the deficit set to more than double to $23.1 billion, as reported by AFP. Parliament members from the predominantly Sunni areas devastated by the anti-Islamic State (IS) campaign accuse the Shia-dominated government of not allocating sufficient funds to their areas' reconstruction. The International Monetary Fund (IMF) has calculated Iraq would need more than $88 billion to rebuild those areas, but international commitments have yet to meet even half of that goal.
Reconstruction works continue in Mosul, Iraq after 9 months long anti Daesh operations on January 25, 2018. Hemn Baban | Anadolu Agency | Getty Images
And to Kadhim's point, the money allocated to public sector salaries is dramatically higher than in previous years, with significant windfalls for the Kurdistan Regional Government (KRG) and the Peshmerga, the KRG's military force, a move thought to be aimed at easing tensions between the autonomous region and Baghdad. But critics of the budget package called it a bid for short-term popular gains that avoids more painful, yet necessary, reforms.
'Just short-term wins'
"A quick glance at the 2019 federal budget and you can tell this government is not here to make unpopular decisions like continuing economic reforms undertaken by the previous government during low oil prices," Hamzeh Hadad, an Iraqi writer and analyst, wrote on Twitter. "No long-term economic vision, just short-term wins with the public." Oil revenues make up nearly 90 percent of Iraq's budget. This year's is based on a projection of oil exports at 3.88 million barrels per day (bpd), up from 3.8 million in 2018, and at $56 per barrel, compared to the $46 a barrel price that last year's budget was based on. For Kadhim, hinging the budget on oil production and prices is irresponsible. "Neither variable is totally in the hands of the Iraqi government, as the former can be interrupted by any number of problems and the latter can sink significantly below the $56/barrel on which the budget is based," he said.
A worker is seen at the new CPF3 oil station in the Halfaya oilfield in southern of Maysan province, Halfaya, Iraq December 12, 2018. Essam al-Sudani | Reuters
International benchmark Brent Crude is currently hovering around $60 per barrel, with forecasts for 2019 mixed -- the IMF predicts Brent's price at just under $60 a barrel for the coming year, while a number of banks see it in the range between $65 and $70. Iraq has been enjoying record levels of crude production in the last year, pumping upwards of 4.6 million bpd in the second half of 2018, according to OPEC.
A lack of bold reforms
But the budget is also a reflection of the political pressures and competing priorities in Iraq's fragmented government, whose Prime Minister, Adel Abdel Mahdi, lacks a firm base of support and whose cabinet remains incomplete more than 8 months after national elections. Neither the prime minister's office nor the Iraqi Embassy in London were available for a comment at time of publication. "The result is far from perfect," said Omar al-Nidawi, a country analyst and Iraq director at advisory firm Gryphon Partners, who noted the dearth of resources facing Baghdad. "It's a budget that's big in its spending, big in its deficit, but small in its investment allocations. It also does not promise much in the way of the bold economic reforms Iraq needs. Operational spending (read: salaries) will eat up the largest part, about 75 percent compared to under 25 percent for investment." Some of those bold reforms include greater support for private enterprise and non-oil sectors to diversify revenue sources and reduce dependence on the private sector, more efficient and transparent business procedures to facilitate investment, and perhaps most importantly, dedicated efforts to combat and punish endemic state corruption. Transparency International ranks Iraq 168 out of 180 countries on its 2018 Corruption Perception Index, while the World Bank's "Ease of Doing Business" ranking places Iraq at 171 out of 190 economies.
An urgent need to diversify
On the other hand, the budget selected a few areas where spending can be particularly effective at enabling economic growth down the road, al-Nidawi said, pointing to "significant allocations for the electricity sector and the allocation of about $340 million for a major port project in Basra." The southern Iraqi city of Basra, mired in poverty and lacking basic public services including reliable electricity and clean water, erupted in violent protests last summer that saw attacks on number of government buildings and foreign consulates, including those of the U.S. and Iran.
Iraqi protesters gather outside the burning headquarters of the Iranian consulate in the southern city of Basra on September 7, 2018 during demonstrations over poor public services. Haidar MOHAMMED ALI | AFP | Getty Images Haidar MOHAMMED ALI | AFP | Getty Images
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Rick Scott (State of Florida)
By now it’s pretty obvious that President Donald Trump hires the worst possible person for the job. It’s not the best people, it’s the worst. Secretary of Education Betsy DeVos is a great example. She’s in charge of the Education Department even though she has never worked in public education, either as a teacher or an administrator. Her track record in education consists of lobbying to get government money for religious schools and wrecking the education system in her home state of Michigan. Even though DeVos lobbied heavily for the expansion of charter schools in her state, the academic outcomes of the students in these schools only showed a minimal increase.
“The results of this free-for-all have been tragic for Michigan children, and especially for those in Detroit, where 79% of the state’s charters are located,” said Valerie Strauss in a Washington Post article. “A yearlong Free Press investigation found that 20 years after Michigan’s charter school experiment began, Detroit’s charter schools have shown themselves to be only incrementally stronger, on average, than traditional public schools. They have admirable graduation rates, but test scores that look nearly identical to those of public schools.”
Now, DeVos seems to be trying to do the same thing on a national scale. Her lack of experience in education is obvious anytime she opens her mouth. She recently embarrassed herself when she claimed bigger class sizes could enhance a student’s experience. She also cited no information to back this up.
But DeVos isn’t the only one. Hope Hicks, the vapid former head of White House communications, had never worked in politics before Trump tapped her to oversee media for his campaign. Previously, she worked as a model and did PR for the Trump organization. And we all know how that turned out.
Trump is also rumored to be considering naming former Kansas Sec. of State Kris Kobach as “immigration czar.” Kobach is a white nationalist who pioneered voter suppression laws in his home state. FOX News commentator Lou Dobbs recently urged Kobach to start detaining migrants in prison camps! I dread to think what he will do with the powers of the federal government behind him.
“Scott resigned as CEO in July 1997, less than four months after the inquiry became public. Company executives said had Scott remained CEO, the entire chain could have been in jeopardy,” said PolitiFact. The wise residents of Florida decided to overlook this small fact and elected him twice as governor and recently made him a senator. But that was a regional issue. Now Trump wants to put him in charge of overhauling health insurance? Scott represents everything wrong with the system. He oversaw a company that drove up costs. That’s the exact problem with health care in this country.
Trump often seems to hire the first person he knows, because it doesn’t require much thought. He once tried to make his personal pilot, John Dunkin, head of the Federal Aviation Administration.
However, Trump’s latest choice is shocking. He has tapped Voldemort look-alike Sen. Rick Scott (R-Fla.) to oversee the GOP’s nonexistent replacement for Obamacare. If that doesn’t scare you, Scott’s background should. Before he became governor of Florida, Scott served as CEO of Columbia/HCA, a health insurance company. Just before he resigned, the company settled a case with the government for overbilling Medicare to the tune of $1.7 billion! And it wasn’t a moment too soon, according to PolitiFact.
“Scott resigned as CEO in July 1997, less than four months after the inquiry became public. Company executives said had Scott remained CEO, the entire chain could have been in jeopardy,” said PolitiFact.
The wise residents of Florida decided to overlook this small fact and elected him twice as governor and recently made him a senator.
But that was a regional issue. Now Trump wants to put him in charge of overhauling health insurance. Scott represents everything wrong with the system. He oversaw a company that drove up costs. That’s the exact problem with health care in this country. Since it’s run as a for-profit business, the only way companies can make money is by squeezing the consumers. That kind of track record doesn’t fill me with confidence.
Also, Scott is your average hypocritical Republican. While he might claim he’s for smaller government, he makes sure government contracts line his pockets. As governor, he signed an executive order requiring everyone on public assistance and all state employees to be drug tested. And it just so happened Solantic, the company that got the contract for the testing, was owned by his wife! As I’ve said before, Republicans claim they hate the government, but they love those government checks. Scott’s drug testing crusade turned out to be a waste of time and money. Only 2 percent of the people tested were found to have drugs in their system. But Scott’s wife’s company got $400,000 worth of business. The state also spent $400,000 defending the case after they were sued by the ACLU.
It’s amazing someone with Scott’s track record managed to get elected governor and a U.S. senator, but the idea of him crafting national health care policy is plain ridiculous. Whatever plan he concocts is likely to provide poor service while further enriching him. Scott has a track record of ripping off the government, let’s not give him another chance.
The long-term goal of these shysters overseeing major government agencies is to deliberately run them into the ground. Then conservatives can turn around, declare these organizations are incompetent and farm out their duties to contractors — who also happen to be their cronies. DeVos’ brother, Erik Prince, a long-term operator of mercenary companies like Blackwater, has lobbied Trump to outsource America’s wars claiming he can run them better. But Prince is really after a bigger share of the Pentagon’s military budget.
In the real world, if you screw up royally, like DeVos and Scott, it’s usually the end or at least a black mark on your career. But not in Trump world. Run a company into the ground and Trump moves you to the front of the line.
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Shemale Angelina Torres gets her Ass fucked at Shemale XXX. Shemale Angelina is a sexy Spanish transgirl with a sexy body, beautiful tits and a hot ass! She is a horny girl ans she sure turned Christian on! A smoking hot hardcore sex scene with lots of fucking! Click here to see more from this sexy Cock Lady at Shemale XXX !!
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| 0.051988 |
Captain's Honour - Luke Steele
Reds goalkeeper Luke Steele insists it’s a huge honour to captain the club he’s been with for five-and-a-half years, and has matured into one of the finest goalkeeper’s the Championship has to offer.
“That’s probably the top of the tree, I’ve learned not to get too down about things,” revealed Steele. “As Micky Mellon says, one goal can change our world. If we get the first goal in the next game it can change everything. Two losses is nothing. Football isn’t about the long period, it’s about one at a time. We have to keep reiterating that to ourselves - it’s about the next ten minutes, the next half. It’s a long season, people make mistakes, they play bad but that happens to every team in the country.”
The Reds may not have picked up a point in the league from their first two matches, but find themselves in the second round of the Capital One Cup.
“It’s been a bit of a slow start,” he admitted. “It’s not the end of the world at all. I’d like to think we’d judge ourselves come the end of the season rather than a handful of games in.”
For the full interview with Luke, pick up your copy of U Reds this Saturday from Oakwell.
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#!/bin/sh
# SPDX-License-Identifier: GPL-2.0
echo "BAR tests"
echo
bar=0
while [ $bar -lt 6 ]
do
pcitest -b $bar
bar=`expr $bar + 1`
done
echo
echo "Interrupt tests"
echo
pcitest -i 0
pcitest -l
pcitest -i 1
msi=1
while [ $msi -lt 33 ]
do
pcitest -m $msi
msi=`expr $msi + 1`
done
echo
pcitest -i 2
msix=1
while [ $msix -lt 2049 ]
do
pcitest -x $msix
msix=`expr $msix + 1`
done
echo
echo "Read Tests"
echo
pcitest -i 1
pcitest -r -s 1
pcitest -r -s 1024
pcitest -r -s 1025
pcitest -r -s 1024000
pcitest -r -s 1024001
echo
echo "Write Tests"
echo
pcitest -w -s 1
pcitest -w -s 1024
pcitest -w -s 1025
pcitest -w -s 1024000
pcitest -w -s 1024001
echo
echo "Copy Tests"
echo
pcitest -c -s 1
pcitest -c -s 1024
pcitest -c -s 1025
pcitest -c -s 1024000
pcitest -c -s 1024001
echo
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Three Dommes and the Fucking Machine
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the fucking cops are fucking keen
to fucking keep it fucking clean
the fucking chief's a fucking swine
who fucking draws a fucking line
at fucking fun and fucking games
the fucking kids he fucking blames
are nowhere to be fucking found
anywhere in chicken town
the fucking scene is fucking sad
the fucking news is fucking bad
the fucking weed is fucking turf
the fucking speed is fucking surf
the fucking folks are fucking daft
don't make me fucking laugh
it fucking hurts to look around
everywhere in chicken town
the fucking train is fucking late
you fucking wait you fucking wait
you're fucking lost and fucking found
stuck in fucking chicken town
the fucking view is fucking vile
for fucking miles and fucking miles
the fucking babies fucking cry
the fucking flowers fucking die
the fucking food is fucking muck
the fucking drains are fucking fucked
the colour scheme is fucking brown
everywhere in chicken town
the fucking pubs are fucking dull
the fucking clubs are fucking full
of fucking girls and fucking guys
with fucking murder in their eyes
a fucking bloke is fucking stabbed
waiting for a fucking cab
you fucking stay at fucking home
the fucking neighbors fucking moan
keep the fucking racket down
this is fucking chicken town
the fucking train is fucking late
you fucking wait you fucking wait
you're fucking lost and fucking found
stuck in fucking chicken town
the fucking pies are fucking old
the fucking chips are fucking cold
the fucking beer is fucking flat
the fucking flats have fucking rats
the fucking clocks are fucking wrong
the fucking days are fucking long
it fucking gets you fucking down
evidently chicken town
|
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| 0.049848 |
Q:
Where to put the email sending?
There is a "news" system, when a "new" is added, an email should be sent too.
class ModelNews extends NewsORM
{
public function add ($new)
{
INSERT INTO newstable
}
}
but I also need to send an email, so:
class ModelNews extends NewsORM
{
public function add ($new)
{
INSERT INTO newstable
mail->send
}
}
but it looks odd. It looks like SRP is violated
A:
It looks like SRP is violated
It does indeed. When you need to do multiple things you can apply the open/closed principle and decouple everything.
interface AddNews
{
public function add($new);
}
class SaveNews extends NewsORM implements AddNews
{
public function add($new)
{
// INSERT INTO newstable
}
}
class SendNews extends NewsORM implements AddNews
{
public function add ($new)
{
//mail->send
}
}
class AggregatorNews implements AddNews
{
private $news = [];
public function addNews(AddNews $news)
{
$this->news[] = $news;
}
public function add($new)
{
foreach ($this->news as $obj) {
$obj->add($new);
}
}
}
Then you can use it like this:
$news = new AggregatorNews();
$news->addNews(new SaveNews);
$news->addNews(new SendNews);
$news->add('bla bla');
|
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| 0 |
Cumming With My Pussy And Ass. Pushing The Ass Plug Out At The End
|
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| 0.060606 |
teens wants guy to cum in her pussy anal, teens wants guy to cum in her pussy erotic, teens wants guy to cum in her pussy porn video, teens wants guy to cum in her pussy adult, teens wants guy to cum in her pussy hot, teens wants guy to cum in her pussy erotic video, teens wants guy to cum in her pussy porn, teens wants guy to cum in her pussy milf, teens wants guy to cum in her pussy sexxx, teens wants guy to cum in her pussy pornxxx,
|
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| 0.059226 |
Ługi, Pomeranian Voivodeship
Ługi () is a settlement in the administrative district of Gmina Nowa Wieś Lęborska, within Lębork County, Pomeranian Voivodeship, in northern Poland. It lies approximately east of Nowa Wieś Lęborska, east of Lębork, and west of the regional capital Gdańsk.
For details of the history of the region, see History of Pomerania.
References
Category:Villages in Lębork County
|
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| 0 |
..x....
.x.x...
.......
xx...x.
x.....x
...x.x.
..xx...
|
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| 0.089286 |
Cedar Council approves Eminent Domain action
CEDAR CITY–The Cedar City Council has approved filing an Eminent Domain Action in order to move forward on a project to extend a sewer line.
The city’s desired pathway for the sewer line goes through private property owned by Kathleen Slack and Christine Imlay, who are opposed to having the line run through it. They asked the city to go around their property either to the west or east, but those pathways are less feasible for the city.
“Both of those options would cost at least $800,000 to $1 million more in capital expense,” City Manager Paul Bittmenn said. “They would both increase our operational expense because they would both entail putting in new lift stations, because they’re not gravity fed options and we wouldn’t eliminate any of the existing pump stations.”
The extra cost and maintenance that going around the private property is the reason City Council members decided to approve an Eminent Domain action, in order to move forward with the planned extension line.
Bittmenn said there are several reasons the city wants to extend the sewer line. Currently, the majority of the city’s waste is transported to the wastewater plant via one of the two major sewer lines. The planned extension will not only ease some of the stress being placed on one line by splitting it up more, but will also eliminate one of the city’s pump stations as it would be entirely gravity-fed. Additionally, the extension is planned to help manage the city’s projected growth.
Bittmenn said the city acknowledges the property owners’ reluctance to have municipal improvements done on their property, but the city is trying work with them.
“With these lines going through these agricultural properties, we’re going to bury them so deep, and we’ve even engineered them so we can bury the manholes deep enough, that once we’re out of their way, they can farm them like normal,” Bittmenn said. “We’ll do installation in their off-season so that we don’t have an impact on their operation while they’re producing whatever crops they want to produce. We want to be there and be good neighbors and be almost invisible to them and have them be able to use their land and be as productive as possible.”
|
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| 0 |
Q:
Update a field after Linking / Unlinking Many-Many records in SilverStripe
I have created a Customer DataObject by extending Member. Customer has a many_many data relation with a Package DataObject.
I would like increment/decrement a Credits field in the Customer DataObject when a Package is linked / unlinked through the CMS based on the Limit field in the Package table.
Customer
class Customer extends Member {
private static $db = array(
'Gender' => 'Varchar(2)',
'DateOfBirth' => 'Date',
'Featured' => 'Boolean',
'Credits' => 'Int'
);
private static $many_many = array(
'Packages' => 'Package'
);
public function getCMSFields() {
$fields = new FieldList();
$config = GridFieldConfig_RelationEditor::create();
$config->removeComponentsByType('GridFieldAddNewButton');
$packageField = new GridField(
'Packages',
'Package',
$this->Packages(),
$config
);
$fields->addFieldToTab('Root.Package', $packageField);
Session::set('SingleID', $this->ID);
$this->extend('updateCMSFields', $fields);
return $fields;
}
}
Package
class Package extends DataObject {
private static $db = array(
'Title' => 'Varchar(255)',
'Limit' => 'Int'
);
private static $belongs_many_many = array(
'Customers' => 'Customer'
);
}
A:
When you create or delete many to many relationship just one record is modified in your database - the one in table which joins elements of both sides of the relationship. Therefore neither object the relationship is based on is updated. This is why methods like: onBeforeWrite, onAfterWrite, onBeforeDelete and onAfterDelete will not be called at all and you cannot use them to detect such change.
However, Silverstripe provides class ManyManyList which is responsible for all operations connected to many to many relationships. There are two methods which are of your interest: add and remove. You can override them and put inside action to do what you need. These methods are obviously called on each link or unlink operation no matter object types are, so you should make some filtering on classes you are particularly interested in.
The proper way to override the ManyManyList class is to use Injector mechanism, so as not to modify anything inside the framework or cms folder. The example below uses relationship between Members and Groups in Silverstripe but you can easily adopt it to your need (Customer -> Member; Package -> Group).
app.yml
Injector:
ManyManyList:
class: ManyManyListExtended
ManyManyListExtended.php
/**
* When adding or removing elements on a many to many relationship
* neither side of the relationship is updated (written or deleted).
* SilverStripe does not provide any built-in actions to get information
* that such event occurs. This is why this class is created.
*
* When it is uses together with SilverStripe Injector mechanism it can provide
* additional actions to run on many-to-many relations (see: class ManyManyList).
*/
class ManyManyListExtended extends ManyManyList {
/**
* Overwritten method for adding new element to many-to-many relationship.
*
* This is called for all many-to-many relationships combinations.
* 'joinTable' field is used to make actions on specific relation only.
*
* @param mixed $item
* @param null $extraFields
* @throws Exception
*/
public function add($item, $extraFields = null) {
parent::add($item, $extraFields);
if ($this->isGroupMembershipChange()) {
$memberID = $this->getMembershipID($item, 'MemberID');
$groupID = $this->getMembershipID($item, 'GroupID');
SS_Log::log("Member ($memberID) added to Group ($groupID)", SS_Log::INFO);
// ... put some additional actions here
}
}
/**
* Overwritten method for removing item from many-to-many relationship.
*
* This is called for all many-to-many relationships combinations.
* 'joinTable' field is used to make actions on specific relation only.
*
* @param DataObject $item
*/
public function remove($item) {
parent::remove($item);
if ($this->isGroupMembershipChange()) {
$memberID = $this->getMembershipID($item, 'MemberID');
$groupID = $this->getMembershipID($item, 'GroupID');
SS_Log::log("Member ($memberID) removed from Group ($groupID)", SS_Log::INFO);
// ... put some additional actions here
}
}
/**
* Check if relationship is of Group-Member type.
*
* @return bool
*/
private function isGroupMembershipChange() {
return $this->getJoinTable() === 'Group_Members';
}
/**
* Get the actual ID for many-to-many relationship part - local or foreign key value.
*
* This works both ways: make action on a Member being element of a Group OR
* make action on a Group being part of a Member.
*
* @param DataObject|int $item
* @param string $keyName
* @return bool|null
*/
private function getMembershipID($item, $keyName) {
if ($this->getLocalKey() === $keyName)
return is_object($item) ? $item->ID : $item;
if ($this->getForeignKey() === $keyName)
return $this->getForeignID();
return false;
}
}
The solution provided by 3dgoo should also work fine but IMO that code does much more "hacking" and that's why it is much less maintainable. It demands more modifications (in both classes) and needs to be multiplied if you would like to do any additional link/unlink managing, like adding custom admin module or some forms.
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Impacts of natural weathering on the transformation/neoformation processes in landfilled MSWI bottom ash: a geoenvironmental perspective.
Natural weathering processes are significant mechanisms that noticeably affect the fundamental nature of incineration ash residues. To provide a greater understanding of these processes, a MSWI (mono)landfill site in the north east of the US was selected as the target for systematic investigation of the natural weathering of bottom ash residues. Samples of various ages were collected from locations A (1 yr), B (10 yrs), C (13-14 yrs) and D (20 yrs) of the landfill in 2009. We investigated the phase transformation of the collected bottom ash particles, neoformation processes as well as the behavior and distribution of certain heavy metals (Cu, Pb, Zn, Ni, and Cr) in the neoformed phases using optical microscopy, SEM-EDX, and bulk examinations. at the preliminary stage, the waste metallic particles (Al, Fe, and Cu) and unstable minerals such as lime, portlandite, ettringite and hydrocalumite convert to oxide and hydroxide (hydrate) phases, calcite, alumina gel and gypsum. At the intermediate stage, the decomposition of melt products including magnetite spinels and metallic inclusions is triggered due to the partial dissolution of the melt glass. At the longer time horizon it is possible to track the breakdown of the glass phase, the extensive formation of calcite and anhydrite, Al-hydrates and more stable Fe-hydrates all through the older ash deposits. Among the dominant secondary phases, we propose the following order based on their direct metal uptake capacity: Fe-hydrates>Al-hydrates>>calcite. Calcite was found to be the least effective phase for the direct sorption of heavy metals. Based on overall findings, a model is proposed that demonstrates the general trend of ash weathering in the landfill.
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| 0 |
The Foundation is pleased to offer our grantees the opportunity to share information about their grant on our website. We hope it will offer the public increased visibility for your work.
Terms and Conditions. This form is intended for those who have received a Puffin Foundation grant. By filling out this form, you will be requesting Puffin to post information about your granted project on our web site. Please fill out the form carefully. It includes the option to provide an email address for the public to contact you, as well as providing an email address for the Foundation to use internally that would not be made public. Note that if you include personally identifiable information in your public content, it can be used and viewed by others. We are not responsible for the information you choose to include in public content. The Foundation reserves the right to edit any submissions for size and appropriate content. If you wish to give photo, audio or video credit for submissions, such credit should be included in your text under the description of your project.
Satirical "ImBLEACHments of political figures are incorporated into woven blankets that are then given away to Occupiers,and the homeless. These satirical portraits are photographed off the TV, printed as "C" prints, and then splashed with household bleach. The blankets are woven and reversable, and the portraits are barely descernable, allowing the owners to consider the colors an abstraction or a political statement. Five blankets were given away in three cities, by first contacting local Occupy groups, touching base with a local who knew those who were truly in need, and then distributing the blankets to those individulas. The "give" was documented in stills and video, which can be seen on Youtube. U.S.A. Projects helped crowdfund the initial production, and The Puffin Foundation helped with publicity. The Nevada Arts Council helped provide funding for the Las Vegas "give", and other donated time and energy to keep the give going. Any future sales of blankets or the ponchos (blankets with a hole in the middle) helps fund another blanket that is donated to a homeless person. Hopefully, I will be able to repeat the project in other cities, in a kind of Johnny Appleseed fashion, with a few trips every year to new locations.
|
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Piss and Cum for the Slut - Part 2
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09:01
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|
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| 0.051282 |
Q:
Not able to read read xml attribute using JaxB
I have one XML file which I am trying to load using JaxB.
<TABLE NAME="EMPLOYEE">
<ROW>
<EMP_ID>1002</EMP_ID>
<EMP_NAME>Suraj</EMP_NAME>
<EMP_DEPT_ID>3</EMP_DEPT_ID>
<EMP_DES>SE</EMP_DES>
</ROW>
<ROW>
<EMP_ID>1034</EMP_ID>
<EMP_NAME>Birendra</EMP_NAME>
<EMP_DEPT_ID>6</EMP_DEPT_ID>
<EMP_DES>SSE</EMP_DES>
</ROW>
</TABLE>
Alos created POJO for the same as follow
@XmlRootElement
public class EmpTable {
private String NAME;
private EmpRow ROW;
public String getNAME() {
return NAME;
}
@XmlAttribute
public void setNAME(String nAME) {
NAME = nAME;
}
public EmpRow getROW() {
return ROW;
}
@XmlElement
public void setROW(EmpRow rOW) {
ROW = rOW;
}
}
Similar for EmpRow too.
Reading Xml by using following code
File file = new File("C:/Users/navnath.kumbhar/Desktop/ImportDataXml.xml");
EmpTable objEmpTable = JAXB.unmarshal(file, EmpTable.class);
Now the problem is I am able to read full object and it's data properly except NAME attribute of TABLE tag. Can any suggest me what is there any wrong implimentionation or anything else is required?
A:
MAPPING TO XML ATTRIBUTES
You should annotate your the NAME property as follows:
@XmlAttribute(name="NAME")
public void setNAME(String nAME) {
NAME = nAME;
}
Although I would recommend using the following naming convention:
@XmlAttribute(name="NAME")
public void setName(String nAME) {
NAME = nAME;
}
MAPPING THE ROOT ELEMENT
Also it appears as though you should use the @XmlRootElement as follows.
@XmlRootElement(name="TABLE")
public class EmpTable {
Although you would probably be better off just having a Table class:
@XmlRootElement(name="TABLE")
public class Table {
JAXB RUNTIME
The following is a single line of code, but is not very efficient,
EmpTable objEmpTable = JAXB.unmarshal(file, EmpTable.class);
Instead you should create a JAXBContext which is a thread safe initialized version of the mapping metadata from which marshallers and unmarshallers can be created.
JAXBContext jc = JAXBContext.newInstance(EmpTable.class);
Unmarshaller unmarshaller = jc.createUnmarshaller();
EmpTable objEmpTable = (EmpTable) unmarshaller.unmarshal(file);
|
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}
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{
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}
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}
| 0.074074 |
geometry exploring geometry saddleback
MathSkills reinforces math in three key areas: Pre-Algebra, Geometry, and Algebra. These reproducible activities supplement any math textbook. Pages can be used in the classroom as lesson previews or reviews. The activities are perfect for homewo......
|
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}
| 0 |
Q:
Hold out in R and k fold
I have a question, I'm wondering if the holdout function in R is a k fold cross validation ? It seems to be the same with the parameter "hldSettings" thing but I am not sure.
for example :
holdOut(learner('my_learner',
pars=list(Threshold=0.2,
statsProds=globalStats)),
dataset(target_to_predict,my_dataset),
hldSettings(10,0.3,1234,T),
itsInfo=TRUE
)
Thank you for your answers :)
A:
A useful way to learn about what an R function does is to consult the documentation. Entering ?holdOut into the console, we can see
The idea of this function is to carry out a hold out experiment of a given learning system on a given data set. The goal of this experiment is to estimate the value of a set of evaluation statistics by means of the hold out method. Hold out estimates are obtained by randomly dividing the given data set in two separate partitions, one that is used for obtaining the prediction model and the other for testing it. This learn+test process is repeated k times. In the end the average of the k scores obtained on each repetition is the hold out estimate.
But in this case, it's not a $k$-fold CV since it does not specify that the method uses $k$ partitions. Instead, we have a train/test split repeated $k$ times at random. The difference is that $k$-fold CV would create $k$ splits of the same size, and iterate $k$ times between leaving out one partition, whereas in this method, the data set is split into train/holdout sets randomly each of $k$ times, so there is positive probability that two holdout sets will contain the same observations. By contrast, all holdout sets in $k$-fold CV are mutually disjoint.
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05:01
Please Cum onto my Panties.
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| 0.058824 |
Q:
How to turn off line wrap when opening from terminal
I'm trying to open a file from terminal and ensure that line-wrap will be off. I'm trying the following code, but it won't work
emacs --no-window-system --eval '(setq truncate-lines 1)' file
I don't want to set it as default or to change init. Just to open this specific file without wraping lines.
A:
truncate-lines is buffer-local. To set the default for all buffers, use (setq-default truncate-lines t). Major-modes and minor-modes can reset this variable and it will be necessary to use a major-mode or minor-mode hook in that case, or directory-local variables, or file-local variables.
EXAMPLE [assumes we want to load a file with an extension of el, which will default to the emacs-lisp-mode]:
/path/to/emacs --no-window-system --eval "(add-hook 'emacs-lisp-mode-hook (lambda nil (setq truncate-lines t)))" /path/to/file.el
When the file loads, check the value with M-x describe-variable RET truncate-lines RET or C-h v.
EDIT: In the commentary below, the O.P. has indicted that certain files may be opened in fundamental-mode because a particular file extension may not be associated with a major-mode. While it is possible to use file-local variables or directory-local variables, the O.P. has expressed a preference to handle this entirely on the command-line. One way to accomplish that is as follows:
/path/to/emacs --no-window-system --eval "(progn (find-file \"/path/to/file.csv\") (setq truncate-lines t))"
NOTE: find-file (with its underlying functions) set the buffer of the newly opened file as the current-buffer. When (setq truncate-lines t) is called subsequent to (find-file ...), it is applied to said current-buffer. If the target buffer did not have focus for whatever the reason (e.g., find-file-noselect), then it would be necessary to use something like (with-current-buffer ...) to ensure that truncate-lines is applied to the correct buffer.
|
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}
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| 0.0625 |
The mechanism(s) by which estrogens control the growth of reproductive tissues such as the uterus, mammary gland and vaginal epithelium is not completely understood. Recent information in the scientific literature suggests that epidermal growth factor (EGF) may be a putative agent in mediating estrogen- stimulated uterine growth. A clearer picture of the relationship between EGF and estrogen in producing uterotrophic effects is important in further understanding the mechanism of action of estrogen at the cellular level and how the hormone may serve to temporally integrate disparate components of the growth process. This knowledge base might have useful clinical applications for endometriosis, estrogen responsive carcinomas and other reproductive tissue neoplasia, and certain aspects of infertility. The purpose of this study is to critically explore casual correlations among hormone estrogenicity (potency), uterine estrogen receptor availability, uterine EGF receptor content, uterine and serum EGF levels and the degree of the uterotrophic response. Specifically, ovariectomized rats will be administered estrogens of differing biological potency on long-term uterine growth (diethylstilbestrol, estradiol-17 beta, estriol or estradiol-17 alpha) or antiestrogens (nafoxidine, tamoxifen or CI-628) and the relationship between dose of hormone administered and extent of uterine growth ascertained with respect to tissue levels of EGF receptor and EGF peptide as measured by radioimmunoassay. The linkage between the estrogen receptor and the stimulation of uterine EGF receptor by exogenous steroid will also be assessed through altering estrogen receptor availability by prior antiestrogen treatment to differentially inhibit synthesis and turnover of the steroid receptor. Estrogen receptor-dependent and receptor-independent impairment of uterine growth can be induced by certain neonatal hormone treatments to provide models to further assess the relationship between estrogen receptor function, uterine growth and EGF receptor content. Finally, EGF secretion during the estrous cycle, the ability of EGF antibody to inhibit estrogen-induced uterine growth and a possible role for the submandibular salivary gland in the process of growth will also be studied.
|
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| 0 |
Thumbtack’s Manual Action
If you do a search for “Thumbtack”, you will not find them anywhere in the Google search results… nor will you see them for any of the estimated 25,000 keywords they were previously ranking for. They have been hit with a manual action penalty courtesy of Google.
Thumbtack does not rank for their own brand name, which is usually the first sign to SEOs that something in their SEO has gone awry.
Loss of Traffic and Rankings
And SEMRush shows a definite drop in traffic starting this weekend.
They also show a loss of 25% of their rankings. However, this loss percentage will likely get much worse in the coming days.
Discovering the link spam campaign
Last week, attention was brought to Thumbtack’s questionable link building tactics. Donnie Strompf (@donniestrompf) received a link request from Thumbtack with some pretty hefty anchor text for a client of his.
“While removing a link penalty for a client’s site, I discovered Thumbtack’s improper ranking methods,” says Strompf, on seeing the link spam issue.
The email received promised 30 points for including a profile link, placed in the following manner.
Instructions: 1. Copy and paste your profile link to your website with a description of your profile
<a href=”https://www.thumbtack.com/mo/kansas-city/personal-injury-lawyers/“>legal</a>
If you would prefer to add a button or a badge instead of a link, you get one here. 2. Once you are done, respond to this email with the URL of the link, badge, or button.
I’ll verify the link and will credit the points and badge to your profile.
Obviously, even though money isn’t explicitly exchanging hands, this is a violation of Google’s webmaster guidelines.
Google’s Link Schemes
In fact, they specifically state that money doesn’t have to be exchanged in order for it to be considered a “link scheme” in the eyes of Google.
From the Link Schemes section of the Quality Guidelines.
The following are examples of link schemes which can negatively impact a site’s ranking in search results: Buying or selling links that pass PageRank. This includes exchanging money for links, or posts that contain links; exchanging goods or services for links; or sending someone a “free” product in exchange for them writing about it and including a link
They also include specifics about widgets as well, which badges would fall under as well.
Keyword-rich, hidden or low-quality links embedded in widgets that are distributed across various sites, for example:
Visitors to this page: 1,472
car insurance
Questionable Practices
As early as last summer, some were raising questions about Thumbtack’s link building practices on the Moz forums.
We have a business registered on Thumbtack so we receive their newsletters. I’m aware that review sites offering a “badge” or verification logo which links back to your profile is nothing new. But the email I received from Thumbtack is a fairly blatant attempt to game Google for popular keywords. I was just curious on your thoughts about this. I believe it was Overstock who did something like this and got slapped by Google pretty hard for a while. Could Thumbtack be heading down the same path?
The original poster also shared a link to the request, which is similar to the one Strompf was sent.
“Not Buying Links”
But the co-founder and director of marketing, Sander Daniels, saw nothing wrong with building links this way. He argued on Twitter that they weren’t paid links because they were in exchange for points and not cash, stating “not buying links, points have nothing to do w/ $$”.
@garthobrien not buying links, points have nothing to do w/ $$ — Sander Daniels (@sanderdaniels) June 5, 2015
What was notable about this exchange was that the person who initially tweeted it did not tag either Thumbtack or Daniels into the original tweet, but he tweeted a response to it anyways, before the penalty was discovered.
But despite Daniels assurances that they were not “buying links”, both the quality guidelines, and the Google manual action penalty, show otherwise.
“Resolving the Issue and Misunderstanding”
Others have also been pointing out to Thumbtack on Twitter that they had vanished from the search results, starting yesterday.
@ThepuncherG This is due to a site issue. We're aware of the situation and are working hard towards a solution as quickly as possible. ^VG — Thumbtack (@thumbtack) June 7, 2015
And again they are claiming they are working on resolving the “issue and misunderstanding.”
@nichesiteazon @ThepuncherG Credits are different and separate from points. We're working on resolving the issue and misunderstanding. ^ST — Thumbtack (@thumbtack) June 8, 2015
Working with Google?
They have made a few more tweets claiming they are “working with Google” to fix the “misunderstanding”. However, it isn’t clear if they are saying that to make it look as though their problem will be resolved soon, or if they are working with Google in some capacity.
@DavidRFrank We're currently working with Google on the issue. We're hoping to have the misunderstanding resolved soon. ^CW — Thumbtack (@thumbtack) June 8, 2015
Spammy Anchor Text
Now, once you start looking at their backlink profile, it is clear this is link spam, and nothing to do with a mere “misunderstanding.” Looking at the anchor text in Majestic, it is clear there is a spam issue once you get beyond the first handful that are related to the brand name. It then becomes a list of keyword spam.
It becomes a list of anchor text, including some competitive search terms, for terms such as wedding photography, web design, DJ services, oil tank removal and Chicago locksmith.
One of the examples in the original article shows up in a variation in Majestic for “legal services.” As you can see, there are 18 referring domains who linked to Thumbtack in this fashion, almost all with extremely low Trust Flow and Citation Flow.
SEM Rush also shows a similar spammy backlink profile.
Google Capital Connection
What many people are thinking about with Thumbtack’s link building practices is the fact it received funding from Google Capitol, in its last round of funding last summer. Last week some were speculating whether this could have been why Google was letting this site slide with its spammy link building tactics.
Strompf also made the connection to Google. “Looking further, I then discovered that Google was the company’s largest investor,” says Strompf. “Although Google seems to already taken some action against Thumbtack, will they penalize them like they did everyone else?”
Google does seem to have penalized them like they would anyone else when you look at it. It has the classic signs of a manual action penalty, such as the loss of a huge number of keywords and the telltale sign where they don’t rank for even their own brand name. So the fact it has manual action against it seems to show that Google is treating this site like any other who is caught in violation Google’s guidelines.
Deny, Deny, Deny
With Thumbtack in denial that they did anything wrong, which isn’t that unusual for a webmaster caught for doing something against the quality guidelines, it will be interesting to watch and see just how quickly Thumbtack moves to clean up the link spam on their customer’s sites. They could either bite the bullet, dive in and start removing and disavowing links, or they could try and submit a reconsideration request without the cleanup and hope for the best.
Others have asked for further details from Thumbtack, but they have stopped responding to questions.
Are They Really Working with Google?
I couldn’t find a thread in Google Webmaster Help forums to determine if that was where they were “working with Google” or if they were messaging someone from Google on Google+, as webmasters will sometimes ping John Mueller there. They could also consider “working with Google” as merely being the submission of a reconsideration request.
But it seems unlikely they would have access to someone in search through the Google Capital investment end, as Google tends to keep their various departments pretty separated.
They have ramped up their paid ads campaign through AdWords, but again, Google keeps the ads side pretty separated from the search side, so they would not be able to appeal through AdWords regardless of how much money they put into it.
Thumbtack’s Next Move?
I am sure people will be watching to see Thumbtack’s next move, when they start ranking for their name and other search terms again, and if any visible clean up was done. I am sure many will be disappointed if it seems they can reverse the manual action penalty by appealing through a reconsideration request. Everyone except Thumbtack themselves seems confident that this as a clear-cut case of link spam.
I will continue to update with any news or announcements.
|
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| 0 |
'xxx' || true
|
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| 0.071429 |
Introduction {#Sec1}
============
Blood plays an essential role in supplying nutrients and oxygen, and removing waste molecules. The first call of treatment in an accident is to staunch blood loss from injured blood vessels, usually with physical adhesive treatments, such as bandage-pressing or surgery. Biological and chemical adhesive are also available to be used as adjuvants for light injuries and internal bleeding^[@CR1]--[@CR3]^. In cases of complex injuries or defects on major vessel, surgical treatment is required, since bandage-pressing method is usually temporary, hard to apply, and ineffective^[@CR4]^, especially, when main vessels, such as the aorta, which plays a role in sending blood to whole body to maintain organ status, are injured. The aorta can be injured by external causes (e.g., rupture) or internal causes (e.g., hypertension, aneurysm, etc.)^[@CR5]--[@CR8]^, which causes trauma or other vascular diseases. Cases of trauma need to be treated within the optimal 'therapeutic window', while physical properties that can be used as adjuvant and treating agent during surgery should be identified in cases of vascular disease^[@CR9],[@CR10]^. High blood pressure and heart beat frequency or complex injuries make it difficult to treat wounds using bandage-pressing for extended periods of time. Although adhesive substances are in demand for emergency treatment before surgical intervention, they are not well commercialized^[@CR11]^.
An ideal adhesive must have low cytotoxicity, appropriate adhesiveness, and mechanical strength. Generally, animal-testing is required to evaluate the ability of the adhesive substance to effectively close a bleeding wound^[@CR12],[@CR13]^. Although, these animal models are well-defined and present appropriate physical (i.e., flow volume, beating rate, and blood pressure) and histological environments (i.e., vessel structure and blood composition) to evaluate adhesive substances, larger animals are required to adequately mimic humans^[@CR14],[@CR15]^. In hemostasis tests, a critical wound in the circulation system can cause animal death, which can lead to ethical problems. When the test is performed in a way that involves critical structures, such as the aorta and arteries, the possibility of error cannot be excluded, which critically affects the survival of the experimental animals. In addition, since the characteristics of animal tissue can vary with age, weight and so on, it is hard to standardize animal models for reliable and reproducible data. Moreover, it is challenging to aptly evaluate injury to the aorta, which is characterized by high blood pressure and active pulsation^[@CR16],[@CR17]^, in models, which brings about issues of reliability and reproducibility of experiments.
In the current work, a bio-tissue/mechanic hybrid system was developed to mimic the injured aorta, with a regular and high frequency of blood flow, and bleeding (Fig. [1](#Fig1){ref-type="fig"}). Since several models already exist for evaluating cytotoxicity and safety of adhesives, this system focuses on efficacy test without sacrificing test animals. Our experimental model was superior to a system that does not adequately mimic the injured artery environments, as demonstrated by proof-of-concept test using a rapid emergent adhesive, cyanoacrylate.Figure 1Schematic design of whole circulation system.
Results {#Sec2}
=======
Confirmation of structural stability of the decellularized vessel {#Sec3}
-----------------------------------------------------------------
The decellularized vessel was created using the freeze-thaw method. The vessel maintained its morphology, after 10 repeated freeze/thaw cycles, with no observed additional denaturation or collapse at the vessel (Fig. [2a,b](#Fig2){ref-type="fig"}). The results of the hematoxylin and eosin (H&E) staining also showed that the cytosol stained by eosin was removed from the decellularized sample, compared to the original sample, but both samples had abundant extracellular matrix (ECM) and both ECM structure were observed well at microscopy images (Fig. [2c,d](#Fig2){ref-type="fig"}) and SEM images (Fig. [2e--h](#Fig2){ref-type="fig"}). Except decellularized vessel was shown more porosity, the microscopic images confirmed that the layer-by-layer structured ECM was not apparently different between non-decellularized (Fig. [2c](#Fig2){ref-type="fig"}) and decellularized vessel (Fig. [2d](#Fig2){ref-type="fig"}). The difference of porosity not effective to collapse of vessel is formed by removal of cells in decellularized vessel. In SEM images, non-decellularized vessel had dense ECM layer (Fig. [2e,g](#Fig2){ref-type="fig"}) and decellularized one maintained a layer-layer structure of ECM well (Fig. [2f,h](#Fig2){ref-type="fig"}). Thus, although cells in the vessel were removed, the ECM was well maintained even after decellularization.Figure 2Structural observation of decellularized vessel. Photography of (**a**) cellular vessel and (**b**) decellularized vessel. Cross sectional image of hematoxylin and eosin (H&E) staining of (**c**) cellular vessel and (**d**) decellularized vessel. Scanning electron microscopy (SEM) image of microstructures of the extracellular matrix (ECM) fibrils of cellular vessel at (**e**) low resolution (**g**) and high resolution and decellularized vessel at (**f**) low resolution (**h**) and high resolution.
The aorta vessel retained its mechanical strength after decellularization {#Sec4}
-------------------------------------------------------------------------
Mechanical strength was compared between original and decellularized vessels with three different diameters in terms of physical characteristics: maximum load, tensile strain, and Young's modulus. The maximum load was not significantly different between samples that were 2 cm and 2.5 cm in diameter, although the decellularized vessel with 3 cm, which are closer to the heart's ventricles, showed significantly lower value (Fig. [3](#Fig3){ref-type="fig"}). This position difference made 3 cm vessel thicker than the other vessels. For this reason, the original 3 cm-thick vessels have a higher maximum load than the other vessels before decellularization. However, decellularization removed much more cells from the vessels of 3 cm diameter compared with the small sized ones, which is thought to lead to less integrity of ECM in 3 cm-thick vessels. In short, much more decellularization resulted in much less integrity of ECM, resulting in a sharp drop in mechanical strength in 3 cm-thick vessels compared with the small sized vessels.Figure 3Mechanical characteristics of vessels by treatment. (**a**) Maximum load of cellular vessel and decellularized vessel. (**b**) Tensile strain and (**c**) Young's modulus of cellular vessel and decellularized vessels. (**d**) Transepithelial electrical resistance (TEER) of the cellular and decellularized vessels. \*P \< 0.05; \*\*P \< 0.01 (Student's t-test). Error bars indicate standard deviation.
The tensile strain and Young's modulus were also not significantly different between cellular and decellularized samples, at any diameter. Tensile strain and Young's modulus are influenced dominantly by GAGs. GAGs functionalize protein to proteoglycan and possibly the formation of a collagen fiber network with increased interstitial spaces and porosity modulus^[@CR18]^. The GAGs can be removed easily by decellularization using detergents, but in the research, we used freeze-thaw method without detergents. For the reason, tensile strain and Young's modulus were not changed significantly when the maximum load was decreased after decellularization. The porosity of vessel was quantitatively measured by trans-epithelial electrical resistance (TEER). Diameter of vessel did not make any significant differences in TEER values for both decellularized and non-decellularized vessels. However, TEER value was lower in decellularized vessels than in non-decellularized vessel (Fig. [3d](#Fig3){ref-type="fig"}). This implied that vessel lost its t-junction during cell removal by decellularization, even though the layer-by-layer structure did not look significantly different from that of non-decellularized vessel.
Development of heart-mimicking circulation system (HMCS) {#Sec5}
--------------------------------------------------------
The system was assembled and operated continuously to mimic heart beating and pumping (Fig. [1](#Fig1){ref-type="fig"}). As shown in Fig. [4a](#Fig4){ref-type="fig"}, the pump was controlled by an Arduino control box. The speed of the pump depended on the strength of the voltage applied from the power source. The Arduino sent an on/off signal to the transistor and controlled the voltage from power source to pump. The pump aspirated and emitted media to the decellularized vessel and then the media fed back to the pump.Figure 4Schematic of the circulation system and its operation. (**a**) Circuit diagram of the system from controller to pump. The operating patterns of the circulation system was as follows: *in vivo* heart, input signal, and output signal, of (**b**) gradient type and (**c**) bang-bang type operation.
The pumping frequency and volumetric flow rate were used to mimic the hydrodynamic environment of an aortic site connected to the heart. In the control box, voltage was adjusted to regulate ON/OFF time and be responsible for regulating volumetric flow rate out of the pump. Heart beat profile has monotonous shape at systolic phase and the blood is spewed out. After systolic phase, there presents diastole phase where pressure drops slowly and blood is not spewed out even if there is residual pressure in heart valve. In case of gradient type, each 38.4, 70.5 92.5, 100% voltage/maximum voltage was transmitted to pump at 0.1 s interval and it took rest period for 0.6 s. The bang-bang type transmitted 62.0% voltage/maximum voltage for 0.4 s and rest for 0.6 s. As a demonstration, heart beats at 60--100 beats/min, sending approximately 17 L/min of blood to the aorta, and the heart pumps 70 ml of blood during each systole phase, which usually has duration of 0.4 s^[@CR19]^. In order to mimic blood flow, HMCS was manipulated to pump at 60 times/min, sending 70 ml/s of media to the aorta vessel. Finally, the heart pumping and the flow blood pattern were mimicked in the similar way to those of heart (Fig. [4b](#Fig4){ref-type="fig"}).
Structural stability of the decellularized vessel connected to HMCS {#Sec6}
-------------------------------------------------------------------
The decellularized vessel connected to HMCS was evaluated of its structural stability after exposed to pressure of flow emitted from HMCS. As seen in Fig. [5a](#Fig5){ref-type="fig"}, the mechanical strength of decellularized vessel (Max load: 19.40 ± 7.12 N, tensile strain: 0.84 ± 0.30 MPa, modulus: 1.32 ± 1.51 MPa) were slightly decreased than those of cellular vessel (Max load: 20.42 ± 8.26 N, tensile strain: 0.89 ± 0.36 MPa, modulus: 1.46 ± 0.50 MPa) but there were no significant differences through statistical comparison.Figure 5Universal testing machine data (UTM) data for stress test with alternative vessels, i.e., cellular and decellularized vessels. The UTM data (maximum load, tensile strain and Young's modulus) of (a)stress test and (b)adhesive test using cellular vessel and decellularized vessel. \*P \< 0.05; \*\*P \< 0.01 (Student's t-test). Error bars indicate standard deviation.
Usefulness of the decellularized vessel as a test model for an adhesive {#Sec7}
-----------------------------------------------------------------------
To verify if the decellularized vessel is useful for efficacy testing of adhesive, both decellularized and original vessels took 1 cm length rupture and then was treated with adhesive; cyanoacrylate. The testing system must present leaking pressure after rupture to evaluate adhesives in a similar situation with aorta. The pressure applied to the rupture of 2 cm or more was lowered and the fluid was not ejected to the rupture area. But, 1 cm and 1.5 cm rupture expressed significant flow ejection, not showing much difference in both (data not shown). For the reasons, 1 cm length rupture was selected to demonstrate the effect of leaking pressure on adhesive efficacy. After adhesive treatment, the vessel was followed by exposure to flow pressure from HMCS, which resembled frequency and volumetric flow rate of heart-pumping. No significant differences in mechanical strength were detected between them. Original vessel showed 17.90 ± 6.30 N at max load, 0.78 ± 0.27 MPa at tensile strain and 1.23 ± 0.42 MPa at modulus. Decellularized vessel showed 19.10 ± 3.89 N at max load, 0.83 ± 0.17 MPa at tensile strain and 1.76 ± 1.11 MPa at modulus. There were no significant differences of each parameter between the samples by student t-test (Fig. [5b](#Fig5){ref-type="fig"}).
Significance of the HMCS for a test model of adhesive {#Sec8}
-----------------------------------------------------
Flow into vessel is a major momentum to mechanical stress against vessel wall and thus is an essential point that must be overcome in adhesives. The volumetric flow of heart is 70 ml/beat but frequency may not be consistent because of systolic trend of heart, leading to each different hydrodynamic pressure with respect to a flow pattern. For this reason, adherent and fixing efficacy needs to be evaluated according to a flow pattern. In this research, the two pumping types; gradient and bang-bang types, were compared for cyanoacrylate adhesiveness. Gradient type showed different mechanical properties according to the time of treatment with the adhesive. The maximum load was significantly decreased, compared with that of bang-bang type with a treatment time of 3 min. The maximum load was recovered to just 63.9% of non-torn site. When the rupture was torn again during operation, leaks were observed, suggesting that the adhered site was not uniformly maintained. Further, the tensile stress at maximum load and modulus were also decreased. The adhered site was too weak and could not resist stress before the other non-damaged area was fully extended. In addition, cyanoacrylate hardens during polymerization, making the treated site inflexible. However, it took more than 5 min of treatment, before the mechanical characteristics were recovered to a similar level as the bang-bang vessel. Adhesive-treated vessel for 5 min showed no significant differences compared with no-torn vessel and re-tear of the rupture site was also not observed (Fig. [6](#Fig6){ref-type="fig"}, Table [1](#Tab1){ref-type="table"}). All these results implied that pumping frequency and strength is critical to test adhesive efficacy.Figure 6Universal testing machine (UTM) data of adhesive evaluation with gradient types and bang-bang type system, with different fixing times and operation types as outlined in Table [1.](#Tab1){ref-type="table"} (**a**) Maximum load value of vessel for each test condition. (**b**) Tensile strain and (**c**) Young's modulus for each test condition. \*P \< 0.05; \*\*P \< 0.01 (Student's t-test). Error bars indicate standard deviation. Table 1Test conditions and numerical values of the mechanical characteristics of each condition (Fig. [6](#Fig6){ref-type="fig"}).TypeFixing timeMax load (N)Tensile strain at max load (MPa)Modulus (MPa)Bang-bang3 min9.59 ± 2.710.42 ± 0.120.79 ± 0.125 min8.28 ± 3.380.36 ± 0.150.93 ± 0.21Gradient3 min3.89 ± 0.210.17 ± 0.0180.40 ± 0.0165 min8.15 ± 4.990.35 ± 0.280.76 ± 0.44Control---12.76 ± 10.360.55 ± 0.451.23 ± 1.18
Discussion {#Sec9}
==========
A standard evaluation system to develop an adhesive for injured aorta requires both standardized aorta vessel and beating flow system to mimic blood pumping from the heart. The efficacy of the incorporated both system must also be assessed, prior to its use to evaluate candidate adhesives.
The use of aorta vessel that is regenerated using a standard tissue engineering protocol would be best in such a system. However, the development of an artificial aorta by tissue regeneration is limited due to the specificity of its structure, i.e., blood vessels are composed of the three following layers; intima, media, and adventita^[@CR20]^. The media layer consists of smooth muscle cells and ECM (typically collagen and elastin) that is so densely packed, it dominantly affects the mechanical characteristics of blood vessel. Further, the 4-mm thickness of the media layer is also too hard to mimic by tissue engineering. Thus, use of a real aorta is an alternative to address this problem. Swine aorta is one of the best choices since swine tissue is similar to humans. However, since the characteristics of tissue can vary with age, and the cells in the tissue are difficult to standardize, using the tissue in its intact form would increase statistical uncertainly in the evaluation. In addition, the vessel was already densely packed by the ECM of endothelial cells and smooth muscle cells of the intima layer and external layer, respectively^[@CR21],[@CR22]^, and these cells are a risk factor for tissue collapse due to ribosomes or several enzymes, such as collagenase that are critical to the external layer, which is collagen-rich and dominates to tissue structure^[@CR23]^. Further, since the adherent material is applied to outer surface of the tissue, it is also important to evaluate the effect of adhesives on the ECM structure. For these reasons, decellularized aorta, which maintains its intact ECM structure, was proposed as the standardized tissue system.
As demonstrated by its structural and mechanical properties (Figs [2](#Fig2){ref-type="fig"} and [3](#Fig3){ref-type="fig"}), the decellularized swine aorta represented structural integrity and mechanical strength comparable to that of intact tissue, although the t-junction was removed. The maximum load is the major characteristic that gives rise to resistance against mechanical stress derived from fluid flow^[@CR24]^. It affects system robustness, required a stronger pump to mimic heart pressure. The tensile strain and modulus affects the strain and movement of the tissue layer^[@CR25]^. The lateral expansion by the pulse of fluid is changed by these physical properties^[@CR26]^. However, since the physical properties of the decellularized sample were not changed significantly; this meant that the vessel beating or expansion would be well-mimicked in the current model. These results implied that ECM was mainly configured by structural proteins, such as collagen fibrils and elastin, which are dominant contributors to strength among tissue^[@CR27]^, and were not destroyed or denatured by decellularization^[@CR28]^.
These results corroborated with previous findings, demonstrating that decellularization had no effect on the mechanical characteristics of the media layer and that removing cells enhanced its storage ability^[@CR29],[@CR30]^. Meanwhile, t-junction seals the gap between cells and separates inner/outer layers^[@CR31]^, but it was concluded not to significantly affect mechanical strength compared with the layer-by-layer structured ECM, judging from the fact that the decreased TEER in decellularized tissue was not consistent with the non-varying mechanical strength of the vessel (Fig. [3](#Fig3){ref-type="fig"}). All these results implied that the major factor of tissue strength was ECM, rather than the t-junction. Since decellularization did not affect the physical properties of vessel tissue, again these results highlighted that the current system was adequate in mimicking the circulation system.
The *in vivo*-like pulsation and blood flow system was realized by controlling a pump with a pre-determined schedule. The beating frequency and strength of blood flow varies among people, according to their age and health. However, the use of an Arduino controller coupled with actuator pump, allowed pumping to reflect the parameters in reference to healthy and adult^[@CR32]^. As demonstrated in Fig. [4](#Fig4){ref-type="fig"}, the blood flow emitting from the heart was successfully realized through this system. It was easy to change the frequency and strength of the flood, using the mechanical pump and controller, and these could be reliably reproduced. Thus, the system developed in the current study could be regarded as a standardized HMCS. Furthermore, the decellularized vessel could retain its mechanical strength similar to that of original vessel even after exposed to flow pressure out of HMCS. Therefore, the hybrid system securely modeled an *in vivo* aorta vessel. Although the decellularized and cellular samples had different TEER values as shown in Fig. [3a](#Fig3){ref-type="fig"}, it did not affect the mechanical resistance against the pressure derived from the pump, but the retained ECM of the decellularized vessel guaranteed its resistance to flow pressure.
Two rationales were applied to prove the efficacy of the developed system. The first requirement was that the model adhesive efficiency must be similar, in both intact and decellularized aortas, so that the decellularized aorta could be validated as a modeling standard tissue. To investigate this, the pumping condition was fixed in both cases, mimicking the blood flow emitting from heart. As illustrated in Fig. [5](#Fig5){ref-type="fig"}, application of cyanoacrylate showed similar mechanical properties in both vessels, implying that decellularized aorta could be useful in evaluating adhesives, overcoming the challenge of standardizing the use of intact aorta. As shown in the results, mechanical strength was not critically different between original and decellularized tissue (Figs [5a and b](#Fig5){ref-type="fig"}). As shown in Fig. [5a](#Fig5){ref-type="fig"}, the physical properties of each vessel (original and decellularized vessel) were the same in intact form without application of adhesive. Also, the mechanical property of each vessel was not significantly different after treatment of the adhesive (Fig. [5b](#Fig5){ref-type="fig"}). Therefore, the porosity of the decellularization did not significantly affect the performance of the system. For the reason, we can suggest that the decellularization removes cytosol and interaction between cytosol and collagen fibril, then maximum load is decreased but collagen fibril and its network still remains in intact form and are dominant to maintain mechanical strength in tissue. The second requirement was that the efficiency of an adhesive to decellularized aorta must be dependent on pumping frequency and strength of HMCS. To investigate this, we compared the efficiency of cyanoacrylate in the heart pumping-mimicking system and bang-bang type pumping system. The mechanical properties were weaker in HMCS, which implied that the pumping frequency and strength affected the adhesive efficacy. This finding highlighted and validated the importance of evaluating adhesives using HMCS.
Therefore, HMCS developed in the current study met all the requirements to evaluate an adhesive for the injured aorta. Further, the system and evaluation protocol was standardized. There are several other advantages of this system too. In cases requiring such a formalized system, decellularization saves resources as the aorta section is easier to prepare. Further, there is strength in having a standardized system, since results are replicable and comparable. Moreover, this system minimizes the use of experimental animals, overcoming the ethical challenges of conducting preclinical studies. HMCS that was developed in the current study has the potential to allow researchers to conduct more accurate preclinical studies.
Adhesive is an effective treatment to blood vessel injury, but its development is limited by the lack of an appropriate evaluation system to assess its efficacy in hard-to-accessible vessels, such as the aorta. In the current study, a standardized and biomimetic system was developed to replace animal-testing models in evaluating circulation-system drug. HMCS mimicked the parameters of an *in vivo* circulation system, such as pumping frequency and volumetric flow rate, which were easily and reproducibly adjusted using an automatic pump system. Further, we conducted a proof-of-concept experiment to demonstrate the efficacy of HMCS in evaluating the adhesive properties of cyanoacrylate. Overall, we validated the use of the developed system in evaluating novel adhesives, and demonstrated that it can help save resources and overcome the ethical challenges of using animals during preclinical studies.
Materials and Methods {#Sec10}
=====================
Vessel part formation: Decellularization {#Sec11}
----------------------------------------
For organizing a vessel part of circulation system, we decellularized a swine aorta from a butcher in Incheon, South Korea. The vessel was cut to 3 cm in length, and washed with ethanol to remove fat and contaminants. Before freezing, ethanol was exchanged with distilled water. The vessel was frozen using liquid nitrogen for 30 s, thawed fully in ambient temperature for 10 min. The freeze-thaw routine was repeated 10 times. The distilled water contained the residue was changed and the decellularized sample was stored at −20 °C.
Sectional structure observation {#Sec12}
-------------------------------
The cross-sectional morphology was observed to confirm vessel decellularization. The swine vessel was cut into an area of 1 × 1 cm^2^, and immersed in 30% and 60% sucrose solutions, for 4 h, each. After the treatment, optimal cutting temperature compound was poured on the vessel to make a block and the block was sliced at a thickness of 40 µm. Cell nuclei were stained using 4′,6-diamidino-2-phenylindole (DAPI) and tissue histology was observed with hematoxylin and eosin staining.
Vessel decellularization: Analysis using an universal testing machine {#Sec13}
---------------------------------------------------------------------
Universal testing machine (UTM; Instron, MA, USA) was used to confirm differences in physical characteristics (e.g., maximum load, tensile strain, and Young's modulus) of the vessel following decellularization. The vessel was cut in the horizontal direction into equal areas of 1 × 3 cm^2^. The pieces of vessel were steadily elongated at 2 mm/min by UTM and physical characteristic values were recorded.
Decellularized vessel trans-epithelial electrical resistance {#Sec14}
------------------------------------------------------------
TEER was measured to confirm the intercellular junctions by decellularization. The vessel, from which an area of 1 × 1 cm^2^ was cut, was measured with a TEER sensor. Measurements were replicated at least three times per sample.
Circulation system formation {#Sec15}
----------------------------
The following items were used to form the system: water pump, silicon tube, connector, and an Arduino control box. The decellularized blood vessel was placed between connectors, which linked it with the motor, which controlled the flow and frequency. The pump, which was operated by the Arduino control box, pumped 60 times/min. A total of 70 mL of media was ejected as once during systolic work, which was 0.4 s in duration.
Application of decellularized vessel supplemented to cellular vessel {#Sec16}
--------------------------------------------------------------------
The decellularized vessel was compared with a cellular vessel. The samples were installed into the system and the system was operated for 30 min with distilled water at 37 C. The samples were harvested and their physical characteristics were evaluated using UTM.
Adhesive evaluation using a tissue adhesive {#Sec17}
-------------------------------------------
We tested the effect of cyanoacrylate (Sigma-Aldrich, MO, USA), a major tissue adhesive, on the circulation model system to confirm that the system could be used to evaluate potential candidates for vessel adhesion. After operating the circulation system, a 1-cm-sized cut was made on the vessel. Cyanoacrylate was applied to the cut, and differences in leaking volume through the cut and flow rate in the vessels were measured. The vessel was harvested and its physical characteristics were measured using UTM. We evaluated the potential of cyanoacrylate as a vessel adhesive based on these results.
Statistical analysis {#Sec18}
--------------------
All experiments were repeated at least 3 times. The asterisks were added when the statistical differences were observed by a Student's t-test as follows: \*p \< 0.05; \*\*p \< 0.01; and \*\*\*p \< 0.001.
Electronic supplementary material
=================================
{#Sec19}
Supplementary Video S1 Supplementary information
A correction to this article is available online at <https://doi.org/10.1038/s41598-018-24839-5>.
**Electronic supplementary material**
**Supplementary information** accompanies this paper at 10.1038/s41598-017-16814-3.
**Publisher\'s note:** Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This work was supported by the Marine Biotechnology Program (Marine Biomaterials Research Center) funded by the Ministry of Oceans and Fisheries, Korea.
All authors wrote all of main text, prepared figures and conducted all assays, H.S. supervised the overall process for the completion of this study. All authors reviewed the manuscript.
Competing Interests {#FPar1}
===================
The authors declare that they have no competing interests.
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Administrative
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Parish Pastoral Council
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The rise and fall of malignant fibrous histiocytoma.
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>>702666133He would have to pass as a woman publicly and to my family, that's the only way it would work for me. But if a qt girl could do that I'd make a wife out of them and provide for them financially and sexually.
>>702663795GET THE FUCK OUT OF /b/ FUCKING FAGGOT GET THE FUCK OUT OF /b/ FUCKING FAGGOT GET THE FUCK OUT OF /b/ FUCKING FAGGOT GET THE FUCK OUT OF /b/ FUCKING FAGGOT GET THE FUCK OUT OF /b/ FUCKING FAGGOT GET THE FUCK OUT OF /b/ FUCKING FAGGOT GET THE FUCK OUT OF /b/ FUCKING FAGGOT GET THE FUCK OUT OF /b/ FUCKING FAGGOT GET THE FUCK OUT OF /b/ FUCKING FAGGOT GET THE FUCK OUT OF /b/ FUCKING FAGGOT GET THE FUCK OUT OF /b/ FUCKING FAGGOT GET THE FUCK OUT OF /b/ FUCKING FAGGOT GET THE FUCK OUT OF /b/ FUCKING FAGGOT GET THE FUCK OUT OF /b/ FUCKING FAGGOT GET THE FUCK OUT OF /b/ FUCKING FAGGOT GET THE FUCK OUT OF /b/ FUCKING FAGGOT GET THE FUCK OUT OF /b/ FUCKING FAGGOT GET THE FUCK OUT OF /b/ FUCKING FAGGOT GET THE FUCK OUT OF /b/ FUCKING FAGGOT GET THE FUCK OUT OF /b/ FUCKING FAGGOT GET THE FUCK OUT OF /b/ FUCKING FAGGOT GET THE FUCK OUT OF /b/ FUCKING FAGGOT GET THE FUCK OUT OF /b/ FUCKING FAGGOT GET THE FUCK OUT OF /b/ FUCKING FAGGOT GET THE FUCK OUT OF /b/ FUCKING FAGGOT GET THE FUCK OUT OF /b/ FUCKING FAGGOT GET THE FUCK OUT OF /b/ FUCKING FAGGOT GET THE FUCK OUT OF /b/ FUCKING FAGGOT GET THE FUCK OUT OF /b/ FUCKING FAGGOT GET THE FUCK OUT OF /b/ FUCKING FAGGOT GET THE FUCK OUT OF /b/ FUCKING FAGGOT GET THE FUCK OUT OF /b/ FUCKING FAGGOT GET THE FUCK OUT OF /b/ FUCKING FAGGOT GET THE FUCK OUT OF /b/ FUCKING FAGGOT GET THE FUCK OUT OF /b/ FUCKING FAGGOT GET THE FUCK OUT OF /b/ FUCKING FAGGOT GET THE FUCK OUT OF /b/ FUCKING FAGGOT GET THE FUCK OUT OF /b/ FUCKING FAGGOT GET THE FUCK OUT OF /b/ FUCKING FAGGOT GET THE FUCK OUT OF /b/ FUCKING FAGGOT GET THE FUCK OUT OF /b/ FUCKING FAGGOT GET THE FUCK OUT OF /b/ FUCKING FAGGOT GET THE FUCK OUT OF /b/ FUCKING FAGGOT GET THE FUCK OUT OF /b/ FUCKING FAGGOT GET THE FUCK OUT OF /b/ FUCKING FAGGOT
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Fit teen gets ass to throat fuck and takes anal creampie eating it. Mia
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Busty Sex Crazed Milf Sophie Anderson gets her Tight Ass DAP’ed by 3 Cocks
400 67%
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It doesn't take much to set off a Pakistani fan. The recent movements on the Test-rankings table have provided plenty of fodder for discourse, to say the least. The irony of it is that in trying to discredit others, Pakistanis often fall back upon the same tropes that have been used against them, talking about discrepancies between teams' home and away records, and the quality of opposition faced.
Yet for those within the dressing room, that equivalence is considered false, particularly the notion that Pakistan playing in the UAE is like any other team playing at home. According to one Pakistani player, you can consider it the same the day a Pakistani team gets the crowd and control over the pitches that other Asian nations do. According to another, you can consider it truly Pakistan's home the day another team can't put out their best XI for a home Test because of visa issues. There have even, finally, been some public utterances about the difficulty of being nomads.
But if Pakistan really want to prove their point, all they have to do is point towards their "home" ODI record. Of course that's not exactly likely to happen since many of those complaining were responsible for that record.
If you leave out the current series against West Indies, since moving to the Emirates in 2009, Pakistan have played 12 bilateral ODI series there (against nations from among the top nine), winning three. Outside of the Emirates the record reads: won seven, lost ten. The most obvious divergence was under Misbah-ul-Haq, when Pakistan won just two of their seven "home" series and four of the eight series away from home against teams in the top nine, including historic wins in India and South Africa. While the rest of the world uses home ODIs to induct new players and pad up their records, Pakistanis have struggled to even compete in them.
In a way, the recently concluded series against West Indies was a window into an alternative world, where Pakistan are like any other team in the world, stronger at home. Of course, if the ICC rankings did weigh home and away results differently from each other, as they ought to, maybe Pakistan wouldn't be struggling to qualify for the World Cup right now.
The reasons for Pakistan's record are pretty obvious. Their wins were led by their bowling attack. From the 2011 World Cup through the 2015 one, no team had a better economy rate than Pakistan, and their collective bowling average was in the top tier too. This was due to the efforts of Saeed Ajmal and Mohammad Hafeez, and to a lesser extent Shahid Afridi. But spin wasn't the only reason for it. In 2013, when Pakistan played more ODIs outside Asia than they did in it, both Junaid Khan and Mohammad Irfan averaged under 23 with the ball. (Note: all these stats are against the top nine ODI nations only.)
But now, devoid of pace bowlers of that level (the occasional Wahab Riaz or Mohammad Amir spell aside), bereft of the spin trio, and without Misbah to handle it all, Pakistan's bowling has fallen off a cliff. Whatever they have gained on the batting front has failed to compensate for their bowling deficiencies.
The ODI game in general has, over the past decade and a bit, gone from treating bowlers as equal citizens to considering them glorified bowling machines. And it is here that Pakistan won't be able to catch up, regardless of whether Babar Azam becomes the most complete batsman Pakistan have had in 20 years or whether Umar Akmal reaches his destiny.
The reductionist viewpoint would blame it on individuals or selection matters, because trying to scratch the surface requires too much effort. The most common prescription heard is that Pakistan's batting needs to attack relentlessly, like other teams' batting line-ups do. This, of course, is followed by a smug look from the deliverer of that insight, as if no one else had thought of it before. In response to this wisdom, all one has to do is point to a simple stat: in the third ODI in England, the one with more broken records than a vintage vinyl shop, each of the English top eight had T20 strike rates in excess of 125, while only two of the Pakistanis (Sharjeel Khan and Sarfraz Ahmed) did by contrast. So even if Pakistan attack relentlessly, will it change much?
In the last two years of the Royal London One Day Cup, over 13% of all completed matches had first-innings scores in excess of 325. In the premier 50-overs competition in Australia last season, that number was 13% as well. In Pakistan's national one-day competition in 2015-16 it was under 6%.
"If the ICC rankings weighed home and away results differently from each other, as they ought to, maybe Pakistan wouldn't be struggling to qualify for the World Cup right now."
Pakistan are stuck in an era the world has moved on from. Without any scrutiny, thanks to the absence of international cricket at home, cricket in Pakistan has been damaged on a level that is evident only now. And that really is the true cost of Pakistan's exile. The ecosystem of cricket - and this includes everything from the sponsors the board attracts to the understanding of the game among the cricket-following fraternity - has stagnated as cricket has been outsourced. (That's why former commentators take offence to the standard of local broadcasting being compared to the 1980s, saying, "It was so much better than this in the '80s.") Nowhere is this more obvious than in the tools the players use.
Much has been made in recent months of modern bats, but it's a discussion Pakistanis can't even participate in. In a TV show last year Saqlain Mushtaq spoke of how the finances available to Pakistani cricketers do not even suffice for them to have the diet and nutrition that athletes needs, let alone extend to enabling them to buy the equipment they require. Current Pakistani players tell of using bats made in England or India and then realising they have to change their games - because it's the first time they can actually time the ball for boundaries, thanks to these bats, rather than having to thrash at everything. One player said he had to learn the art of batting afresh this year just because he finally has bats similar (but not the same, it is pointed out) to those used by players from the richer boards. Long gone are the days when Sachin Tendulkar would ask Wasim Akram for bats from Sialkot.
And when asked how many players from outside the national team use such bats, the answer is: never more than a handful. Big bats are just not available to Pakistanis, and even if they were, they would struggle to afford them. And then we wonder where all the big hitters went.
There is a living embodiment of the stagnation of Pakistan cricket. Located at one end of the Gaddafi Stadium are the offices of the PCB; at the other end is a stand that has been under construction since 2008. Or to put it another way, since construction on that stand began, Rio de Janeiro bid for the Olympic Games, won the bid, invested close to US$30 billion in infrastructure and stadiums, dealt with the public fallout from that spending, had multiple changes in government, hosted the Games and the Paralympics, and now doesn't know what to do with its white elephants. In all that time, construction on that stand at the Gaddafi Stadium has still not been completed. And this, you have to remember, is in the city and the stadium seen by the rest of Pakistan as the one that is given preferential treatment.
The base salary of a player in Pakistan's national team is barely a third of what their New Zealand or Sri Lankan counterparts earn, let alone what the Big Three offer. And that base salary in turn is extravagant compared to what Pakistani domestic players earn.
Thus the achievements of Pakistan, particularly the Test team, need to be seen in another light. Maybe comparing them to Leicester would be unfair on both parties, but there is some equivalence to be drawn with Diego Simeone's Atletico Madrid - another team with far fewer resources and much less talent than their rivals; one that momentarily reached the top before that was taken away from them by those with far deeper pockets.
But even Atletico had the Calderon. Even they were no nomads.
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Introduction
============
Gaucher disease (GD; OMIM: 230,800, 230,900, and 231,000) is the most common autosomal recessive lysosomal disorder, first described by Philippe Gaucher in 1882. GD is caused by the deficiency of the lysosomal hydrolase acid -- β-glucosidase (GCase). This enzyme is present in the lysosomes of all nucleated cells and cleaves the β-glucosidic linkage of glucosylceramide (GlcCer) yielding glucose and ceramide. GCase deficiency leads to the progressive lysosomal accumulation of GlcCer and other glycosphingolipids and subsequent multiorgan dysfunction. The storage predominantly occurs in cells of the monocyte--macrophage lineage, but an increase in GlcCer concentration is detectable in most of the body tissues.[@b1-tcrm-12-053]
GD is a rare panethnic disease, presenting an estimated prevalence in the general population of 1:30,000--40,000 people. However, it is the most frequent genetic disease in the Ashkenazi Jewish population, where it shows a prevalence of 1:1,000.[@b2-tcrm-12-053]
Clinically, based on the presence and progression of the central nervous system involvement, the disease has been traditionally classified into three different phenotypes: chronic non-neuronopathic (GD1), acute neuronophatic (GD2), and chronic neuronopathic (GD3) forms. GD1, the most common phenotype (accounting for 90%--95% of GD patients), is characterized by visceral symptoms that include hepatosplenomegaly, bone marrow infiltration causing thrombocytopenia and anemia, and skeletal involvement with osteoporosis, bone lesions, and bone pain. Patients affected by GD2 manifest visceral symptoms with early and severe neurological impairment, involving the brainstem, leading to death in the first 2--3 years of life. In patients affected by GD3, symptoms are associated with neurological alterations, presenting an onset that might range from childhood to early adulthood, and include abnormal eye movements, seizures, and mental retardation.[@b3-tcrm-12-053] Although the classification of GD in these three main phenotypes is still widely accepted, and will also be used in this review, the clinical presentation of GD is currently considered as a continuum spectrum of phenotypes, ranging from very mild to extremely severe forms.[@b4-tcrm-12-053] Moreover, patients affected by GD1 cannot be considered free of neurological complications anymore, since an increased risk of parkinsonism has been widely documented in these patients, and a high prevalence of peripheral neuropathy has been recently demonstrated.[@b5-tcrm-12-053],[@b6-tcrm-12-053]
The β-glucosidase gene, *GBA1* (GenBank accession no J03059.1), is located on chromosome *1q21* and contains 11 exons spread out in \~7.5 kb of the genomic sequence. A highly homologous 5.7 kb pseudogene (GenBank accession no J03060.1) is located 16 kb downstream from the active gene.[@b7-tcrm-12-053] To date, \>430 mutations have been described (<http://www.hgmd.org>).
Mutations *N370S*, *84GG*, *L444P*, and *IVS2*+*1G*\>*A* account for 90% of mutant alleles in the Jewish population, while they represent fewer than 75% of alleles among non-Jewish Caucasian patients, with some differences in defined subpopulations. In any case, *N370S* and *L444P* alleles are the most prevalent alterations throughout most populations. Although, no consistent correlation between the genotype and phenotype has been found, some general conclusions can be drawn regarding the neuroprotective nature of the *N370S* mutation and the association between the *L444P* allele and the severe phenotype.[@b8-tcrm-12-053],[@b9-tcrm-12-053]
With regard to GD pathophysiology, all cells of the mononuclear phagocyte system, in particular macrophages of the liver (Kupffer cells), spleen, bone (osteoclasts), bone marrow, central nervous system (microglia), lungs, and others, can be altered by lipid accumulation.[@b1-tcrm-12-053] Nevertheless, the levels of GlcCer and other glycophingolipids in these cells are increased, but are not high enough to completely justify the tissue damage. Thus, other mechanisms have been hypothesized to be involved in GD pathogenesis. Abnormal macrophage activation is considered as one of the key GD pathways. In fact, chitotriosidase, a product of the macrophage activation, is usually elevated in GD plasma, and since its levels correlate with disease severity, it is commonly used to monitor the disease response on treatment.[@b10-tcrm-12-053] Moreover, proinflammatory cytokines secreted by macrophages, such as interleukin-1β, interleukin-6, and tumor necrosis factor-α (TNFα), and chemokines like CCL18 are elevated in GD plasma.[@b11-tcrm-12-053] Modified macrophages also change their surface molecules, dysregulating the immune system, in fact, it is common in patients with GD to detect a monoclonal gammopathy, and there is also an increased risk of hematological malignancies (especially multiple myeloma).[@b12-tcrm-12-053]
With regard to therapy, until the 1990s, the therapeutic approach for GD was mainly palliative. Then, the first specific treatment for GD, enzyme replacement therapy (ERT), aimed to correct the metabolic defect by intravenous infusion of a purified or a recombinant human GCase enzyme, was developed and it is still considered the standard of care for GD.[@b13-tcrm-12-053],[@b14-tcrm-12-053]
More recently, an alternative therapeutic approach, substrate reduction therapy (SRT), which can be administered orally, has been introduced. SRT inhibits the synthetic pathway of GlcCer. Miglustat was the first SRT approved for GD, but because its tolerability profile was licensed only for patients who are not suitable for ERT.[@b15-tcrm-12-053] Eliglustat tartrate is a new promising SRT, which acts as a specific and potent inhibitor of glucosylceramide synthase (GCS).[@b16-tcrm-12-053]
In this review, we illustrate the rationale for the currently approved therapeutic approaches for GD, summarize the results of the preclinical studies and clinical trials, which experimented with eliglustat, and finally discuss the possible role of this new drug in the management of GD, when compared to the already available therapies and the new experimental approaches.
The development of ERT and SRT for GD
=====================================
The rationale of ERT for lysosomal storage disease treatment is based on the observation that most cell types release small amounts of lysosomal enzymes and that these secreted forms could be internalized by other cells. Therefore, the periodically infused recombinant enzyme can be internalized by the cells, trafficked to the lysosomes, where it can metabolize the accumulated substrate.[@b17-tcrm-12-053] The first experimented enzyme for GD treatment, called alglucerase (Ceredase^®^), was placenta-derived. Its introduction in the early 1990s changed the approach to lysosomal storage disorders, paving the way to the development of ERT for the treatment of many disorders. Alglucerase was soon replaced by imiglucerasi (Cerezyme^®^), the first human recombinant enzyme produced in Chinese hamster ovary cells, which was approved by the US Food and Drug Administration in 1994. More recently, other two preparations have been licensed in some countries: velaglucerase alfa (Vpriv^®^), produced in human fibroblast cell lines, and taliglucerase alfa (Elelyso^®^), produced in modified carrot cells. Many studies have demonstrated the efficacy of ERT in reducing mortality, improving/normalizing hematological parameters and organ volumes, and improving or stabilizing bone pathology in GD.[@b13-tcrm-12-053],[@b18-tcrm-12-053]--[@b20-tcrm-12-053] However, due to its high molecular weight, the enzyme does not cross the blood--brain barrier; therefore, patients with neurological features only benefit from the effect of ERT on visceral, hematological, and skeletal features.[@b21-tcrm-12-053] ERT is usually well-tolerated and except for possible anaphylactic reactions, side effects are usually mild and include nausea, abdominal pain, rash, fatigue, and headache.[@b22-tcrm-12-053]
SRT is an alternative treatment strategy, based on the administration of small molecules that are able to reduce the biosynthesis of the substances that accumulate in the disease-affected organs, restoring the balance between the rate of production and the rate of degradation.[@b23-tcrm-12-053] The first compound approved for SRT in GD1 patients was miglustat (Zavesca^®^), an imino sugar (*N*-butyldeoxynojirimycin) that inhibits the ceramide -- glucosyltransferase, which catalyzes the first step in glycosphingolipid biosynthesis. The drug showed its efficacy on peripheral GD symptoms.[@b24-tcrm-12-053] Moreover, since the molecule is able to cross the blood--brain barrier, its role in the management of the neuronopathic forms has been hypothesized. A clinical trial was conducted in GD3 patients; however, this study did not demonstrate any beneficial effect of this approach on the neurological symptoms.[@b25-tcrm-12-053] The main advantage of miglustat treatment in GD patients is its oral administration. The main disadvantages are the side effects that include gastrointestinal dysfunction, tremors, and peripheral neuropathy, which is probably due to its nonspecific inhibitory effect on other enzymes, including the intestinal disaccharidases.[@b26-tcrm-12-053] Therefore, its indication was limited only to adult GD1 patients with mild-to-moderate phenotype, in whom ERT is unsuitable (eg, hypersensitivity or poor venous access).[@b15-tcrm-12-053]
Eliglustat tartrate is a newly developed SRT for GD, which is created to specifically inhibit GCS, with the aim to reduce substrate accumulation with limited side effects.
Eliglustat tartrate, preclinical studies
========================================
Genz-112638, lately called eliglustat is a synthetic analog of 1-phenyl-2-decanoylamino-3-morpholino-1-propanol formulated as a tartrate salt.[@b27-tcrm-12-053],[@b28-tcrm-12-053] Its inhibitor activity toward GCS was detected in vitro by measuring the cell surface levels of glycolipids, showing high inhibition potency at nanomolar concentrations. Its specificity toward GCS was determined by testing its inhibiting activity on several different enzymes. Of note, even at low micromolar concentrations, the compound did not display an inhibitory action on intestinal disaccharidase activities or lysosomal GCase.[@b29-tcrm-12-053]
The safety and efficacy of eliglustat were first tested in a murine model of GD (gbaD409V/null mouse). Young presymptomatic mice were treated with 75 mg/kg/d or 150 mg/kg/d of Genz-112638, for 10 weeks, and then the measurement of GlcCer in mice tissues evidenced a significant dose-dependent substrate reduction in liver, spleen, and lung tissues and prevention of the Gaucher cell formation, when compared to untreated mice. Moreover, older symptomatic mice were treated with 150 mg/kg/d of the drug for 10 weeks, showing an inhibition of further accumulation of GlcCer, without gastrointestinal issues or other important side effects.[@b29-tcrm-12-053] These important findings paved the way for the following human studies.
Eliglustat tartrate, clinical trials
====================================
Three Phase I trials on eliglustat tartrate, involving 99 healthy volunteers were published in 2011. With regard to safety, the drug was generally well-tolerated at single doses \<20 mg/kg and multiple doses \<200 mg twice daily. However, there was a warning for doses \>10 mg/kg, because mild electrocardiogram modifications (with increase in PR, QRS, and QT/QTc intervals) were observed. Side effects included nausea, dizziness, and vomiting, which were exhibited in increased frequencies with the dosage. Considering pharmacokinetics, maximum plasma concentrations were achieved after 2 hours, with a half-life of around 6 hours. No changes in pharmacokinetics were observed with food ingestion. Notably, higher drug exposure was seen in slower CYP2D6 metabolizers, CYP2D6 being the main hepatic cytochrome involved in eliglustat catabolism.[@b16-tcrm-12-053]
Following these results, a Phase II trial was initiated involving 26 naïve GD1 patients, 20 of whom completed the 2-year assessment and 19 completed the extended study with 4-year evaluation. Patients were treated with a dosage of 50 mg or 100 mg twice a day. After 2 years of treatment, significant improvement in four target parameters (platelet count, hemoglobin levels, spleen volume, and liver volume) was obtained. Considering the therapeutic goals for these four parameters established for ERT by Pastores et al in 2004, 90%--95% of patients met the criteria for hemoglobin, liver, and spleen and 60% patients for platelets.[@b30-tcrm-12-053],[@b31-tcrm-12-053] After 4 years, an improvement was seen, with 100% of the patients meeting the therapeutic goals for hemoglobin level and spleen volume, 94% for liver volume, but only 47% for platelets. This minor therapeutic effect on thrombocytopenia is still unexplained, since there was no correlation with baseline platelet level or splenomegaly. Remarkably, the most evident effect of eliglustat treatment was on spleen size (63% reduction after 4 years). With regard to bone pathology, the mean T-score for the lumbar spine increased after 4 years from the osteopenia range to the normal range, and femur MRI resulted in being stable. Results were also good for GD biomarkers, in fact chitotriosidase levels significantly decreased by 75% and 82% after 2 years and 4 years, respectively. One hundred and ninety-one adverse events were reported after 4 years, of which 74% were considered mild, and 95% were not drug related. Among those considered as being related to treatment, none was classified as serious.[@b32-tcrm-12-053],[@b33-tcrm-12-053]
Subsequently, two Phase III studies[@b34-tcrm-12-053],[@b35-tcrm-12-053] were conducted: the first (called ENGAGE) was a placebo-controlled trial involving 40 naïve GD1 patients in 12 different countries; the second was a noninferiority study (called ENCORE), comparing eliglustat to the standard treatment with imiglucerasi, which involved 160 patients belonging to 39 centers in the four continents. The latter was the largest prospective trial of any treatment for GD1. At the end of the ENGAGE study, after 9 months, comparing the eliglustat group with the placebo group: the mean spleen volume (the primary end-point) decreased by 30.3%, liver volume decreased by 6.64%, Hb level increased by 1.22 g/dL, and platelet count increased by 41.06%, with the largest improvement seen in the most severely affected patients. These results suggested a possible role of eliglustat as first-line treatment for GD1 patients, without prior amelioration of target parameters with ERT. No serious adverse events were reported, the main adverse events in the eliglustat group being arthralgia, nasopharyngitis, and headache. As expected, in the eliglustat group, substrate levels (glucosylceramide and GM3 ganglioside) decreased. Of note, an increase in sphingomyelin levels was detected, probably due to increased bioavailability of ceremide with treatment. However, its levels remained in the normal range.[@b34-tcrm-12-053]
The results of the ENCORE study were recently published, and these demonstrated the noninferiority of eliglustat toward standard ERT (imiglucerase) in maintaining stable hematological parameters and organ volumes, after 1 year of treatment, in patients who had already achieved the therapeutic goals after being on ERT for at least 3 years. The noninferiority margin chosen by design was 25%. Interestingly, 94% of all patients expressed their preference for oral treatment when asked. The number of adverse events reported in the eliglustat cohort was higher than that in the imiglucerase group (656 vs 141), involving, respectively, 92% of patients compared to 79%. The authors explained these differences by the fact that expected adverse events of imiglucerase typically occur in the first year of treatment, and the patients of this study were already on ERT for at least 3 years. The most common side effects deemed related to eliglustat were diarrhea (5% of patients), followed by arthralgia, fatigue, and headache. No significant effect of eliglustat on electrocardiogram was found. Given the results of this study, the authors suggested that eliglustat might be proposed as a maintenance treatment in patients who switched from ERT.[@b35-tcrm-12-053]
Considering the above trials, eliglustat received the US Food and Drug Administration approval in August 2014, and more recently the European Union approval.
Discussion
==========
The advent of the ERT for GD in 1990s changed the natural history of the disease, and this therapeutic approach is still considered as the standard of care for GD. ERT is effective in counteracting the peripheral symptoms, especially hepatosplenomegaly and hematological disturbances, with generally poor side effects. However, ERT has several limitations that prompted the development of new therapeutic strategies. First, ERT must be administered intravenously and, since it cures the symptoms but not the disease, it is required as a lifelong therapy. Regular frequent intravenous infusions for a lifetime can understandably affect patients' quality of life. Second, although ERT is usually well tolerated, some patients develop allergic reactions during infusions, which can contraindicate further treatment, or produce autoantibodies, which can decrease the efficacy of ERT in the long term. Third, it has no effect on central neurological symptoms, especially in type 2 and 3 forms, since the recombinant enzyme is a macromolecule, which is not able to cross the blood--brain barrier.[@b36-tcrm-12-053] Furthermore, long-term complications of GD1, like an increased risk of malignancy, especially multiple myeloma, and association with parkinsonism, are emerging despite the classical therapy.[@b37-tcrm-12-053]
SRT has the main advantage of being administered orally, increasing therefore the patients' quality of life. The first attempt of an SRT for GD with miglustat treatment did not achieve the expected results due to its low benefit--risk profile. The second available SRT, eliglustat tartrate, recently approved by USA and European regulatory agencies, seems to be more promising for GD1 treatment.
There are important structural differences between eliglustat and miglustat: the first resembles the ceramide moiety of glucosylceramide, while the second resembles the glucose moiety and, therefore, is less-specific as a GCS inhibitor. Indeed, its inhibitory activity on different enzymes is considered responsible for its main side effects. The trials on eliglustat showed its effectiveness, both in naïve GD1 patients and in patients who switched over from ERT, in reaching and maintaining the therapeutic goals for visceral symptoms, with good safety. In fact, the reported side effects were generally mild, diarrhea being the most frequent, but was notably less frequent than what was experienced with miglustat (5% vs 80%).[@b26-tcrm-12-053],[@b31-tcrm-12-053],[@b34-tcrm-12-053],[@b35-tcrm-12-053] Nevertheless, concerns exist about the use of eliglustat in patients with heart disease or arrhythmias, since a single dose ≥10 mg/kg (more than five times higher than the suggested therapeutic dose) caused electrocardiogram abnormalities in Phase I studies.[@b16-tcrm-12-053] Although no cardiac events considered related to treatment were reported in clinical studies, it must be taken into account that patients with previously known cardiac diseases were excluded from clinical trials. Of note, both the USA and European Union regulatory bodies prescribing information includes warnings and precautions for eliglustat use in cardiopathic patients. To avoid high blood concentration of the drug, the dosage should be personalized on individual capacity to metabolize eliglustat (predictably analyzing the cytochrome CYP2D6 genotype), and patients who result in poor metabolizers should not be treated with this drug. Moreover, several medicines that can interfere with eliglustat metabolism must be avoided. Further safety concerns due to the poor data available on children and the unknown effects of the drug in the long term will be probably be clarified in the near future.
Besides the advantage of being administered orally, eliglustat may have other positive effects, when compared to ERT. Considering that eliglustat is a diffusible small molecule that can reach different organs and tissues, it has been hypothesized to play a possible role in addressing skeletal, pulmonary, and other systemic manifestations that are refractory to ERT, which selectively targets macrophages.[@b33-tcrm-12-053],[@b35-tcrm-12-053] Eliglustat seems, in fact, to be promising in preventing the development of monoclonal gammopathy and multiple myeloma, with a proven effect on controlling clonal B cell expansion in GD mice; although studies on humans are needed to confirm this potential effect.[@b38-tcrm-12-053]
Since eliglustat does not inhibit glucosylceramidase activity, it is also possible to hypothesize a combined therapy, ERT with SRT, for those cases who do not respond properly to ERT alone or in poorly compliant patients, to try to reduce the frequency of ERT infusions. However, a combined effect has not been studied.
Considering that eliglustat inhibits the first limiting step in the glycosphingolipid biosynthetic pathway, other lysosomal disorders associated with the accumulation of complex glycosphingolipids could benefit from eliglustat treatment. Unfortunately, since it does not cross the blood--brain barrier, its potential effect would be limited in glycosphingolipid disorders, such as Tay Sachs or Sandhoff disease, whose pathology is mainly neurologic. Other analogs of 1-phenyl-2-decanoylamino-3-morpholino-1-propanol, which are able to reach the central nervous system, are under evaluation for these disorders, and could potentially be helpful also for GD2 and GD3.[@b39-tcrm-12-053]
The main limitation for both ERT and SRT is their effect only on the consequence of the disease and not on the disease itself. To completely counteract the disease, other approaches have been tried, such as bone marrow transplantation, or are under study, such as gene therapy or combined gene therapy and stem cell transplantation. Bone marrow transplantation has been performed in severe affected GD patients. However, it requires human leukocyte antigen-matched donors and its correlated morbidity and mortality are still high.[@b40-tcrm-12-053] Gene therapy has the advantage of being a one-off procedure, curing the origin of the disease. Unfortunately, several attempts in the past failed to find safe gene vectors. However, the use of self-inactivating lentiviral vectors carrying the *GBA1* gene under the control of human promoters has recently been successfully experimented with in mice and a study on humans is required to confirm the safety of this approach.[@b41-tcrm-12-053]
Finally, it must be considered that all therapies available for GD until now (both ERT and SRT) are costly and difficult to be performed, and so their availability is limited worldwide.
Conclusion
==========
SRT is an alternative treatment strategy for GD, with the main advantage being that it is administered orally. Eliglustat tartrate seems to be a promising SRT for GD, although its long-term efficacy and safety need to be further defined.
**Disclosure**
The authors report no conflicts of interest in this work.
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Rhinosinusitis and mold as risk factors for asthma symptoms in occupants of a water-damaged building.
Mold exposure in damp buildings is associated with both nasal symptoms and asthma development, but the progression of building-related (BR) rhinosinusitis symptoms to asthma is unstudied. We examined the risk of developing BR-asthma symptoms in relation to prior BR-rhinosinusitis symptoms and microbial exposure among occupants of a damp building. We conducted four cross-sectional health and environmental surveys among occupants of a 20-story water-damaged office building. We defined BR-rhinosinusitis symptom (N=131) and comparison (N=361) groups from participants' first questionnaire responses. We compared the odds for the development of BR-asthma symptoms between these two groups over the subsequent surveys, using logistic regression models adjusted for demographics, smoking, building tenure, and first-survey exposures to fungi, endotoxin, and ergosterol. The BR-rhinosinusitis symptom group had higher odds for developing BR-asthma symptoms [odds ratio (OR)=2.2; 95% confidence interval (CI)=1.3-3.6] in any subsequent survey compared to those without BR-rhinosinusitis symptoms. The BR-rhinosinusitis symptom group with higher fungal exposure within the building had an OR of 7.4 (95% CI=2.8-19.9) for developing BR-asthma symptoms, compared to the lower fungal exposure group without BR-rhinosinusitis symptoms. Our findings suggest that rhinosinusitis associated with occupancy of water-damaged buildings may be a sentinel for increased risk for asthma onset in such buildings. Exposure to mold is associated with the development of asthma in damp building occupants, and rhinitis is known to be a risk factor for asthma. However, there is little information about the degree of risk for the progression of rhinosinusitis to asthma owing to mold exposures in damp buildings. Our study of damp building occupants demonstrates that building-related (BR) rhinosinusitis symptoms were a risk factor for the development of BR asthma symptoms and that exposure to mold (fungi) or other dampness-related agents augments risk for the development of BR asthma symptoms among those with BR rhinosinusitis symptoms. Our findings suggest that occurrence of BR upper respiratory illness in water-damaged buildings may presage future endemic asthma.
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What is True and What is Fiction
I have been bass fishing for 21 years and have read and heard all types of stories about bass and why certain things like slot limits and size limits work and don’t work. I have read and heard arguments on the difference between native bass and Florida bass and how they affect the numbers and size of fish we are catching. Many different anglers have different opinions on many different things and I thought why not go talk to a professional and get his side of things. The professional I’m talking about is not a pro-fisherman but rather a guy who studies fish and their habitat for a living. I set an appointment to interview a Louisiana Wildlife and Fisheries Biologist, Bobby Reed. I called Bobby and told him I wanted to write an article for Ultimate Bass and the interview would consist of questions that the members of Ultimate Bass had for him. Bobby gracefully agreed to do the interview and I will do my best to put his answers and views in this article.
Before I get started with the questions and answers I want to make it clear that I will not quote Bobby word for word and if I don’t express his view points in the way he wanted them expressed I apologize to him now. The one thing I learned as a police officer is reporters will miss quote you in a heart beat, not intentionally of course but it happens, and if I do that in this article I want it understood that these are not direct quotes. Also Bobby used some fancy terminology when he was talking to me and I won’t be using that because one I can’t pronounce most of it and two I wouldn’t be able to come close to spelling any of it correctly, so I will keep it simple.
One of the first questions I asked Bobby was what freshwater bodies of water were affected by hurricanes Katrina and Rita. Bobby told me that there is about a thirty mile stretch North of the Gulf from one end of the state to the next that was affected. He said that bass can live in salt water as long as the levels of salt are not more than 8 parts per 1000 gallons. Now some bass can adapt to higher levels but for the most part that is the equation they use. This thirty mile stretch he spoke of has the salinity way higher than 8 parts per thousand. He also said that all the leaves and sticks that were blown into the water in causing oxygen depletions in many of the bodies of water. These factors are causing fish kills all along this stretch. He told me they went to the Calcasieu River this past week and tried to get some fish samples by shocking them up. Normally they shock up between 20 to 60 bass in a hour on the Calcasieu River. When they did their sample this past week they did not shock up a single fish in the hour they were out there. That should give an idea of the severity of this fish kill. He went on to tell me he believes their will be further fish kills later in the year if we do not get some significant rain this winter.
The next question I had for him was why did the state of Louisiana not have a state wide size limit on bass. He told me that you in order to place a size limit on a body of water you should have one of four conditions. The first condition would be a very slow growth rate. The state Of Louisiana does not have a slow growth rate on bass, in fact most bass will reach maturity, 11 inches, in a year or two. Now when I say they reach maturity I mean they are capable of reproducing. The second reason would be the fish in a particular body of water does not have a good spawn for whatever reason. The third reason is the bass is not the primary predator in the lake . And the forth reason is it’s a new body of water and they are introducing the new stock. They will put a size limit on the new lake to protect the new stock. He told me that marsh bass, which there are lots of marshes in this area, generally only live for about four years and that about 90% of bass in any certain marsh are in the 14 inch size range. He went on to say that a size limit puts a target size for fisherman to start harvesting fish. The problem with this is the fish that reach that size limit are harvested while all the smaller ones are not. The fish that are that target size and are not caught are now forced to compete for forage. What you end with is an over population of small fish and an unhealthy fish population. Remember there are a lot of fish under that size limit that have reached maturity and they will spawn. The target fish are being harvested, the smaller ones are reproducing and the ones that made it to a larger size can’t keep up with eating the smaller ones. This cycle continues and you end up hurting the fishery more than helping it. Think about it, if you ever fished a lake with a size limit on it you generally catch a bunch a fish just under the size limit, a few fish at or just above the size limit and a few bigger ones. Putting a state wide size limit in Louisiana would not help the fisheries.
I had a question from one of the members as to why there were seasons on bass in some of the Northern states. He told me the reason was because the fish up there have a very slow growth rate and it takes them a long time to reach maturity. They need the mature fish to be able to have a successful spawn and keep the population up. In the Southern states the fish grow almost year round but that is not the case in Northern states and they have to have seasons to have a healthy fish population.
I also asked him if slot limits were working in this state and if they weren’t why? He told me the main reason slot limits don’t work on certain bodies of water is because the fisherman don’t keep the small fish. In order for the slot to work anglers need to understand they must keep fish, especially the small ones. He said what has happened is the slot has basically turned into a size limit. Instead of keeping small fish the anglers are throwing them back and keeping the ones that are just over the slot. What has happened is we have made the upper size of the slot a target fish and you fall into the situation I talked about with size limits. Educating anglers and getting them to keep small fish is a task. With the great push for catch and release and the idea that if they throw the small ones back they will grow for the next year is having an opposite affect on slot lakes. He told me if there are people out there that don’t eat bass or just don’t want to mess with cleaning them they need to keep the smaller fish and give them to someone who will utilize them. He also told me they determine to make a lake a slot lake only if the fish can grow out of that slot in a year or two. If the lake is not capable of producing fish that grow that fast they will not make it a slot lake.
I also asked him about vegetation and what they are doing to control it. He told me that they have a big budget for weed control and they use bugs and chemicals to control it. He said due to the hurricanes they will more than likely have a lot more money to control weeds in the Northen portion of the state. The hurricanes have killed a lot of vegetation down south so the need for weed control down here will not be that great. He also told me that spraying the vegetation does not harm the fish.
Another hot topic I wanted to ask him about was Florida Bass and wether or not they are less aggressive than native bass. Here is what he had to say. He told me that Florida bass digest their food a little more proficiently than the native black bass. He got into all kinds of technical terms on this but like I said at the beginning I will keep it simple. Basically a Florida bass gets more out of what it eats than a black bass, therefor he doesn’t need to feed as often. He did say however that when the Florida bass feeds it is more aggressive than the black bass. He also said that a bass does not only feed when it’s hungry. There are three reasons a bass feeds: 1. The obvious, he is hungry. 2. He is in a feeding frenzy. What this means is he is greedy. An example of this would be if there are 5 bass just hanging around and some type of prey comes by one of them will swim out and eat it before another can. It’s not that he is hungry he just doesn’t want anyone else to have it. 3. He acts on reaction. This is where a bait comes by and he just can’t take it he has to have it.
Another thing he discussed with me was the stocking of fish in our fisheries. He said that in many cases stocking fish is not really helpful. Here is the reason for that. A single bass can produce thousands and I mean thousands of fry. If they are stocking lets say 200, 000 finger lings into an impoundment what type of impact do you think that really makes. Really and truly a few fish can do that so the actual need to stock in many places is just not there. Stocking fish in impoundments that have already been established is, from my understanding, just a way to introduce genetics into that impoundment. Now stocking new impoundments is needed just to get things rolling.
Bobby Reed had all kinds of good information and to put it all down would almost be impossible, well at least not with out messing it all up. He changed my views on many things and helped me understand things I never understood. The fact that Bobby is a biologist is not what made me change my mind. It was the way he presented everything to me with great detail and explanation. I gave him the address to the website and I asked him if he would come give a seminar at the UBCS. He said he would come to the UBCS if he did not have anything conflicting on his schedule.
In closing I would encourage you to go to you local fish biologist and ask him the questions that concern you. They are an untapped resource who are available to all anglers. Instead of believing everything you read in magazine articles written by people who think they know what going on go straight to the source. These guys study fish and their habitat for a living. I hope that some of your questions were answered and that you learned a little something, but don’t take my word for it go and do some research on your own . You may be surprised at some of the answers you will find.
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Whose nipple do I have to suck to get a nipple to suck
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:Fuck You Github!
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OPM (album)
OPM is the first ever compilation album by Filipino singer Sarah Geronimo, released on December 22, 2008 in the Philippines by VIVA Records. It consists of OPM songs that she has released, may it be a single, an album track or a soundtrack. In 2010, it has been certified Platinum by the Philippine Association of the Record Industry, selling 25,000 copies in the country.
Track listing
Personnel
Credits were taken from Titik Pilipino.
ACNE (at Homme et Femme) - black dress
Paul Basinillo - creative director
Grace Castaneda - creative team, digital imaging
Comme De Garcon - black and white dress
Vic Del Rosario, Jr. - executive producer
Vincent Del Rosario - executive producer
Denim, Inc. - album concept and design, creative team
Dittle - creative team, illustrations
Sarah Geronimo - lead vocals
Baby A. Gil - supervising producer
Guia Gil-Ferrer - associate producer
Mia Marigomen - creative team
Joel Mendoza - recording, mixing and mastering
Joy Mongado - creative team, digital imaging
MG O. Mozo - A&R direction
Tony Ocampo - executive producer
Eric Pe Benito - styling
Ronnie Salvacion - photography
Cary Santiago - black and white gown
Juan Sarte - hair and make-up
Certifications
References
Category:Sarah Geronimo albums
Category:2008 compilation albums
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The Boston Celtics organization received awful news today when it was announced that starting point guard Rajon Rondo would miss the rest of this season with a torn ACL. This is just a killer injury for a team that relies so much on their starting point guard. Rondo makes getting a triple double look so easy and the team does not have a backup point guard on the roster. Rondo hopes to heal quickly as it is no guarantee that he will be ready for the start of next year either. He injured the leg during the team’s Friday night loss to the Atlanta Hawks in double overtime. Recent video footage has been leaked that shows him possibly suffering the injury during the second overtime.
What does the team do now to solve its current point guard problem? If they keep the same roster for the rest of the year, it appears that Courtney Lee would take Rondo’s place in the starting lineup, sharing ball-handling duties with Avery Bradley. This is obviously not the situation the Celtics would prefer, but they have no choice. When Jason Terry enters the game off the bench, he will also shoulder some of the load. As you can see, there are not a lot of great options at head coach Doc Rivers’ disposal. Paul Pierce will obviously have to continue the majority of the team’s scoring output on the offensive end. Teams will focus more on him now knowing that the Lee-Bradley backcourt lacks scoring potency.
Life without Rondo is certainly not a positive scenario for the Celtics and it will be quite some time until we see him wearing a Celtics uniform again.
Rob Lunder covers the Boston Celtics for Rant Sports. For all Celtics news go to the team homepage on Rant Sports. Follow him on Twitter @rlunder18
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Introduction {#S1}
============
Toward the end of the last millennium, Francisco Varela, the Chilean biologist, philosopher, and neuroscientist, put forth an ambitious proposal, the neurophenomenological research program (NRP). The NRP attempts at paving a methodological path for bridging the 'explanatory gap' in our understanding of how to integrate first-person (1P) phenomenological and third-person (3P) physiological features of the mind. Instead of ineffective attempts to close the conceptual gap between subjective experience and physical matter, also referred to as the 'Hard Problem of Consciousness' ([@B39]), the NRP suggests reframing the gap. To this end, it defines a methodological strategy for integrating phenomenological and neurobiological accounts under one research program, or in Varela's words, for creating "meaningful bridges between two irreducible phenomenal domains" ([@B182], p. 330). The NRP has been described as "a quest to marry modern cognitive science and a disciplined approach to human experience" (Ibid. p. 340) and it is this harmonious relationship which we pursue.
With more than two decades since its introduction, numerous theoretical studies have illuminated the importance, ingenuity and potential of the NRP, yet not as many have succeeded in actually implementing it as an empirical methodology (for a short review see [Tables 1](#T1){ref-type="table"}, [2](#T2){ref-type="table"}; for other reviews, see [@B115]; [@B15]; [@B172]; [@B109], [@B110]; [@B26]; [@B36]; [@B7]; [@B18]). Clearly, NRP's strong philosophical appeal is merely the grounds from which a scientific paradigm may grow and mature to address the highly ambitious and demanding challenge at stake -- "an open-ended quest for resonant passages between human experience and cognitive science" ([@B182], p. 346). If the challenge is to be met on Varela's terms, it can only be done based on rigorous empirical practice. It is the goal of this paper to support those who wish to embark on this journey and implement the NRP by highlighting some of the important lessons learnt in neurophenomenological studies done in recent years, including our own.
######
A list of papers relating to neurophenomenology (NP) on the theoretical level.
Theoretical perspectives Papers
--------------------------------------------------------------------- ------------------------------------------------------
What is NP [@B182]; [@B108], [@B110]; [@B115]; [@B152]; [@B171]
'Front-loading' phenomenology into experimental design [@B72]
Neurofeedback useful for NP [@B13]
Hypnosis useful for NP [@B106]
Astronaut simulation and challenges of NP [@B36]
Dreams and challenges of NP [@B164]
Kantian perspective on NP [@B96]
NP in the context of in dyadic movement [@B170]
Application of NP in affective neuroscience [@B43]
NP usefulness in psychology [@B78]
NP usefulness in ECoG [@B136]
NP justification in practice [@B169]
Philosophical attack and justification [@B29]; [@B99]
Advantage of training scientists in contemplation [@B53]
NP applied to time consciousness [@B183]
NP usefulness in pain [@B146]
Combining descriptive experience sampling with 3P [@B86]
Combining 2P methods [@B65]; [@B130]
Philosophical roots of NP and enaction [@B190]
An externalist extension of NP [@B16]
Adding a cardiac-affective dimension to NP [@B50]
Distinguishing mild vs. radical NP [@B135]
The feasibility of NP [@B7]
Neurofeedback useful for NP [@B25]
NP usefulness to understand trauma [@B11]
Application of NP to microdreams [@B125]
Phenomenological matrix of mindfulness [@B112]
Phenomenologically constrained neurocomputational model of the self [@B192]
Brain dynamics from the perspective of NP [@B60]
NP of surprise [@B28]
Neuroscience and inner experience [@B145]
######
A list of papers employing neurophenomenological empirical paradigms.
1P/2P 3P Papers
---------------------------------------------------- ----------------- --------------------------------
Attentional state EEG [@B113]
Behavior [@B180]; [@B197]
Epilepsy EEG [@B103]; [@B141], [@B137]
Sense-of-self (time/space/boundary/identification) MEG [@B19]; [@B56]; [@B10]; [@B57]
fMRI [@B74]
Hypnosis EEG [@B38]
Astronaut simulation EEG/fNIRS [@B150]
Mind-wandering fMRI [@B42]; [@B3]
Emotion fMRI [@B127]
Yoga/attention/emotion HRV [@B116]
Neuro inspires pheno [@B45]; [@B178]
Resting state fMRI/EEG [@B54]
Intention to act EEG [@B80]; [@B95], [@B94]
Dreaming PET/fMRI [@B61]
Memory HRV/GSR [@B117]
Pain under hypnosis PET [@B148]
Language/auditory processing fMRI [@B102]; [@B87]
Descriptive experience sampling Verbal behavior [@B89]
Approach-avoidance Behavior [@B14]
Surprise in depression ECG [@B51]
Meditative state Behavior [@B1]
Psychedelic state EEG [@B174]
EEG, electroencephalography; MEG, magnetoencephalography; fMRI, functional magnetic resonance imaging; HRV, heart rate variability; PET, positron emission tomography; GSR, galvanic skin response; fNIRS, functional near-infrared spectroscopy
.
In the first part of the paper, we present Varela's NRP while specifically focusing on various issues regarding the execution of an empirical phenomenological investigation. We point toward an inherent tension within the NRP concerning the challenge of naturalization in the face of the complexity and intricacy of 1P data. In this regard, we offer a diverse typology of bridges which exemplifies the concept of 'mutual constraints,' and argue for the need to gradually and interchangeably weave them through the developmental stages of an evolving research program.
The second part of this paper demonstrates our own decade-long implementation of the NRP focused on breaking new ground in the scientific understanding of self consciousness, with particular interest in alterations in the sense of embodied self and the minimal self in meditative experience. We found it helpful to repeatedly circulate between different forms of phenomenological inquiry and a variety of cognitive and neuroscientific tools, and argue that it is the ongoing development of a dialogue between these two perspectives that enables novel insights. We close the paper by presenting our current aims of advancing the understanding of self consciousness by employing an ongoing mature and pragmatic neurophenomenological study of the sense of self boundaries and their dissolution.
Varela's Neurophenomenological Research Project (NRP) {#S2}
=====================================================
The Archimedean point of the NRP is acknowledging the irreducible nature of conscious experience: "Lived experience is where we start from and where all must link back to, like a guiding thread" ([@B182], p. 334). Stemming from the phenomenological tradition (see [Supplementary Appendix 1](#SM1){ref-type="supplementary-material"} for an outline of its historical roots), this notion has far-reaching implications for how we conceptualize nature and our place as embodied cognitive agents within it. It reminds us of the ineradicability of our own standpoint as humans (or cognitive scientists) and motivates a search for an understanding of the co-determination of mind and world as a middle way between the dead-ends of realism or idealism ([@B185]). Theoretically, this aim is pursued within the enactive approach, which is increasingly becoming a stronghold in cognitive science driving manifold research agendas (see [@B167]; [@B190] and [@B124] for overviews). Given their common theoretical starting point, neurophenomenology can be considered as a promising methodology of enactivism ([@B190]). It seeks to provide a pragmatic methodological framework in which cognitive neuroscience can rigorously integrate a disciplined examination of conscious experience. This notion stresses the necessity of acquiring refined and reliable 1P descriptions in order to advance toward "a model that can account for both the phenomenology and neurobiology of consciousness in an integrated and coherent way" ([@B172], p. 87). The emphasis here is on forming constant circulation and dialogue between these two domains of inquiry which would allow an exploration of "the bridges, challenges, insights and contradictions between them" ([@B182], p. 343).
Inspired by the phenomenological tradition, the call for a systematic exploration of lived experience put forward by the NRP has received considerable attention in recent years. In essence, such exploration is grounded in a set of practices that generally allow subjects to increase their sensitivity to their moment to moment experience ([@B186]; [@B142]). Stemming from Edmund Husserl's concepts of the phenomenological reduction and the epoché ([@B90]; [@B27]; for elaboration, see [Supplementary Appendix 1](#SM1){ref-type="supplementary-material"}), there are currently various first person (1P) and second person (2P)^[1](#footnote1){ref-type="fn"}^ methods that promote a shift in attitude from the natural theory-laden absorption with the contents of one's experience, to an awareness of the various affective, attentional and structural features of experience (discussed further in section "Investigating Lived Experience -- From Thin to Thick Phenomenology"). In other words, instead of focusing on the 'what,' subjects are encouraged to bracket assumptions and presuppositions *about* their experience and become aware of the 'how' of experience, that is, the subjective mode of appearance and the dynamic intentional acts involved in the flow of experience ([@B134]; [@B27]). This dimension of experience is often termed by phenomenologists as pre-reflective awareness pointing toward the tacit, direct and non-inferential awareness of one's experience as it is lived through, prior to any second-order reflection *on* experience ([@B123]; [@B118]; [@B194]).
1P accounts have a vital role to play, along neuroscience and physiology, in beginning to bridge the explanatory gap *a la* Varela. The working hypothesis of the NRP is that "phenomenological accounts of the structure of experience and their counterparts in cognitive science relate to each other through reciprocal constraints" ([@B182], p. 343). It is this type of circulation between the two perspectives which is at the focus of this paper and is described in more detail in Section "Building Bridges Between Phenomenology and Physiology -- Mutual Constraints." By reciprocal constraints Varela means both using neuroscientific accounts to illuminate previously unnoticed aspects of mental experience, and on the other hand, guiding the empirical questions, analysis and interpretation of neurobiological findings in light of the phenomenal invariants of the mental experience. 1P data generated from the phenomenology of mental processes "can provide additional, valid information about externally uncontrollable aspects of mental activity, and this information can be used to detect significant patterns of dynamic activity at the neural level" ([@B172], pp. 45--46). Thus on a methodological level, the NRP suggests explicitly and rigorously incorporating phenomenological investigation into experimental setup and design.
Investigating Lived Experience -- From Thin to Thick Phenomenology {#S2.SS1}
------------------------------------------------------------------
The question of the importance, validity and place of the investigation of lived experience within science has seen many diverse conceptualizations throughout history. It is obviously beyond the scope of this paper to address the often-encountered notion (in cognitive neuroscience circles in particular) that subjective experience cannot be fully studied using the scientific method (but see [@B186]; [@B52]; [@B65]; [@B130]; [@B100]). The aim of this section is to briefly present the state of the art in the developing field of 1P research, highlighting the demands, obstacles and practical implications imposed on neurophenomenological studies. We then present the concepts of 'thin' and 'thick' phenomenology as an organizational tool for the different levels of depth which specify 1P data in the context of the NRP.
As lived experience is a constantly changing, multi-layered and highly complex flux, its exploration is challenging. It requires employing a certain mental gesture of reflection toward one's own experience that differs considerably from casual 'introspection.' Though formulated in various ways, it is often argued by 1P researchers that "becoming aware of lived experience is a skill that can and should be learned and practiced" ([@B65], p. 254). Indeed, a rather demanding element in Varela's radical vision is that cognitive science students interested in mental experience "must inescapably attain a level of mastery in phenomenological examination" through sustained training ([@B182], p. 347). While such training may intuitively seem valuable to researchers' own understanding of the phenomena they are investigating ([@B92]; [@B73]), in the context of experimental neurophenomenological studies this effort is often centered on the rigorous acquisition of reliable 1P data from study participants. One suggested way to acquire such data is by using phenomenologically trained subjects (discussed in section "Cooperation With Meditators As Skilled Participants"), while another is based on interview techniques collectively known as second-person (2P) methods. Thus, first and second -person methods serve as supports for the examination of lived experience. 1P methods cultivate the capacity for sustained awareness, helping subjects gain access to aspects of their experience that are lived through but mostly remain unnoticed ([@B134]; [@B65]); while the disciplined nature of 2P methodologies enables the systematic gathering of reliable phenomenological reports which can then be incorporated in various ways into neuroscientific research (elaborated in the following sections).
Recently, several interview techniques designed for detailed and careful description of subjective experience have been developed (for an overview, see [@B65]; [@B130]). Mediated by the guidance of a skillful interviewer, they allow "a person, who may not even have been trained, to become aware of his or her subjective experience, and describe it with great precision" ([@B134], p. 334). Two notable 2P methods, Micro-phenomenology ([@B134]; also known as 'Elicitation Interview,' [@B187]) and Descriptive Experience Sampling ('DES,' [@B85]), are based on retrospective examination of past experiences framed and guided by an empathetically tuned phenomenological investigator. In the context of neurophenomenology, these methods systematize the phenomenological research procedure, thus serving as valuable tools for performative coherence and scientific rigor. While the issue of validity of such procedures remains widely contentious ([@B48]; [@B158]), progress has been made in recent years in cultivating pragmatics that help reduce the influence of bias, increase authenticity and evaluate reliability ([@B134]; [@B130]; [@B101]; [@B138]; [@B179]). Following other scientific domains, data obtained through phenomenological inquiry is not taken at face value as infallible but examined, interpreted, analyzed for invariant structures and generalized in various ways. Eventually, the status of 1P accounts is not determined by their facticity, but evaluated through procedural standardization, potential replication of its findings and intersubjective validation with other first, second and third -person methods. As Varela suggests:
> "The usual opposition of first-person vs. third-person accounts is misleading. It makes us forget that so-called third-person, objective accounts are done by a community of concrete people who are embodied in their social and natural world as much as first-person accounts \[...\]. The line of separation --- between rigor and lack of it --- is not to be drawn between first and third person accounts, but determined rather by whether there is a clear methodological ground leading to a communal validation and shared knowledge" ([@B182], p. 340).
It is this methodological ground which we aim to advance. As practitioners of integrated 1P and 3P research, we have gained some experience in the pragmatics of neurophenomenology. Thus, we are far from naively suggesting that 1P methods can be added into neuroscience without reflection, but rather hope to further illuminate some practical considerations that address inherent challenges.
Embracing the pragmatic spirit of the NRP, we suggest framing the diversity of possible forms of 1P data on a continuum of complexity ([Figure 1](#F1){ref-type="fig"}). On one pole there is data obtained through in-depth phenomenological interview methods ([@B30]; [@B140], [@B139]; [@B131]) characterized by highly refined, detailed and dynamic accounts of singular subjective experiences (such as data gathered through micro-phenomenology). We call this thick phenomenology, to denote the high complexity of 1P data. On the other pole are thin methods (e.g., self-reports and questionnaires), acquiring data which provides information relevant to subjective experience, but limited due to its reductive nature (using pre-defined rigid phenomenal invariants) which also makes it prone to biases ([@B144]; [@B88]). We call it thin, to denote the low level of complexity of this kind of 1P data. In between these two poles, various methods can be placed, for example structured interviews and Descriptive Experience Sampling (DES, [@B85])^[2](#footnote2){ref-type="fn"}^.
{#F1}
The continuum directly relates to the possibility of naturalizing subjective experience, which in this specific respect refers to the prospect of integrating 1P account within an experimental neuroscientific setup^[3](#footnote3){ref-type="fn"}^. At the thinner end of the continuum, data can be acquired rapidly, repeatedly and uniformly, facilitating intersubjective and cross-situational generalization. This is often relevant for its integration with neural measures because these typically require a larger number of sampled timepoints and individuals in order to yield reliable results. Furthermore, thin 1P data is easier to formalize and often quantifiable and thus more suitable for guidance of 3P data analysis, as well as easier accessible for scientific dialogue and cross-validation. Conversely, it is often limiting, unreliable and tainted by artifacts as it fails to address the multi-layered intricacy and dynamics of lived experience and to bracket assumptions and presuppositions of respondents ([@B88]; [@B31]).
Thicker methods of investigation result in much more refined accounts of experience, potentially amounting to more authentic descriptions of experience sensitive to its multi-dimensional and diachronic nature. Their skillful execution, analysis and formalization are thus far more cumbersome and require meticulous effort. They are, on the one hand, less accessible for generalization and quantification, but on the other hand, their high resolution may permit the bridging of experiential and neural microdynamics (as proposed by [@B136]). Refined accounts of experience are also more receptive to novel insights which can guide future research. Overall, the naturalization of these methods through efficient integration within an experimental setup remains a challenging endeavor.
Rather than advocating the use of one method over the other, we suggest that this methodological trade-off is essential to the open-ended circulation envisioned by the NRP. As elaborated in the next section, we found it helpful in our own studies to alternate between different methods depending on factors regarding the available neuroscientific and phenomenological resources, as well as considering the current level of understanding of the studied phenomena. Such an integrative mixed-methods approach is useful in the triangulation of acquired data, and enjoys the advantage of using precise techniques that access specific and distinct dimensions of lived experience (further discussed in section "Building Bridges Between Phenomenology and Physiology -- Mutual Constraints").
Cooperation With Meditators as Skilled Participants {#S2.SS2}
---------------------------------------------------
As 1P data is fundamental for the NRP, scientific cooperation with "phenomenologically trained subjects" has been suggested to be useful ([@B172], p. 45). While such training is effortful and time-consuming, senior meditation practitioners have been proposed by several authors as pre-trained subjects suitable for such inquiry, based on the similarity between the epoché and certain meditative techniques ([@B185]; [@B186]; [@B52]; [@B27]; [@B49]; [@B101]; [@B189]). For example, [@B27] argues that the common characterization of mindfulness, "namely as concentrating on the present moment and staying non-judgmental, captures a fundamental feature of the epochè: not only the suspension of elaborate judgments, but even before that, the suspension of the semantic function of both mental and verbal activities, that tends to expel us from our present." (Ibid., p. 136). Similarly, Varela suggested that certain forms of meditation from the Buddhist tradition can be conceived of as epoché:
> The exercise of samatha, best translated as mindfulness meditation practice, is based on an examination of the nature of our mind, (and hence of the origin of habitual patterns) by paying meticulous attention to every moment of appearance. In other words, using the activity of mind to go beyond mind, looking at the givenness of experience with a fresh, inquiring glance ([@B184], p. 5).
In addition to the cultivation of the ability to suspend judgments and maintain a fresh conceptual-free perspective, other potential assets trained meditators bring to phenomenology are the ability to volitionally reproduce specific features of experience as cultivated in a given meditative practice ([@B108]; [@B111]; [@B53]), as well as the ability to stay with the experience being studied, i.e., reduce getting 'lost in thought' and mind-wandering as is typical in untrained subjects ([@B121]).
While a number of authors have claimed that the cultivation of mindfulness improves the quality of introspection, it has not yet been sufficiently empirically established, yet some supportive evidence is available. For example, meditative practice was shown to correlate with the predictive accuracy of self-reports regarding behavior ([@B1]), neuroanatomy ([@B62]) and peripheral physiology ([@B133]). The latter was also confirmed in a recent meta-analysis indicating a small but statistically significant positive relationship between mindfulness and objective measures of body awareness ([@B176]). This issue is still a matter of debate due to the complexity of its assessment.
It is important to mention that alongside substantial benefits, there are also concerns and drawbacks of harnessing qualified meditators as "phenomenologically trained subjects." First, it might be hard for some meditators to examine their experience beyond the elements prescribed by their practice school, or to let go of the conceptualizations of their respective traditions ([@B101]). Second, the goal of the observation is different: while Buddhist practices aim at alleviating human suffering, the central motivation of phenomenology is knowledge ([@B27]). Thus, in the long-term it might be beneficial for science to establish its own paradigms of contemplative (phenomenological) training as envisioned by Varela.
With this in mind, cooperation with meditators has proved to be useful for the NRP not only for their alleged familiarity with the phenomenological attitude, but also for their enhanced sensitivity to subtle aspects of their experience (see [@B95]), as well as their capacity to volitionally control and stably maintain specific conscious (and neural) states (for some empirical evidence, see [@B74], [@B75]). This last ability increases the signal-to-noise ratio and renders these features scientifically tractable. It is the combination of these elements borne by meditative practice that supports the scientific exploration of subtle aspects of consciousness as exhibited in our own research and that of others ([@B19]; [@B56], [@B57]; [@B197]; [@B95]; [@B10]; [@B112]; [@B1]).
Building Bridges Between Phenomenology and Physiology -- Mutual Constraints {#S2.SS3}
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The working hypothesis of neurophenomenology is that phenomenological accounts of the structure of experience and their counterparts in cognitive science relate to each other through reciprocal constraints. According to [@B182]:
> It is quite easy to see how scientific accounts illuminate mental experience, but the reciprocal direction, from experience toward science, is what is typically ignored. What do phenomenological accounts provide? At least two main aspects of the larger picture. First, without them the firsthand quality of experience vanishes, or it becomes a mysterious riddle. Second, structural accounts provide constraints on empirical observations (p. 343).
There are different ways to create bridges between the two irreducible phenomenal domains of experience and physiology. In this section, we offer a typology of previously proposed bridges, give an example to each of them, and schematically illustrate their directionality in [Figure 2](#F2){ref-type="fig"}.
{#F2}
### Bridge A: Front-Loading Phenomenological Insights Into Experimental Design {#S2.SS3.SSS1}
[@B67] and [@B72] suggested as a bridge between phenomenology and physiology the 'front-loading' of phenomenological insights onto experimental design. In other words, to design experiments informed by phenomenological insights -- developed in independently conducted phenomenological analyses, or from previous neurophenomenological experiments. Such an approach was successfully implemented in a series of neuroimaging studies on ownership and agency (e.g., [@B40]; [@B59]), which relied on previously generated phenomenological insights ([@B66]), rather than implementing 1P measures in the studies themselves (detailed in [@B72]). Additionally, the researcher's direct access to his own lived experience inevitably influences the design and interpretation of the results. Rather than sweeping it under the carpet, such influences are here acknowledged, reflected upon and refined so that they could enhance the quality of the research^[4](#footnote4){ref-type="fn"}^ ([@B92], [@B73]). In [Figure 2](#F2){ref-type="fig"}, 'front-loading' phenomenological insights onto experimental design is illustrated as an arrow from 1P to 3P, signifying the use of 1P to design 3P studies.
### Bridge B: Phenomenological Validation of Neurobiological Accounts {#S2.SS3.SSS2}
[@B182] proposed that disciplined 1P accounts ought to play be an integral element in the validation of a neurobiological proposal, i.e., that any attempt to scientifically explain mind and consciousness must directly relate to the nature of our lived experience ([@B182], pp. 344--345). An adequate theoretical framework is thus needed to characterize neurophysiology in suitable terms that can also address the essential structure and dynamics of experience (further explored in bridge e). Such an approach proved highly productive in the important works of Petitmengin, Navarro, and Le Van Quyen concerning seizure anticipation ([@B103]; [@B141], [@B137]). Since 1975, researchers have used EEG analysis for the prediction of seizures, including a preictal state, which is detectable a few seconds before the actual seizure onset on EEG. The group's EEG work showed that seizures do not arise suddenly, but as a transition from the interictal to the ictal state. It also showed that seizures do not correspond to deficient functioning of localized brain areas, but rather to deficient functioning of neural networks. However, the authors write, "the synchrony analysis does not tell us anything about the way this transition and this deficit are (or are not) felt by the patient. It indicates the structure of the cerebral activity, not the nature of the subjective experience that could correspond to it." ([@B137], p. 750). Indeed, a phenomenological investigation showed that all nine investigated patients experienced auras (ictal phenomena), while six experienced prodromes (preictal phenomena). Studying the phenomenological dynamics showed that seizures are preceded by (often pre-reflective) symptoms. In [Figure 2](#F2){ref-type="fig"}, phenomenological validation of neurobiological accounts is illustrated as an arrow from 1P to 3P, signifying the use of 1P to enhance insight into 3P.
### Bridge C: Joint Analyses of 1P and 3P Person Data {#S2.SS3.SSS3}
[@B108] emphasized joint analyses of 1P and 3P data, which actually means that phenomenal reports guide the analysis of the neuroscientific data^[5](#footnote5){ref-type="fn"}^. The utility of this approach was illustrated in the seminal work of [@B108] and [@B113], which received much discussion ([@B92]; [@B67]; [@B15]; [@B132]). In this study, subjects were trained to recognize stable categories of experience ('phenomenal invariants'), which related to their state of 'preparedness' for the onset of simple visual stimuli presentation. Reports were then grouped into 'phenomenological clusters.' The results provide an outstanding example of the tailored use of 1P data, as the 'phenomenological clusters' were shown to reflect variability in neuronal response which otherwise would have been considered as noise. For example, only one cluster (when subjects reported "steady readiness" to the stimuli, in contrast to either "fragmented readiness" or "spontaneous un-readiness") correlated with high gamma band EEG synchronization over frontal electrodes before stimulation. Importantly, EEG synchronization and behavioral measures of reaction time both correlated with the subjective reports. In [Figure 2](#F2){ref-type="fig"}, joint analyses of 1P and 3P data is illustrated by a double-headed arrow connecting 1P and 3P, signifying the mutual use of both domains: grouping 3P for analysis according to 1P categories determined within the same experiment (or the other way around).
### Bridge D: Using Physiological Data to Guide Investigation of Subjective Experience {#S2.SS3.SSS4}
A meaningful bridge could be constraining and guiding 1P data via the physiology itself. An illuminating demonstration of such an approach is the fMRI-neurofeedback study by [@B74] and [@B181]. This study assessed how the 1P experience of meditation relates to neural activity in a core region of the default mode network -- the posterior cingulate cortex. Activity in this region was measured and displayed on a screen in real-time, enabling participants to realize how their experience related to changes in the graph. The researchers then analyzed 1P data consisting of meditators' accounts of their subjective experience during runs of a real time fMRI neurofeedback, and 3P data consisting of corresponding PCC activity during the same runs. The results showed that for meditators, subjective experiences corresponding with PCC deactivation related to "undistracted and effortless awareness," while the subjective experiences of "distracted and effortful awareness" corresponded with PCC activation. In [Figure 2](#F2){ref-type="fig"}, using 3P data to guide 1P is illustrated as an arrow from 3P to 1P, signifying the use of 3P to constrain and study 1P data.
### Bridge E: Re-analyzing the 1P According to the 1P-Enriched 3P Analyses {#S2.SS3.SSS5}
Another way of creating meaningful bridges between 1P and 3P data is implementing iterative processes, i.e., re-analyzing the 1P according to the 1P-enriched 3P analyses ([@B108]). This is actually the 3rd stage of the formal NRP as proposed by Varela, and hence represents a maturation of one's project. To the best of our knowledge, the only work which implemented this approach is described by [@B137] as a "neuro-phenomenological circulation process." In this work focusing on seizure anticipation (detailed in bridge b), the discovery of a new neuro-dynamic structure (the preictal neuro-electric desynchronization) permitted a refinement of the corresponding experiential dynamics (preictal phenomenological symptoms and therapeutic countermeasures). In [Figure 2](#F2){ref-type="fig"}, re-analyzing the 1P according to the 1P-enriched 3P analyses is illustrated by a double-headed arrow connecting 1P and 3P, signifying the iterative dynamic process connecting the two irreducible phenomena.
### Bridge F: Mathematical or Cognitive Modeling {#S2.SS3.SSS6}
The two irreducible domains have been suggested to be bridged by developing formal mathematical or cognitive models with variables that can refer to either phenomenal or neurophysiological states, an approach previously referred to as "generative passage" ([@B108]). As a general approach to the study of consciousness, this notion has been gaining traction in contemporary theories of consciousness, notably the Integrated Information Theory ([@B129]; [@B175]). Other promising theoretical developments build on the free energy principle ([@B63]; [@B64]), offering ways of specifying formal computational models of the autopoietic, embodied and enactive mind ([@B2]; [@B37]; [@B98]; [@B149]). The concept of predictive processing is here transformed into "predictive engagement" ([@B71]), and proposals of how core predictive processing dynamics relate to (pre-reflective) aspects of experience have been put forth (e.g., [@B161]; [@B4]; [@B58]; [@B114]), calling for rigorous neurophenomenological evaluation. An exceptional project, which puts into practice this approach, is the Projective Consciousness Model (PCM), a mathematical model of embodied consciousness, which is based on the hypothesis that the spatial field of consciousness is structured by a projective geometry and controlled by active inference processes ([@B151]). While still under development, the PCM helps to account for aspects of subjective character including pre-reflective self consciousness, the 1P point of view, the sense of ownership, and social self consciousness ([@B192]), hence providing a mathematical model tying together phenomenological and neural levels of descriptions. In [Figure 2](#F2){ref-type="fig"}, Mathematical or cognitive models are illustrated by a double-end inflated arrow connecting 1P and 3P, signifying the need for formal language to connect the two irreducible domains.
Let us close the first part of the paper by suggesting to cease looking for one meaningful bridge between neuronal activity and subjective experience, and rather aim for multiple and diverse feasible bridges. Accordingly, we believe that it is a mistake to think about the NRP as one experiment in which the researcher should choose one of the phenomenological attitudes (thin vs. thick). A fruitful dialogue between 1P and 3P is created by using different kinds of methods on the proposed continuum, at different developmental stages of the NRP, aiming at different insights -- each of which can be re-integrated to inform other stages.
One can start a neurophenomenological investigation by implementing the bridge of front-loading (preliminary) phenomenal insights into the NRP study design (bridge a). While executing the study, the phenomenological thickness applied can be guided by various factors such as the number of subjects and available experimental resources, the quality and specificity of the studied phenomenon (in terms of availability and temporal dynamics), the adequacy of available questionnaires and other behavioral measures. Likewise, it is fruitful to use a variety of experimental technologies, as different technologies are useful for different bridges. For example, electrophysiological complexity measures can be suited for comparison with thick phenomenological data and phenomenal validation of neurobiological data (bridge b); specific cognitive tasks might be best suited for measuring underlying mechanisms of specific aspects of experience which can then be analyzed jointly with 1P data (bridge c); neurofeedback is best suited for using physiological data to guide subjective experience (bridge d); and mathematical modeling is highly suitable for creating cognitive models (bridge f). Importantly, bridge e requires a mature NRP, with iterative experiments, and is thus rarely implemented (but is demonstrated in or studies, as detailed subsequently).
In the second part of the paper, we will show how creating a variety of bridges improved our understanding of both the phenomenological side, as well as the neural side, of the embodied self phenomenon we were studying. Yet more importantly, none of these neural or phenomenological aspects by themselves could have led to our current understanding of the embodied, minimal self. The gained insight was a result of re-analyzing 1P data according to the 1P-enriched 3P analyses, representing the maturation of the NRP.
Some Lessons From Our Journey With NRP: Studying Self-Dissolution {#S3}
=================================================================
In this section, we lay out a series of studies, demonstrating how harnessing neurophenomenology can advance the study of self consciousness. This direction of inquiry goes back to Varela, Thompson and Rosch's seminal work, The Embodied Mind:
> We believe that mindful awareness practices can provide a natural bridge between cognitive science and human experience (phenomenology). Particularly impressive to us is the convergence that we have discovered among the main themes concerning the self and the relation between subject and object ([@B185]; The Embodied Mind, p. 33).
We start with a brief review of the field of self consciousness, including basic phenomenological conceptualizations of types of self consciousness, related cognitive and neural counterparts, and methods of scientific inquiry. This is meant to provide a broad context for our series of studies, highlighting their contribution to the readers who are less familiar with this field (while others can skip to the next section).
Studying Self Consciousness {#S3.SS1}
---------------------------
An increasing number of publications in philosophy, psychology and neuroscience investigate "self consciousness" -- or the "sense of self," referring here to subjects' consciousness of themselves. The concept of self is highly ambiguous and includes various aspects, thus it may be best construed as a multidimensional construct including somatosensory, agentive, narrative and social components ([@B66]; [@B168]; [@B68], [@B70]), involving various brain regions ([@B41]; [@B188]; [@B128]). As part of a dialogue between philosophy of mind and cognitive neuroscience, a fruitful distinction has been made between two types of processes contributing to the sense of self: self-related and self-specific processing ([@B104]; [@B41]). The first, self-related processing, attributes or evaluates stimuli with respect to one's perceptual image or mental concept of oneself, giving rise to an enduring sense of identity (such as when contemplating one's own personality, traits, memories or appearance). The second, self-specific processing, specifies the self as an embodied subjective knower and agent. Self-specific features are defined as being exclusive and non-contingent, meaning that they characterize oneself and no-one else, and that changing or losing them entails changing or losing the distinction between 'self' and 'non-self.' Thus, self-specific processes are considered more primal as they implement a functional self/non-self, or self-world distinction in perception, action, cognition, and emotion ([@B41]; [@B160]). This distinction overlaps with previous differentiations in the literature, such as the 'Me' as opposed to the 'I' ([@B93]), 'extended' vs. 'core' self ([@B44]), and 'narrative' vs. 'minimal' self, respectively ([@B66]; [@B73]).
Self-related processes have received the bulk of empirical attention, given that they can be easily manipulated in the lab through cognitive tasks. Neural activations during those tasks overlap strongly with the default-mode network (DMN, [@B147]), a large-scale intrinsic network which is highly active at rest (as compared to externally focused goal-directed tasks) as well as during internally focused cognition including self-reflection, episodic memory, future planning, theory of mind, and personal moral reasoning ([@B81]; [@B147]; [@B128]; [@B166]; [@B122]).
Studies of self-specific processing and the minimal self, on the other hand, are less common. Of particular relevance are studies on the neural basis of the senses of agency and ownership ([@B91]), the subjective experience of owning and being in control of one's body and thoughts ([@B47]; [@B91]; [@B165]; [@B84]), as well as the sense of being localized within one's physical body ([@B33]; [@B177]). Cleverly designed experimental setups have managed to create whole body illusions in virtual-reality environments ([@B5]), which have been used to directly investigate the experiential and neural implications of manipulating the self-body unity in terms of self-identity, self-location and 1st-person perspective ([@B97]; [@B159]; [@B82]). Regarding the underlying neuroanatomy, more than any other region, the above studies converge on the right temporoparietal junction and its neighboring regions, involved in multisensory integration and self-other distinction ([@B55]). Another approach to the study of self-specific processing is to investigate real-world cases in which senses of agency or body -ownership appear to be radically disrupted, including psychopathologies such as schizophrenia ([@B154]), post-trauma ([@B8]), depersonalization disorder ([@B77]), and neurological disfunctions involving out-of-body-experience and autoscopy ([@B33]).
Importantly, however, an understanding of the neural processes underlying the fully fledged minimal self experience is still lacking. This is due to limitations of the above-mentioned approaches who study local alterations and disruptions of single features of self experience, such as the sense of agency (e.g., thought insertion), body ownership and self-location (e.g., full-body illusions). By contrast, there is emerging empirical evidence suggesting that some non-ordinary states of consciousness involve a more dramatic, global dissolution of the sense of self, and self-specific features in particular ([@B119]). This might be the case during dreamless sleep ([@B193]), drug-induced ego dissolution ([@B105]; [@B120]) and deep meditative states (as shown by our neurophenomenological studies discussed below: [@B56], [@B57]; [@B10]). Of these, the only condition which can be non-chemically and volitionally manipulated in the lab is the deep meditative state. Thus, in addition to meditators' general proficiency in experiential awareness (as discussed above), their specific meditative skills in generating states of global dissolution of self experience render them a uniquely apt cohort for the study.
Our approach to tackling this issue has been as a multidisciplinary team consisting of cognitive neuroscientists, empirical phenomenologists, and in collaboration with an expert meditator (who later became an integral part of the team), who demonstrated in the lab for the first time volitional malleability of the sense of boundaries (SB). Subsequently, we have been exploring meditation-induced neuro-oscillatory and experiential fingerprints of different modes of self consciousness, and 'selfless' states in particular, in highly adept meditators, via the neurophenomenological method ([@B19]; [@B56], [@B57]; [@B10]; [@B17]). These studies are subsequently described in some detail.
Previous Neurophenomenological Studies on Self-Dissolution {#S3.SS2}
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The studies outlined below demonstrate an evolving research effort, a blueprint, for taking a subject matter which is notoriously difficult to study, and of which very little is known -- in terms of both its phenomenology as well as its neural mechanisms -- and rendering it tractable to robust scientific investigation. In the present case, this process required three discrete stages to implement a full NRP. The first stage was a proof-of-concept feasibility study in which trained meditators produced deep contemplative states such as timelessness, spacelessness and selflessness under neuroscientific examination ([@B19]; [@B56]; [@B17]). The second stage ([@B6]; [@B10]; [@B57]) consisted of a zooming-in process in which we: (1) gained more precision on the exact phenomenological construct under study by using thick phenomenological inquiry, (2) developed a suitable experimental setup and research environment, and (3) identified the necessary personnel -- both expert meditators and researchers -- for carrying out a more refined neurophenomenological study. The third stage, which is a project still underway (see section "A Mature and Comprehensive NRP on SB Dissolution"), lays out a robust, mature and comprehensive neurophenomenological research program centered on sense-of-boundaries dissolution and building on the insights gained from the first two stages. It is important to emphasize that exercising a gradual approach in this project was necessary, given how little was previously known regarding the experiential, as well as neural, dimensions of deep self-dissolution states. And furthermore, given that an established methodology for conducting such studies is still virtually non-existent.
### Proof-of-Concept (Building the First Bridges) {#S3.SS2.SSS1}
The working basis for the study's design was the assumption that long-term Buddhist-oriented mindfulness meditators would be able to produce and hold, volitionally and on demand, certain states pertaining to the self and its dissolution. This assumption was partly based on a preliminary pilot study, which reported two cases of altered states spontaneously occurring during meditation in two proficient practitioners ([@B17]). These states of self dissolution are not uncommon occurrence for insight meditation practitioners and are considered the culmination of mindfulness-induced stages of consciousness. They are characterized by little-to-no conceptual thought and a disintegration of the ordinary subject-object intentional structure of consciousness, which is usually centered on the embodied sense of self. In the Buddhist tradition, these states are deemed highly valuable as they lead to important insights and realizations: "This comprehension of an object noticed, as being impermanent, painful, and without a self (impersonal) \[...\], by means of simply noticing, without reflecting and reasoning, is called "knowledge by comprehension through direct experience" ([@B155], pp. 10--11; [@B163])." In this study, participants signaled immediately after the occurrence of such states in the lab, while electroencephalography (EEG) was continuously measured. After the meditation, the participants were asked to freely describe the signaled episodes. The preliminary results demonstrated a unique EEG pattern \[an increase in global long-range gamma (25--45 Hz) synchronization\] during the signaled states, compared to the background meditation state. Importantly, this preliminary case-study illustrated the feasibility of experiencing spontaneous deep meditative states of self-dissolution in the lab. The phenomenology employed was rather thin, due to the researcher's lack of training in the phenomenological method, yet it allowed the creation of the very first bridge: front-loading 1P insights to 3P study design (bridge a). The neural analysis employed dynamic connectivity within ongoing EEG measurement, thus also enabling phenomenological validation of neurobiological accounts (bridge b).
The next study already recruited a larger cohort of experienced meditators for investigating a range of facets specific to the sense of self. In designing tasks for producing the desired phenomena, we relied on [@B66] influential conceptualization of self consciousness as "narrative self" (personal identity with temporal extension) and "minimal self" (momentary awareness rooted in bodily and multisensory processes, endowed with a sense of agency, ownership and 1st person perspective). Our aim was to map the patterns of neural activity underlying narrative and minimal states. However, by front-loading previous phenomenological insights, we also added what we called 'selfless' states, a present-moment awareness devoid of a subjective self core^[6](#footnote6){ref-type="fn"}^. Rather than define it beforehand, the study's aims were to both characterize this state phenomenologically, as well as to capture its underlying neural fingerprint. The experiment's sample consisted of sixteen long-term meditators tasked with repeatedly producing and holding states pertaining to the narrative self, minimal self, as well as states devoid of the sense of self ([@B56]). Simultaneously, their brain activity was recorded by magnetoencephalography (MEG), a technology directly measuring the magnetic fields produced by the brain's neurophysiology at a high resolution. It enables differentiating brain activity occurring at different frequency bands including fast brain rhythms, as well as reconstructing their cortical sources. Furthermore, the MEG is setup in a quiet, dark and heavy magnetically shielded room. It is non-invasive and there is no interference from the equipment during the experiment. These factors allow creating a relaxed and intimate environment suitable for the generation of deep meditative states. Each state was produced three times in succession, for 30 s.
As the study was exploratory, and we were not yet experienced with the NRP, we employed retrospective self-reports, as well as two different measures of 1P reports. One was extremely thin, to enable direct naturalization, and the second somewhat thicker:
1. First, participants evaluated on a 1--3 scale their degree of success in producing each state. The purpose of these numerical reports was to exclude from neural analyses the subjectively non-successful selfless states (ratings of 1). This was done in the MEG immediately after producing each state. Retrospective reports regarding the meditators' perceived (relative to past experiences) success and stability in performing the tasks (on a 1--10 scale, with 1 denoting "very low" and 10 denoting "very high") were collected after the MEG session. Using a similar design, the participants also produced dissolution states in the time and space dimensions (reported in [@B19]). The finding that emerged from these self-report measures was that our participant population, i.e., Buddhist-oriented mindfulness practitioners, were more capable of successfully producing and stably maintaining dissolution states in the self dimension relative to the time and space dimensions ([@B19]; [@B56]). This finding is coherent with the emphasis placed in Buddhist practice on such experiences. It echoes Varela's suggestion that long-term meditators are especially suitable subjects for studying self experience ([@B185]), and in particular its subtler pre-reflective aspects ([@B184]), within the NRP framework.
2. Second, following the neural recordings, while still lying within the MEG and via an intercom, participants were asked to briefly describe their experience in the 'selfless' condition freely and in their own words, without reflection or judgment ([@B92]; [@B157]; [@B115]). The collected phenomenology was of medium degree on the thin-to-thick continuum due to the lack of skilled phenomenological investigators, as well as technical limitations of conducting interviews during MEG recordings. The short descriptions did, however, make their categorization and validation simpler. The 'selfless' phenomenological descriptions were analyzed and divided into three categories which were then validated by 12 independent judges. These categories indicated either (1) a quieting of experience, (2) an altered dream-like state, and (3) a state lacking sense of ownership or agency. Interestingly, but not surprisingly, the phenomenal categorization was found to be linked with the degree of meditative experience (such that the most experienced meditators were all in the third category). The three phenomenal invariants produced by this process were later used to contrast the third group with the other two, in order to underpin the neural signature of this radical phenomenological shift.
The experiment's neural results indicated that different modes of self-processing involved dissociable frequency-dependent networks ([@B56]). Narrative, time-extended reflective self-related processing was marked by extensive frontal, and medial prefrontal gamma band (60--80 Hz) power, marking attenuation of default-mode activity, in line with fMRI ([@B191]) and intracranical EEG studies ([@B126]). In contrast, minimal self processing was linked with beta-band (13--25 Hz) power in a more posterior network including medial (precuneus and posterior cingulate) and inferior parietal lobule (IPL) regions. Contrasting the last phenomenal category with the first two revealed a further right IPL beta-band power reduction, thus linking together phenomenology, meditation experience as well as a distinct neural signature.
To summarize, the neurophenomenological bridging principles we used in this study included: Front-loading 1P insights to the 3P study design -- building on the participant's ability to produce 'selfless' states on demand (bridge a); 1P validation of 3P accounts -- by collecting phenomenology of the 'selfless' states (bridge b); and joint analyses of 1P and 3P data, by creating three *post hoc* phenomenal categories and using them to contrast the sub-groups and gain new insight which otherwise would not have been available (bridge c).
### Zooming-In {#S3.SS2.SSS2}
The next steps involved thick phenomenology, zooming into the selfless experience with the aim of understanding the phenomenon in terms of both phenomenology and neurophysiology. This thickening of the phenomenological data collection and analysis was enabled by the close collaboration with Y. A., an expert in the phenomenological method.
We began with an in-depth phenomenological study in which 27 advanced mindfulness meditators were interviewed ([@B6]). The goals of this study were:
1. Mapping the subjective experience during meditation in general terms.
2. Defining the ability of different meditators to describe their own experience during meditative states (in terms of depth and thickness).
3. Identifying specific structures in the intentional arc that underwent changes during meditation.
4. Identifying changes in the meditators' sense of boundaries and sense of self.
5. Exploring the sense of body ownership during meditation.
6. Identifying meditators with the ability to volitionally replicate their experience.
At this stage, we were ready for a more detailed case study, examining both the phenomenology and the mediating neural substrate of a well-defined phenomenological construct which emerged from [@B6] study, namely, the sense of self-world boundaries. At this point, building on insights from an intimate workshop on neurophenomenology^[7](#footnote7){ref-type="fn"}^ which highlighted the necessity to engage in a real and deep dialogue with experts well familiarized with deep contemplative states, we started working in full cooperation with a highly qualified meditator. We were lucky to be connected with a uniquely suited meditator, S.F., a former scientist and well-known meditation teacher with over 40 years and tens of thousands of hours of meditation experience. S.F.'s qualifications were based on both phenomenological as well as neural considerations. Based on phenomenological descriptions provided in previous studies ([@B19]; [@B56]; [@B6], [@B9]) and summarized in [@B10], S.F. stood out as a uniquely apt candidate, able to produce deep meditative states on demand, in a differentiated, replicable and stable manner. In addition, S.F. could describe his experience in clear and precise language, as it was unfolding. Furthermore, S.F.'s neurophysiological data from previous MEG ([@B19]; [@B56]), EEG ([@B20], [@B21]), and fMRI ([@B22], [@B23]) studies on self consciousness, indicated clear and strong effects, which reflected group-level processes (see [@B10]). In other words, it was likely that S.F. would be able to produce the required states, describe them in clarity and detail, and that the corresponding neural data would be differentiable between-conditions and generalizable (not idiosyncratic).
The decision to focus on the sense of boundaries (SB) was a result of a discussion between the researchers (Y.A., A. B-O., and S.F.), regarding what would be the best phenomenological dimension that S.F. could alter by demand in the lab. S.F. identified the SB as a phenomenal continuum he could traverse very skillfully, moving along it in a precise way, and stopping in several reliable and differentiated states. SB dissolution is a central goal and skill of Buddhist meditation and has profound implications to the study of self. Albeit a relatively novel research field, there are indications regarding its prevalence among long-term meditators ([@B107]). We decided to focus, for the sake of simplicity, only on 3 highly differentiated phenomenal states ranging from a normal sense of boundaries (SB1) to a state in which the SB was beginning to dissolve (SB2) to a state in which the SB was completely absent (SB3).
The case-study design inherently included the three bridging principles practiced in our previous study: (1) Front-loading 1P insights to 3P study design -- building on a series of preliminary phenomenological interviews and discussions with the practitioner S.F., as well as our prior studies; (2) 1P validation of 3P accounts -- by collecting phenomenology of all three SB states; and (3) Joint analyses of 1P and 3P data, by creating ad-hoc three phenomenal categories and using them as 'cognitive tasks' to guide the MEG data acquisition and analysis.
The study was set up such that the phenomenological interview was conducted in similar conditions to the subsequent MEG experiment. SF generated the default, dissolving, and disappearing states, SB1, SB2, and SB3, for 1 min each, in succession, for four cycles, while his brain activity was recorded by MEG. We employed thick phenomenology -- lengthy in-depth interviews conducted and analyzed by an expert empirical phenomenologist (for more details see [@B10]). The thick phenomenology significantly advanced our understanding of the lived experience underlying the 'no-self' state in a number of important respects. While in the previous study care was taken to elicit 1P descriptions of the selfless state, their phenomenology was thin with little detail, richness and specificity. Additionally, the thin methodology was not conducive of the practice of 'bracketing' and thus a layer of Buddhist conceptualization (terms such as 'emptiness,' 'liberation,' and 'witnessing') could still be detected in the descriptions. Third, despite the emphasis placed by Buddhist traditions on 'no-self' experiences as a key to liberation, hardly any phenomenological documentation of such experiences exists due to taboos around discussing such experiences with anyone but one's teacher. The thick analysis revealed SB dissolution experience to be a graded phenomenon, manifesting as nine experiential categories such as diminished or absent sense of agency, ownership, location, egocentric perspective and internal vs. external ([@B10]).
In accordance with the diminishing quality of the phenomenal categories, at the level of the brain these changes were mediated only by beta band reductions, with no increases in activity. These beta reductions were localized to bilateral medial and lateral parietal regions ([@B57]), in particular the right temporal-parietal junction (TPJ, which includes the IPL), in line with our previous study ([@B56]). These results were coherent with the existing literature as the TPJ, more than any other region, has been shown to mediate the experiential unity of self and body, relying on multisensory integration and contributing to a sense of ownership, agency and self location ([@B177]; [@B91]).
While highly interesting and informative, these results still raised two important concerns. The first regarded the uniqueness of SF in terms of neural patterns. Could these results be generalized to a large population? The second concern regarded the gap between the high complexity of the phenomenology as compared to the neural findings. In other words, while the phenomenology produced nine phenomenal categories, the underlying neural mechanism was linked in previous literature to only some of these categories, so we were unable to discriminate which of the involved SB dissolution phenomenological categories was driving the neural results.
The need to further develop an understanding of the specification of the neural activity related to these experiential changes necessitated a novel study to be designed (the current team project, see section "A Mature and Comprehensive NRP on SB Dissolution"). However, we were already in position to address the first issue based on our previously collected data. By doing so, we implemented for the first time the advanced bridging principle of re-analyzing 1P based on 1P-enriched 3P data (bridge d). Specifically, our better grasp on the SB phenomenology shed new light on group data from our previous study ([@B56]), and it became apparent that they too demonstrated a form of SB dissolution during the selfless state. Hence, armed with the 1P-enriched 3P data, we could go back to their data and study the exact frequency and regions of interest. As a result, the case study's neural results were partially validated (right hemisphere only) in a larger group (*n* = 10), and their specificity to the domain of self (not manifesting in control states focusing on the time and space domains) was demonstrated ([@B57]).
To summarize, this series of studies enabled us to show that it was possible to create, and validate, multiple advanced bridges between thick phenomenology and neuronal activity. The insight gained from both the thick phenomenology, as well as the MEG results, led our team to the third stage, a robust, mature and comprehensive NRP centered on volitional^[8](#footnote8){ref-type="fn"}^ SB dissolution^[9](#footnote9){ref-type="fn"}^. This project is still underway and is subsequently briefly described.
A Mature and Comprehensive NRP on SB Dissolution {#S3.SS3}
------------------------------------------------
The earlier studies provided phenomenological support for the notion that meditators can profoundly alter their SB in meditation, and the neurophysiological results showed that these alterations were mediated by neural processes linked with embodied self experience in other streams of research ([@B34]). These advancements set the stage for a mature, larger ongoing study aiming to take our NRP one step further. The main aims of this project are (1) specifying underlying neurocognitive models explaining the experiential categories and neural results, and (2) exploring individual differences (neural and phenomenological) borne of the mapping of SB dissolution into phenomenological clusters.
### Specifying Underlying Neurocognitive Mechanisms {#S3.SS3.SSS1}
We aim to specify a cognitive model that is coherent with both the phenomenological and physiological levels of description. Neurophysiologically, this requires the specification of measurable neural parameters relating to key processes within such a model. In the current study, we approach this goal by assessing three candidate neural processes arising from previous empirical research and theoretical reasoning:
1. The first potential mechanism is the integration of interoceptive signals, previously suggested to give rise to an affectively colored sense of the embodied self ([@B160]; [@B162]). This mechanism is indexed in our study using the heartbeat evoked potential, a neurophysiological brain response time-locked to the heartbeat, shown to reflect interoceptive processing of cardiac signals ([@B156]; [@B79]). This measure is recorded and computed during various levels of SB production.
2. A second potential mechanism is the integration of (motor) efference copies with their actual sensory consequences (re-afferences) ([@B41]). Similar and more specific suggestions have been made for the sense of agency ([@B66]; [@B83]), where the suppression of neural responses to self-caused events (as compared to externally caused events) is regarded as the result of efferent/re-afferent integration (i.e., cancelation of sensory changes predicted through efference copies) ([@B12]). This effect has been shown to correlate with the subjective experience of agency ([@B76]; [@B173]). This mechanism is indexed in our study using action-induced sensory suppression in a simple task involving button pressing and auditory events, in combination with meditative modulation of the SB.
3. Finally, a third candidate mechanism is based on multisensory integration accounts of bodily self consciousness ([@B32]; [@B35]), which among other methods, has been investigated in peripersonal space paradigms ([@B35]; [@B153]). We test for peripersonal space modulations during SB dissolution experiences by adapting a previously used neurophysiological multisensory stimulation paradigm ([@B24]).
By measuring these candidate processes and mapping participants onto related phenomenological dimensions, we aim to establish robust empirical bridges intertwining these two domains.
### Individual Differences in Phenomenological Mapping {#S3.SS3.SSS2}
We aim to explore whether individual differences in phenomenal characteristics map onto different mechanisms. For this purpose, we have recruited a large sample of 50 meditators with a large variance in meditation expertise (115--24,837 h). For creating a mutual phenomenological language regarding the concept of the "sense of boundaries," as well as for increasing the meditators' prospects of successfully producing in the lab clear and stable dissolution experiences, we implemented a 3-week specially tailored meditative training developed and guided by S.F. Following the training, participants were invited to the lab and underwent a varied array of neural and behavioral tasks, phenomenological interviews, self-rating as well as questionnaires. This project is, to our knowledge, the most comprehensive examination to date of the nature of human self-boundaries experience and its neural, behavioral and experiential manifestations.
While the specific training helped focusing participants specifically on this aspect of their meditative practice, the large cohort of meditators entails an unavoidable heterogeneity and richness in participants' meditative experiences of SB alteration. Therefore, an in-depth phenomenological investigation is necessary to make sense of the experiential diversity in a systematic manner. The phenomenological investigation is being conducted using a mixed-methods approach featuring epoch-based self-ratings of stability and depth of the meditative experience (thin phenomenology), follow-up questionnaires and semi-structured qualitative interviews (thick phenomenology). The interviews are conducted based on the open-ended, iterative questioning principles of the Micro-phenomenology method, producing detailed in-depth descriptions of the lived experience of the study participants ([@B134]).
Integrating these methods will allow specifying and differentiating the various types of meditative experiences associated with SB alteration, and address the different phenomenological features described by the participants. The interview analysis will capture such diversity by assessing these experiences according to fundamental facets of self-experience such as the sense of location, sense of agency, attentional disposition and affective state. These facets were defined in a top-down fashion, partially based on the previous characterization of SB dissolution (described above), and partially in order to provide subjective parameters corresponding to candidate processes available in the literature (described in the previous section). Within each of these phenomenological categories, there are emerging patterns of variability that characterize and distinguish distinct types of SB dissolution. An additional category that emerged from the preparatory training and preliminary interview analysis is the type of technique (or inner gestures) involved in the dissolution process. Although trained together, participants performed a diverse set of meditative techniques which accordingly produced several distinct variations of the state of SB dissolution. We thus hope that by relying on a larger and diverse sample we can enlighten specifics and commonalities in the enactive dynamics of SB constitution and dissolution. In addition to these thicker aspects of SB dissolution phenomenology, repeated self-ratings throughout the experiments provide temporal tracking of fluctuation in the degree of depth and stability of meditation for each subject.
This full-blown NRP project attempts to implement all the proposed bridges: (1) Front-loading 1P insights to 3P study design -- building on the fine-grained phenomenological analysis from the previous case study; (2) 1P validation of 3P accounts -- by collecting phenomenology of reduced and enhanced SB states; and (3) Joint analyses of 1P and 3P data, by creating *post hoc* phenomenal categories and using them to guide the MEG data analysis; (4) Using 3P data to define 1P -- by using cognitive tasks which engage different aspects of the embodied self (e.g., peripersonal space), we harness the accumulated 3P knowledge related to these tasks to constrain the phenomenology; (5) Using 1P-enriched 3P data to reanalyze 1P -- by utilizing the previously found neural markers (in the case study and the small, described in [@B57]) to refine and build a semi-structured interview focusing on agency, ownership and self location; and (6) Cognitive modeling -- we hope to be able to elucidate specific cognitive mechanisms underlying SB flexibility which might, eventually, be integrated into a comprehensive model of embodied self experience.
Discussion {#S4}
==========
In this paper, we outlined the NRP's requirements, explored its inherent tensions and suggested a typology of bridging principles, constraining the two irreducible domains of 1P and 3P. We then demonstrated the usage of these bridges by describing the unfolding of a series of studies investigating the experience of boundaries of the self, both phenomenologically and neurally. In both realms, the accumulated knowledge was quite limited due to taboos on publicly sharing such 1P accounts and experiences, the difficulty of manifesting such states volitionally, on demand and under experimental settings, and the lack of suitable cognitive modeling to guide the study. Hence, it is not only that exploring the subtle aspects of self consciousness supports and validates the NRP, but also the reverse, that the NRP is needed to handle such a subtle, profound, fascinating and challenging research topic as conscious experience.
We hope to have been able to demonstrate the potential of the NRP to inform the science of consciousness. We further hope that this account suitably narrates both the challenges and the creative solutions which were needed to be implemented along the way, in order to push this project forward. The guiding intuitions were always in the spirit originally put forth by Varela's NRP of harnessing a pragmatic and flexible stance along the way, collaborating with well-trained participants, and above all, the indispensable need to treat human experience with equal importance as physiological data.
We consider this ongoing circulation between the two realms of physiology and human experience as an act of art, a deep listening, an improvisational dance, which slowly develops into a skillful scientific dialogue. It is not meant for those who use science as a battle to win, or as growing a tail to wag. What is required is passionate teamwork, a willingness to be re-enchanted with the realm of the living and to tackle the mystery of human consciousness from as many angles as possible while practicing pragmatism, flexibility and humility along the way.
Author Contributions {#S5}
====================
AB-O: conceptualization, resources, supervision, investigation, and writing -- original draft. YD-Z: methodology, software, data curation, formal analysis, investigation, and writing -- original draft. F-MT, YS, and ON: investigation and writing -- original draft. SF: writing -- review and editing. YA: conceptualization, supervision, investigation, and writing -- original draft. All authors contributed to the article and approved the submitted version.
Conflict of Interest {#conf1}
====================
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
**Funding.** This study was supported by the Bial Foundation grant 45069 to AB-O. F-MT was funded by a DFG individual fellowship (GZ: TR 1587/1-1). YD-Z was funded by an institutional post-doctorate fellowship from the University of Haifa. YS was funded by an excellence Ph.D. fellowship from the University of Haifa. ON was partly funded by Khyentse Foundation.
This therefore is a method enabling the gathering of "first person" data, i.e., data that express the viewpoint of the subject himself, in the grammatical form "I...". But as these data have been gathered through another person (a "You"), it has been dubbed a "second person" method ([@B134], p. 231).
In DES, pre-trained participants are 'beeped' randomly, thus ordered to record (verbally or in writing) their inner experience in that particular moment. DES would be placed in between the two poles, as the resolution of the lived experience obtained in this method is lower, in part, in order to minimize bias of reconstruction. Importantly, it is used to inspect random, rather than specifically meaningful instants of experience.
The issue of naturalization of phenomenology clearly exceeds the specific context in which it is discussed here. It is further explored through the typology of bridges provided in Section "Building Bridges Between Phenomenology and Physiology -- Mutual Constraints." For theoretical accounts of naturalization of phenomenology, see [@B143], [@B46], [@B132], [@B195], [@B69].
This is especially crucial in the skillful execution of 2P research ([@B138], [@B139]).
This is also an example of front-loading, as [@B113] did pilot runs to identify the categories, which were then incorporated into the design.
The word 'selfless' is used to denote the state of lack of minimal self features, but some authors define it as a minimalist notion of self consciousness which implies its essential reflexivity or first-personal givenness ([@B196]).
A round table on neurophenomenology (December 2011) with scholars from different fields as well as meditators organized by AB-O and YA at the Inter-Disciplinary Center (IDC), Herzliya, Israel.
It is important to clarify that 'volition' as expressed here is more about a radical letting go than about control; more like a state that can be intentionally cultivated, or recognized.
Volitional SB dissolution cannot be equated with full realization of no-self; rather, it should be viewed as an experiential manifestation of a degree of no-self/emptiness insight.
Supplementary Material {#S7}
======================
The Supplementary Material for this article can be found online at: <https://www.frontiersin.org/articles/10.3389/fpsyg.2020.01680/full#supplementary-material>
######
Click here for additional data file.
[^1]: Edited by: Wenjing Cai, Shanghai Jiao Tong University, China
[^2]: Reviewed by: Urban Kordes, University of Ljubljana, Slovenia; Sucharit Katyal, UC Davis Medical Center, United States
[^3]: This article was submitted to Consciousness Research, a section of the journal Frontiers in Psychology
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Mr. Mueller's indictments show that Russian agents interfered with the 2016 election by sowing discord on social media and hacking and disseminating Democrats' emails. Yet it now seems wiser to point to our intrinsically American shortcomings, more than Russian interference, for Mr. Trump’s victory. And in rushing to blame Russian collusion, we have wasted time and political opportunity that we might better have spent reckoning with how to prevent a Trump-like catastrophe from happening again.
I’m spelling all this out starkly, because in the spinning to come, it will be all too easy to lose yourself in misdirection. If you are a liberal, you might be especially tempted to give in to the aggrieved and embarrassed #resistance-tweeting punditocracy now throwing up endless reasons for downplaying Mr. Mueller’s finding: We still haven’t seen the whole report! The attorney general is a toady! Don’t forget about all those other investigations of all those other crimes!
These are all important points. But don’t overlook the headline finding. Like the Trump victory itself, Mr. Mueller’s no-collusion conclusion should leave a mark. It lands like a rotten egg on a political and media establishment that had gone all-in on its own self-serving — and wrong — theory of the case. Before we embark on yet more investigations, it is worth examining, now, why the collusion fantasy proved so irresistible to so many of us — and what we all might have done with our time instead.
Here’s my theory: Collusion was a seductive and convenient delusion. For many Americans, the simple truth that Mr. Trump really had won was too terrible to bear. The ease with which a racist, misogynist, serial con man had slipped past every gatekeeper in American life suggested something deeply sick at the core of our society.
In particular, Mr. Trump’s win pointed to tectonic failures within the mainstream news media, whose leading brands had fanned the showman’s rise with copious television coverage; indulged his every gimmick with yet more attention; and elevated his opponent’s trifling email-management kerfuffle into a scandal of world-historic import.
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Thylactomimus albolateralis
Thylactomimus albolateralis is a species of beetle in the family Cerambycidae, and the only species in the genus Thylactomimus. It was described by Stephan von Breuning in 1959.
References
Category:Lamiini
Category:Beetles described in 1959
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Q:
greet with/through eyes
What is the difference between
They exchange greetings through eyes
and
They exchange greetings with eyes
or even
They exchange greetings by eyes
This might seem like a simple and basic question about prepositions, but I want to know the subtle conecptual differences, through these examples.
Thank you.
A:
You ask an excellent question about three prepositions of agency -- (1) through, (2) with, and (3) by -- used with the word eyes. Eyes have two capacities: (A) they are one way the world communicates to us (as the organs of sight) and (B) they are one way we communicate to the world. Sense A is seeing; sense B is looking at.
For sense B, we have the saying the eyes are the windows to the soul, i.e., our eyes reveal to others who we truly are. We say, "Her eyes flashed with anger" to indicate that somebody looks angry. And in your examples, two people send wordless messages to each other by a glance, a wink, or some other action using their eyes. All three prepositions are used in both senses.
through (A) From Their Eyes Meeting the World: the drawings and
paintings of children by Robert Coles and Margaret Sartor
(1992)
She told us that you have to think of other people, and not just yourself, and try to see yourself through their eyes, and not
just your own — but it's hard.
This is a common metaphorical expression for using another's eyes to mean to see what they see.
(B) From Return Trip Tango and Other Stories from Abroad by F MacShane
and M Carlson (1992)
It's through their eyes that I understand that animals are something else.
This is the other sense. The narrator is looking at animals' eyes for her understanding.
with(A)With Blood in their Eyes by S G Lawrence (1961):
They'd simply followed his every footstep with their eyes,....
That is, they saw the footsteps.
(B) From Secrets from the Casting Couch: On Camera Strategies for
Actors from a Casting Director by Nancy Bishop (2009):
I believe that this was in part because they had so much practice with communicating with their eyes.
That is, they had other people looking at their eyes.
by(A) From Intellectual Repository and New Jerusalem Magazine (Vol 5, 1839)
But spirits may be made sensible of the existence of the natural world by communication with the spirits of men while in the body, so
as to see, as it were, by their eyes,
That is, inhabitants of the spiritual world may become aware of the
natural world by seeing things by using the eyes of humans.
(B) Holding the Dream by Nora Roberts (1997):
You can tell by their eyes. You can tell if you look in their eyes.
And here again, the other sense, of people looking at eyes.
Prepositions often have numerous shades of meaning and idiomatic usages, but in this context, they all mean the same thing, whether it's taking signals in (i.e, seeing) or by sending signals out.
As a side note, eyes in your examples needs a preceding determinative, probably their.
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Seven Backdoors to Learning for Exhausted Moms
Let’s face it; there are times when formal homeschooling is impossible.
Such as…
…when you are experiencing debilitating morning sickness,
…when there is a new baby in the house,
…when the whole house is recovering from the flu,
…when the family is experiencing a move,
…during a time of upheaval, boredom, or burnout.
If you are going through any (or all) of the above, I know you are worried right now. You are certain your child (or children) will fall back, never to recover the ground you worked so hard to gain.
The first word I want to speak to you is rest.
I have been homeschooling for 27 years now, through morning sickness and teething and moving and illness.
For instance, I spent yesterday with our 15-year-old daughter as she underwent an appendectomy (she is at home recovering nicely). There is no way the kids were hitting the books while I was away. The books won’t be cracked open the moment we return home, either. In fact, it may be a number of days before learning gets back to “normal” (whatever that is).
Am I concerned?
Never.
I am at perfect peace because I know that one-on-one tutoring is one of the most powerful methods of instruction. In fact, every 15 minutes of focused attention at home is worth two hours of “batch learning” in school. Since I have been spending consistent, quality time learning with my children, I have no worries!
But what if you are expecting a longer interruption?
A quick illness with a happy ending is one thing. Long periods of craziness are another.
I personally believe learning never stops. Even without adult intervention, children are constantly gathering, storing, and analyzing scads of information. If done right a break can encourage natural learning (as long as the kids don’t turn into mindless drones chained to screens).
You can think of it as “homeschool light.”
Some days this means you let the children find their own way.
Since my daughter is recovering from surgery I set the children free. This week my seven and ten year old daughters decided to work through their first real novels. My other girls are pursuing hobbies such as Korean, piano, and economics. If children are used to thinking of learning as fun they naturally use their free time to pursue their interests.
However, there are times when even the most interested children can become antsy or restless. The most angelic children can turn into a mob of mischief-makers if they don’t have anything to do. Sometimes we are forced to flip through the channels or get out the Xbox and waste some brain cells, but this isn’t a long-term solution!
Eventually we have to intervene with some productive alternatives. Since the brain and/or body is probably not functioning on all thrusters, our choices must be simple, sweet, and easy to put together.
Over the years I have developed a short list of things to do when there is nothing else to be done. Here it is in a nut shell:
1. Reading aloud.
This is some of the sweetest learning I can think of. Reading aloud connects our hearts and minds as we experience a rich, narrative feast.
I am currently reading Bound for Oregon to my little girls. Besides teaching us a bit about American history, it also helps with English grammar and composition. As an added bonus we are asking questions about everything from what oxen look like to where the Kaw River is. Science comes in when we talk about cholera and dysentery and what germs are.
The wonderful thing about it is you can read aloud anywhere; on the couch, at bedtime, in the car, or even at a doctor’s appointment. Many times I have put my children to sleep in their rooms by sitting in the hallway and reading aloud while nursing an infant in my lap.
2. Discussion.
Here is another one that will work even in the worst of circumstances. It can be done while driving somewhere, while working on a family project, or even while waiting in an office. Children learn a lot when adults talk to them. They love to ask questions, even hard questions, and have someone take them seriously enough to give a thoughtful answer.
Sometimes it’s even more instructive to turn the tables by asking pointed questions and listening to what the children have to say!
3. Maps.
Looking for a way to spend a rainy afternoon? Why not pull out some maps and atlases, spread them out on the floor, and talk about them? Even old road maps from a thrift store can yield hours of learning fun (we like the ones from older issues of National Geographic Magazine).
To take this activity even further, how about drawing your own maps of places that are either real or pretend? One year my children and I created free-hand drawings of the entire United States. This was the perfect way to get us intimately acquainted with our own country and gave us lots to talk about and investigate.
Since you are an amazing genius mother who takes advantage of every opportunity, you can turn a decent flick into a huge octopus of learning, with arms reaching out into almost every other discipline.
Here are some ideas for branching out:
Have the children narrate the movie back to you.
Discuss the plot, the concepts, the fallacies or inaccuracies, the character development, the cinematography, cost of production, filming method, etc.
Research key figures/events/concepts by using maps, encyclopedias and other reference books, or the Internet.
Get out blank sheets of paper and some drawing materials for creating lovely notebooking pages about the movie or the subject of the movie.
5. Library books.
We live in an area with a fabulous library system with multiple branches and a website that allows us to reserve books and pick them up close to home.
The library can be a great place to take the kids if repairs are being done or you need a place to rest while waiting for appointments, etc. When we go I try and give the children the task of picking three books up for their personal use while I peruse the shelves and look for 10 or so others that I hope they will get interested in.
When we get home the house is so quiet! The children are all tired from the trip, so they are ready to settle down and rest. Besides, opening and enjoying the books is like opening Christmas presents.
If things are a bit hectic I can always go online and reserve a number of titles, or even let the kids take turns reserving lists for themselves. The fun comes after I pick the books up on one of my errand trips and then pass them out when I return home.
6. Internet.
This is almost a no-brainer, but we sometimes feel guilty about it (especially when we get caught up and forget to make lunch).
If you are like me, you need to sit and write a list of possible questions to be answered and set a timer before you start on your wild adventures together. You also need to be willing to drag everyone back on point, especially if you find yourself laughing wildly at one crazy monkey video after another…
7. Board games
If you feel like a boring nag and your children are threatening mutiny, throw the books in the corner and break out the games!
Chutes and Ladders, Sorry, and checkers teach concepts to younger children, while older children enjoy more challenging games such as Scrabble, Monopoly, and Yahtzee. One game that has become a favorite in our family is Apples to Apples, which is great for language arts development, history, and even science.
Even when mom is not 100%, learning doesn’t have so suffer. This may be hard to believe, but this unconventional learning has lead to some of our greatest breakthroughs.
You can view some great photos of our unconventional learning if you follow me on Instagram.
Related
14 thoughts on “Seven Backdoors to Learning for Exhausted Moms”
I’m so thankful for the encouragement! I am on my first year homeschooling my Kindergartener. We also moved two months ago and had our 4th baby one month ago. So, we have a lot going on right now! This post was well-timed for what I’m going through!
The new “Cinderella” is my favorite one too! I wish I could watch it once a month! Just wanted to throw this out there for a curve ball: checking out what happened on this day or week in history and following that rabbit trail with some documentaries that tie in (lots of free ones online), maps, coloring sheets, crossword puzzles, and the like are great ways to spend time engaging and entertaining the brain.
Sending up prayers for your daughter and your family:)
Your comment about 15 minutes of one-on-one time being equiv to 2 hrs in school is so helpful! I have been thinking much the same thing, and it helps to have it confirmed by an experienced homeschool mom. Thank you!
Thank you for this encouraging post! I have 5 kids under 7. My oldest is very bright and we started “school” early but we are all burnt out. I don’t want to quit learning but we need to slow down. I have no idea how to school without schooling if you know what I mean. Anyways, thanks! Today we will be playing our new clue Jr. Game, doing our read aloud and tackling a much needed laundry task.
Laci Brinn, with, wwwngracefilledtrenches.com
Spot on, Girl! While I try to keep a simple routine that can run whether I’m present or not, I’ve also come to appreciate that not every day needs to be a ‘school’ day. One-on-one time with grandparents, a spontaneous field trip, a house full of sickies that leads to an Andy Griffith marathon…those are the days I love the most. There is so much more to learning and living than what any textbook could ever hold. The Lord helped me see long ago that while school is important, enjoying each other and our time together is essential.
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Twitter CEO Jack Dorsey appears to have retweeted tweets from an account with links to a Russian "troll farm."
A now-deleted account with the username @Crystal1Johnson was flagged by the independent Russian news agency RBC as a Russian-backed account. Dorsey retweeted the account twice, prior to it being suspended, the Daily Beast reported, confirming part of RBC's report.
"Rihanna collects her Humanitarian of the Year award from Harvard. She kicked off #WomensHistoryMonth with a bang!" reads the tweet Dorsey first retweeted in March.
He also retweeted the account one week later.
"Nobody is born a racist. This picture is so sweet! Teach your children to judge others by the kind of person they are inside," the tweet read to accompany a photo.
The account, which appeared to be managed by a black woman from Richmond, Va., occasionally tweeted inflammatory content about Hillary Clinton.
"Clinton's True Face.. KKK leader claims he gave $20K to Hillary Clinton campaign," read one tweet from May 2016.
Earlier this week, it was reported that members of Trump's family and campaign staff, including Donald Trump Jr. and Kellyanne Conway, promoted tweets from an account with the username @Ten_GOP, an account affiliated with a Russian "troll farm" during the 2016 campaign.
Twitter officials met with congressional investigators last month to discuss how Russia interfered with the election on Twitter. The Senate Intelligence Committee also invited Twitter, Facebook, and Alphabet, Google's parent company, to testify publicly on Nov. 1.
Editor's note: This story has been updated to say congressional investigators met with Twitter officials in September, not October.
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Rhodium-catalyzed denitrogenative thioacetalization of N-sulfonyl-1,2,3-triazoles with disulfides: an entry to diverse transformation of terminal alkynes.
An efficient and useful rhodium-catalyzed denitrogenative thioacetalization of N-sulfonyl-1,2,3-triazoles has been developed for the first time. The protocol uses readily available N-sulfonyl-1,2,3-triazoles and diaryl disulfides as the starting materials. The corresponding hydrolytic and reductive products with thioacetals were obtained in good to excellent yields, and the reactions were carried out easily under mild conditions with tolerance of some functional groups. Furthermore, the generated thioacetals could be transformed into some useful compounds. Therefore, the present method provides a novel and valuable strategy for the diverse transformation of alkynes.
|
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Svein Bakke
Svein Bakke (23 June 1953 – 16 December 2015) was a Norwegian footballer who played for Sogndal Fotball from 1971 to 1990. Bakke was central player when Sogndal faced SK Brann in the 1976 Norwegian Football Cup. Bakke played 514 matches over his nineteen-year career and scored 321 goals (in all competitions, including friendlies).
Bakke served Sogndal in an administrative position until 2005, aside from one year (1999) with Wimbledon F.C. in England. Bakke later worked in the private sector.
Svein Bakke was the father of former Leeds United and Norway midfielder Eirik Bakke, who is currently Sogndal's manager.
References
Category:1953 births
Category:2015 deaths
Category:Sogndal Fotball players
Category:Norwegian footballers
Category:Association football forwards
Category:Wimbledon F.C. non-playing staff
Category:Norwegian expatriate sportspeople in the United Kingdom
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| 0 |
Q:
How to call permission dialog again when user clicked don't ask again
Hello guys i make a xamarin.forms app. I need to ask the user to allow app use his location. This is my code:
var location = await Geolocation.GetLastKnownLocationAsync();
if (location == null)
{
location = await Geolocation.GetLocationAsync(new GeolocationRequest
{
DesiredAccuracy = GeolocationAccuracy.Medium,
Timeout = TimeSpan.FromSeconds(30)
}); ;
}
if (location == null)
LabelLocation.Text = " NO GPS LOCATION";
else
LabelLocation.Text = $"{location.Latitude} {location.Longitude}";
}
catch (FeatureNotSupportedException fnsEx)
{
// Handle not supported on device exception
await Application.Current.MainPage.Navigation.PushAsync(new MainMenu());
}
catch (FeatureNotEnabledException fneEx)
{
// Handle not enabled on device exception
await Application.Current.MainPage.Navigation.PushAsync(new MainMenu());
}
catch (PermissionException pEx)
{
// Handle permission exception
await Application.Current.MainPage.Navigation.PushAsync(new MainMenu());
}
catch (Exception ex)
{
// Unable to get location
await Application.Current.MainPage.Navigation.PushAsync(new MainMenu());
}
when user click never show again , everytime open the page it goes on PermissionException which is ok. But i want to show again the permission dialog because without location can't show data. Is it possible to do this?
A:
The short answer again is, no you can't. As you can see in the Requesting permissions documentation (when the user denies a permission and checks that no prompt should be shown from this moment forward):
Explain to the user that the feature is unavailable because the features requires a permission that the user has denied. At the same time, respect the user's decision. Don't link to system settings in an effort to convince the user to change their decision.
The best practice is to explain in detail to the user before you ask for the permission. If the user still decided to deny you this permission, then display a message describing that this particular logic simply won't work. It is against the best practices, but if you wish, you can redirect the user to Settings where the user can enable the permission. However, I strongly advise you not to do so.
One important side note, again from the documentation:
If the ContextCompat.checkSelfPermission() method returns PERMISSION_DENIED, call shouldShowRequestPermissionRationale(). If this method returns true, show an educational UI to the user. In this UI, describe why the feature, which the user wants to enable, needs a particular permission.
Also, use Xamarin.Essentials for permission checking. Everything is very well documented there.
P.S. I strongly suggest you read App permissions best practices where you will find other useful practices from the official Android team.
|
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The Dick Show
By Dick Masterson
You want Dick. You love Dick. You need Dick.
|
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| 0.064103 |
Teenager beats his classmate to death in school
January 14, 2016, 11:31 PM IST
Aurangabad:A 15-year-old student of class X was allegedly beaten to death by his classmate on the campus of a reputed residential school at Sulibhanjan in Khuldabad tehsil of the district, police said today.
The incident occurred on Tuesday when Shaikh Afroz Amin and another teenage boy were fighting on some issue on the campus of the school, said Shivlal Purbhe, inspector of Khuldabad police station.
The deceased was the resident of Rabale in Thane district adjoining Mumbai.
Police had initially registered the case as accidental death, but later booked the juvenile for murder after a CCTV grab purportedly showed him beating up Amin.
Interestingly, the school had informed Amin’s father on Tuesday that his son had fainted on campus and admitted to rural hospital in Khuldabad.
However, when he reached the hospital he was shocked to learn that his son had died.
“The boy’s father lodged a complaint with us saying that his son did not die a natural death,” the inspector said.
During the course of investigation, police found the CCTV footage of the purported assault.
|
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| 0 |
Nesty – The Wheels On The Bus Go Fuck, Fuck, Fuck
4581 65%
|
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| 0.050847 |
Q:
Spool Over Quota. Queue or Topic endpoint limit exceeded - Solace 3560 Message Router Appliance
I am getting the following error while trying to publish a message on Solace Box:
Spool Over Quota. Queue or Topic endpoint limit exceeded
Note : I have checked all 3 level of Quota (Endpoint/MessageVPN/Appliance) but everything is under assigned quota.
A:
This error message means that the message that the application is trying to publish would cause a queue or topic endpoint to exceed its quota. For example, the endpoint could be under the assigned quota by 50 kB but if the message is over 50 kB, you will see this error message. The next sentence in the error message should specify the name of the topic that the message is being published to.
Verify that every queue or topic endpoint that contains this topic subscription is under the configured maximum quota for that queue or topic endpoint. If spooling the message will cause the spool usage of any of these individual endpoints to go over the maximum quota, the message is rejected with the error message you have provided.
If the topic is in the format #P2P/QUE/[queueName], then the application is publishing messages directly to the that queue. In this case, you should check that specific queue to make sure that the message you are publishing will not cause the queue's spool usage to go over quota.
|
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| 0 |
xxx
|
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| 0.25 |
Like
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Big Cock Sucks His Cum and takes his cum
|
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| 0.05 |
Apple uses water damaged boards in Apple refurbished devices? [video] - tbirdz
https://www.youtube.com/watch?v=4TZ_ZGCLaiA
======
ChuckMcM
Ok, first I am always in awe of people who have the skill to disassemble, fix
at the component level, and reassemble modern electronics. I am also not
surprised that both the independent repair folks get told they aren't as good
as Apple, and that Apple isn't doing anything more or less magical in their
repairs.
I do however take a bit of issue with generalizing from one or two instances.
Just as there are "bad" independent repair techs, there are no doubt "bad"
Apple repair techs. And bad techs make sloppy repairs, period. The reality is
that the "best" your electronic device will be, is likely just after it comes
off the assembly line and passes QA, that entire assembly process and the
components used are tightly controlled so you get the best possible outcome.
Rework inevitably it hard on components, traces, and often has to use
materials that differ from the ones usable in the original manufacture.
~~~
ratsmack
Apple should maintain a standard of quality control. If this is representative
of that control, then what she is saying is correct in that their work is not
representative of what they espouse.
------
georgespencer
Can someone tell me what the big deal is here? Apple's refurb devices are
guaranteed. Isn't it binary whether or not the water damage kills the device?
I.e. if they're able to sell a water damaged board with a few replaced chips
on it, then the water damage by definition isn't an issue because the board is
working.
~~~
jschwartzi
The biggest issue I see is that the original tech didn't replace the
underfill. As a result the PMIC would not have the same drop resistance as a
factory installed chip.
I would expect anything sold as refurbished to meet the same spec as a new
device, and this one absolutely doesn't. This includes mechanical specs, which
would not be fully tested when smoke-testing a rework.
~~~
Someone
I'm not saying anything about this example, but why would you expect a
refurbished unit, _sold at a lower price than a new device_ to meet the same
specs as that new device?
Surely, something must be different about it?
~~~
troisx
Yes, it is different because it's used. It's also supposed to be have been
brought back to new condition on the inside where damaged and faulty parts
have been replaced by as-new parts, not by replacement parts that are also
damaged.
~~~
jschwartzi
This is what is meant by refurbished, as opposed to repaired.
------
r0m4n0
This is an interesting case because dropping a phone is the customer's fault
(and thus that action voids the Apple warranty) but based upon the videos
claims, the refurbish process did appear to alter the overall durability of
the phone.
I suppose there is a risk involved with buying anything refurbished... whether
from the manufacturer or not.
For anyone that is interested, Apple has published a few QA and inspection
processes involved with refurbishment. Would be surprising if 1. it slipped
through this process 2. Apple doesn't actually perform these inspections 3.
this device was deemed fit for resale under Apple's standards
[http://www.apple.com/shop/browse/home/specialdeals/refurbfaq...](http://www.apple.com/shop/browse/home/specialdeals/refurbfaq_popup)
I'm still not completely convinced this was an unaltered Apple refurbished
phone though (and I'm not sure we will ever know)...
~~~
bbchase
I did repairs at an authorized store for about 5 years. It's unlikely that her
customer both knew the repair history of that iPad and reported it truthfully.
It's also extremely unlikely they they knew and reported truthfully whether
the iPad had every been exposed to liquid while in their possession. People
just usually aren't honest about these things (and who can blame them when it
means the difference between a free iPad replacement and a repair that costs
almost as much as buying a new one?).
And no matter how clear we tried to be at my shop, we could not seem to
convince customers that we were not owned and run by Apple. I can't even get
my friends and co-workers to stop saying that I worked for Apple, so the fact
that her customer reported to her that this iPad was replaced by a corporate
Apple Store means just about nothing. Funnily enough, if her shop was an
authorized repair center, it would have been trivial for her to verify the
repair/purchase history.
It's also really frustrating that the video is blurry when she's trying to
point out the water damage. All I could make out of flux from the solder job.
I also suspect, but can't say authoritatively, that the "heat damage" she
pointed out was just an artifact of after-factor solder work on the board, not
from the board shorting or overheating. Unless a chip is visibly burned or
blown out, you really need to test it to know whether it's been damaged.
------
542458
In addition to what other commenters have said: Maybe I missed something (it
is a 10 minute video), but how do we know whoever brought in the water-damaged
iPad in for repair hadn't caused the water damage themselves? They could have
gotten it a bit wet, but not enough to kill anything.
I also find the evidence for the iPad never having been worked on before
fairly tenuous - I've done repairs using swapped Apple parts in the past (ie
Apple original digitizers), and I doubt _everybody_ who does aftermarket
repairs uses the same adhesive.
Also, this is really a n of 1. So Apple maybe shipped a single crappy refurb.
I'm not sure that's cause for huge alarm, or enough to make broad claims about
their entire refurb program.
I guess what I'm saying is while the allegation might be true, the evidence
here seems fairly shaky IMHO.
~~~
jessa_ipadrehab
It is at least n=2. I have seen the exact same thing once before. Keep in mind
that I will only see an iPad that was from a user who went to Apple for a
refurb after a problem with their original, and then went to independent
repair rather than back to Apple for a subsequent problem. That is less common
than someone going straight to independent repair with a problem on the
original or sticking with Apple for a problem with a refurb
------
ICS_tech_repair
I've seen something worse! Once had a 5C come in for repair. Still under
warranty, so sent it to and Apple Store in the USA for replacement. We don't
have an Apple Store in my country. Got back a unit that upon reception didn't
start. Lifted the screen to inspect it out of curiosity, because it looked
somewhat used from the outside, before proceeding to send back to Apple (and
waiting another 3 week for the trip back and forth) and saw a device missing
plates, screws, with a sticker inside with some Chinese words, and the red LCI
(water indicators) were tripped (meaning the unit was water damaged prior). We
sent it back and they declined to replace it again because... it had liquid
damage and was tempered with!! After much aggravation, they accepted to
replace it OOW (they usually don't replace devices that had been tempered with
even OOW). Since then Apple Certified Service Providers in my country were
allowed to replace iOS devices under warranty, and we did receive defective
units on a few occasions that were fortunately replaced. But the second worse
"incident" was my 15" 2011 laptop that had the logic board replaced 3 times
under the Apple logic board program, before I got back a working unit! The
ACSP told me that it happened many times over, but only (?) twice did they
have to replace the same board 3 times in row! They're all refurbished boards
of course (nothing wrong with that), but their QA after refurbishing seems to
let a lot of bad Apples (pun intended) through!!
------
Yetanfou
What worries me more than the evidence for water-damaged components is what
seems to be a substantial amount of hair on that 'refurbished' board. It did
not notice any hair on the 'factory-stock' board, so I assume that the source
of the hair is not this repair shop. If this is the (lack of) quality of work
Apple refurbishments get, Apple has some serious issues wrt. quality control.
The other option is that this device was in fact repaired by a third party
which used the proper adhesive procedure (which seems to be to apply more than
one layer of adhesive).
------
j45
Outside of a warranty, this should be a concern.
In warranty, it's important to remember you are not buying a computer, as much
as a guaranteed computer.
Apple has decent warranty for replacements if a machine has multiple issues in
a short amount of time.
I would never buy any laptop I can spend 8-10 hours a day on most days without
a laptop. In fact, the replacements that Apple has ended up fairly replacing
if my machines have misbehaved too often have been priceless.
Jas
------
jwildeboer
TL;DR there was no underfill injected after a chip was replaced in an iPad
mini that was repaired/refurbished by Apple or an authorised repair shop.
That's all. We don't know if that was an oversight or not. We don't know if
Apple requires underfill to be applied. So this is all just speculation
AFAICS.
------
benguild
I can definitely say that the quality of Apple refurbs has gone downhill.
I lost radio access randomly in Europe while traveling with a Genius Bar
replaced iPhone 6. No cellular service whatsoever. Awful. Kept cutting in and
out for days and then stopped working completely.
Had to buy a new phone for cash.
------
DanBC
Can someone explain how those two capacitors exhibit "clearly water damage"?
(about 6:25 onwards)
Is it the dull grey (not shiny silver) solder?
------
exabrial
Misleading title... Of course they use damaged boards in the refurbished
devices. Otherwise it'd be "new."
The woman here makes a great point about repairability though, a quality shop
should can do just as good (or better in this particular case) of a job as
Apple. Apple wants you to throw away expensive devices at a whim...
~~~
ams6110
I agree -- by definition a "refurbished" device is one that was returned and
repaired. That's why they are cheaper. You can expect it is not quite as good
or reliable as a new one -- though Apple does warranty them so that's the
tradeoff for the lower price.
~~~
jessa_ipadrehab
The point to add is that if you pay for a new device, and you notice anything
faulty about it and take it back, you will be handed a refurb like this one as
your in warranty replacement if it has been 15 days or more since the
purchase.
------
zer0her0
I kind of find this video to be disingenuous. She claims that the device was
direct from Apple and only proof is by the parts they used and the
craftsmanship, in the comments she does mention receipt, but no timeframe so
could've been replaced by Apple the later repaired by someone else, also she
implies 3rd party vendors parts and craftsmanship is just as good. So wouldn't
it stand to reason that it's equally possible they got the repair done
somewhere else and not mention it?
I've worked as a tech long enough to know customers often forget to mention
all damage, issues & past repairs. Sometimes out of malice, but generally
simply because they forgot, they don't know better or they weren't privy to
all the info (bringing it in for some other family member, so on).
Also, bad boards happen regardless if they're refurbished or new. With Apple
supplied boards I find that to be the exception rather then the rule. Wish I
could say the same about 3rd party vendors, I understand it's a cut throat
business and Apple getting into the business a decade and a half ago didn't
help, but this video really seems to want to make Apple out as the villain
trying to pass off crap products/repairs as ok.
~~~
jessa_ipadrehab
After opening thousands of iPads, there is no question whether you are opening
an iPad sealed by Apple, or if has had a prior repair and been resealed.
Independent repair screen swaps can be very good, especially when 100% of the
old adhesive is removed, the frame cleaned, and the aftermarket adhesive is of
original quality. But even with this, the pressure required to remove the
sealed screen is less than an original screen. The dust seal between the LCD
and digitizer can't be replicated (or isn't replicated) by independent repair.
The dust seal in this mini was intact.
There is no question, from experience, that this mini was an Apple refurb.
Also, I don't know of any other shop that would replace the iPad mini PMIC. We
only do it under duress since the effort required to CNC drill out the old
chip, combined with the cost of the new chip is not amenable to profitable
board repair compared the market value of a used iPad mini first gen.
There is no question that this board was an Apple refurb, and it's not the
first one that I've seen that is like it. In reality, it is a very good
refurb. Those damaged caps are not likely to cause any practical problems, and
replacing the PMIC underfill was probably deemed not that important--which I
would agree with.
I have no problem with Apple putting out refurbs like this, it is a great
environmental move. But own it. It is what it is. I'd like to see Apple say
"You betcha, that's our work and we're damn proud of it."
~~~
zer0her0
Thank you for the explanation, I left the repair industry just as iOS devices
started to take the forefront and there wasn't much left to "repair" w/o
getting out (de)soldering and reflow equipment.
Pretty sure they do "own it", that's what the whole warranty, either original
or 90 days from last repair is all about. ;) I just think a single digit # of
boards, that should've possibly failed QA, making it out to the public
compared to the thousands you've seen is a pretty good testament to them being
damn proud of their work.
Re-reading the description for your video, I think the issue is for non-AASP
repair centers, much like any 3rd party repair location (whether it be Apple,
or some other name brand electronic, appliance, or vehicle) is guaranteeing
the quality of parts and labor one gets from the plethora of independents out
there. I think the real issue to rail against is the plethora of poor 3rd
party repairs that aren't certified or backed by any sort of warranty vs these
outliers, as they're the ones that really cast a bad light on the independent.
~~~
jessa_ipadrehab
I agree that poor third party repair shops are an incredible nuisance to the
independent repair industry. But on par with that is how entrenched the
opposite viewpoint seems to be among Apple fans--that "only Apple is qualified
to repair Apple devices" The reason I made this video is to shine a light on
what Apple refurbishment really means. I don't believe this case is an
outlier. I have only ever seen two iPads that I knew for sure were Apple
refurb and both were like this. More strikingly, is the iPhone 6/6+ touch ic
epidemic. There is widespread failure of the touch ic(s) leading to a
characteristic gray flashing bar at the top of the screen and loss of touch
function. What stinks is that many people turning in their in-warranty new
iPhones for this defect are leaving with Apple refurb phones that contain
boards that once had another life in someone else's hands. The problem is
exacerbated by drop, so these refurb boards that made their way back to Apple
have a high percentage of having sustained a drop severe enough to warrant
trading in the phone for out of warranty replacement. When Apple puts these
boards straight into new housings with a new screen and battery, the refurb is
set up for touch ic failure---and we are seeing tons of reports of touch
failures in refurb phones.
Compare that to independent repair where a new touch ic is soldered on the
board to replace the weak original chip--that is a much more robust solution,
and carries a longer warranty.
I was prompted to make this video to just float the idea that "Apple always
has superior repair because only they are 'authorized' to fix their products"
is not true.
My motivation largely came from aggressive bullying and harassment, by some of
the regulars at the Apple Support Community forum at any mention of
independent repair as a viable option. I was banned from the forum for
continuing to suggest that some problems could best be served by independent
repair (such as data recovery after water damage) I did another video on my
experience there. [http://youtu.be/3VqYui3piV8](http://youtu.be/3VqYui3piV8)
|
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| 0 |
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| 0.064171 |
Drilling His Ass with My Massive Cock
|
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| 0.054054 |
Firstpost caught up with MP Dr Shashi Tharoor in the run-up to a conference marking the 126th birth anniversary of Dr BR Ambedkar, organised by the Congress govt in Karnataka
To mark Dr BR Ambedkar’s 126th birth anniversary, the Congress government in Karnataka is organising a three-day international conference titled ‘Quest for Equity – Reclaiming Social Justice, Revisiting Ambedkar’. The conference, which will commence on 21 July, will feature speakers like American civil rights activist Martin Luther King III, who is the oldest child of Martin Luther King Jr, the man who defined America’s civil rights movement; Lord Bhikhu Parekh, a political theorist and Labour member of the House of Lords; Cornel West, a leading member of Democratic Socialists of America; and Samuel Myers, a professor of economics who fought to sustain the establishment of Historically Black Colleges by providing them access to a billion dollars of federal aid.
Public intellectuals like Dr Ramchandra Guha and Nobel laureate Kailash Satyarthi will also deliberate on the proverbial idea of India. The objective of the conference, which will be held at the University of Agricultural Sciences in Bengaluru, is to lay constructive focus on promoting society as becoming more equitable, fair and just.
Firstpost caught up with Member of Parliament from Thiruvananthapuram Dr Shashi Tharoor in the run-up to the conference, where he stated that ours is a constitution clearly written for a plural society, one that has been inspired by the spirit of people like Mahatma Gandhi. “It recognises that individual freedoms have to be balanced with group interests, that you cannot have compulsion on any matters of social behaviour, and that conformity beyond a point is not realistic if you want to preserve a diverse democracy,” Tharoor said.
He elaborated that these are the very principles that are being violated day in and day out by those who are part of the ruling dispensation, suggesting that the current polity isn’t governing in the spirit of the constitution laid down by Dr BR Ambedkar. He explained that a lot of what happens also happens in the name of non-governmental actors who seem if not blessed, at least condoned by the government, adding that Dr Ambedkar didn’t have particularly complimentary things to say about the kind of political tendency that is today represented by the successors of the Hindu Mahasabha, namely, the Rashtriya Swayamsevak Sangh.
When asked about whether the BJP can appropriate Ambedkar’s legacy, Dr Tharoor stated that the entire process of historical appropriation has been a fairly deliberate tactic on the part of the BJP in its most recent incarnation. “We didn’t see a similar attempt the last time the NDA was in power. But Narendra Modi, during the election campaign in 2014, tried to don the garb of Sardar Patel. We pushed back very strongly because we felt that there was such a contradiction between the way in which Sardar Patel handled the communal disturbances that accompanied the partition in 1947 and the way in which Mr Modi, confronted with similar challenges, did not rise to the same sort of approach,” adding that there was simply no legitimate argument to be made for appropriating Sardar Patel’s mantle with the record of the BJP candidate.
Going forward, Dr Tharoor articulated the sociological challenge that the Muslim community is not the only community that has been “profoundly out of sympathy with that party and that the Dalits have also been effectively marginalised to a great extent.” This in his view, is partly because the BJP has had a sort of assimilationist narrative in theory that overlooks any claims of special consideration for Dalits and partly because there’s been a certain agenda in the upper caste Hindutva movement that disparages the livelihoods and activities of the Dalit community. He cites the example of the many Dalits who make their living through animal hide, the skinning of animals, the curing of the skin, leather work and so on.
He also raised the issue of the Dalit community’s marginal representation in the ruling party. “Once they (the BJP) came to power and only after coming to power, they probably decided they needed to expand their base of governance. What we are seeing with the attempted appropriation of Ambedkar is both factors: First, you seize upon leaders from the historical past when you were actually not involved in their struggle and therefore had no claim to their activities, such as Sardar Patel few years ago and now Dr Ambedkar. Second, you simultaneously use the appropriation of this individual to reach out to a community you have been excluding from your political purview.” He called this an electoral calculation to win over the Dalits, who comprise more than 15 percent of the population.
Dr Tharoor emphasised that to this day, the BJP would not be comfortable with other things that Dr Ambedkar said, did and believed. For instance, he made a reference to Dr Ambedkar’s western suit, which was a conscious rejection of Indian traditional social behaviour that had oppressed the Dalits. “Even in the hot Indian climate, pre-air conditioning, he was often in a three-piece suit. This is not something that our friends in the BJP are going to have much understanding for.”
Dr Tharoor next asked how Dr Ambedkar’s uncompromising language on Hinduism fits in with the party of Hindutva. “I happen to believe that Dr Ambedkar was a broadminded, understanding person. Sometimes when you state certain things, you do so with a vehemence to make a point. So, I would not call Dr Ambedkar ‘anti-Hindu’, but he had a strong critique of Hinduism as it was practised. That critique would embrace many of the beliefs of today’s BJP leadership.”
Dr Tharoor highlighted that the man who gave India its constitution was a profoundly convinced democrat. “Dr Ambedkar’s speeches in the constituent assembly and speeches about whether we might lose the democracy that the founding fathers were in the process of giving us, those are things which, in many ways, call for a certain resonance in the present governance that is lacking.”
Dr Ambedkar’s commitment to equity and social justice has inspired the theme of the conference. It is said that he may have named his party the Justice party, but that name had been taken in Tamil Nadu. “Justice” Dr Tharoor emphasised, “means redressing injustices” and that “if a party is in many ways guilty of perpetrating certain injustices, how is it exactly claiming to imbibe the spirit of the man who wants to overthrow those injustices.” It’s all very well saying we love Dalits and naming an app Bhim, but what lies beyond that, he asks.
In the last couple of years, communitarian groups like the gaurakshaks and khap panchayats seem to be playing a greater role in shaping public life. Would Ambedkar have been in favour of this trend? “A khap panchayat may have social, but no legal, political and jurisdictional sanction. For them to give an order that is binding on an individual and often involves punishment and duress of various sorts is something that can be taken to a court of law, and be objected to. Because of traditional social sanction, many khap panchayats have been allowed to essentially continue to exercise such unconstitutional influences and functions,” Dr Tharoor said, adding that if the decisions of such groups infringe upon individual civil liberty, then the victims of their decisions should have recourse to the judicial system of the country.
In Annihilation of Caste, Dr Ambedkar’s undelivered speech written in 1936, he wrote: “I have no hesitation in saying that if the Mohammedan has been cruel, the Hindu has been mean; and meanness is worse than cruelty.” With the conference in Bengaluru, the Congress party hopes to refresh in public memory, many such theories laid down by the social reformer of the last century. Dr Tharoor told Firstpost that although the conference will acknowledge negative elements like discrimination and deprivation, it will ultimately aim at building a positive spirit and a concrete agenda to steer the country forward.
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Giraffes are the tallest land animal in existence. Males reach heights of 5.5 meters (18 ft) and weigh up to 1900kg. At birth, calves are approx 1.8 meters (6ft) tall and weigh approximately 50-55kg. Giraffes have extremely long necks which they use to reach browse high in the trees. Surprisingly, they have only seven vertebrae in their neck - the same as humans, mice and most other mammals! However, the vertebrae in a giraffe’s neck are far more elongated.
(Giraffa camelopardalis)
Habitat
Giraffes are native to Africa and are reasonably widespread. They are found in open woodlands and savannah habitats.
Diet
A very long neck allows giraffes to reach all the leaves that the smaller browsing animals cannot. In fact, the only competition giraffes have for food is the elephant which can use its trunk to reach branches, or simply push the tree over! Giraffes are selective browsers feeding mainly from varieties of Acacia and Combretum plant species. From time to time, they are seen eating vines, herbs or even chewing on bones for extra minerals. They spend a whopping 16-20 hours-per-day browsing. Giraffes have a prehensile tongue which they use like fingers by curling it around the leaves to pluck them easily from the branch. Their tongue is very long– growing up to 40cm in length!
Communication
Giraffes are quiet animals and generally rely on sight as their primary sense. However, they do possess vocal chords which allow them to make a variety of sounds. Adults bellow, grunt and make a whistling noise, while calves bleat and moo. They are also able to communicate with infra-sound; a low frequency sound which is undetectable to humans.
http://www.australiazoo.com.au/our-animals/mammals/giraffe
These cheeky lemurs can be easily recognised by their long black and white-ringed tails. They are very social and live in troops which are lead by the dominant female lemur. Yes that’s right, the girls are the boss of Lemur troops! Troop sizes range from 11 to 17 generally, however numbers into the high 20s have been recorded. They live in multi male, multi female groups centred around related females and their offspring.
Habitat
Ring-tailed Lemurs live along the south and south western portion of Madagascar. They can be found in a variety of forests such as, rainforests, gallery, deciduous and spiny bush forests.
Diet
Their diet consists of fruit, leaves, flowers, other plant parts and the occasional insect and small vertebrates.
http://www.australiazoo.com.au/our-animals/mammals/lemurs/black-and-white-ruffed-lemur
this image is not for Sale
Cheetah are not classed as 'big cats'. Big cats have the ability to roar - cheetahs have instead retained the ability to purr, just like your domestic cat at home.
(Acinonyx jubatus)
The cheetah has a slender, elongated body supported on tall, thin legs with blunt semi-retractable claws and a flattened rudder-like tail that measures half of the cheetah's head and body length. Black "tear marks" run down the face from the corner of the eyes down to the mouth. It is believed that the "tear marks" aid in hunting by helping to keep the sun out of the eyes. The coat colour is tan with evenly spaced black spots. The coat is coarse and short. Adult body length 112-135cm; tail length 66-84cm; shoulder height 73-90cm; weight 34-65kg.
Habitat
Cheetahs prefer vast areas of open country, such as grassy plains or savannahs, although they can survive in a variety of different habitats including open woodlands, semi-desert, sandy plains, dense vegetation, and mountainous terrain.
Diet
Cheetahs are diurnal meaning they are active during the day. Cheetahs usually hunt in the late morning and early evening. They capture their prey by stalking until the prey is within 10-30 metres before initiating the chase. Because cheetahs store heat internally they will only chase over very short distances before they must stop and cool down. Chases usually last around 20 seconds and no longer than 1 minute. About half of all chases are successful. Cheetahs use a bite to the throat in order to suffocate their prey. Their diet consists of Thomson's and Grant's gazelles, springbok, reedbuck, waterbuck, kudu, steenbok, duiker, warthog, hare, game birds, and wildebeest. Because of their relatively small size in comparison to other large predators in Africa, cheetahs commonly lose 10-50% of their kills to lions, hyaenas and leopards. Cheetahs are well adapted to living in arid environments and are not obligate drinkers. They appear to be able to satisfy their moisture requirements from their prey's blood and urine or by eating tsama melons.
Breeding
Cheetah breed once a year. The female raises the cubs ranging from 2-8 (but usually 3 or 4) herself. They will stay with her for up to two years.
Survival Threats
The primary threat to the cheetah is loss of habitat due to human settlement and agriculture. Decline in prey, poaching, and indiscriminate trapping and shooting as a livestock predator also threaten the survival of the cheetah throughout its range. As a protected species in Namibia, people are allowed to remove cheetahs only if they pose a threat to livestock or human life. Unfortunately, some farmers will capture cheetahs indiscriminantly, often removing or killing those that have not taken any livestock. In North Africa and Iran, severe depletion of the prey base has brought cheetahs to near extinction.
Distribution
Once widely distributed throughout Europe, Asia, Africa, and North America, the cheetah can now only be found scattered in various countries in Sub-Saharan Africa and a small population in Iran. The major strongholds of the cheetah are in eastern and southern Africa, primarily Kenya, Tanzania, and Namibia.
Only 10,000 cheetahs remain in 25 African countries and a further 100 cheetahs survive in Iran. The largest population of cheetahs occurs in Namibia where 95 percent of wild cheetahs live on commercial farms.
http://www.australiazoo.com.au/our-animals/mammals/cheetahs
Tiger fur is usually coloured with black stripes on a orange base and white underbelly. White tigers are rare with dark pink noses and blue eyes. Stripeless tigers have also been recorded but are the rarest to be seen. Tigers have the largest canine teeth of any land carnivores, and they have extremely powerful jaws.
Habitat
The Bengal tiger is a large, striped cat found in India, Bangladesh, Nepal, Bhutan, and Burma. It lives in a variety of habitats, including rainforests and dense grasslands.
Diet
Tigers, as with all animals at the top of the food chain, help balance populations. When a tiger has eaten its portion, the leftovers become food for a an array of other mammals, reptiles and birds. Tigers are meat eaters (carnivores). Their prey includes small to medium sized mammals like badgers, rabbits, boars, deer and wild cattle ranging in size from 25-1000kg. Their hunting method is a slow patient stalk through cover until they are close enough for the final spring.
The usual method of killing is to ambush their prey from behind and bite its neck, killing it instantly. Approximately, only one hunt in 20 is successful. The tiger will then drag the kill to a safe place where they will consume it. Tigers can eat as much as 30-40 kilograms of meat in one sitting and can then go for days at a time without eating anything at all.
http://www.australiazoo.com.au/our-animals/mammals/tigers/bengal-tiger
Isn't he just beautiful?
The blue-and-gold macaw is not a species of bird which is native to the Australian country side. This macaw is very easily recognised by its stunning golden chest, large white cheek patch and a beautiful blue back and tail. One of seven species inhabiting the Amazon Basin, the blue and gold macaw is definitely one of the worlds more stunning parrots.
Belonging to the parrot family, the blue-and-gold macaw will quite often be seen in very large flocks, even mixing with a range of other species without any conflict occurring. Each individual macaw has a unique pattern of feathers on the bare patch of skin on its face. This can almost be used as a fingerprint to identify individual birds. Their very long and colourful tail they use as a rudder and a brake when flying through the forest canopy.
Habitat
Like all of the macaws this particular species can be found inhabiting a vast range of the forests in and around the central northern regions of South America.
Diet
This particular species is very adept at utilising its rather large beak to break into even the toughest nut, yet it can also delicately remove fruits and berries to eat as well.
Bird Size
Of the sixteen species of macaws found throughout South America, the blue-and-gold macaw is definitely up there in regards to parrot size. Averaging between 900 and 1200 grams and with a body length of almost two feet, this particular species belongs to one of the most well recognised group of birds any where in the world.
http://www.australiazoo.com.au/our-animals/birds/exotic-parrots/blue-and-gold-macaw
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Antipyretic effects of nimesulide, paracetamol and ibuprofen-paracetamol.
The antipyretic effect of nimesulide has not been adequately compared with paracetamol and ibuprofen-paracetamol combination in children. Hence, a randomized, double blind, and parallel groups' design and multicenter study was conducted on children with respiratory tract infections. Eighty-nine patients with temperatures above 38.5 degrees C were randomly administered nimesulide (1.5 mg/kg/dose), paracetamol (10.0 mg/kg/dose), or ibuprofen-patients combination (10.0 mg/kg/dose), thrice daily for five days. The axillary temperature was recorded at the baseline and at different time intervals post administration of drugs. The hematological and biochemical investigations were performed at the basal level and at the end of the treatment period. The adverse drug reactions were monitored during the trial. All the drugs produced a significant fall in temperature as compared to their respective basal values (p < 0.001). However, on looking at the change in temperatures at different time intervals from the respective basal levels, no significant difference was found among all the drugs. Surprisingly, nimesulide had a tendency to raise serum glutamate pyruvate transaminase and serum glutamate oxaloacetate transaminase levels as compared to its baseline values. There was no marked adverse effect of the drugs on other hematological and biochemical parameters investigated. No other serious adverse reaction occurred in the study. Ibuprofen-paracetamol combination, nimesulide, and paracetamol had almost similar antipyretic effects in children.
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Parents have company over Stay in your room until they leave
469 shares
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