text:
Symantec says that users of Windows 8 running its venerable Norton Internet Security software will experience a faster PC and computing experience than if they rely on and run the freely included Windows Defender security software from Microsoft.
{loadposition alex08}Remember back in 2008, when Symantec���s Norton Internet Security range of software had progressively morphed into ever slower versions of Norton Internet Bloatware from about the year 2000 onwards?
Then, later in 2008, came a real surprise. A press event held by Symantec���s Norton executive David Hall revealed a startling revelation: a totally stunning ���whoa!��� rewrite of the entire Norton Internet Security 2009 suite, emphasising ultra-fast speed and a new commitment to totally minimising the NIS overhead.
Ever since then, every version of Norton Internet Security since has, amazingly, gotten faster and faster still, thus utterly reversing the Norton of the past into the V8 Supercar powering Internet Security range of the future.
In that time, every other security suite has gone on the same journey, with Kaspersky, BitDefender, Trend, AVG and others all promising ever faster performance, too.
Symantec seems to have been the catalyst to this change, although as it came smack-bang in the midst of the netbook revolution, this kind of radical software transformation to emphasise speed was definitely both overdue, and definitely coming, and not just in Internet Security suites, but also in operating systems.
After all, witness the transition from Windows Vista to the lightspeed Windows 7 in comparison, and even Apple���s Leopard OS X 10.5 to the much better Snow Leopard OS X 10.6.
Now, operating systems do tend to get filled with cruft and slow down after some months, and while Windows 8 promises the easiest ways yet to restore Windows to ���as new��� levels of speed, the world is yet to see the final Windows 8 code and use that final code for any length of time to see whether Windows 8 Pro machines are any better at preventing slow-down, or not.
However, none of that has stopped Symantec from coming out to definitively state that a Windows 8 PC running the latest version of Norton Internet Security will be a lot faster than one simply running the in-built (and free) Windows Defender security suite Microsoft is including with each copy of Windows 8.
The news comes forth from TechRadar which shows an Symantec internally produced graph, indicating a Windows 8 PC with Norton running 52% faster than one running Windows Defender.
Windows Defender is naturally switched off when a third-party Internet Security suite is running, thus enabling Symantec to make a genuine comparison between a Windows 8 PC with Norton, and one without.
TechRadar naturally notes that no independent testing of Symantec���s claims have yet been done, and I personally wonder how long it will be before Kaspersky Lab, AVG, BitDefender, Trend Micro and the other companies also claim something similar, but Symantec has certainly staked its claim, and it will be fascinating to see how all the other security vendors respond.
After all, with Windows 8 coming with anti-virus and anti-malware built in, you���d have to imagine that selling third party protection will be a tougher sell, but the facts are that third-party security products are always vastly more capable and protective than the free security suites, whether from Microsoft or others.
TechRadar quotes Symantec���s head of development Collin Davis talking about Windows Defender, stating that Symantec has ���an entire team that work on nothing but performance. Now we get to say, Norton makes Windows faster. Because Defender is slower than Norton.���
Davis explains that ���if you turn off Defender, your PC will be faster. We always have overhead, we still do. We add less overhead than Defender does���, while also indicating that Norton���s security suites will also soon be able to update themselves to the latest versions ���without reboots���.
The article also goes on to quote Davis explaining that future retail versions of Norton may well come without a ���year��� or ���version��� designation, as all versions of Norton will be designed to simply, easily and effortlessly upgrade themselves to the very latest version ��� as long as a valid subscription is in place, of course - again, without those pesky reboots being needed.
So��� the Internet Security wars, which have never ended (and probably never will), are about to enter their next exciting new level ��� not only that of defending against incredibly sophisticated threats out there ��� but also in capturing the hearts, minds and wallets of vast upcoming swathes of brand new Windows 8 users.
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|Message view
|« Date » · « Thread »
|« Date » · « Thread »
|Dean Gaudet <dgau...@arctic.org>
|Re: Removing ap_dummy_mutex from API
|Fri, 02 Oct 1998 22:22:08 GMT
Yup, and this is also why multiprocess models are still interesting :) Dean On Fri, 2 Oct 1998, Ben Hyde wrote: > Dean Gaudet writes: > > ... race conditions due to signals that I don't think are > >solveable. For example, if you take a signal inside a 3rd party > >library... you're toast. You can't expect it to continue properly (some > >do, some don't), and you can't longjmp out of it because it could leak > >resources. The only way around it is to not take the signal. > > That does seem to be the industry solution. Nobody (aka 3rd party > code) implemented interrupt handling right in their code and meanwhile > longjmp is rarely dependable either. So we all end up deciding to > forswear interrupts. > > Tuning in latter... > Mr. Application say: > "What happens when a thread/process gets stuck, errors, or runs out of time?" > Mr. OS say: > "You could have another thread kill it." > A: "Can I clean up?" > O: "Not really, but the thread that kills it can." > A: "Oh so I build my own stack of cleanup." > O: "You got it." > A: "wonderful" > O: "Don't worry the OS data structures will be reclaimed." > > Good thing we got those pools and with their cleanup routines per thread in 2. > > - ben >
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ATHENS, Ga. — Aaron Murray is reaching a milestone for durability as he chases yet another SEC record.
Murray will make his 50th consecutive start when Georgia takes a break from its Southeastern Conference schedule to play Appalachian State on Saturday. Murray's endurance stands out in a year where every other starting quarterback in the SEC East has missed at least one game.
Murray already has set SEC career records for yards passing and total offense this season. He needs two touchdown passes Saturday to top Danny Wuerffel's conference record of 114 at Florida from 1993-96.
Murray is completing his career as a graduate student. He completed his degree in psychology in 2011 with a 3.3 GPA.
He has never missed a start for Georgia (5-3), and sounded surprised this week when told he was approaching his 50th start.
"Is this it?" Murray asked. "Oh, wow. I mean, that's a lot of starts. It's definitely an honor to have played this long at this university, at this type of program. I'm definitely blessed."
Murray has been the reliable constant as Georgia has had to overcome injuries to most of its other top starters on offense.
Tailback Todd Gurley returned for last week's 23-20 win over Florida to preserve Georgia's hopes of catching Missouri in the SEC East. Gurley had 100 yards rushing, 87 yards receiving and two touchdowns against the Gators.
Georgia tight end Arthur Lynch has bruised ribs and is not expected to play.
Appalachian State (2-7) is struggling in its last year playing as a Football Championship Subdivision team.
The Mountaineers are moving to the Sun Belt in 2014 and are looking for their first win over a Football Bowl Subdivision team since their famous 2007 upset of No. 5 Michigan in 2007.
First-year coach Todd Satterfield, an assistant in 2007, said there is no comparison with the 2007 Appalachian State team that was on its way to its third consecutive FCS national championship.
"I think we're too far away from that," Satterfield said. "There's not anybody on this team that was around during that time. Back then we were coming off a couple of national championships ... I just think that was just a different era, a different time and different kids."
The Mountaineers have four losses by no more than seven points, including last week's 35-28 loss to Chattanooga.
Here are five things to watch, in addition to Murray's pursuit of the SEC record for career TD passes:
HOMECOMING: Appalachian State has 22 players from the state of Georgia, including freshman Marcus Cox, who rushed for 158 yards with three touchdowns against Chattanooga. Cox, from Dacula, Ga., has more than 100 yards rushing in three straight games. He leads the team with 857 yards rushing and nine touchdowns. "Obviously, those guys are excited about it," Satterfield said. "Growing up in that state, everybody talks about Georgia. For them it's a great opportunity to go out and show what they can do in front of a lot of their family and friends and guys they know from that state."
AVOID LETDOWN: Georgia will play at No. 7 Auburn next week and then will play Kentucky in its final home game on Nov. 23. This is late in the season for the Bulldogs to play a nonconference game other than Georgia Tech. Georgia is 50-9 in nonconference games under Richt, including 35-1 in home games against teams outside the SEC.
REMEMBER US? Georgia suffered a free-fall from No. 7 to out of the AP Top 25 with back-to-back losses to Missouri and Vanderbilt. Even though Appalachian State has a poor record, an impressive win by Georgia might be enough to catch the attention of some AP voters. Georgia was No. 2 among teams also receiving votes this week.
WATCHING WASHINGTON: Washington, a senior, stays busy for the Mountaineers. He has 46 catches for a team-leading 637 yards with two touchdowns and also returns punt and kickoffs.
ANOTHER SPREAD OFFENSE: Satterfield says his team can't outmuscle the Bulldogs so instead will try to create good matchups by spreading the field. The Mountaineers, led by dual-threat quarterback Kameron Bryant, average 414.2 yards per game, third in the Southern Conference.


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RALEIGH, N.C. -- Edmonton Oilers forward Shawn Horcoff isn't
impressed by the faceoff technique of Carolina captain Rod Brind'Amour.
In fact, he doesn't even think it's legal.
Brind'Amour has won 310 of his 514 faceoffs (60.31 percent) in
the playoffs -- including 28 of 34 in Game 1 of the Stanley Cup
finals. He was third in the NHL during the regular season at 59.1
percent and has finished in the top five in three of four seasons.
Horcoff, who dropped 18 of 27 in the Oilers' 5-1 loss in the
opener, has already complained about Brind'Amour's methods and the
things he is allowed to get away with.
"It's just a problem that I tried to talk to the linesman a
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really anything that I really need to comment on, it's just the
fact that I thought he was cheating a little bit and hopefully
we'll change that."
Horcoff had enjoyed success on faceoffs before the finals,
taking 55 percent against Detroit, San Jose and Anaheim.
Brind'Amour didn't buy into the claim that he gets special
treatment from the officials.
"I can't even comment on that. I've never heard of that,"
Brind'Amour said. "I'd be surprised if there was special
treatment, but I'd sign up for it."
Talking back
Erik Cole is staying busy during the Stanley Cup
finals even though he is sidelined by a neck injury.
Cole watches his Carolina Hurricanes teammates from a high perch
in the press box. Then he covers their backs away from the rink.
The right winger got into his car Tuesday, the day after the
Hurricanes' 5-4 win over Edmonton in the series opener, and heard
someone take a shot at Carolina captain Rod Brind'Amour.
An Oilers fan sent an e-mail to talk-show host Jim Rome that
said even though he was disappointed his team gave up the winning
goal on a busted play behind the net in the final seconds of Game
1, and the fact that starting goalie Dwayne Roloson was knocked out
of the series, he was happy his players didn't resemble Brind'Amour
-- whose face bears the markings and wear-and-tear of a 17-year NHL
Cole picked up his cell phone and speed-dialed the show's
producer. Once his identity was confirmed, Cole was on the air.
"You might not look like Rod Brind'Amour, but nothing was
uglier than that miscommunication behind the net," Cole said.
After Roloson was hurt with less than 6 minutes remaining,
backup Ty Conklin flubbed the puck behind the net with teammate
Jason Smith, allowing Brind'Amour to take it and stuff it in for
the game-winner.
Bottled up
The Hurricanes offered bottles of the wine
"Relentless" Syrah on Wednesday night to the first 20 fans who
donated at least $200 to the Eastern North Carolina chapter of the
Leukemia & Lymphoma Society.
Carolina coach Peter Laviolette took on the fight against blood
cancers after family friend Julia Rowe was diagnosed with leukemia.
Her parents gave Laviolette a bottle of the wine -- signed by Julia
-- earlier this year. It has since become an inspirational piece for
the coach and his players.
Laviolette carried the bottle to the podium after the Hurricanes
won the Eastern Conference championship last week.
"What Coach Laviolette did at his press conference was to bring
enormous attention to the families and individuals suffering with
lymphoma and leukemia," said Doug Shafer, president of Shafer
Vineyards in Napa Valley. "It sure got our attention."


text:
US: Nissan breaks ground for engine JV with Daimler
Nissan's US unit has broken ground for a second engine plant at the automaker's complex in in Decherd, Tennesee. It will produce I4 petrol engines for Infiniti, and Mercedes-Benz C-class cars assembled at Daimler's plant at Tuscaloosa, Alabama.
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Hobart Morning or Afternoon Tea Cruise On Board The SV Rhona H Tall Ship
Experience tall ship SV Rhona H; a 1942 Ketch vessel. Enjoy morning or afternoon tea as you see the best of Hobart from the decks of this historic boat. Sails are always set and you are welcome to assist the crew or sit back and relax.
Depart Sullivans Cove and set sail as soon as the SV Rhona H is out the docks. Turn and head towards the Tasman Bridge. Sail under the bridge and hear about the shipwrecked "Lake Illawara". Continue on towards Montagu Bay and experience what it was like on the old trading ketches as they come close to the shore.
Tea, coffee and hot chocolate are offered for those who would like it, as well as the choice of a glass of wine or Willie Smith cider.
See Government House as you make your way back under the Tasman Bridge. You will be served morning or afternoon tea by the crew; sit back, relax and enjoy your Tasmanian Cheese and Fruit Platter.
Once back on the southern side of the bridge, sail towards Bellerive or Battery Point and Sandy Bay before arriving back at the docks.
About the SV Rhona H
SV Rhona H is one of the last of the beautiful fishing ketches built by Ned Jack in Launceston. The 52' sailing ship is a perfect way to experience traditional sailing and the beauty of this part of Tasmania.
Having plied the waters of Bass Strait and its islands, SV RHona H remained in continuous commercial survey from the time she worked as a fishing boat, before being converted for sailing charters in 1988-1989. She is still in commercial survey making SV Rhona H a working example of Tasmania's maritime heritage.
All the crew on SV Rhona H are volunteers and love to share their passion for the oceans, traditional sailing and the SV Rhona H herself. The work on SV Rhona H is being done to restore the vessel to her former glory both above the deck and below. Come aboard to see the results so far, hear how this part of Tasmanian history is being kept alive as a real working boat.
Come aboard and share the adventure!


text:
"The sled test simulates the kind of crash that frequently occurs when one vehicle rear ends another in commuter traffic. People think of head restraints as head rests, but they're not. They're important safety devices. You're more likely to need the protection of a good head restraint in a collision than you are to need other safety devices because rear-end crashes are so common."
Related quotes
"The difference between school and life? In school, you're taught a lesson and then given a test. In life, you're given a test that teaches you a lesson."
"I think Armin is a better slider, but Georg is a better sled builder. If you combined the two, they'd be unstoppable."


text:
Kim Kardashian West expecting second child
Kim Kardashian West is pregnant.
The 34-year-old reality TV star revealed she is expecting her second child with her husband, rapper Kayne West, in a teaser at the end of the midseason finale of 'Keeping Up With The Kardashians' last night (31.05.15).
The couple - who welcomed their 23-month-old daughter North in June 2013 - have been open about their desire to expand their family and a thrilled Kim expresses her relief at having finally fallen pregnant for the second time as she chats to sister Khloe Kardashian, 30, in the clip from an upcoming episode of the E! series.
She says: "I just got the blood test back, and I am pregnant!"
E! quickly took to their Twitter account to congratulate the star, writing: "Congrats! @KimKardashian reveals she's pregnant with baby number two (sic)"
And Kanye, 37, is said to be equally excited at the prospect of adding to his brood.
Kim's trainer, Gunnar Peterson told PEOPLE: "A lot of people worry that being a dad will take away from work or couplehood, but Kanye has gotten better at everything since he's become a dad."
The brunette beauty has documented the challenges she has faced conceiving baby number two on the reality show and admitted to feeling exhausted after undergoing IVF.
Speaking on a recent episode she said: "I'm like so over it. Like I'm exhausted, so I'm sure everyone gets to that point. I'm like, 'Okay, I'm done'."
She also told her half sister Kendall Jenner when the series aired in April: "I complain so much about how I hated being pregnant, and I never thought I would be begging to be pregnant.
"Trying for baby number two is just not fun like baby number one ... I'm like, 'I'm ovulating in five minutes! Get over here!'"


text:
The School of Légèreté Volume 2, PAL
39,90 €
This second part shows the advanced work of the School of Légèreté. These films are an excellent opportunity to watch Philippe Karl working with his students.
Hands-on training with students of the School of Légèreté
Philippe Karl
riding master and advocate of "Légèreté" (lightness)
is a much sought-after riding instructor all over the world. In his clinics
he sensitively
yet consistently conveys the basic principles of classical riding.
These films are an excellent opportunity to watch Philippe Karl working with his students—licensed instructors and instructors-in-training of his School of Légèreté. He teaches riders on horses that we see every day: the charming heavy horse
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he systematically focuses on the specific level of schooling of each horse-and-rider pair.
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Katherine Cooper, Maricopa County Superior Court Judge, Had Ex-Con as Live-In Boyfriend
Maricopa County Superior Court Judge Katherine Cooper's live-in boyfriend of two years is a convicted sex offender under indictment for extortion in New York.
After Donna Rossi, reporter for Channel 5 News, (KPHO-TV) broke the story on Monday, Cooper issued a brief statement saying she's booted her boyfriend out and hadn't known of his criminal past.
See also: -Arizona Ordered to Pay Up for Under-Funding Public Schools
Cooper ruled on some very high-profile cases in the last couple of years, including an order in August that Arizona has short-changed its schools by $317 million and must pay them back. In March, she declared that Arizona's medical-marijuana law made cannabis concentrates legal for authorized users, thwarting the plans of County Attorney Bill Montgomery to prosecute medical users caught with "shatter" or food products made with pot resin.
Michael Kent Krause's most-recent mug shot.
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The judge's boyfriend, Michael Kent Krause, 52 was indicted recently in New York on a felony charge of grand larceny due to extortion, and detectives tracked him down to a Mesa trailer. Krause listed the trailer's address as a requirement for New York's sex-offender registry, but detectives soon learned he didn't really live there.
Reportedly, California Department of Corrections and Rehabilitation records show that Krause has spent time in prison for burglary, assault with a deadly weapon and assault with intent to commit a sex offense.
During his initial appearance in court, Krause was represented by high-dollar, highly decorated Phoenix attorney Michael Morrissey...
A check of Morrissey's background revealed that he and Cooper earned their undergraduate and law school degrees from the same university in the same year and have known each other for more than 30 years.
"CBS 5 News tried to contact Cooper and she issued this statement:
"'I was shocked when I learned of the allegations regarding Michael Krause on Tuesday. I had no knowledge of any of the charges against him. I have no further relationship with Mr. Krause, and he no longer resides at my residence.'
"Cooper also denied knowing that Krause was a convicted felon and registered sex offender. When asked if she hired Morrissey to represent Krause and if she put up his bond money, CBS 5 News was told the judge would not make additional comments."
Katherine Cooper
A former assistant Scottsdale city attorney and private lawyer, Cooper was appointed to the bench by Governor Jan Brewer in 2011. Voters decided in November to retain her as a judge.
News of her naughty boyfriend could harm her career, possibly.
But if true love really is blind, then perhaps Cooper can be forgiven for failing to see Krause's rap sheet.
Got a tip? Send it to: Ray Stern.
Follow Valley Fever on Twitter at @ValleyFeverPHX. Follow Ray Stern on Twitter at @RayStern.
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Courteney Cox taking wedding tips from Jennifer Aniston
Courteney Cox wants a wedding like Jennifer Aniston's.
The 'Cougar Town' star - who reunited with fiance Johnny McDaid earlier this year after a brief split - was "really impressed" with the way her best friend was able to tie the knot with Justin Theroux in secret last year, and has been getting tips and contacts from her pal in order to plan a similar ceremony at her own home.
A source said: "Courteney was really impressed by Jennifer's wedding to Justin Theroux.
"It all went without a hitch and they managed to keep it secret.
"Courteney loves the idea of having a backyard homespun wedding, just like Jen, who has been sharing all of her best contacts.
"Courteney is thought to have already met with jewellery designer Jennifer Meyer to talk about wedding rings, as well as Charm City Cakes to discuss the wedding cake."
Although the couple got back together earlier this year, it is only recently they have got engaged again and told friends they are putting marriage back on the agenda.
The source said: "They tentatively gave things another go earlier this year and have since decided they're serious about going ahead with the marriage.
"Now they're moving full steam ahead to get everything arranged."
The 52-year-old actress - who has 12-year-old daughter Coco with ex-husband David Arquette - and the Snow Patrol musician, 39, are keen to keep their nuptials as relaxed and low-key as possible.
A source told Britain's Grazia magazine: "Courteney and Johnny haven't hidden the fact they called off their engagement before giving things another go, and have told friends they feel stronger than ever.
"Still, because it hasn't been an entirely smooth ride, they're keen to keep things low-key. They want something relaxed that's just a celebration of their love."


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Christmas (God's Love) - Poem by ESPN CHICK
Everyone has heard the story
The Christmas story and what its about
Jesus being born in Bethlehem
But thousand years later
Controversy about it
Whether to say Merry Christmas or Happy Holidays
It should be about God sending his one and only
To a virgin girl
So young but knew God had something great in store
Didn't know that her baby boy was going to die on the cross
Die for everybody's sin
We take it for granted each and everyday
It shouldn't be about gifts
It should be about our greatest gift that we received
Even though we wasn't there
God knew we were going to be born
He knew we are all sinful
Thats why he sacrificed his son for us
His perfect sinless son to be crucified
That should be the greatest gift
He is the reason why we are here
It shouldn't be about celebrating Christ's birth once a year
It should be about celebrating God's love everyday of our life
Christ is in Christmas but we act like Christ is a bad name
God so loved the world he gave is one and only begotten son
We all know the verse John 3: 16 but how many times do we take that at heart
Take it to heart and spread God's love for us and what he has in store above
Comments about Christmas (God's Love) by ESPN CHICK
Scott Austin (1/1/2008 10:18:00 PM)
This was a very enjoyable read, with a great message to be learned for all. Thank you for sharing it with us. May peace and joy fill your heart each and everyday.
Scott (Report) Reply
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text:
Liver damage leads to an inflammatory response and to the activation and proliferation of mesenchymal cell populations within the liver which remodel the extracellular matrix as part of an orchestrated wound-healing response. Chronic damage results in a progressive accumulation of scarring proteins (fibrosis) that, with increasing severity, alters tissue structure and function, leading to cirrhosis and liver failure. Efforts to modulate the fibrogenesis process have focused on understanding the biology of the heterogeneous liver fibroblast populations. The fibroblasts are derived from sources within and outwith the liver. Fibroblasts expressing α-smooth muscle actin (myofibroblasts) may be derived from the transdifferentiation of quiescent hepatic stellate cells. Other fibroblasts emerge from the portal tracts within the liver. At least a proportion of these cells in diseased liver originate from the bone marrow. In addition, fibrogenic fibroblasts may also be generated through liver epithelial (hepatocyte and biliary epithelial cell)–mesenchymal transition. Whatever their origin, it is clear that fibrogenic fibroblast activity is sensitive to (and may be active in) the cytokine and chemokine profiles of liver-resident leucocytes such as macrophages. They may also be a component driving the regeneration of tissue. Understanding the complex intercellular interactions regulating liver fibrogenesis is of increasing importance in view of predicted increases in chronic liver disease and the current paucity of effective therapies.
- fibroblast
- fibrosis
- hepatocyte
- Kupffer cell
- myofibroblast
- stellate cell
The adult human liver typically weighs approx. 1.5 kg. It is the largest internal organ and plays many pivotal roles in intermediary metabolism, and in the metabolism and clearance of xenobiotics. The liver is responsible for the disposal of bile pigments and for the generation of bile acids that are central to the maintenance of cholesterol homoeostasis and the absorption of dietary lipid from the intestine. The liver also plays an important role in lipoprotein metabolism and cholesterol homoeostasis. It is the site of synthesis for major serum proteins, including albumin, complement and clotting factors, and of catabolism of amino acids and the generation of urea. In the normal state, the liver is maintained at a size which provides substantial overcapacity. It also has a remarkable ability to regenerate in response to functional parenchymal loss and can return to normal size and functional state, even after 70% of the parenchyma is lost.
Chronic liver injury, irrespective of cause, is generally associated with the accumulation of matrix proteins, a process referred to as fibrosis. In parallel with this, there is a continued stimulus for regeneration, leading to further distortion of the hepatic architecture and vascular structures (portal veins, hepatic veins). This results in a transformation to a nodular architecture, so-called cirrhosis (Figure 1). Given the normal functional overcapacity of the liver, patients with cirrhosis can have apparently normal (compensated) liver function for long periods of time, but, with many, there is ultimately decompensation with catastrophic effects on the various strands of intermediary metabolism referred to above. In addition, the altered vasculature leads to the development of portal hypertension. To date, most therapies for chronic liver disease have targeted the aetiological agent: for example, there are now several effective antiviral agents for the treatment of hepatitis B and C. Similarly, there are a number of immunosuppressive agents that can be given for immune-driven processes such as autoimmune hepatitis. Although these agents often have a beneficial effect on the degree of fibrosis, there are currently few agents that are specifically developed to interfere with fibrosis. For some patients with end-stage liver disease, the only available option for treatment is orthotopic transplantation.
The present review will examine our current understanding of fibrosis, the experimental models available for its study and the potential therapeutic options currently being tested.
Accidental (e.g. adverse reaction to a normally therapeutic drug dose [1]) or deliberate (e.g. paracetamol overdose [2]) poisoning can lead to massive liver necrosis, acute liver failure and death. However, chronic liver damage and its associated progressive fibrosis is, quantitatively, a more significant clinical problem [3]. Table 1 outlines the major causes of chronic liver disease in the human population. Viral infections are currently the major global cause of liver fibrosis. However, alcohol abuse is another important cause of chronic liver disease. Furthermore, over the last 25 years, it has become increasingly apparent that a similar spectrum to that observed with alcohol can be seen in individuals who are obese and/or diabetic. This so-called NAFLD (non-alcoholic fatty liver disease) can lead to end-stage liver injury and cirrhosis. The long-term socioeconomic impact of the 'epidemic' of NAFLD and obesity is yet to be established.
Liver tissue is composed of functional units that contain all the cells of the liver arranged around point(s) of entry (portal tract) and exit (central veins) of blood. There remains a debate about the structure of the functional hepatic unit with several models proposed. In part, this is because there is no impermeable barrier between the units in most species, including humans and rodents. A review of the various proposed functional units is beyond the scope of this review (for more information, see [4]); however, the most favoured in their simplest terms are referred to here as the liver lobule (first proposed by Kiernan) and the liver acinus of Rappaport (Figures 2A and 2B). Zonal expression of many genes fits with a lobular functional structure for the liver. However, the acinus is the unit of choice for histopathologists because it aids in the explanation of many pathological lesions (Figure 2C).
The liver receives a dual blood supply: there is a portal circulation which brings partially oxygenated blood from the gut, rich in compounds absorbed following digestion, and, in addition, some 30% of the hepatic blood comes via the hepatic artery. The two blood inputs become mixed at the edge of the portal tracts where the liver sinusoids are found. These, in essence, are the liver's capillaries and are lined by specialized fenestrated endothelial cells, controlling the flow of materials to and from the space between hepatocytes and endothelial cells (space of Dissé) [5]. The space of Dissé contains a low density of extracellular matrix proteins and the hepatic stellate cell. Hepatocytes constitute the major epithelial cell type of the liver and extend along the sinusoids to the centrilobular region (lobule) or zone 3 (acini) as polarized epithelial cells. Liver macrophages (Kupffer cells) reside within the sinusoids. The major cell types of the liver and their functions are summarized in Table 2.
A striking feature of the liver is the heterogeneous expression of many genes along the sinusoid. A classic example is the expression of CYP (cytochrome P450) genes which are expressed at their highest levels in hepatocytes surrounding central veins [6] (see also Figure 2B). Xenobiotics requiring metabolism by CYP cause predominantly centrilobular/zone 3 damage, despite the fact that periportal/zone 1 hepatocytes are exposed first to ingested xenobiotics. The majority of exposure to toxins is through ingestion of pro-toxins that require enzyme-mediated conversion into a cytotoxic product (many directly cytotoxic substances are obviously avoided). Thus pro-toxin damage is located in the regions where the activating enzyme is expressed. Additionally, oxygen levels are also at their lowest in the centrilobular/zone 3 regions, which may have an impact on the ability of cells to respond to and survive injury. Hepatocytes are therefore more often the cell type that is damaged by hepatotoxins (although they are not intrinsically sensitive and have a number of active defence mechanisms, such as a capacity to maintain high levels of reduced glutathione to defend against oxidative stress [7]).
Enzyme-mediated toxicity has particular relevance to acute mechanisms of xenobiotic hepatotoxicity, but is the cause of only a minor proportion of chronic liver disease cases. Indeed, the major chemically induced cause of liver disease, alcohol, induces changes in gut permeability to bacterial membrane components, leading to a pro-inflammatory hepatic environment as a major part of its mechanisms of action [8,9]. Most experimental models of fibrosis employ pro-toxin/enzyme-mediated mechanisms to cause liver damage. An understanding of how toxins work in experimental models of fibrosis is therefore essential to avoid misinterpretation of data, particularly when the efficacy of a potential anti-fibrogenic agent is being examined.
Fibrogenesis is predominantly viewed as a repercussion of the wound-healing response that occurs after persistent liver tissue damage. These events are therefore discussed (Figure 3 and Animation 1 at http://www.BiochemJ.org/bj/411/0001/bj4110001add.htm).
Liver injury and the inflammatory response
In most cases of acute liver injury, hepatocytes are damaged and undergo both necrosis and apoptosis. Figure 2(C) demonstrates the typical effects observed shortly after treatment with the hepatotoxin CCl4. Hepatocytes located mainly around the central veins are damaged because CCl4 is a pro-toxin that requires metabolism by CYP for toxicity (mainly by CYP2E [10], see Table 4). Cell death is primarily via necrosis, although a proportion of hepatocytes may undergo an apoptotic mechanism of cell death, particularly following chronic exposure [11]. Kupffer cells in damaged areas detect the release of intracellular contents and/or apoptotic cells and release a range of cytokines and chemokines that activate local resident leucocytes and promote the recruitment of circulating leucocytes to the region of damage [12,13]. Sinusoidal endothelial cells play a complementary role in this process through changes in the expression of adhesion proteins that promote the tethering of passing leucocytes, leading to their trans-endothelial migration to the site of injury [14]. Major factors contributing to fibrogenesis include cytokines, of which many are released from Kupffer cells, but some are derived from myofibroblasts themselves (Table 3).
The response to tissue damage and infection is therefore analogous with activation of the innate immune system and the potential activation of the adaptive immune system. In some cases, the latter is followed by a breakdown in tolerance to self-antigens and therefore to the generation of T-cells and antibodies to self-antigens [15,16]. In cases where liver damage is drug-induced, it is probable that the drug and/or a metabolite(s) reacts with a protein(s), which is then seen by the immune system as foreign. Once the drug and neo-antigen are cleared, immune tolerance to unmodified protein is lost, resulting in continued attack of the self-antigen and a chronic autoimmune hepatitis. Typically, antibodies against smooth muscle proteins and/or a nuclear antigen are detected in affected individuals (in type 1 autoimmune hepatitis) or to microsomal xenobiotic-metabolizing enzymes such as CYPs (in type 2 autoimmune hepatitis) [16]. Ticrynafen (tienillic acid) is converted into a metabolite which reacts with the generating enzyme (CYP2C9), against which antibodies are produced [17,18].
The inflammation associated with hepatic injury forms part of a regulated response to cell damage resulting in the removal of necrotic material. The liver, presumably because of its precarious function as a protector from endobiotics and ingested xenobiotics, has evolved the ability to regenerate [19]. The cytokines involved in marshalling the inflammatory response to tissue damage also play an important role in the replacement of hepatocytes. Cytokines, such as TNFα (tumour necrosis factor α) and IL (interleukin)-6, prime remaining hepatocytes to be responsive to growth factors such as HGF (hepatocyte growth factor) and EGF (epidermal growth factor) [19]. The stimulus for liver growth appears to be through a sense of its own functional output. The surgical removal of part of the liver (partial hepatectomy) in which there may be relatively minimal cell death, results in regeneration of the remaining liver to the required size, as if responding to the rise in the levels of a factor normally metabolized by the liver. This factor may be serotonin [20,21], which is primarily synthesized by the gut and would therefore pass directly to the liver via the hepatic portal vein.
Hepatocyte regeneration in most diseased states therefore comes from existing viable hepatocyte mitosis [19]. Previous work suggesting that hepatocytes can be derived from the bone marrow [22,23] has now been shown, at best, to be a rare event (the presence of donor genetic material in recipient hepatocytes is now thought to occur via donor bone-marrow-derived macrophage fusion with recipient hepatocytes [24,25]). Liver-resident leucocytes (e.g. Kupffer cells) are derived from the bone marrow in addition to a proportion of other non-parenchymal liver cells [26,27]. A hepatocyte/bile duct epithelial cell progenitor cell, termed 'oval cells' in some species, is present in portal tract regions (at the level of the so-called 'canal of Hering'), but only gives rise to hepatocytes when existing hepatocytes are prevented from replicating [28,29]. In this respect, the 'streaming' hypothesis in which hepatocytes are normally replenished (potentially from an oval cell progenitor) from replication in the periportal region [30], which could replace hepatocytes after acute centrilobular injury, is not now widely accepted [31,32]. Many of the factors which drive the innate immune system to clear away the damage also act in an apparent co-ordinate fashion to prime hepatocyte renewal. A less well understood component of this process is the remodelling of the extracellular matrix that occurs in damaged parenchyma. An additional factor, however, is that myofibroblasts may be essential for effective liver regeneration. Plasminogen (Plg)-deficient mice spontaneously develop liver fibrosis [33]. The neurotrophin receptor p75NTR is expressed in myofibroblasts and appears to function in the transdifferentiation from hepatic stellate cells [34]. Plg−/− p75NTR−/− mice have exacerbated pathology compared with Plg−/− p75NTR+/+ mice due to inhibited hepatocyte proliferation [34].
(Myo)Fibroblast proliferation
Fibroblasts were hitherto considered to be a relatively inert 'space-filling' cell type secreting extracellular matrix proteins. However, there is increasing evidence in the liver to suggest that they play a role in tissue regeneration; they are now known to express a range of cytokines and chemokines [35–38]. In generic terms, a population of fibroblast-like cells is activated by (or activation is significantly enhanced by) the release of cytokines and ROS (reactive oxygen species) from Kupffer cells and other leucocytes [39–41] to proliferate and secrete proteases, extracellular matrix proteins and other factors. In the acute setting and under some chronic conditions in which fibrosis may be reversible, the fibroblast-like cells undergo apoptosis and Kupffer cells release factors which remodel the extracellular matrix through secretion of matrix metalloproteinases [42,43]. The end result is that the liver sinusoidal structure returns to normal, and the current theory is that the process of fibroblast-like cell activation is an essential component of this process, although this remains to be experimentally tested.
If damage to the liver persists, either continuously or through repeated acute episodes within a timeframe such that resolution has not had a chance to occur, fibroblast numbers increase and fibrosis develops (see Animation 2 at http://www.BiochemJ.org/bj/411/0001/bj4110001add.htm). As the liver disease progresses, the scarring becomes more extensive, impeding hepatocyte regeneration, and the function of the organ is compromised. For a period of time, fibrosis remains reversible if the primary cause of liver damage is removed or suppressed [44,45].
Early work on liver fibrosis originally proposed that hepatocytes were responsible for the production of scarring extracellular matrix protein in liver fibrosis [46]. It was subsequently shown that hepatic stellate cells were a major source [47,48]. In a normal liver, the cells are referred to as 'quiescent' and function to store much of the body's vitamin A [49]. Hepatocytes esterify vitamin A with fatty acids which are then stored by quiescent hepatic stellate cells [49,50]. In response to liver damage, quiescent hepatic stellate cells lose their vitamin A and transdifferentiate into a myofibroblast phenotype expressing α-smooth muscle actin [51–53], an actin isoform restricted to smooth muscle cells.
Heterogeneity of hepatic stellate cell-derived myofibroblasts
Under the appropriate in vitro culture conditions (see below) quiescent hepatic stellate cells undergo a phenotypically similar process of transdifferentiation to myofibroblasts as that which occurs in vivo in response to liver damage [54]. It has recently emerged that quiescent hepatic stellate cells are not the only fibrogenic cell in the liver. Quiescent hepatic stellate cells can be found in the centrilobular and perisinusoidal regions of the liver lobule (Figure 4). Injury to the centrilobular region (e.g. in alcoholic liver disease) results in their activation. However, Ramadori and co-workers first suggested that portal tract fibroblasts rather than stellate cells were predominantly responsible for fibrogenesis in cases where damage was located in the periportal regions of the liver lobule (e.g. cholestasis) [55], a view that is now broadly accepted [56–58]. Figure 5 compares the fibrosis that occurs in rats treated with CCl4 (a centrilobular hepatotoxin) and bile duct ligation, which preferentially damages hepatocytes in the periportal region of the lobule. Both injuries result in fibrosis, but extensive α-smooth muscle actin myofibroblast immunostaining is only seen in the former, with cells positive for vimentin in the latter. Thus it is probable that a different population of vimentin-positive hepatic fibroblasts located in the periportal region is responsible for fibrogenesis in cases where periportal damage occurs. However, with more extensive injury, the disease progresses, and populations of cells from other regions probably contribute to fibrogenesis.
The complexity of establishing liver myofibroblast identity is compounded by the fact that each population of hepatic fibroblasts may be heterogeneous in its expression of fibrotic marker genes (and potentially other genes). In an elegant study from Brenner and co-workers, transgenic mice were generated in which red and green fluorescent protein reporter gene expression were driven by the α-smooth muscle actin and collagen IA1 promoters respectively [59]. Both reporter genes were expressed in culture-activated hepatic stellate cells, but they were not co-expressed in all cells. In bile duct-ligated mice, pericentral and perisinusoidal myofibroblasts were both α-smooth muscle actin- and collagen IA1 marker gene-positive, whereas periportal fibroblasts only expressed the collagen IA1 reporter gene.
Embryological origin of hepatic stellate cells and liver myofibroblasts
Establishing the embryological origin of hepatic stellate cells (i.e. the germ layer from which the cells are derived) is complicated by their apparent heterogeneity as a myofibroblast. To date, it has not been formally determined. Given that adipose, smooth muscle cells and fibroblasts are derived from the mesoderm and that stellate cells are lipid-storing cells with an ability to transdifferentiate into myofibroblasts, it is likely that at least a proportion of both hepatic stellate cells (and myofibroblasts) and liver fibroblasts are mesodermal in embryological origin. However, hepatic stellate cells and liver myofibroblasts express several genes normally associated with neural tissue, such as synaptophysin, nestin and glial fibrillary acidic protein [60]. This supports the possibility that hepatic stellate cells (or a proportion of them) have an ectodermal origin, perhaps from the neural crest given its ability to generate a range of mesenchymal-like cells [61]. However, this has recently been tested in transgenic mice [61a]. A transgenic mouse expressing the Cre recombinase transgene under control of a WNT-1 promoter /enhancer sequence (specific to neural crest cells) was crossed with a transgenic for a fluorescent protein whose expression was dependent on removal of a lox P-flanked stop cassette by Cre recombinase [61a]. Although fluorescent protein was found in all tissues known to be derived from the neural crest, there was no expression in desmin-positive perisinusoidal cells of the liver [61a]. This suggests that hepatic stellate cells are not derived from neural crest cells.
In the adult mouse, recent work suggests that some hepatic stellate cells are derived from the bone marrow [62]. When bone marrow cells expressing GFP (green fluorescent protein) were transplanted into normal mice, hepatic stellate cells in the recipient mice were found to express GFP. In culture, the GFP-positive stellate cells transdifferentiated into α-smooth muscle actin-positive myofibroblasts [62]. In CCl4-treated fibrotic animals, GFP also co-localized with α-smooth muscle actin [62]. This observation has been confirmed in irradiated female mice receiving bone marrow from male donor mice. Myofibroblasts containing a Y chromosome were detected in approx. two-thirds of recipient fibrotic liver myofibroblasts, with little evidence of cell fusion [27]. More recently, the scar-producing cells associated with bile duct ligation (periportal myofibroblasts) have also been shown to originate from the bone marrow in an animal model, but yet remain distinct from hepatic stellate cells in that they are CD45-positive [63]. Examination of human liver sections from non sex-matched recipients of either bone marrow or liver transplants confirmed that bone marrow contributed to myofibroblast populations in patients who subsequently developed liver disease [64].
These data suggest that hepatic stellate cells and liver fibroblasts at least in part originate from a mesenchymal stem cell within the bone marrow in the liver disease state. However, there remain a number of observations which suggest that there are other sources from which fibrogenic cells may be generated. For example, Zeisberg et al. [65] reported that liver fibroblasts are derived from hepatocytes in vivo during fibrosis through an "epithelial-to-mesenchymal transition", although most of these fibroblasts were not α-smooth muscle actin-positive. Similarly, Robertson et al. [66] have shown biliary epithelial cell "epithelial-to-mesenchymal transition" in a patient with primary biliary cirrhosis, which may account for the bile ductopenia and portal tract fibrosis that occurs with this disease.
There is an increasing body of literature concerning the plasticity of cells from several tissues which have normally been considered mature and terminally differentiated. In this respect, quiescent hepatic stellate cells (specifically the proportion that are CD133-positive) have been proposed as a progenitor cell not only for liver myofibroblasts, but also for hepatocytes and endothelial cells [67]. Mesenchymal stem cells from the adult bone marrow have also been stimulated to form multiple cell types (including hepatocytes) in vitro [68,69]. However, it is possible that the in vitro environment imparts an unusually potent plasticity to many cells that enables them to differentiate in a way that would not occur in vivo (since bone marrow cells do not differentiate into hepatocytes appreciably in vivo [23,24]).
Pivotal role for Kupffer cells in fibrogenesis
Although the status of hepatic myofibroblasts (their number and degree of activation) may directly control fibrosis severity, increasing attention is now been given to the role of other cells in the process. Macrophages within the liver or monocytes/macrophages recruited to the tissue are now known to exert a considerable influence. Their number increases in damaged liver and they are principally located around the regions of damage and fibrosis (Figure 6).
Thurman's group showed that inhibition of Kupffer cell function (using gadolinium chloride), reduced fibrosis in a CCl4 model of liver fibrosis [70]. More recently, Duffield et al. [71], using a transgenic mouse model in which CD11b-positive cells can be conditionally stimulated to undergo cell death, have shown that liver-resident monocytes and macrophages not only promote fibrogenesis, but also are instrumental in the removal of fibrosis during any recovery phase.
The promotion of fibrogenesis by Kupffer cells is associated with the release of a range of pro-fibrogenic cytokines and ROS as part of their inflammatory response to liver damage. It is notable that the presence of Kupffer cells (normally present in low numbers in most isolations) in hepatic stellate cell cultures promotes a myofibroblast phenotype closely similar to the cells in vivo [54], but macrophages, in response to the milieu of cytokines and other factors, respond by releasing different mixtures of cytokines. It may be appropriate to suggest that macrophages differentiate into a variety of states. With regard to recovery from fibrosis, macrophages may differentiate into an anti-inflammatory phenotype and/or secrete proteinases that promote the degradation of scarring extracellular matrix proteins.
In vivo models of liver fibrosis
In view of the complex intercellular communication between cell types within the liver, and that extrahepatic cells may contribute to fibrogenesis, animal models remain an important experimental tool. In studies where the aim is to test the efficacy of a potential anti-fibrogenic agent, it is generally considered that drugs should be tested in at least two animal models (where the region of lobular damage is different so that effects on hepatic myofibroblasts derived from different regions of the lobule can be determined). Table 4 summarizes animal models of liver fibrosis most commonly employed. A vital issue with regard to the use of these models is that their use should be carefully matched to the mode of action of potential anti-fibrogenic agents. It is clear that treating the primary cause of liver damage in the human population would be the mode of therapeutic choice when available. The use of a potential anti-fibrogenic agent would be indicated when the primary cause of liver damage cannot be treated and/or fibrosis has progressed to cirrhosis. Accordingly, it is essential to ensure that the potential anti-fibrogenic agent does not modulate the hepatotoxicity of the experimental agent used to generate liver damage (i.e. that a potential anti-fibrogenic agent was not a CYP2E inhibitor if using the CCl4 model of liver fibrosis [72]) when using an animal model. Reductions in fibrosis could therefore be associated with reduced levels of liver damage, and not due to action of an anti-fibrogenic agent. Commonly used markers of liver fibrosis are given in Table 5.
Although the various animal models developed previously have served an important function in identifying basic mechanisms of liver fibrogenesis and testing new anti-fibrotic agents, it must be appreciated that all show some significant morphological differences with their human 'counterparts'. This is perhaps least so with cholestatic models, particularly common bile duct ligation where the pattern of fibrosis is very similar to that seen when there is interruption of bile flow in humans. On the other hand, the commonly used CCl4 model is probably the most frequently used tool for investigating regression of fibrosis and cirrhosis, but the fibrous septa observed in animals, even on long-term CCl4, are generally much less developed compared with most human cirrhoses. Probably one of the most important differences between human and animal model diseases is the lack of significant alteration of vascular relationships in the latter; human cirrhosis is often confounded by liver cell loss through secondary hypoxic events, leading to parenchymal extinction. This does not occur in the commonly used animal models.
In vitro models of liver fibrosis
The most commonly used in vitro model of liver fibrosis is the isolation of quiescent hepatic stellate cells and their culture on plastic culture dishes in serum-containing culture medium. Under these conditions, cells commence a phenotypically similar process of transdifferentiation to the activated myofibroblast phenotype apparent in the liver in response to chronic liver damage (Figure 7), particularly when Kupffer cells are present (as a minor impurity) within the culture [54]. The cells are amenable to trypsin subculture, although, once the cells have activated to a myofibroblast phenotype, the cells remain in the myofibroblast phenotype in subsequent passages. Where possible, cells should be used in primary culture since this period is the only time to examine effects on transdifferentiation.
There is a concern that differences in laboratory protocols may result in differences in the nature of hepatic myofibroblasts, and that hepatic stellate cell-derived myofibroblasts may be overgrown by portal tract myofibroblasts [55–57]. Indeed, at present, there is no universally agreed diagnostic marker for quiescent hepatic stellate cell populations that could be used to establish cell identity and purity. Nevertheless, the in vitro culture system will remain a valuable tool for studying liver fibrosis and can readily be used in high-throughput screening assays for potential anti-fibrogenic agents.
A technically more challenging in vitro model is the culture of liver slices [73,74]. Liver slices from normal or diseased liver will retain their native extracellular matrix, cell–cell contacts and cell density and may be a valuable model for short-term studies. However, even the thinnest tissue slices (∼200 μm thick, ∼10 cells thick) prevent effective access of nutrients to cells, and a large proportion of the slice, particularly hepatocytes, die after 24 h [75,76].
Hepatic stellate cells from rodents are readily subcultured for many passages and therefore, for studies using myofibroblasts in their pro-fibrogenic state only, immortalized cell lines are often not required. To study the process of transdifferentiation from the quiescent state, cells must be isolated repeatedly from animals, as myofibroblasts do not readily revert to the quiescent state. The value of a rodent hepatic stellate cell line (see Table 6) lies with their propensity for being transfected with plasmid constructs, because cells isolated from rodents are difficult to transfect with high efficiency. Human hepatic stellate cell lines are more common because of difficulties in most laboratories of accessing human tissue. Furthermore, in our hands, most human myofibroblast cultures appear to senesce at passage 2–5 (from 58 human preparations, only two cultures have remained proliferative for more than five passages). This may be due to isolation of cells primarily from elderly patients (mainly from partial hepatectomy specimens from individuals with a secondary tumour in the liver). Human myofibroblasts are also resistant to transfection, and, in our hands, only nucleofection was sufficiently effective (with repeatable high efficiency) for the transfection of a range of reporter gene plasmid constructs [38]. Viral vectors have therefore been investigated from time to time for their ability to infect cells with high efficiency, including adenoviral [77,78], retroviral [79] and baculoviral [80] vectors. Although reported to be effective, the resources required to generate recombinant vectors has probably contributed to their lack of widespread use.
The in vitro model systems outlined above remain an effective way to screen a large number of potential compounds at an early stage for their ability to modulate the fibrogenic process using a variety of endpoints. However, as with many in vitro systems, there are limitations that prevent the identification of anti-fibrogenic agents with 100% accuracy. In vitro systems are closed artificial units that cannot allow for the absorption, distribution, metabolism and excretion of drugs that you see in whole-body studies. Liver myofibroblasts also reside next to the major drug-metabolizing cells of the body in vivo, but these are arguably functionally absent from most in vitro systems. Thus the replacement of in vivo animal models with in vitro models has yet to be achieved, and the former will probably always have a role to play in studies of liver fibrosis.
A number of reviews have appeared on approaches to the treatment of liver fibrosis [81–83] and so only brief discussion is given here. Currently, there is no therapeutic agent indicated and licensed for the primary treatment of liver fibrosis, although a number of therapies are in clinical trials (Table 7). A variety of potential drug targets have been shown to exist within hepatic myofibroblasts in experimental systems, but many of these are associated with other cell types which presents problems of drug specificity. Indeed, the surprisingly varied number of targets available suggests that there may be redundancy for each pathway in myofibroblasts. Thus the drug-mediated block of a pathway promoting fibrogenesis may be overcome by the remaining unrelated fibrogenesis-promoting pathways. For these reasons and because myofibroblasts produce a number of factors which act in an autocrine fashion to promote fibrogenesis, the efficacy of drug treatments that lead to myofibroblast apoptosis have been examined [84,85].
In animal models recovering from chronic liver damage (i.e. the cause of damage is stopped), fibrosis reversal is associated with the apoptosis of liver myofibroblasts [44]. NF-κB (nuclear factor κB) is a transcription factor that regulates the expression of a range of genes associated with inflammation [86]. NF-κB becomes constitutively active in myofibroblasts in vitro and induces the expression of several pro-inflammatory genes [e.g. ICAM (intercellular adhesion molecule) and nitric oxide synthase 2] [87]. NF-κB is also constitutively active in myofibroblasts in vivo, suggesting that it is not an artefact of the in vitro culture system (F. Oakley, personal communication). NF-κB functions to prevent the apoptosis of myofibroblasts [84,87] as it does in other cells (e.g. hepatocytes) when they are exposed to pro-inflammatory mediators such as TNFα [89,90]. Inhibition of NF-κB therefore leads to the apoptosis of myofibroblasts in vitro [87] and in vivo [84,85]. The stimulation of liver myofibroblast apoptosis using gliotoxin (a fungal toxin that inhibits NF-κB [91], but which also works directly on the mitochondria to promote apoptosis [92]), resulted in a rapid recovery from fibrosis, and using this compound provided the first evidence in vivo that myofibroblast apoptosis may be an effective therapeutic approach to liver fibrosis treatment [84]. Using existing licensed NF-κB inhibitor drugs such as sulfasalazine to achieve the same ends may be a realistic treatment option [85]. More recently, targeting gliotoxin to hepatic myofibroblasts using a recombinant single-chain antibody to a surface antigen on the cells (thereby retaining functional liver macrophages), reduced fibrosis in vivo in a sustained injury model in contrast with free gliotoxin [93]. The specific removal of liver myofibroblasts in a 'non-inflammatory' manner while leaving macrophages in place therefore appears to be an effective anti-fibrogenic approach. By removing the liver myofibroblasts, the potential of specific drug targets within these cells becoming redundant with time is avoided. The converse, however, is that employing cell-death mechanisms as a therapeutic approach requires careful targeting to avoid adverse effects. Furthermore, it remains to be seen whether myofibroblast reductions as part of an anti-fibrogenic approach has any deleterious effects on liver regeneration.
Treatments in which drug targets have opposite effects in hepatocytes and liver myofibroblasts may turn out to be safer options, particularly when disease progression is to be slowed (in contrast with stimulating a reversal of cirrhosis). The PXR (pregnane X receptor) is a nuclear receptor transcription factor that regulates the expression of genes associated with endobiotic and xenobiotic clearance in hepatocytes [94]. PXR function is normally activated through contact with a range of ligands, including existing licensed drugs (e.g. rifampicin) and endogenous compounds (steroids, bile acids) [94]. Recent work from our laboratory has shown that the PXR is expressed in myofibroblasts, is capable of binding to its DNA enhancer response element in myofibroblast nuclear extracts and is transcriptionally functional on transfected reporter gene constructs [38]. The PXR regulates a specific set of genes in myofibroblasts. Ligand activators of the PXR reduce the expression of pro-fibrogenic cytokines such as TGF (transforming growth factor) β and inhibit proliferation [38]. PXR activators therefore act in an anti-fibrogenic manner in human liver myofibroblasts in vitro [38]. Using mice with a disrupted PXR gene, the role of the PXR in mediating an anti-fibrogenic effect was unequivocally established [72].
The fibrotic response in the liver is dependent on multiple cell types, both resident and recruited to the liver, and is regulated by a vast array of factors in vivo. A full understanding of the response remains a goal at present, particularly the benefit of fibrosis to tissue function and viability. The ability to specifically 'knock out' cell types in a tissue should help to resolve many questions in the same way that transgenic technology has resolved questions surrounding a specific gene's function. Clinically employed anti-fibrogenic agents may then become available.
Abbreviations: CYP, cytochrome P450; EGF, epidermal growth factor; GFP, green fluorescent protein; IL, interleukin; NAFLD, non-alcoholic fatty liver disease; NF-κB, nuclear factor κB; Plg, plasminogen; PXR, pregnane X receptor; ROS, reactive oxygen species; TGF, transforming growth factor; TNF, tumour necrosis factor
- © The Authors Journal compilation © 2008 Biochemical Society
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text:
Submit News
HTC Considers "Senseless" One Smartphone
Shane McGlaun
May 24, 2013 8:00 AM
Recipient E-mail
Sender E-mail
HTC One with plain old Android expected this summer
One of the biggest headaches in the Android smartphone realm is the
lag time between when Google releases an OS update
and when smartphone manufacturers release their own customized version. That can mean when Google releases a new version of Android, it can be months before some users are able to get it on devices that use custom user interfaces.
HTC is now reportedly considering offering a version of the popular HTC One smartphone that lacks the
unloved Sense user interface
. Multiple sources are now indicating that HTC has a software build in the works for a plane
HTC One
running nothing but Android 4.2.2.
At this point, the rumors don't offer any indication of exactly how people will go about purchasing a version of the HTC One running plain Android. The device could be sold via the Google Play Store, but that is unconfirmed.
Sources did indicate that HTC will make the Sense-less version of the One available first in the U.S. The one caveat to a Sense-less version of the HTC One could be the lack of software support for some of the features that make the phone so good, such as BeatsAudio the HTC ImageSense software.
HTC also already has a Developer Edition of the One, and a Senseless version could muddy the waters for the company.
At this year's Google I/O conference, Google announced a
"pure" version of the Samsung Galaxy S IV
that uses the stock Android operating system.
"It's okay. The scenarios aren't that clear. But it's good looking. [Steve Jobs] does good design, and [the iPad] is absolutely a good example of that." -- Bill Gates on the Apple iPad
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February 8, 2013, 8:37 AM
HTC Admits to Sense UI "Bloat", Says Sense 4.0 is Less Complex
March 1, 2012, 11:03 AM
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text:
We help you find a Sheerness mandolin tutor. Mandolin tuition are an excellent method to begin an entertaining new hobby, pick up a new skill and attain confidence with mandolin. Use our site to find Sheerness mandolin tutors and determine which best matches your needs so you can enjoy your mandolin tuition in Sheerness immediately!
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So ... I checked out my weekly flyer from Michaels ... and OMG ...they had a fabulous half-price deal going on ... just had to go see! They had a great selection of their "Loops & Threads" ... and my mind was virtually racing with ideas as to what I could/would create with these beauties.
Somewhere in the back of my mind I had the notion to pick up another pair of needles ... to use to play with the new Zig Zag stitch ... welll ... lo & behold ... I spied the very size I did not have & wanted to get ... 6.50 mms ... and huh??? ... they're $2.99??? All the other sizes were 2 or 3 bucks more. Double checked the price at the cash ... no mistake ... it was right! Sold!
Coincidentally ... they are exactly a size between the other two I was contemplating trying for this stitch. When I did a test swatch with them ... the result was exactly what I wanted.
Oh ... I also clipped out the flyer coupon for 40% off one regular priced item ... but wasn't quite sure what I'd use it for ... until I found a lovely 300g ball of Phentex yarn ... perfect for a baby blanket ... called "Sweet Summer" ... it has pastel shades of white, yellow, green, blue, pink & purple.
It all came together ... the yarn & the needles & the stitch ... another project will soon be on the go.
Somewhere in between the other projects on the go ... I threw in a crochet project for another shawl using another Loops & Threads yarn that has a multi-coloured metallic thread through it in jewel tones. Have since completed it ... so feel no guilty about starting another creation.
I'm such a yarn junkie!
A Designer's Musings on Creativity & A Forum to Share the Inspiration ..... Whether in Silk Ribbon, Crazy Quilting or Beading ............................ With a Bit of "What Ever" Tossed in for Good Measure!
Wednesday, July 23, 2014
The Best of Both Worlds
Posted by Marie Alton at 11:14 PM
1 comment:
- Magpie's Mumblings said...
Don't you just love it when the universe aligns and you get a deal!
- July 24, 2014 at 2:43 PM
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text:
Cinderella: First Trailer Released
Watch Disney's Live Action Film "Cinderella"
First Trailer Released.
Get ready for the magic movement
of Disney which is released the first teaser trailer for its live action
version of "CINDERELLA" which will out in MARCH 2015. The excitement and twist
on the classic fairytale movie which has a story of fabulous characters.
Click here to watch the Trailer
The stars are LILY JAMES as a
Young Ella and RICHARD MADDEN as her Prince Charming.


text:
This just might be my favorite iteration of the infamous pussy hat yet!
The GENEie Pussyhat is designed by Rebecca Roush Brown of ChemKnits who says, "I believe in evidence based legislation. This is one of the reasons why I will March for Science. I believe that women's rights are human rights and that human rights are women's rights. I believe in standing up and letting my voice be heard, and this is why I spliced my DNA cable knitting motif with the pussyhat shape to create the GENEie Pussyhat."
Hear, hear! Will you be marching on April 22? Better knit a GENEie Pussyhat or two, or thirty-three!
Visit ChemKnits for the FREE pattern and more.
VN:F [1.9.22_1171]Knit a GENEie Pussyhat for April's March for Science - LOVE That DNA Double Helix Cable - FREE Pattern!,


text:
| This article does not cite any references or sources.
Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (December 2009)
|This article is an orphan, as few or no other articles link to it. Please introduce links to this page from related articles; suggestions are available. (December 2009)
'Lex' is Latin for one sense of the English term, law. In the Canon Law of the Catholic Church, lex refers to law which has been formulated in written form and promulgated by competent authority. While this is the usual sense of "law" in modern legal systems, the legal system of the Catholic Church includes another form of law, ius, which refers to the oral teachings, practices, customs, theological understandings of liturgy and liturgical practices generally prior to the Council of Nicea in 325 a.d., when written legislation became the normative means of communicating Church law.
"Lex" takes several forms:
- Decrees or canons of ecumenical councils.
- Decrees or canons of regional Church councils or synods (regionally binding)
- Decrees (or decretals) of the Pope.
- Canon Law (binding either universally or by rite)
It is important to understand that much of Church legislation (unless otherwise stated) is either a development of earlier law or a restatement of earlier law, particularly law contained in the oral tradition from apostolic teaching, or ius.


text:
An 18-year-old from Murfreesboro, Tennessee may owe his life to Siri, reports FOX17.
The teen was working under his truck when it fell on him, trapping his arms. Alone he tried to yell for help but nobody heard his cries. Then the teen heard the familiar Siri activation coming from the iPhone in his back pocket. He was able to "push up on his hip" to activate Siri and call 911.
Murfreesboro EMS, LifeFlight, and Vanderbilt University Medical Center's trauma team took over from there but if it were not for Siri, they may not have had the chance.


text:
anyia marie Model
Deme T DavisModel Female Saint Petersburg, Florida, US
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text:
Thank you for your interest in making a donation to Kenya Wildlife Trust.
As our core costs are covered by a generous few, 100% of your donation will go to your intended project.
If you would like your donation to go where the need is greatest, you can leave it 'unrestricted' for us to determine how best to direct it.
Donating in the USA
Donations can be made by check to Friends of Kenya Wildlife Trust, c/o Rick Weyerhaeuser, 105 Coolidge Hill, Cambridge, MA 02138. Friends of Kenya Wildlife Trust USA is a registered public charity, tax ID No. 01-0909843.
Donating in the UK
Donations can be made by check to Friends of Kenya Wildlife Trust, c/o Mr Robin Cullen, Inglewood, 6A Reeves Lane, Wing, Rutland LE15 8SD. Friends of Kenya Wildlife Trust UK is a registered charity in England & Wales, No. 1162781.
Donating in Kenya
Donations can be made by check to Kenya Wildlife Trust, PO Box 86-00502, Nairobi, Kenya. Kenya Wildlife Trust is a legally registered Trust in Kenya.
Ways You Can Help
$300 can buy a camera for predator monitoring
$1,500 pays for mobile health clinics to engage 1,500 people
$5,300 provides a scholarship for a Kenya Wildlife Service Training Institute Diploma


text:
What is JotForm?
JotForm is a free online form builder which helps you create online forms without writing a single line of code. No sign-up required.
At JotForm, we want to make sure that you're getting the online form builder help that you need. Our friendly customer support team is available 24/7.
We believe that if one user has a question, there could be more users who may have the same question. This is why many of our support forum threads are public and available to be searched and viewed. If you'd like help immediately, feel free to search for a similar question, or submit your question or concern.
Not Receiving EmailsAsked by Scott on September 16, 2015 at 02:05 PM
Does jotform have some sort of cache for emails DNS? I have a form for Eshenaurs which the emails @eshenaurs are not receiving, but other emails are. Is there a way to find a log to figure out what happened, as 2-3 weeks ago they were receiving them, but then changed DNS records and are now not. (That could not be the problem) The IT company says there are no blocked emails from jotforms. I need help troubleshooting whats going on.
JotForm Support
After inspecting your website I see that in real you are not using JotForm form. Basically if you were using it previously than you used source of JotForm form to embed form to the website. When you create Jotform form inside of Jotform Builder and get embed source code, source code has following form tag e.g.
<form class="jotform-form" action="https://secure.jotformpro.com/submit.php" method="post" name="form_52344406104949" id="52344406104949" accept-charset="utf-8">
where action attribute specifies where to send the form-data when a form is submitted. If that is coming from jotform, logic of jotform will send notification to the users which submitted the form.
In your case, inside of your website you have:
<form class="jotform-form" action="http://forms.consumerfocusmarketing.com/submit.php" method="post" name="form_23165651002" id="23165651002" accept-charset="utf-8">
and action that you have inside of form tag is some php page that is located on some other domain, not jotform. Probably someone changed logic of your website and form you have inside of your website.
Also ID attribute is representing of ID of the form but when I searched for ID 23165651002 inside of our system I could not find form connected to that ID. Also I see that you posted this question from guest account.
Can you provide us ID of form that is causing you a problem? Under which account form is created?
Also sometimes email can be inside of bounce list and because of that emails notifications are not received. We can not check if the domain is inside of the bounce list, only full email address.
Looking forward to your reply.
We are having the same issue again. I don't understand how it "cannot be using jot form". http://forms.consumerfocusmarketing.com/ is where I log into jot forms.
Is there any way to get mail records that show any logs with mail history for this form. It seems as though when I change the from address their server will allow the emails through for a short amount of time, but eventually will mark as spam, but they were not even able to see any emails hitting the server at all. To the @eshenaurs email addresses, although I am getting the submissions to my address.
I don't know how to find the form ID as you asked, I assume it is the number at the end of the link. Is it not normal for someone to be using jot forms and have their own domain? I have no idea how it is set up. After I log in it says jot forms on the page?!
JotForm Support
I have checked one more time and you are using standalone version of JotForm Engine.
You should go to http://www.interlogy.com/contact.html and from there contact the team that works on standalone JotForm Engine, since the forum is for Online JotForm Form Builder and a different team works on each.
You should have your IT people check the email server for logs.
Feel free to contact us if you have any other questions.


text:
7647 Snow Avenue, Alto 49302
See more homes for sale in Alto, MI
This property has been Sold!
07/22/2016 at $215,000
Classic 50's brick ranch on 5 acres in the Caledonia School district! Nice floor plan with 3 main floor bedrooms and 2 baths. Very tidy and well maintained, hardwood floors, newer well and septic, and newer central air. Big Red Barn and a machine shed round out the great setting. Home warranty and appliances included. See it today! Note: property may be shown any time. Seller will consider offers not sooner than 5 p.m. on 6/13/16.
Property Information
- Status
- Sold
- Address
- 7647 Snow Avenue
- City
- Alto
- Zip
- 49302
- County
- Kent
- Township
- Caledonia Twp
- Possession
- Zoning
- Residential
- Total Finished SqFt
- 1,914
- Above Grade SqFt
- 1,276
- Garage Desc.
- 2, Detached
- Water
- Well
- Sewer
- Septic System
- Year Built
- 1958
- Taxes
- $3,392
Rooms and Land
- Basement
- Full Basement
- Cooling
- Central
- Heating
- Forced Air, OIl
- Acreage
- 5.0
- Lot Dimensions
- 402 x 542
- Appliances
- Cook Top, Dishwasher, Dryer, Oven, Refrigerator, Washer
- Fireplace Desc.
- Rec Room
- Features
- Attic Fan
- Exterior Materials
- Brick
Listing Video for 7647 Snow Avenue, Alto MI 49302
Mortgage Calculator
Listing Broker
Listing Courtesy of Greenridge Realty (caledonia)
Office Address 9175-12 Cherry Valley Ave Se
Listing Agent Michael A Courtright
Listings last updated: . Some properties that appear for sale on this web site may subsequently have been sold and may no longer be available.
Our Michigan real estate agents can answer all of your questions about 7647 Snow Avenue, Alto MI 49302. Real Estate One, Max Broock Realtors, and J&J Realtors are part of the Real Estate One Family of Companies and dominate the Alto, Michigan real estate market. To sell or buy a home in Alto, Michigan, contact our real estate agents as we know the Alto, Michigan real estate market better than anyone with over 100 years of experience in Alto, Michigan real estate for sale.
The data relating to real estate for sale on this web site appears in part from the IDX programs of our Multiple Listing Services. Real Estate listings held by brokerage firms other than Real Estate One includes the name and address of the listing broker where available.
IDX information is provided exclusively for consumers personal, non-commercial use and may not be used for any purpose other than to identify prospective properties consumers may be interested in purchasing.
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So instead of writing an autobiography as asked by her fans, the singer shares about her life and career in new book 'My Passion for Design'.
Barbra Streisand hopes she has satisfied fans by opening up about her life and career in her new design book - because writing a full-blown autobiography is still "too personal" a task. Streisand shares some details about her life and career that influenced the choices she made in designing her dream home in Malibu, California in new book "My Passion for Design".
But the singer still refuses to embark on a tell-all - because sharing details of her life is too daunting a task. She tells the Associated Press, "People have been asking me to write my autobiography, but I don't want to go there yet and be that personal."
Aside from writing "My Passion for Design", Barbra Streisand recently backed up women's heart campaign by urging fans to help raise $5 million for Women's Heart Center at the Cedars-Sinai Heart Institute in Los Angeles.