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Quest Means Business
Tributes Pour In For US Senator Dianne Feinstein; GOP Plan To Avert Shutdown Fails, Heading For Shutdown; Interview With Rep. Sara Jacobs (D- CA); United Auto Workers Expand Strike At Ford And G.M.; Heavy Rain Causes Flash Floods In New York City Area; Hardline Republicans Hold Out For Budget Cuts. Aired 3-4p ET
Aired September 29, 2023 - 15:00:00 ET
THIS IS A RUSH TRANSCRIPT. THIS COPY MAY NOT BE IN ITS FINAL FORM AND MAY BE UPDATED.
RICHARD QUEST, CNN INTERNATIONAL HOST: Less an hour to go trading on Wall Street, and September is living up to its reputation as the worst month for
stocks. The Dow is down some four percent. If you look at the triple stack, the NASDAQ is off five-and-a-quarter percent for the month so far.
That's where the markets are looking. The events of the day: Sad news, very sad. Dianne Feinstein, the longest serving female senator in US history has
died at the age of 90.
The US is bracing for a potential government shutdown with 33 hours left to reach a budget deal.
And the chief executive of Axel Springer joins me in the C-suite in the sky. Believing AI can be a journalist's friend, not the enemy.
Tonight, I'm live in London. It's Friday, September 29th, the month is just about gone. I'm Richard Quest in London in September, I mean business.
Good evening. Good day.
We believe, we begin, I should say with two big stories from Washington, DC, the US nation's capital.
Firstly, tributes for the late US Senator Dianne Feinstein are being paid, and at the same time showing the dysfunctionality of the US capital, last
ditch efforts to keep the US government open seem to have failed.
The reality, if lawmakers fail to reach a spending agreement, the US government, the federal government will shut down just after midnight on
Congress began their work today. However, on a more personal and a deeply somber note.
(BEGIN VIDEO CLIP)
SEN. CHUCK SCHUMER (D-NY): May I ask that the Senate observe a moment of silence in honor of Senator Dianne Feinstein.
(END VIDEO CLIP)
QUEST: Senator Feinstein passed away at the age of 90. The California Democrat was the Senate's longest serving female member. The word being
used to describe her across the board today is "trailblazer" because she broke gender barriers throughout her political career. She earned a
reputation as someone eager to work across the aisle, a true bipartisanship, so President Joe Biden offered this tribute.
(BEGIN VIDEO CLIP)
JOE BIDEN, PRESIDENT OF THE UNITED STATES: She was a historic figure, a trailblazer for women, and a great friend and made her mark in everything
from national security to the environment, gun safety to protecting civil liberties.
The country is going to miss her dearly, and so will Jill and I.
(END VIDEO CLIP)
QUEST: Jim Sciutto is with me from Washington.
You have much work to do for us this evening on both stories before we get to delve down and deep into them. Let's first hear CNN's Wolf Blitzer, who
looks back at Senator Feinstein's life and legacy.
WOLF BLITZER, CNN HOST, "THE SITUATION ROOM" (voice over): Dianne Feinstein emerged on the national stage after a 1978 tragedy in San Francisco.
SEN. DIANNE FEINSTEIN (D-CA): Mayor Moscone and supervisor Harvey Milk have been shot and killed.
BLITZER (voice over): After the assassinations, Feinstein was sworn in as the first female mayor of the City by the Bay.
Mayor Feinstein quickly got the attention of the National Democratic Party, landing on a shortlist of VP candidates for Walter Mondale in 1984.
FEINSTEIN: We will take back our unity.
BLITZER (voice over): Feinstein made it to Washington when she won a special election in 1992 and went to the nation's capital with Barbara
Boxer as California's first female senators.
FEINSTEIN: I won among men. I won among women. I won in every age level. I won in every ethnic group.
Now what that says is that to me, the fact that I'm a woman is there, but it's incidental.
BLITZER (voice over): The assassinations that made her a mayor also made her an outspoken advocate for gun control. Feinstein was crucial in passing
the 1994 federal ban on assault weapons.
FEINSTEIN: I've seen assassination. I've seen killing. I've been a mayor. I know what these guns can do. Why is it, every man comes before me and says,
nice lady, you really don't know.
BLITZER (voice over): She was unsuccessful in renewing the legislation in 2004, but she didn't give up resurfacing the bill after the Sandy Hook
massacre and going toe-to-toe with conservative senator, Ted Cruz.
FEINSTEIN: I was a mayor for nine years. I walked in, I saw people shot I've looked at bodies that have been shot with these weapons.
BLITZER (voice over): She was the first female member of the Senate Judiciary Committee and the first woman to leave the Senate Intelligence
Committee. Considered a moderate Democrat, she often challenged her own party with their pro-death penalty stance.
After Donald Trump was elected president, Feinstein got groans from hometown Democrats, when she encouraged your party to be patient with him.
FEINSTEIN: I just hope he has the ability to learn and to change and if he does, he can be a good president, and that's my hope.
DONALD TRUMP, FORMER PRESIDENT OF THE UNITED STATES: Senator Feinstein, that's another beauty.
BLITZER (voice over): But Feinstein was hardly a favorite of President Trump, especially when her committee's investigation of sexual misconduct
allegations against Brett Kavanaugh nearly derailed his nomination to the US Supreme Court.
TRUMP: I'd like to find out who leaked the papers. Was it Senator Feinstein?
BLITZER (voice over): As her party shifted to the left during the Trump administration, Feinstein did the same, announcing officially in 2018, that
she no longer supported the death penalty.
FEINSTEIN: I don't want to not grow. I don't want to not learn and the world changes and views change.
BLITZER (voice over): By the time Feinstein was elected to a fifth full term in 2018, she was the oldest sitting US senator.
In February 2023, she announced that she would not be running for re- election. Later that year, health problems kept her off the job for three months holding up approval of several judicial nominees. Some Democrats
called for her to resign, but she kept going.
Dianne Feinstein often led the way for women and men on the Hill with a dedication to public service and an uncommon resilience.
FEINSTEIN: Life is filled with defeats and you just pick yourself up and you go on.
QUEST: Jim is with me in Washington. Every time I see these lives of these tremendous politicians, and she was one of the greats.
JIM SCIUTTO CNN ANCHOR AND CHIEF NATIONAL SECURITY CORRESPONDENT: She was and for folks, more recent observers of Washington, that they would know of
her health issues later in life and might think of her only in those terms, but she was in the Senate for three decades. And as Wolf recounted there,
central to roles to attempt to address gun violence in this country, you know, driven by her own personal experience of it.
She witnessed the assassination of two of her colleagues in San Francisco back in 1978 that helped drive her, but she also -- she rose to the
chairmanship of the Judiciary Committee, so central to choosing judges in this country. She was chairman of the Intelligence Committee, central to
investigating the CIA's use of torture following the 9/11 attack.
So she had a long and illustrious career here in this country, and of course, was a trailblazer for women as well.
QUEST: Now, she was bipartisan in many cases, and in fact, one of the last votes she actually did was on the Senate deal to keep the US government
open, I believe, but the reality is, efforts, Jim, to keep them up have been dealt major blows time and time and time again.
Today, the lawmakers failed to advance and to try to do it.
Have a listen to Kevin McCarthy, and then tell me, where does this go next? Here's the speaker.
(BEGIN VIDEO CLIP)
REP. KEVIN MCCARTHY (R-CA): It's easy to surrender. If you want to surrender, yes, but if you want to fight for the American public to secure
our borders and keep government open, how is that a problem?
(END VIDEO CLIP)
QUEST: So how much trouble -- I mean, first of all, is the accepted wisdom there is going to be a shutdown?
SCIUTTO: Hundred percent. I spoke to a Republican member of Congress just a short time ago who actually voted for this continuing resolution, you know,
too in the weeds, but basically a chance to keep the government open. He voted for it.
But the fact is, McCarthy there, you know, he talks about standing up and not surrendering. I mean, he's got a problem in his own party, right,
because 21 members of his own party have voted against this. And frankly, some of them may want to see a shutdown. I mean, you do have a wing of the
Republican Party here that is sort of bring the temple down, right, to get what they want and that threatens, most crucially, shutting down the
government here, but also his speakership.
I spoke to a Democratic Congressman yesterday who said that if it does shut down, he, when he speaks to his Republican colleagues doesn't see their way
out, right, that this wouldn't be a 24-hour shutdown, but could be days weeks and you know, better than me, Richard Quest that that has genuine
economic consequences for this country.
QUEST: Around six, seven billion a week, about 0.2 percent of GDP. But Jim, listen, he could get a deal through if he is prepared to drop the spending
cuts, thereby getting the Democrats on board and he is home and dry before tea time.
SCIUTTO: Problem with that is he loses his speakership, so this is literally a case of self over country, right, because there's an obvious --
and you would get Republicans and Democrats to vote for that. Believe it or not, you do have some moderates in this country based on the way districts
are drawn. You do have some Republicans who know that a shutdown might put them into trouble in the next political cycle, next election next year.
But McCarthy knows that if he were to make that deal with Democrats, then he loses the razor thin support he has among Republicans for his
speakership. So what's he going to choose? It appears he is -- well, again, we've got some time, but it appears that he is choosing speakership over
keeping the government open.
QUEST: I guess, you didn't have many plans over the weekend, because it looks like you're going --
SCIUTTO: I don't anymore, Richard Quest. I'll be back here tomorrow for our viewers, if they're interested where this goes.
QUEST: Oh, absolutely. Thank you, Jim. Thank you. Have a good weekend, whatever you can enjoy. Thank you.
SCIUTTO: Appreciate it.
QUEST: Now, to the Democratic Congresswoman Sara Jacobs, of California, San Diego.
Congresswoman, before we deal with the gritty unpleasantness of the budget -- of the shutdown, California, Senator Dianne Feinstein, obviously, you
knew her. This is a -- it is sad.
I mean, yes, she was 90. So you know, it is not a tragedy in a sense, but the sadness is great.
REP. SARA JACOBS (D-CA): Yes, it is a very sad day for California and for our country, and my heart goes out to her family and loved ones.
You know, Senator Feinstein was just a giant. I feel so grateful to have grown up in California at a time where I only really knew two female
senators, and thought it was normal, and didn't have to imagine what it would be like to have woman in leadership because I got to see it all the
Senator Feinstein was a real trailblazer, whether it was LGBTQ+ rights, or fighting against torture, or making sure that we were addressing the gun
violence issues in our country with her assault weapons ban.
She will be missed, and her legacy will be long.
QUEST: As I said, one of her last votes was to keep the government open. And it looks like -- I mean, Jim Sciutto says, a hundred percent, this
thing is going to shut tomorrow night, Saturday night, I guess you probably wouldn't disagree.
So the issue for you is, what would it take -- I'm not suggesting that it's on the table yet, but what would it take from the speaker by way of a bill
that you could sign on to? What would he have to drop from the existing measures?
JACOBS: Well, there already is a bipartisan bill. The Senate has passed a bipartisan continuing resolution with overwhelming support from both
parties, and if that bill were to be brought to the House floor, it would pass the House with overwhelming bipartisan majority as well.
So the fact of the matter is, we don't actually -- we just need Kevin McCarthy to bring up the bill that is already passing the Senate and
already has the support of as many members as it needs to, to become law.
QUEST: Do you find it distasteful that the speaker is really putting his -- forgive me, it is a leading question when I put it like that, but you know
what I mean? He is putting his speakership before keeping the government open, because if he were to put that Senate vote to or that Senate bill to
the House, he would lose his speakership.
JACOBS: I think it's incredibly disappointing and infuriating. Kevin McCarthy already made a deal with President Biden, we voted on a deal and
he needs to uphold the deal. And the fact of the matter is, he is putting himself among the servicemembers who are going to have to work without pay,
the mothers and children who are going to get turned away from grocery stores because their WIC won't be funded.
I mean, this is going to be devastating for people, and Kevin McCarthy can stop it by just bringing the Senate continuing resolution up for a vote and
he refuses to do it.
QUEST: Now you have particular interest, I mean, the federal government is vast, but you're from San Diego, your district in San Diego, and you have -
- you're the largest military complex in a sense, or the largest military economy in the country.
So you're going to have soldiers and military officers not paid, but more importantly, in a sense, because, you know, it's all the companies that
suddenly won't get paid, all the contracts will be disrupted.
JACOBS: That's right. I'm incredibly worried about our servicemembers and their families. You know, in San Diego County alone, we already have 45,000
members of military families who visit the food bank every single month and that was while they were getting their paychecks.
So it's going to be so hard on these families to not get paid for the work that they're doing, and while it will be hard for our servicemembers and
federal workers, they will be getting back pay, our contractors like the people who clean federal offices, they might not get back pay and we're
fighting to make sure they do because they deserve it as well.
QUEST: All right, we've got viewers all around the world watching, every nation, and they're looking and they're saying, what's wrong with you? I
mean, other countries have political discussions and they have discord, but they don't close down. As the president said -- oh, he -- the president
believes it's a dangerous time, but has de facto the US become ungovernable?
JACOBS: Look, I think it's incredibly hard for us to lead on the world stage when we can't even keep our own government open. And I think that,
you know, this shows how much work we have to do here at home and why we need to have humility as we partner with other countries in moving things
forward on our shared values.
But I don't think the United States is ungovernable. In fact, House Democrats, Senate Republicans, Senate Democrats and the White House all
agree on what we need to do. It is only a small group of extreme House Republicans who are holding everything up.
And if Kevin McCarthy had a spine, he could bring up the bipartisan package that would get a vote.
QUEST: I am saying to everybody involved in this, I hope, you didn't have any weekend plans and I suspect you're going to have to stay close to the
Capitol in case there's late votes.
But next time we speak, hopefully it'll be in San Diego, which will be a delight for us. Thank you, ma'am. Enjoy your weekend.
JACOBS: I would love that.
QUEST: Thank you.
It's QUEST MEANS BUSINESS. What a day.
Let's go from the United States to the east, to Evergrande, Chinese authorities are now detaining its chairman. It is the latest drama facing
the crisis at the property giant, and one that could derail frankly the Chinese economy in much greater ways to come, in a moment.
QUEST: A NATO country could be about to elect a pro-Russian leader this weekend. He is Robert Fico and his opposition party are leading the polls
ahead of Saturday's voting in Slovakia, which of course is a neighbor and a close ally of Ukraine.
Fico could soon flip the dynamic. He is parroting the Kremlin's justifications for its invasion and he's already said if he's elected,
there is not one more piece of ammunition or military hardware will go from Slovakia to Ukraine.
CNN's Scott McLean has been watching events.
SCOTT MCLEAN, CNN CORRESPONDENT: Slovakia is a NATO member, an EU member. It borders Ukraine and it has been one of its strongest allies since the
outset of the war. It has sent helicopters, air defense, and artillery systems, but that may soon stop. That's because the leading candidate for
prime minister of Slovakia is a man named Robert Fico. He has been prime minister twice before. He is a well known quantity in the country. He is
also openly sympathetic to Moscow, claiming that it was Ukrainian Nazis and fascists in his words who provoked Russia into war.
He says that sending weapons to Ukraine only prolongs the conflict, so he says that if he takes office, he will not send Ukraine even one more round
of ammunition. He is framing this as a Peace Initiative, especially in light of rising inflation, rising cost of living that is squeezing people's
Slovakia has also taken in more than a hundred thousand Ukrainian refugees, which is further straining the public purse. And there's also this, Fico
doesn't think that Ukraine can win. Listen.
(BEGIN VIDEO CLIP)
ROBERT FICO, SLOVAKIAN PRIME MINISTERIAL CANDIDATE (through translator): Please, can someone explain to me why tens, maybe hundreds of thousands of
soldiers should be dying on either side of this conflict? They will have to sit down anyways and find an agreement because Russia will never leave
Crimea, never leave the territories that it controls in Ukraine.
So what is this conflict good for?
(END VIDEO CLIP)
MCLEAN: What is especially remarkable is that Fico was forced out of office by scandal in 2018, but because of at least in part political chaos and
infighting in recent years, Fico has managed to not only rehabilitate his image, he is now the frontrunner.
Slovakia, though has a lot of political parties, and it is very likely that he will need the support of another to govern as a coalition and while Fico
may pair with a more moderate party, he hasn't ruled out the possibility of pairing with a far-right party with even more extreme views on Russia and
Scott McLean, CNN, London.
QUEST: Well, uncertainty now about the future of the embattled giant property company, Evergrande after Chinese authorities detained its
chairman. Officials are calling it suspicion of crimes. It is the latest twist in the saga, and it's one of the major problems facing China's
CNN's Marc Stewart is our correspondent in Beijing.
MARC STEWART, CNN CORRESPONDENT: China's real estate sector is dealing with a long list of troubles, people have invested in a home only to find
construction come to a halt.
Right now, there is a lot of focus on real estate developer Evergrande. Chinese authorities are investigating the company's Executive Director and
chairman of the board over suspicion of crimes.
If we look at the timetable, it comes just weeks after police launched their first criminal probe since the firm defaulted on debt nearly two
years ago. In addition, shares of Evergrande and its two subsidiaries were also suspended from trading in Hong Kong. This comes amid fears about its
ability to restructure its debts and fears of a liquidation.
Evergrande is not the only real estate developer struggling right now. China's economic woes have impacted the real estate market in a broader
sense. We asked one observer to share his observations.
ANDREW COLLIER, MANAGING DIRECTOR, ORIENT CAPITAL RESEARCH: The economy is going to have to reset itself at a lower level. That's the key issue. And
what we don't know is how low a level that's going to be and how much of a political mess in terms of anger towards the central government that's
going to cause.
STEWART: So why is this happening? The housing sector has been seen as a sense of strength in the Chinese economy, but after the pandemic, people
became reluctant to spend money, unemployment rose, housing prices fell as buyers questioned whether a home was a worthy investment.
Those woes have damaged investor confidence in the Chinese housing sector, making it harder for developers to borrow money on the financial market to
fund ambitious projects.
Marc Stewart, CNN, Beijing.
QUEST: And so, at the heart of the US government shutdown fight is a standoff within the Republican Party itself and it is that infighting that
very likely will bring the whole government to a standstill.
We'll talk about that in a moment.
QUEST: Hello, I'm Richard Quest.
So much more QUEST MEANS BUSINESS to bring you across CNN. The US government shutdown, the far reaching consequences, we will do the economic
And I met the chief executive of Axel Springer, who has some extraordinarily good views on artificial intelligence. He says it's a
friend to the media industry, not an enemy. We'll get down to that only after I've updated you with the news because this is CNN and on this
network, the news come first.
Pakistani officials are blaming suicide bombers for deadly attacks on two religious gatherings. The first target is a procession marking the birthday
of the Prophet Muhammad. At least 52 people were killed and dozens of people were injured.
Hour later, two blasts hit Friday prayers near Peshawar City, there at least four people were killed.
Inflation in the Eurozone hit its lowest level in two years. Consumer prices this month rose at an annual rate of 4.3 percent. Now if the slowest
pace since October of '21. The hope is that the European Central Bank will pause in its interest rate hikes, but that level of interest is still twice
as high as the EU CB wants.
The United Auto Workers says it's expanding its strike, an additional 7,000 workers will now picket at Ford and General Motors. The walkout will not be
extended at Stellantis, which makes vehicles in the Jeep and Chrysler brands. There are negotiations in progress which is the reason why.
There are now 25,000 people on strike across the Big 3 US automakers.
A state of emergency has been declared in New York City. Heavy rain is flooding subways, roads, and basements. More than a month's worth of rain,
about 10 centimeters has dropped in parts of Brooklyn over the last three hours. The National Weather Service is warning totals could be more than 20
centimeters, nearly a foot in the course of the region.
There's blame to go around in the budget standoff plenty for all. But at its core probably is a small group of hardline House Republicans who want
to cut federal spending dramatically and drastically. And they're also wanting to cut U.S. aid to Ukraine. Some have threatened to oust the
Speaker Kevin McCarthy who's unable to count on his right-wing lawmakers. Those like Florida's Matt Gaetz and Georgia's Marjorie Taylor Greene.
Doug Heye is the former communications director for the Republican National Committee. He's with me now from Washington. This is really a Republican
problem, isn't it? In a sense, it's everybody's problem. But it's a Republican problem because Republicans could if they wanted to pass this on
DOUG HEYE, FORMER COMMUNICATIONS DIRECTOR, REPUBLICAN NATIONAL COMMITTEE: Well, in theory, they could if they wanted to, but they start with not
wanting to because of internal Republican politics and what we see -- and I'll tell you, Richard, I worked in the 2013 shutdown that we had. And when
did that begin? October the 1st. So, it's very similar territory. The fights that we had then were about Republicans who wanted to fight with
each other, and demonstrate to their base that there were fighters.
That didn't necessarily have to have a strategy to land a punch or win around, or certainly when the fight, just an ability to show that you're
throwing punches is often rewarded in the Republican base. That's precisely what we see now. The outcrop of that is that Republicans will fight with
each other on the House floor. And in statements that's happening now as well. And I'll tell you, Richard, I've heard you ask a couple of guests
earlier, including Jim Sciutto.
You know, I hope that you hope that he didn't have weekend plans. A lot of people in Washington had plans this weekend. Bruce Springsteen was supposed
to play a concert about a mile from the Capitol just tonight, that -- that's gotten postponed. But when the date was announced for September
29th, the e-mails went around. We all know what tomorrow is. And a lot of people were worried weeks and months in advance that they'd have to cancel.
QUEST: And indeed, all things postponed anyway. So, they get another attempt which is more than the U.S. economy will do. Because -- look, the
numbers I've seen, Goldman says it's about point-two-tenths of a percent per week. The six billion $7 billion. Eventually, it will have an effect,
even if everybody who's furloughed gets their money back.
HEYE: Absolutely. And, you know, so often in politics in Washington, you get -- you get caught in your own intraparty or enter Congress house versus
Senate games. You sort of forget sometimes that there's the country watching and the world is watching. And that also means markets. And so,
what we know is whatever happens in this process, that will not be pretty, we don't know how it will end, only that it should end at some point.
It's going to affect markets, it's going to affect the pocketbooks of not just people in the military but essentially on one level, every American.
QUEST: Right. But Doug, there's also another solution which I agree before your answer will cost the speaker his speakership. He could drop many of
the spending cuts, just go for a continuing resolution, and he would have Democratic support to get over the -- over the edge.
HEYE: It -- certainly, that could happen. Ultimately, that may be the result. The challenge there is -- it's been put a lot of, you know, Kevin
McCarthy's being selfish, he needs to put the country's interests in front of his own. And I get that. The reality is if that motion to vacate the
chair is introduced, the House goes into immediate chaos. This isn't replacing a senator or a member of Congress.
This is a constitutional office. The house will go into chaos if that happens. So, by trying to do this, it is may be the least bad option for
McCarthy right now. If he vacates his speakership, the House will be plunged in chaos. And again, the rest of the world and the markets are
QUEST: Thank you, sir. We'll talk --
HEYE: Anytime. Thank you.
QUEST: Actually, no, hang on. Before you go.
QUEST: Did you have tickets for that concert?
HEYE: Of course, I did. Absolutely. This would have been concert number -- like 54 for Bruce for me. And unfortunately, we'll have to wait a few
QUEST: Well, now I can -- now I can see the sort of person we're dealing with here.
HEYE: Yes. Mental one. Yes.
QUEST: Fifty-four. Right. There we go, sir. Excellent. We look forward to it. Thank you very much. Have a good weekend.
HEYE: Thank you. You too.
QUEST: The economic impacts of a U.S. government shutdown, they will be sprawling. As I said, Goldman Sachs says it's about two-tenths of a
percent. A stalemate delays, jobs and inflation data that helps the guide the Federal Reserve.
It also gives transparency and vision to private economists. The top U.S. securities regulator would have to cut staff. That could still deal making
wherever you look, there will be trouble.
U.S. Treasury Secretary spoke earlier. Janet Yellen said a shutdown would threaten economic progress.
(BEGIN VIDEO CLIP)
JANET YELLEN, U.S. TREASURY SECRETARY: To failure of House Republicans to act would hurt American families and cause economic headwinds that could
undermine the progress we're making. A shutdown would impact many key government functions, from loans to farmers and small businesses, to food
and workplace safety inspections to head start programs for children.
(END VIDEO CLIP)
QUEST: Thomas Phillipson was the acting chair of the U.S. Economic Council of Economic Advisers in the Trump White House. He's with me now from Miami.
Sir, good to see you. The reality is, yes, we sort of know what happens when the government shuts down. And yes, everybody does sort of get paid
back when it's over. But the level of uncertainty this time is on a different level.
THOMAS PHILLIPSON, FORMER ACTING CHAIR, U.S. COUNCIL OF ECONOMIC ADVISERS: Yes. I think it's a -- there's two questions, sort of how long is this
going to last and what -- how broad is the spending cuts on how long. Usually these things are pretty short in terms of once the pain goes up
with the population, they start yelling at their representatives. The one that airlines lines at the airport are becoming too long, et cetera.
So, it's usually pretty short. What's covered is this a little bit misguided I think in terms of the disaster looming. There's no, you know,
standards. Mandatory spending is not being shut off. And that's 75 percent of the federal budget. 25 percent of discretionary spending is that what a
steak essentially. But even within that 25 percent bucket, essential operations are still going to go on.
QUEST: You -- right. But we don't know, for example, whether there'll be sick out to the airport, we don't know whether essential operations
actually mean full staffing. And if you take for example, I saw you writing about it earlier. If you take the travel industry, this is a groaning giant
to start with with the FAA, the TSP and all of these things and CVB. The last thing anybody wants is to put more pressure on a system that was
sprouting leaks regardless.
PHILLIPSON: Yes, I think that's right. And that's where you see the pressure points. Once the voters see the implications of this, it's going
to be a lot of frustration with a representative. But even the economic sphere, so the Fed and similar agencies is not under threat here because
they're covered by fees essentially. They're not congressionally funded through appropriation. The White House staff is essentially.
And then when I was in the White House in 2019, the last time we had a shutdown, essentially, there was a lot of empty halls walking around
because non-principals were essentially shut out of work. But certain regulatory agencies, SEC, the Securities Exchange Commissions, CFTC, et
cetera, the data releases coming out of labor department and Commerce Department. They will be reduced essentially.
And that's when real threats, especially for that -- especially for the Fed who relies on those data quite heavily obviously the same policy.
QUEST: To us, the core point tonight is the dysfunctionality in a sense. Look, I don't know how I can -- I don't know how I can sweeten this
question. But the blunt reality is, other well-functioning democracies do not close down their governments as frequently as the United States does,
because of political infighting.
PHILLIPSON: Well, things particularly now we have a left-wing or Democratic party who's run by the left wing of their party, the Bernie Sanders
fraction, essentially, is driving a lot of policies. And then you have the Republican Party who's had mercy of their right wing within the Republican
Party. So, it's no surprise and this is going to continue all the way until the next election that you have a lot of disagreements which are very, very
hard to settle because of that sort of extreme division between the two parties.
QUEST: Did you ever -- did you have plans this weekend? I mean, you know, they'll have gone out the window and a sense of having to watch wait and
PHILLIPSON: I'm fine. I'm doing fine. I've tried to rely on the government as little as possible, put it that way. That's my -- that's my policy.
QUEST: We found somebody's going to have a good weekend. Have a -- enjoy, sir, in Miami. Enjoy the good weather. Thank you.
It's QUEST MEANS BUSINESS on a Friday. Delighted you're with us. When we come back, Axel Springer and some of the most recognizable media brands in
the world. I talked to the chief executive who's told me he's ready to embrace artificial intelligence in journalism.
(BEGIN VIDEO CLIP)
MATHIAS DOPFNER, CHIEF EXECUTIVE OFFICER, AXEL SPRINGER: We have already five projects where we take advantage of the possibilities of large
language models. I don't see it as a structural enemy of journalism. I see it as a potential friend.
(END VIDEO CLIP)
QUEST: This week, Call to Earth, we've turned the spotlight on France and man who believes seaweed is our planet's greatest untapped resource. He's
our guest editor, Vincent Doumeizel and he's determined to spread his message as broadly as possible. He even talked seaweed with French
president Emmanuel Macron. CNN's Zain Asher brings us the story.
ZAIN ASHER, CNN INTERNATIONAL ANCHOR (voiceover): Covered in vineyards, the burgundy region is what a wine connoisseur might refer to as a happy place.
Vincent Doumeizel would agree, particularly when it comes to his home in the quaint riverside town of Arcy-sur-Cure.
VINCENT DOUMEIZEL, FOOD PROGRAM DIRECTOR, LLOYD'S REGISTER FOUNDATION: At the place where my mother come from. It has been in my family for
generations and generation my family use to grow grapes here. I come here since I'm a child for my holidays and enjoying the rivers and the beauty,
full of hills around here.
ASHER (voiceover): Hundreds of kilometers from the nearest coastline, it's not however, what you'd consider a hotspot for another of his favorite
DOUMEIZEL: Or some more seaweeds there.
ASHER (voiceover): But Vincent usually has a backup supply on hand.
DOUMEIZEL: Seaweed is a nutritional bond. It is packed with nutrients, proteins, irons, vitamin C, anything you need.
ASHER (voiceover): Today, the father of three has enlisted the help of his children to prepare a seaweed centric meal to share with friends and family
at a historic picnic spot across town.
The group includes Vincent's bandmates who together form a local rock band called Arcy like the village.
DOUMEIZEL: We often gather and share meals and I like to make them discover seaweed and taste new things.
ASHER (voiceover): But in his day job as the Food Program Director for Lloyd's Register Foundation, Vincent believes that eating seaweed is key to
opening people's minds about its broader potential.
DOUMEIZEL: We need to preach all around the world and tell everyone that seaweed may we it'd be the greatest untapped resource we have on the
ASHER (voiceover): Earlier in the week Vincent traveled to the Brittany region of Northwest France, where the maritime city of Brest was hosting
EPC8. A weeklong conference dedicated to everything algae.
The quadrennial event brings together an international collective of scientists, experts and enthusiasts alike.
Vincent's become a rock star in these circles as well, but not only for a stage presence.
DOUMEIZEL: What's the solution looks like there. It does look like this. Big seaweed farm.
ASHER (voiceover): He first gained international attention in 2020 with the release of the Seaweed Manifesto. A 10-page document outlining how seaweed
can contribute to reaching the U.N.'s 2030 Sustainable Development Goals.
In 2023, the release of his first book, The Seaweed Revolution, upped the ante.
DOUMEIZEL: It led me to meet with our president, Mr. Macron to be invited in many meetings. And that -- that's a big difference. And I think a book
is a very strong way to carry the message.
ASHER (voiceover): Other well-known faces have taken notice too. But to Vincent, the notoriety takes a backseat to the mission.
DOUMEIZEL: We need a lot more seaweed, especially because they are disappearing because of ecosystem disruption. So we don't have enough of
them. We should restore them, we should repair them. And we should more importantly learn how to cultivate it.
QUEST: Seaweed. Who knew? And to see how more seaweed is one of our planet's most vulnerable resources. There's the full documentary it's Call
to Earth's Sea of Hope. It's this weekend at CNN.
QUEST: In Nevada, in Las Vegas, the police have confirmed they've arrested a suspect. In the decades old murder of Tupac Shakur. The rap store was
shot and killed while leaving a boxing match in 1996. In the years since the murder has been a subject of conspiracy theories and numerous
investigations. Now the authorities say Duane Keith Davis has been arrested on Friday morning, two months after his wife' home was searched in
connection with the case. The police have spoken just moments ago.
(BEGIN VIDEO CLIP)
LT. JASON JOHANSSON, LAS VEGAS POLICE DEPARTMENT: -- include members of Mob Piru came to Vegas to attend the Mike Tyson fight at the MGM Grand Garden
Members of the South Side Compton Crips, which included Duane Davis, along with his nephew Orlando Anderson, were also in attendance at the same
event. As both were leaving the fight, members of Death Row Records spotted Orlando Anderson near an elevator bay -- bank inside the MGM, a time they
begin to kick and punch him near that elevator bank.
I will now show you hotel security footage as -- related to the incident. And on this incident, you'll see Tupac Shakur who's wearing a shiny satiny
shirt with Marion Suge Knight who's a large man and a brown suit, punching and kicking Orlando Anderson. Following this incident, you'll see hotel
security intervene and then they will leave the area of the fight.
Little did anyone know that it is this incident right here that would ultimately lead to the retaliatory shooting and death of Tupac Shakur.
Following this incident, Tupac and Suge Knight both left the MGM to make their way to a post-fight party, which was the occur at a local nightclub.
At the same time, where it had spread amongst members of the Southside Compton Crips of what it -- inside the MGM and then that's when Duane Davis
began to devise a plan to obtain a firearm and retaliate against Suge Knight and Mr. Shakur for what occurred inside the hotel against Mr.
After Davis attained a gun, he entered into a white Cadillac along with Terrence Brown, DeAndre Smith and Orlando Anderson. Based on our
investigation, this is where he we know they were seated. At some point in time, as they are in the white Cadillac, Mr. Davis took the gun that he had
attained and provided it to the passengers in the rear see the vehicle. As they were both -- as they were driving west on Flamingo Road near Kobal,
they located the black BMW which was driven by Suge Knight and in the passenger seat was Tupac Shakur.
And as they turned around, they pulled up near the passenger side of that vehicle and immediately began shooting at Mr. Knight and Mr. Shakur.
Following that shooting, the white Cadillac fled the area southbound on Kobal. And as our actor officers arrived on scene, Tupac was later
transported to the University Medical Center where he was treated medically, and died approximately six days later on September 13th.
My homicide section handled this investigation from its onset and for a short amount of time. And within a short amount of time, what we knew was
that we were working on a game investigation where our victims, our witnesses and our suspects were all from Southern California and not local
to Las Vegas. Within the first few months of the investigation, our detectives knew most of the information I just briefed you on.
However, we never had the necessary evidence to bring this case forward and present it for criminal charges. As time went on this case -- viewed more
times by different investigators assigned to my section. But it wasn't until 2018 that this case was reinvigorated as additional -- came to light
related to this homicide. Typically, Duane Davis' own admissions to his involvement in this homicide investigation that he provided to numerous
different media outlets.
In our section, we knew at this time that this was likely our last time to take a run at this case to successful --
(END VIDEO CLIP)
QUEST: Absolutely fascinating. The step by step, abecedarian approach that the Vegas police took into the murder of Tupac Shakur. And what is
fascinating of what we've just heard, is that they have known pretty much since the beginning. It's just after the murder. The series and
circumstances have events but did not have the evidence to proceed further. And what we have still to learn, of course, is what changed.
What was the new evidence that they received in 2018 that now allowed them as the chief said to have another run at this case which they believed
would be the last chance to actually go against Duane. Fascinating and extremely well explained by the police officer there.
September has lived up to its reputation as a rough month. The Dow is set to close significantly lower tonight on the day and on the month. Overall,
the index has fallen about four percent tis month. A lot of red. Travelers is at the bottom. Caterpillar is giving back yesterday's gains. And Wal-
Mart is down which is interesting in recessionary times. But Morgan's off. Nike has popped its reported stronger profits than expected.
Walgreen is higher. It's a real mishmash. Bloomberg supporting Walgreens considering a former executive as chief executive. I'll take a profitable
moment with you after the break. Across the world, across the United States. This is CNN.
QUEST: Tonight's profitable moment. I want to bring together our two top stories for you. The death of Dianne Feinstein and the closure of the U.S.
government because a rump of Republicans won't agree to anything other than burning the House down. Dianne Feinstein's last vote was just yesterday. On
the floor, she raised her hand to say, I had to be helped a bit to pass a Senate -- a Senate measure that was going to pass, but would go no further.
It was an act of bipartisanship that was extraordinary by her. But it also spoke volumes against what we're seeing in the house where we have seen
numerous attempts today to try and keep the U.S. government open and they have failed. And if everything we heard Jim Sciutto told us earlier, it's
almost 100 percent clear that he -- that the U.S. government will shut down.
So, we have acts of bipartisanship from Schumer and Mitch McConnell and Dianne Feinstein and others. We have Democrats who say drop the spending
cuts and we'll help you across the road. We have Kevin McCarthy saying I'm not -- I'm not holding on just for my speakership. It's what's right. But
the truth and reality is, tomorrow night the U.S. federal government shuts down.
And as my late grandfather used to say, that's no way to run a railroad. And that's QUEST MEANS BUSINESS for this Friday night. I'm Richard Quest.
Whatever you're up to in the hours ahead, I hope it's profitable. I'll see you on Monday.

domain: news


text:
Targeting IL-4 for the Treatment of Atopic Dermatitis
Received 27 August 2020
Accepted for publication 16 September 2020
Published 29 September 2020 Volume 2020:9 Pages 151—156
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Professor Michael Shurin
Andrea Chiricozzi,1,2 Martina Maurelli,3 Ketty Peris,1,2 Giampiero Girolomoni3
1Dermatologia, Dipartimento Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; 2Dermatologia, Università Cattolica del Sacro Cuore, Rome, Italy; 3Department of Medicine, Section of Dermatology, University of Verona, Verona, Italy
Correspondence: Andrea Chiricozzi
Dermatologia, Dipartimento Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome 00168, Italy
Tel +39-339 5668320
Abstract: Atopic dermatitis (AD) is an immune-mediated inflammatory skin disease characterized by a predominant type 2 immune response. Type 2 immunity is driven by multiple cytokines, including interleukin (IL)‑4 and IL-13 that are considered central to AD pathogenesis and key therapeutic targets. The dual inhibition of these two cytokines or the selective inhibition of IL-13 proved elevated efficacy in treating AD, whereas the selective inhibition of IL-4 has been poorly investigated as IL-4 inhibiting agents did not show any advance in clinical development programs. This review describes the pathogenic role of IL-4 in AD and briefly resumes the main features of compounds selectively blocking IL-4.
Keywords: atopic dermatitis, IL-4, IL-4 inhibitor, dupilumab, pascolizumab, pitrakinra
Atopic dermatitis (AD) is a common inflammatory skin disease resulting from genetic predisposition and environmental factors that cause skin barrier impairment and predominant type 2 immune responses.1 Genetic susceptibility involves the keratinocyte differentiation process (ie, filaggrin) generating a defective epidermal barrier as well as immune dysregulation with a prevalent Th2 cytokine gene expression.1 The immune activation can be altered by the dysbiosis of the skin microbiota characterized by the marked colonization of Staphylococcus aureus.2 Thereby, AD pathogenesis represents a complicated mechanism wherein skin barrier, immune system, microbes, and, lately, the itch-mediating peripheral and central nervous system are interconnected. The pathogenic model has profoundly changed over the last two decades, overcoming the previous hypotheses based on (i) the immunoglobulin E (IgE)-mediated immune response (type 1 hypersensitivity), (ii) the primary role of the epidermal barrier impairment (“outside-in” theory), or (iii) the primary role of the aberrant immune activation (“inside-out” theory).3–5 The discovery of the role for multiple immune pathways has led to new concepts in AD pathogenesis, and subsequently, to novel therapeutic strategies. It is now clear that the exaggerated immune response and the skin barrier impairment are both necessary for the development of AD, that may be considered a heterogeneous disease, being characterized by different phenotypes/endotypes.1,6,7 The immune hallmark of AD is the type 2 inflammation that includes the activation of T helper (h) 2 cells, T cytotoxic (c) 2 cells, innate lymphoid cells (ILC)2, γ/δ T cells, eosinophils, and mast cells, B cells, while other immune pathways such as Th22, Th17, Th9 and Th1 contribute to the pathogenic mechanism, particularly in some AD subtypes.7,8
Type 2 immunity is driven by multiple cytokines, including interleukin (IL)‑4, IL‑5, IL‑9, IL‑13, IL‑25, IL-31, IL‑33 and thymic stromal lymphopoietin (TSLP). In particular, IL-4 and IL-13 are considered central to AD pathogenesis and key therapeutic targets.5,8–10 Because type 2 inflammation also characterizes other atopic disorders, such as food allergies, asthma, allergic rhinitis and conjunctivitis, which are strongly associated with AD, therapeutic strategies blocking type 2 cytokines may be relevant in treating AD and concomitant atopic disorders.11 In this review, we provide a brief overview about the pathogenic role of IL-4 and the therapeutic agents blocking this cytokine.
Search of the English-language literature regarding the pathogenic role of IL-4 in AD was carried out, in addition to therapeutic agents targeting IL-4 signaling. Different databases, namely PubMed, Embase, ResearchGate, Google Scholar and Scopus, have been consulted using the following terms: interleukin 4, IL-4, IL-4-inhibitor, IL-4-blocker, atopic dermatitis, atopic eczema, pathogenesis, pathogenic mechanism. Ongoing clinical trials and preliminary results concerning investigational use of IL-4 inhibitors in AD were searched on Clinicaltrial.gov. Data from recent international meetings were also taken into account.
Role of IL-4 in AD Pathogenesis
Gene encoding for IL-4 protein maps on human chromosome 5, clustering with other genes involved in AD pathogenesis such as IL-13 and IL-5, other than IL-3 and granulocyte macrophage colony-stimulating factor (GMCSF).12,13 IL-4 is a glycosylated, type I cytokine produced by Th2 cells, Tc2 cells, NK T cells, γ/δ T cells, ILC2, eosinophils, mast cells, and activated basophils.5,14 IL-4 signals through two different receptor complexes: a type I receptor composed by composed of IL-4Rα chain and common γ chain/IL-2 Rγ subunit, and expressed on hematopoietic cells, and a type II receptor consisting of IL-4Rα and IL-13Rα1 subunits, and expressed on nonhematopoietic cells.15,16 Whilst the type I receptor specifically transduces signals for IL-4, the type II receptor can be activated by either IL-4 or IL-13.5,15,16 IL-4 acts on both immune and tissue cells, mediating multiple steps of the pathogenic cascade in AD. On the T cell compartment, IL-4 drives the differentiation of naïve CD4+ T cells into Th2 cells, and similarly induces the development of Tc2 and ILC2 cells.17–20 On the B cell compartment, IL-4 induces IgE production.21 To amplify type 2 inflammation, IL-4 also modulates dendritic cell activity, reducing their expression of IL-12 and MHC class II and costimulatory molecules, and increasing the production of IL-10, and thus, favoring the differentiation of both naïve CD4+ and CD8+ T cells toward type 2 cells.22
The expansion of type 2 T cells results in an elevated frequency of circulating Tc2 and cutaneous lymphocyte‐associated antigen (CLA)+ IL-4‐producing T cells, detected in AD patients and reflecting a significantly higher number of both Th2 cells infiltrating both AD lesional and nonlesional skin.23–28 IL-4 also amplifies CCR4+ Th2 cell recruitment to the skin inducing the expression CCR4-binding chemokines, such as CCL22, CCL5, CCL17, CCL2, in monocytes and dendritic cells.29–31 In addition, it stimulates the expression of CCL26 (eotaxin-3) in keratinocytes, a key chemokine for eosinophil recruitment and, similarly, it induces in fibroblasts the expression of CCL11 (eotaxin-1), another critical cytokine for eosinophil recruitment.32,33
Mouse models have defined the centrality of IL-4 in AD pathogenesis, highlighting its capability in inducing all AD histopathological features.34,35 The overexpression of IL-4 induces IgE production, enhances skin inflammation, favors bacterial skin infection, and mediates pruritus.34,35 On the contrary, the lack of IL-4 reduces allergen-challenged skin reactivity, and attenuates IgE levels and skin eosinophilia.36,37 Besides the effect on immune cells, IL-4 also influences keratinocyte differentiation and their innate immune activation. In vitro, IL-4 stimulation alters early and terminal keratinocytes differentiation, suppressing the expression of both terminal keratinocyte differentiation proteins (ie, filaggrin, loricrin and involucrin), and genes related to differentiating keratinocytes at early stages (ie, keratin [Krt]1, Krt5, Krt10, Krt14, desmoglein [Dsg]1a, and desmocollin [Dsc]1).38–41 In addition, IL-4 alters extracellular lipid content in in vitro AD model similarly to the aberrant stratum corneum lipid structure observed in both AD mice model and human AD skin.42 IL-4 attenuates antimicrobial peptide (AMP) production, suppressing upregulation of beta defensin (HBD)-2, HBD-3, LCN2, and LL-37, even antagonizing IL-17-induced AMP production in keratinocytes.43–47 IL-4 also triggers fibroblast production of collagen, fibronectin, and fibrinogen, serving as adhesion molecules for Staphylococcus aureus.48–50 Thereby, IL-4 contributes to skin barrier function impairment and to the increased susceptibility to bacterial infections. In addition, IL-4 both directly and indirectly, stimulates itch sensory neurons. Indeed, IL-4 is capable of directly activating itch sensory neurons in vitro, and, in mice, intradermal injections of IL-4 induced rapid and significant increase of scratching.51,52 It has been shown, by employing sensory neuron-specific genetic deletion of IL-4Rα, that chronic itch is dependent on neuronal IL-4Rα and Janus kinase 1 signaling.52 Rather than triggering acute itch, activation of neuronal IL-4Rα sensitizes sensory neurons to multiple other pruritogens. IL-4 significantly amplifies scratching behavior to low doses of known pruritogens like histamine.52 The indirect effects of IL-4 in potentiating itch signal may be also due to its capability to enhance the interaction between IL-31, identified as key pruritogen cytokine, and its receptor (IL-31Rα), and increasing the expression of IL-31 receptor, in a dose-dependent manner, in bone marrow-derived dendritic cells.53 The presence of IL-4 increases CCL-17 and CCL-22 production regulated by IL-31, conversely to IL-31 stimulation alone.53 Finally, IL-4, together with granulocyte/macrophage colony stimulating factor, supports the differentiation of monocytes into monocyte-derived dendritic cells, which are abundantly present in AD lesional skin and potently contribute to sustain T cell activation in AD skin.54
Therapeutic Relevance of Targeting IL-4
Inhibition of type 2 inflammation proved elevated efficacy in treating AD. The first approved monoclonal antibody, dupilumab, which blocks IL-4Rα and thus the activity of both IL-13 and IL-4, primed the therapeutic strategy of blocking type 2 cytokines, their receptors, or their coupled intracellular signal transducers such as Janus kinases (JAK) - signal transducer and activator of transcription (STAT) pathway.55,56 Notwithstanding IL-4 signaling is considered a very interesting potential therapeutic target for the treatment of AD, a few attempts in neutralizing soluble IL-4 have been previously performed, but no pharmacologic entity blocking IL-4 is apparently in the current treatment pipeline for AD. The pharmaceutical development of monoclonal antibodies blocking the IL-4Rα subunit, is predominant.57 The therapeutic advantage of blocking this receptor subunit is to contemporarily neutralize the signaling of both IL-4 and IL-13 that show overlapping, but not redundant functions in potentiating type 2 inflammation. Indeed, IL-4, driving T cell differentiation, is thought to have a key pathogenic role in the early steps of AD pathogenesis, whereas IL-13 does not promote Th2 differentiation and its effects seem to be more focused on peripheral tissue cells and the effector phase of the immune response.56,58 Thereby, T cells respond to IL-4 stimulation only as they do not express IL-13 receptors with the exception of Th17 cells that are reported to express a functional IL-13 receptor lessening IL-17 production.59 The hypothesis of an early relevant intervention of IL-4 in the pathogenesis of AD is in line with other findings describing an elevated IL-4 expression in acute lesional skin, which further increase in chronic AD lesions.60,61 Because IL-4 mainly acts on both T cell and ILC differentiation towards a type 2 response, but tissue cell activation in AD is suggested to be preferentially driven by IL-13, the dual blockade of these cytokines has the advantage of blocking multiple steps of the pathogenic cascade, reflecting a both rapid and maintained therapeutic response. The neutralization of IL-4 signaling alone may not directly suppress tissue cell response, which might translate therapeutically into a late-onset response, compared to simultaneous IL-4/IL-13 blockade.
Selective Inhibitors of IL-4 Signaling
In 2017, both the European Medicines Agency and the US Food and Drug Administration approved dupilumab for the treatment of moderate to severe AD. Clinical outcomes derived from Phase 3 trials have been confirmed by a large number of real-life studies, demonstrating high clinical effectiveness and very favorable safety profile.62,63 Targeting the same receptor subunit, other drugs, namely CBP 201 (manufacturer: Suzhou Connect Biopharmaceuticals), AK 120 (manufacturer: Akeso Biopharma), are now tested in Phase II and Phase I trials, respectively (Table 1).64,65 With a different mechanism-of-action, pitrakinra, is able to block both IL-4 and IL-13. It represents an IL-4 double mutein, recombinant protein that binds to IL-4Rα receptor subunit without signaling through, thus not determining receptor activation.66 So far, pascolizumab (SB 240683), is the only humanized monoclonal antibody neutralizing IL-4 that was developed for the treatment of asthma.67 A pilot study, a phase I/II, randomized, double-blind, placebo controlled, parallel-group trial, enrolling 120 patients with symptomatic steroid-naïve asthma, was conducted but results are not reported and no further development has been planned.68
Table 1 Therapeutic Agents Targeting IL-4 That are Marketed or Under Clinical Development for the Treatment of AD
The role of IL-4 in AD is well established and multiple lines of evidence support its relevant contribution in mediating multiple clinical features, including skin inflammation and pruritus. Nevertheless, its therapeutic relevance is still debated as it is usually considered a valid target for AD in conjunction with IL-13 neutralization. Conversely to IL-13 alone that constitutes a target for various compounds currently tested in clinical trials, the selective inhibition of IL-4 is not considered an advantageous therapeutic intervention for type 2 mediated disorders. However, further investigations on developing new IL-4 targeting agents will be worthy to expand and diversify the therapeutic armamentarium in AD and other type 2 inflammation mediated itchy skin disorders.
Andrea Chiricozzi served as advisory board member and consultant, and has received fees and speaker’s honoraria or has participated in clinical trials for Abbvie, Biogen, Fresenius Kabi, Leo Pharma, Lilly, Janssen, Novartis, Sanofi Genzyme, and UCB-Pharma
Ketty Peris reports grants and personal fees for advisory Board meeting from Almirall, AbbVie, Biogen, Lilly, Celgene, Galderma, Leo Pharma, Novartis, Pierre Fabre, Sanofi, Sandoz, Sun Pharma and Janssen, outside of the submitted work.
Giampiero Girolomoni has been principal investigator in clinical trials sponsored by and/or and has received personal fees from AbbVie, Abiogen, Almirall, Amgen, Biogen, Boehringer-Ingelheim, Bristol-Meyers Squibb, Celgene, Celltrion, Eli-Lilly, Genzyme, Leo Pharma, Menlo therapeutics, Novartis, OM Pharma, Pfizer, Regeneron, Samsung, Sandoz and UCB Pharma.
The authors report no conflicts of interest for this work.
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31. Nishi N, Yamamoto S, Ou W, et al. Enhanced CCL26 production by IL-4 through IFN-gamma-induced upregulation of type 1 IL-4 receptor in keratinocytes. Biochem Biophys Res Commun. 2008;376(1):234–240. doi:10.1016/j.bbrc.2008.08.136
32. Gahr N, Fölster-Holst R, Weichenthal M, et al. Dermal fibroblasts from acute inflamed atopic dermatitis lesions display increased eotaxin/CCL11 responsiveness to interleukin-4 stimulation. Br J Dermatol. 2011;164:586–592.
33. Chan LS, Robinson N, Xu L. Expression of interleukin-4 in the epidermis of transgenic mice results in a pruritic inflammatory skin disease: an experimental animal model to study atopic dermatitis. J Invest Dermatol. 2001;117(4):977–983. doi:10.1046/j.0022-202x.2001.01484.x
34. Lee GR, Flavell RA. Transgenic mice which overproduce Th2 cytokines develop spontaneous atopic dermatitis and asthma. Int Immunol. 2004;16(8):1155–1160. doi:10.1093/intimm/dxh117
35. Spergel JM, Mizoguchi E, Oettgen H, et al. Roles of TH1 and TH2 cytokines in a murine model of allergic dermatitis. J Clin Invest. 1999;103(8):1103–1111. doi:10.1172/JCI5669
36. He R, Kim HY, Yoon J, et al. Exaggerated IL-17 response to epicutaneous sensitization mediates airway inflammation in the absence of IL-4 and IL-13. J Allergy Clin Immunol. 2009;124(4):761–70.e1. doi:10.1016/j.jaci.2009.07.040
37. Kim BE, Leung DY, Boguniewicz M, et al. Loricrin and involucrin expression is down-regulated by Th2 cytokines through STAT-6. Clin Immunol. 2008;126(3):332–337. doi:10.1016/j.clim.2007.11.006
38. Howell MD, Kim BE, Gao P, et al. Cytokine modulation of atopic dermatitis filaggrin skin expression. J Allergy Clin Immunol. 2007;120(1):150–155. doi:10.1016/j.jaci.2007.04.031
39. Sehra S, Yao Y, Howell MD, et al. IL-4 regulates skin homeostasis and the predisposition toward allergic skin inflammation. J Immunol. 2010;184(6):3186–3190. doi:10.4049/jimmunol.0901860
40. Omori-Miyake M, Yamashita M, Tsunemi Y, et al. In vitro assessment of IL-4- or IL-13-mediated changes in the structural components of keratinocytes in mice and humans. J Invest Dermatol. 2014;134(5):1342–1350. doi:10.1038/jid.2013.503
41. Berdyshev E, Goleva E, Bronova I, et al. Lipid abnormalities in atopic skin are driven by type 2 cytokines. JCI Insight. 2018;3:e98006.
42. Ong PY, Ohtake T, Brandt C, et al. Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Engl J Med. 2002;347:1151–1160.
43. Nomura I, Goleva E, Howell MD, et al. Cytokine milieu of atopic dermatitis, as compared to psoriasis, skin prevents induction of innate immune response genes. J Immunol. 2003;171(6):3262–3269. doi:10.4049/jimmunol.171.6.3262
44. Howell MD, Wollenberg A, Gallo RL, et al. Cathelicidin deficiency predisposes to eczema herpeticum. J Allergy Clin Immunol. 2006;117(4):836–841. doi:10.1016/j.jaci.2005.12.1345
45. Howell MD, Fairchild HR, Kim BE, et al. Th2 cytokines act on S100/A11 to downregulate keratinocyte differentiation. J Invest Dermatol. 2008;128:2248–2258.
46. Nograles KE, Suárez-Fariñas M, Shemer A, et al. Atopic dermatitis keratinocytes exhibit normal T(H)17 cytokine responses. J Allergy Clin Immunol. 2010;125(3):744–746.e2. doi:10.1016/j.jaci.2009.12.934
47. Cho SH, Strickland I, Boguniewicz M, et al. Fibronectin and fibrinogen contribute to the enhanced binding of Staphylococcus aureus to atopic skin. J Allergy Clin Immunol. 2001;108(2):269–274. doi:10.1067/mai.2001.117455
48. Cho SH, Strickland I, Tomkinson A, et al. Preferential binding of Staphylococcus aureus to skin sites of Th2-mediated inflammation in a murine model. J Invest Dermatol. 2001;116(5):658–663. doi:10.1046/j.0022-202x.2001.01331.x
49. Bhogal RK, Bona CA. Regulatory effect of extracellular signal-regulated kinases (ERK) on type I collagen synthesis in human dermal fibroblasts stimulated by IL-4 and IL-13. Int Rev Immunol. 2008;27:472–496.
50. Campion M, Smith L, Gatault S, et al. Interleukin-4 and interleukin-13 evoke scratching behaviour in mice. Exp Dermatol. 2019;28:1501–1504.
51. Oetjen LK, Mack MR, Feng J, et al. Sensory Neurons Co-opt Classical Immune Signaling Pathways to Mediate Chronic Itch. Cell. 2017;171(1):217–228.e13. doi:10.1016/j.cell.2017.08.006
52. Miake S, Tsuji G, Takemura M, et al. IL-4 Augments IL-31/IL-31 Receptor Alpha Interaction Leading to Enhanced Ccl 17 and Ccl 22 Production in Dendritic Cells: implications for Atopic Dermatitis. Int J Mol Sci. 2019;20:4053.
53. Pastore S, Fanales-Belasio E, Albanesi C, et al. Granulocyte macrophage colony-stimulating factor is overproduced by keratinocytes in atopic dermatitis. Implications for sustained dendritic cell activation in the skin. J Clin Invest. 1997;99(12):3009–3017. doi:10.1172/JCI119496
54. Calabrese L, Malvaso D, Chiricozzi A, et al. Baricitinib: therapeutic potential for moderate to severe atopic dermatitis. Expert Opin Investig Drugs. 2020;1–10.
55. Bieber T. Interleukin-13: targeting an underestimated cytokine in atopic dermatitis. Allergy. 2020;75(1):54–62. doi:10.1111/all.13954
56. Le Floc’h A, Allinne J, Nagashima K, et al. Dual blockade of IL-4 and IL-13 with dupilumab, an IL-4Rα antibody, is required to broadly inhibit type 2 inflammation. Allergy. 2020;75(5):1188–1204. doi:10.1111/all.14151
57. Oettgen HC, Geha RS. IgE in asthma and atopy: cellular and molecular connections. J Clin Invest. 1999;104(7):829–835. doi:10.1172/JCI8205
58. Newcomb DC, Boswell MG, Zhou W, et al. Human TH17 cells express a functional IL-13 receptor and IL-13 attenuates IL-17A production. J Allergy Clin Immunol. 2011;127(4):1006–13.e134. doi:10.1016/j.jaci.2010.11.043
59. Tazawa T, Sugiura H, Sugiura Y, et al. Relative importance of IL-4 and IL-13 in lesional skin of atopic dermatitis. Arch Dermatol Res. 2004;295(11):459–464. doi:10.1007/s00403-004-0455-6
60. Tsoi LC, Rodriguez E, Stölzl D, et al. Progression of acute-to-chronic atopic dermatitis is associated with quantitative rather than qualitative changes in cytokine responses. J Allergy Clin Immunol. 2020;145(5):1406–1415. doi:10.1016/j.jaci.2019.11.047
61. Simpson EL, Bieber T, Guttman-Yassky E, et al. Two Phase 3 Trials of Dupilumab versus Placebo in Atopic Dermatitis. N Engl J Med. 2016;375(24):2335–2348. doi:10.1056/NEJMoa1610020
62. Fargnoli MC, Esposito M, Ferrucci S. et al. Real-life experience on effectiveness and safety of dupilumab in adult patients with moderate-to-severe atopic dermatitis. J Dermatolog Treat;2019. 1–7. doi:10.1080/09546634.2019.1682503
65. Antoniu SA. Pitrakinra, a dual IL-4/IL-13 antagonist for the potential treatment of asthma and eczema. Curr Opin Investig Drugs. 2010;11:1286–1294.
66. Hart TK, Blackburn MN, Brigham-Burke M, et al. Preclinical efficacy and safety of pascolizumab (SB 240683): a humanized anti-interleukin-4 antibody with therapeutic potential in asthma. Clin Exp Immunol. 2002;130(1):93–100. doi:10.1046/j.1365-2249.2002.01973.x
67. Available from: https://clinicaltrials.gov/ct2/show/NCT00024544?term=pascolizumab&draw=2&rank=2. Assessed August 5 2020.
68. Langan SM, Irvine AD, Weidinger S. Atopic dermatitis. Lancet. 2020;396:345–360.
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domain: medical


Rep. Wayne Owens, D-Utah, said this week he is introducing legislation that would force Congress to vote on the proposed 50 percent pay hike for members, and would not allow the raise to go into effect until after the next election.
Others - including Reps. Jim Hansen and Howard Nielson, both R-Utah - have already co-sponsored similar legislation. But most Congressional observers say the pay raise - from $89,500 to $135,000 a year - is almost sure to become law anyway.Once President Reagan proposed the pay raise to Congress in his budget on Monday, both houses of Congress would have to vote within 30 days to reject or it becomes law under complicated procedures set up by Congress.
The Senate will reportedly vote on and likely reject the raise. But House leaders apparently will not allow a vote there, meaning the raise will take effect in both houses. However, the House will vote soon afterward to abolish honoraria - the fees congressmen receive for giving speeches to special interest groups.
Owens said, "I delayed a formal statement on the proposed increase in the hope that the president would reject the proposal and make a final effort at fiscal restraint.
"I was disappointed that he failed to cut the (salary study) commission's recommendation to a level comparable to the maximum in outside income that House members are now allowed to earn through honoraria," which would have been a raise of $26,850.
If, as Owens' bill will propose, a vote does come up on the proposed pay raise, Owens said he will vote against it. If it passes, he said he will support an immediate ban on honoraria.
"At a time when Congress is struggling to bring the budget into line and decrease a staggering deficit, it is improper for us to look first to our own needs and not muster the courage to face a recorded vote on the issue."
He added, "This pay raise issue is being turned by some into a partisan issue, but the irony is that this is the recommendation of the most fiscally conservative president in decades."


text:
I was not quite 11 years old May 14, 1948, when the Declaration of the Establishment of the State of Israel was read by David Ben-Gurion on the eve of Shabbat and rebroadcast the following night on my great aunt’s shortwave radio. We had just finished Havdalah.
I was quite impressed by the words of the text that proclaimed the promise of the state to “foster the development of the country for the benefit of all its inhabitants; it will be based on freedom, justice and peace; it will ensure complete equality of social and political rights to all its inhabitants irrespective of religion, race or sex; it will guarantee freedom of religion, conscience, language, education and culture. … We appeal to the Arab inhabitants of the State of Israel to preserve peace and participate in the up building of the State on the basis of full and equal citizenship and due representation in all its provisional and permanent institutions.”
Seventy years later, the state of Israel has tragically expurgated these promises to the dust bin of history. In just one week, the right-wing coalition that governs the country and controls the Knesset has made a mockery of the democratic principles articulated in Israel’s founding document. Consider:
• It has directed the Ministry of Education to forbid some people and groups opposed to the Israeli occupation of the West Bank from speaking at public schools. It has barred access by Palestinians to Israel’s Supreme Court of land disputes.
• It has prohibited single men and gay couples from becoming surrogate parents.
• And it has enacted a Basic Law statute that bestows upon Israeli Jews the exclusive right of national self-determination while downgrading Arabic as a language, both measures effectively relegating its non-Jewish residents to second-class citizenship.
People suspiciously possessing pro-Palestinian literature are subject to search and seizure operations by security personnel at Ben Gurion Airport and border crossings as well as at the Green Line that separates the West Bank from pre-1967 Israel. Only ultra-Orthodox rabbis may perform marriages and other life-cycle rituals. It is illegal for other rabbis to do so. If they do, they are condemned and even arrested, as was the recent case of a Conservative rabbi in Haifa who married an Israeli Jewish couple.
Israel is rapidly deserting democracy while adopting the characteristics of a right-wing theocracy in a country politically polarized and increasingly isolated from the Jewish diaspora. It is doing so in the name of ethnocentrism.
In 1967, just after Israel’s triumphant victory in the Six Day War, former Prime Minister David Ben-Gurion sounded the alarm against Israel’s continued occupation of territories it had conquered in the conflict. He warned that in doing so, the country was “sowing the seeds of self-destruction” and sacrificing the ideals of democracy and pluralism.
That Israel would do so from within its own borders as well as in the occupied West Bank is less surprising than it might seem in a world of countries, including the United States, increasingly defining themselves as exclusive nationalist identity entities. Israel is no longer the mythically unique and exceptional society it once claimed to be, if ever it was.
It is also no surprise that Prime Minister Benjamin Netanyahu and his ministerial colleagues have forged close relations with Hungary’s proto-fascist prime minister, Viktor Orban, and ultranationalist U.S. President Donald Trump, and developed informal, de facto alliances with the theocratic, monarchial regime of Saudi Arabia and the authoritarian rulers of several Persian Gulf States. They are also seeking a strategic relationship with Russia’s despotic president, Vladimir Putin.
In 1948, the historian Arnold Toynbee memorably wrote that “civilizations die not by murder but by suicide.” Toynbee had America in mind when he penned those words. He was 70 years ahead of his diagnosis, both about the United States and, one might say, about Israel.
This situation cannot and must not stand. Is it too late for an alternative trajectory in both cases?

domain: law


Find the number of a specific division or office to contact them directly or call Service Tasmania on 1300 135 513.
Use the Tasmanian Government Directory to find staff contact details
Follow our social media accounts to keep up to date with specific programs and initiatives.
The Premier, as Minister with responsibility for the Communities, Sport and Recreation portfolio, will oversee Accessible Island: Tasmania’s Disability Framework for Action 2018-2021. DPAC will coordinate the annual reporting to PDAC on Accessible Island through the Disability Action Plan Working Groups in each agency, TasTAFE and THS.
Accessible Island will replace the DFA 2013-2017 as the Tasmanian Government’s implementation plan for the NDS. Tasmania will report on its implementation through the bi-annual Council of Australian Governments (COAG) Progress Report.
PDAC will provide advice and feedback to agencies through its program of regular meetings with the Heads of Agencies.
Agencies, including TasTAFE and THS, will develop Disability Action Plans (DAPs) to implement their commitments under Accessible Island.
Agencies will provide annual DAP progress reports to PDAC. Agencies currently report on the following outcome areas:
Agencies will also be asked to:
Accessible Island is a living document. The annual reports to PDAC and face-to-face meetings with Heads of Agencies will provide a mechanism for PDAC to provide real-time feedback on the implementation and emerging issues.
PDAC will provide an annual implementation/progress report to Cabinet, outlining achievements and identifying areas for further action. PDAC’s report will be published on the DPAC website.
During the implementation of Accessible Island, the Government will continue to consult with PDAC, people with disability, the disability services sector and the Tasmanian community to understand how Accessible Island is contributing to positive outcomes and equitable access for people with disability.
Agencies will be asked to include qualitative and quantitative data in their annual reports to PDAC to map their progress against the three principles underpinning Accessible Island. Some indicators are suggested below.
The proposed data collection is not intended to be exhaustive; however, it will provide a snapshot. Agencies will be asked to continue to provide data that they have previously provided in relation to specific programs and initiatives.
PDAC will also assume an additional reporting role from 2018. This will be to monitor the implementation of the measures in the Disability Justice Plan for Tasmania 2017-2020 (the Plan). DoJ will coordinate annual reporting on the Plan to PDAC. PDAC will provide a response to the Secretary DoJ, if required, and will also have the opportunity to discuss implementation of the Plan with Heads of Agencies during their face-to-face meetings.


Think the unthinkable. Your enterprise has consigned a significant part of its customer data into either Salesforce or Office 365. Imagine that information disappears.
That is not to suggest that Salesforce or Office 365 are unreliable, because their track record so far in securing and preserving data is impressive.
But accidents happen. So does malicious activity. And with data now most important currency in business transactions, loss of this kind could paralyze a business.
AvePoint Online Services
To deal with these kinds of situations, AvePoint just pushed its Azure-based AvePoint Online Services into general availability. It's a Software-as-a-Service (SaaS) offering that comes with the new DocAve Backup for Salesforce service as well as enhancements to its Office 365 back-up and governance service for Office 365.
While many enterprise users are familiar with the Office 365 offering, the new Salesforce version should be a welcome addition to any business that wants to protect customer data and provide added peace of mind to clients.
Struggling With Backup
DocAve Backup for Salesforce introduces comprehensive backup and restore capabilities for information stored in Salesforce CRM and reduces the risk of data loss from human error.
“Many organizations are struggling with finding effective backup for multiple cloud applications. AvePoint has met this need for Office 365 for a while now with DocAve Online. Expanding our backup solution to Salesforce allows more organizations to ensure the safety of their data across multiple cloud platforms," Terence Orpilla, Product Manager at AvePoint, told CMSWire.
Asked about the native security, back up and governance features that come with both platforms, Orpilla said they don’t go far enough for many enterprise with sensitive data.
“Organizations that use SaaS platforms are often under the assumption that all of their high availability and disaster recovery concerns are addressed by their provider," he said.
But most don’t offer ways to easily recover data lost through human error, which includes deletion (accidental or malicious), data being overwritten with incorrect information, data corruption, data migration issues and third-party application errors, he explained.
Additional Salesforce Security
AvePoint offers additional security by providing a fully cloud-hosted solution that allows for quick restore of a single contact to an entire CRM instance. With DocAve Backup for Salesforce, administrators can manage and protect their CRM environment with:
- Single-click back up: With one click, back up content automatically or on demand – with all data stored securely in Microsoft Azure.
- Flexibility: Quickly restore content at the organization, object, and record level. It also offers back-up from specified points in time
- Encryption: All data stored benefits from Azure Encryption in conjunction with user account security
This is all strengthened with an administrator dashboard that provides records of all back-ups, time and job status as well as user activity.
These additional protections along with the native Salesforce security are designed to ensure that nothing gets lost.
All these improvements are available now to new and existing customers. Orpilla added that DocAve Backup for Salesforce offers full fidelity restores at the organization, object, and record level so that information can be restored to your desired state.


text:
Many activities are in question with the pandemic and have left many students and teachers wondering what’s going on with sports. I interviewed Mr. Miazga, the varsity baseball coach about the current situation with spring sports and what he’s doing with his team. Even though sports are unclear as of now, teams are doing what they can to prepare for when they get back together.
I asked him what the current plan is for the spring sports season. He responded that “As of now Baltimore Public City Schools have all three seasons; fall, winter, and spring in 6 weeks intervals starting in February.” He believes that the spring season will happen sometime in April and that teams will have weeks before that for preparation.
When asked if he was doing any online video calls in preparation for the spring season he said that the “baseball team has been meeting virtually on zoom twice a week during knight time. We’ve been doing light weight training during that time…we’ve been stretching our shoulders and legs with weights.” He said that during knight time they had been checking up with everyone and watching baseball movies as well. “It’s been hard, spirits are low because we lost the season last year and a lot of my older players have other commitments during knight time.” Even with the difficulties, he was quick to say that “we’ve been doing the best we can.”
I asked if he thought the seniors would have a final sports season this spring, he thought if things go according as planned they will get the spring season, but he’s unsure if that will truly happen.
I asked what type of precautions would you as a team take to keep players safe. He was clear that he would follow medical advice and safety precautions if they were to go back in person. The locker room and changing situations worried him more because “ they’re close quarter and player have to be near each other”
I followed up by asking if he thought fans would be allowed to watch or not. I didn’t realize, but he mentioned that the baseball field doesn’t have any stands. He expects “that the directives will be people can watch, but you have to maintain social distances…I don’t think that the system will ever be your not allowed to come and watch your kid play, because if I’m a parent concerned about the virus, I would want to know if the protocols were being followed.” He said that the baseball games in particular don’t get very crowded and that people can spread themselves out along the hill.
Lastly, I asked if the spring sports season happens would schools be allowed to play other schools or not. He said “I expect that we will be playing other teams…I don’t know if the risk to other teams is that much more than the risk to ourselves.” He said that they will have to be safe regardless, but there’s no way for them to be able to be in a bubble and that they’ll do everything they can to be safe.
From what I gathered after talking to Mr. Miazga about the spring sports season, many things still seem undecided as of now. Teams are doing all they can to stay together during these hard times while staying safe. Even though times are hard right now we’ll get through them and remember to keep your head up.

domain: sports


text:
WASHINGTON DC TRIP
This is some info on some of the things I learned
The Washington Monument was built to commemorate our first president. It stands at a towering 555 feet tall and no building in DC is to be taller than it. Once you make the top you can see for 30 miles.
The Vietnam and Korean War memorials
The Vietnam memorial is a huge wall where more than 58,000 veterans are remembered
The Koren War memorial has a huge wall and statues as well as a fountain on the end. It was built to honor Koren War veterans.
The Supreme Court
The Supreme Court has nine members and deal with problems related to the constitution. The judges include Ruth Ginsburg, and John Roberts.
The Natural History museum
This museum has fossils of ancient creatures. Some of these include Megalodon, Opobania, and Dunkleosteus. The museum also had an area where you can look at fossils.
The White House
The home of the president is a huge building with over 100
rooms! The Oval Office is where the president passes and vetoes bills that went through Congress.
The dinner cruise
The dinner cruise is a fun, filled with laughter place where they play your favorite songs and most importantly eat. This event left people with good memories of great times.

domain: history


text:
Brookfield Bottling Co Bottle, shows triangle
Quantity available: 2
Brookfield Bottling Co Bottle, shows triangle in the center of design 7 3/4 x 2 1/4 inches, BBC on the bottom, This bottle was collected by a fisherman that fished up bottles from the river and does have some water staining ect, but still in nice condition, no nicks., clear glass
TCAC Mall, Inc.
Dealer accepts: Money Order, Cash, Check, PayPal
Shipping: Negotiated with Seller
Items Similar To "Brookfield Bottling Co Bottle, shows triangle"
Retired Swarovski set - miniature Flowers - Crystal SCS Renewel stand - Tulip flower holder display...

domain: design


text:
An eighteen year-old Regina woman is charged with Robbery and a Breach of Probation after an incident that occurred in the 400 block of North McCarthy Boulevard today, Friday, September 24, 2010.
At approximately 12:20 p.m., police officers were dispatched to a location in the 400 block of North McCarthy Boulevard for a report of a robbery. The preliminary information indicated that the male victim was an off-duty police officer. The investigation indicates the 28 year-old victim, a member with the Regina Police Service who was on days off, was exiting a store when a female allegedly attempted to rob him of his purchase. The victim got into a struggle with the female suspect and gained control of her before police arrived to make the arrest. The suspect sustained a bloodied nose from the struggle. There were no other injuries. The responding police officers obtained victim and witness statements and transported the suspect to Police Headquarters. Further investigation led to two charges against the woman.
Eighteen year-old Autumn Rain SANDERSON, DOB: 1992-04-10, of Regina is charged with Robbery [344(b) CC] and Breach of Probation [733.1(1) CC]. She was released on an undertaking to appear in Provincial Court on October 25, 2010.


text:
Susan Meiselas’ A ROOM OF THEIR OWN – POP-UP INSTALLATION.
We have taken over two stalls at West Bromwich Indoor Market for our pop-up installation as part of #16DaysofActivism. Come visit us from Saturday 25th Nov to Saturday 9th Dec 2017. Open daily from 10am until 4pm (except Sunday).
Visit our Pop-up installation which includes a selection of digital narratives from Magnum Photographer Susan Meiselas’ A Room of Their Own, a project made in collaboration with Multistory and women in refuge. It’s a rare opportunity to see Susan’s work in the UK; she is showing work from A Room of Their Own at the Tàpies Foundation, Barcelona until 14 January 2018 and at the Jeu de Paume–Concorde in Paris, from 5 February to 20 May 2018.
Join us on one of our art workshops across the 16 days.. from going beyond a ‘Selfie’.. to making your own slogan tote bags.
Support women and children in refuge by buying an item from the market and drop it off at our donations box. All items will be donated to refuges in time for Christmas.
While you’re there have a free portrait taken by photography students at Sandwell College and leave a ‘message of hope’ to be part of the ongoing conversation around #domesticviolence.
We look forward to seeing you there!
For more info about our art workshops all our events across the 16 days visit multistory.org.uk/events
To find us:
West Bromwich Indoor Market
8 Kings Square

domain: artistic


Blackworks's forged lug nuts are forged with AL7075 magnesium alloy, each lug nuts are hard anodized for strength and durability.
These Lug Nuts feature a 60 degree acorn lug seats, they are for aftermarket tuner wheels with 60 degree acorn lug seats.
5 lug pattern vehicles with 12x1.5mm thread size wheel studs, such as:
Acura Honda Prelude, S2000, NSX, RSX, TSX, Integra Type R, 06-up Civic Si
Mitsubishi Lancer, and EVOLUTION
note: these lug nuts will NOT work on most XXR wheels
Blackworks Racing Forged Lug Nuts 12x1.5 Neo Chrome (20 pcs)


text:
|LEGO → System → Star Wars → Episode VI: Return of the Jedi|
6207 A-Wing Fighter was released in 2006 as part of the Classic Star Wars line. Included are one Rebel Mechanic, and one A-Wing Pilot Minifigures. It is the second and was the latest model of A-Wing released until a green version appeared in the 7754 Home One Mon Calamari Star Cruiser in 2009.
"Excellent fighter with superior speed and maneuverability. Well suited to destroying or luring enemy fighters" ―- Description of the A-Wing in Empire At War
Simply put, the A-wing was a cockpit attached to twin engines. Like its Clone Wars predecessor, the Eta-2, the A-wing required pilots of exceptional skill to take full advantage of the vessel's speed, agility, and special features—and the Alliance lacked the Galactic Republic's Jedi pilots.
An A-wing, view on its engines. The A-wing's Event Horizon engines remained some of the most powerful sublight thrusters two decades past the A-wing's creation and were linked to highly sensitive controls. The vessels presented a number of challenges to pilots. Pilots had to adjust two dorsal and two ventral stabilizer wings with great care, as even a minor turn could send the speedy A-wing into a massive spinout.
The slight A-wing's wing-mounted laser cannons could rotate up and down sixty degrees for greater fire control. Some of those designs even had their guns modified to swivel in a complete 360-degree arc, thus providing a nasty surprise to any chasing fighter. While a tactical boon, the A-wing had no astromech droid to manage its weapons systems, requiring further attention from the pilot.
The combination of sensitive controls, unmatched sublight thrust, maneuverable weapon systems, advanced sensory and stealth packages, fragility, and heavily exposed cockpit strained even the best pilot. A-wings earned the nickname "slims" for their small frame made of carbo-plas, but also for the "slim" chance of a pilot surviving a direct hit on the ship after the shields were down, and the cramped cockpit that prevented larger pilots from flying the A-wing.
- Other sets containing A-Wings
- See current value on BrickEconomy.com
- See a 360º view of the set on BrickFile.com
|view · talk · editLEGO Star Wars sets of 2006|
|Regular sets:||6205 V-Wing Fighter | 6206 TIE Interceptor | 6207 A-Wing Fighter | 6208 B-Wing Fighter | 6209 Slave I | 6210 Jabba's Sail Barge | 6211 Imperial Star Destroyer | 6212 X-wing Fighter | 10174 Ultimate Collector's AT-ST (UCS) | 10175 Vader's TIE Advanced (UCS)
|Other products:||M228 LEGO Star Wars Yoda Magnet Set | 851683 Imperial Royal Guard Key Chain | 4224472 Stormtrooper Key Chain | 4269242 Star Wars Magnet Set | 4269244 Yoda Magnet Set | 4270898 Anakin Key Chain | 4270900 Clone Pilot Key Chain | 4270902 Chewbacca Key Chain | 4274291 Yoda Keyring | 4294201 Boba Fett Key Chain | 4297461 Imperial Royal Guard Key Chain | KC091 R2-D2 Key Chain | M229 LEGO Star Wars Darth Vader Magnet Set | LEGO Star Wars II: The Original Trilogy | LEGO Star Wars II: The Original Trilogy Prima Guide|
|[ full list ]|

domain: entertainment


text:
New patients are always very welcome at Pure North Dental!
Thank you for considering Pure North Dental Clinic for your dental care. We are proud to offer practical treatments plans that take your oral health, overall well-being, and individual needs into consideration.
Our team is dedicated to providing everything you need for a healthy smile, including restorative procedures, cosmetic services, and regular hygiene cleaning. Even if you have not been to the dentist for some time, please don’t be embarrassed, give us a call!
We offer several spoken languages including English, Filipino, Russian, Punjabi, French, Spanish, and Ukrainian.
We look forward to meeting you!
To schedule an appointment just give us a call at 587-293-0722
Our reception team will connect with you prior to your visit to remind you of the appointment.
If you need to cancel your appointment, we request 48 hours’ notice
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(“vulyk” in Ukrainian — beehive)
The energy of self-healing earth, endless nature cycles is reproduced in this amazing washbasin, which resembling (resembles) a beehive and made of natural clay. VULYK – will bring you closer to nature. In this way you will constantly receive strength from your native land.
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text:
The Asterix books represent the very summit of our achievement as a literary race. In Asterix one finds all of human life. The fact that the books were written originally in French is no matter. I have read them all in many languages and, like all great literature, they are best in English. Anthea Bell and Derek Hockridge, Asterix's translators since the very beginning, have made great books into eternal flames.THE TIMES
Asterix and the Golden Sickleby Rene Goscinny, Albert Uderzo
Getafix has broken his golden sickle, so Asterix and Obelix visit Lutetia to buy a new one for him. But the sicklesmitha cousin of Obelixhas vanished without a trace. Where could he have gone? And can Asterix solve the mystery and bring Getafix what he needs?
Meet the Author
Rene Goscinny was born in Paris in 1926, and spent most of his childhood in Argentina, before eventually moving to Paris in 1951. He died in 1977. Albert Uderzo was born in 1927 in a small village in Marne, France. He met Rene Goscinny in 1951 and on 29 October 1959 their most famous creation, Asterix, made his first appearance on page 20 of Pilote. Asterix the Gaul, their first album, was published in 1961 and there have now been 35 Asterix albums.
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Most Helpful Customer Reviews
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This is a book for kids or adults who are kids at heart! it has vibrant cartoons'almost like a comic book'