Category: oatprige

  • Welcome consolation as Adamson closes in on PVL bronze, 4 players bag awards

    first_imgLights inside SMX hall flicker as Duterte rants vs Ayala, Pangilinan anew Adamson celebrates after a play against UST. INQUIRER PHOTO/ Sherwin VardeleonRiding high after having four of its players bagging individual awards, Adamson welcomed a much-needed confidence boost to beat University of Santo Tomas, 15-25, 25-20, 25-20, 25-19, and get the inside track for the bronze medal in the PVL Collegiate Conference Wednesday night.By winning in four sets, Adamson will end up locking the bronze if University of the Philippines, which took the finals opener, beats Far Eastern University in Game 2 later.ADVERTISEMENT Carpio hits red carpet treatment for China Coast Guard PLAY LIST 02:14Carpio hits red carpet treatment for China Coast Guard02:56NCRPO pledges to donate P3.5 million to victims of Taal eruption00:56Heavy rain brings some relief in Australia02:37Calm moments allow Taal folks some respite03:23Negosyo sa Tagaytay City, bagsak sa pag-aalboroto ng Bulkang Taal01:13Christian Standhardinger wins PBA Best Player award Nadine Lustre’s phone stolen in Brazil MOST READ Sports Related Videospowered by AdSparcRead Next “It was like a reminder that all the hard work that we’ve been doing is not for nothing. You are more prepared to play UST and win in three and four sets.”The four also validated their awards against the Golden Tigresses, who were looking to seal third place after taking Game 1 in five sets on Sunday.Soyud scored a team-high 14 points, Flora added 12, Ponce had 19 digs and Igao dished out 12 excellent sets as Adamson achieved its goal of winning in three or four sets.Fil-Italian spiker Milena Alessandrini led UST with 22 points, four nights after dropping 31 in Game 1.ADVERTISEMENT “I’m rooting for UP,” head coach Air Padda said, smiling.“These last two weeks have been the hardest weeks after we got booted out of the championship round,” said Padda. “It’s been really hard to try and push them to finish the fight and finish strong. Basically, we sucked that’s been our energy in training.”FEATURED STORIESSPORTSGinebra beats Meralco again to capture PBA Governors’ Cup titleSPORTSJapeth Aguilar wins 1st PBA Finals MVP award for GinebraSPORTSGolden State Warriors sign Lee to multiyear contract, bring back ChrissBut things changed after the Lady Falcons were informed that Eli Soyud (Best Opposite Spiker), Bernadette Flora (2nd Best Outside Spiker), Tonnie Rose Ponce (Best Libero) and Mary Jane Igao (Best Setter) will be recognized for their individual brilliance in the awarding ceremony.“Today, it was just so amazing, that four of our players got awards and it came at a perfect time that they all needed confidence going into this match,” Padda said. Gov’t to employ 6,000 displaced by Taal Lights inside SMX hall flicker as Duterte rants vs Ayala, Pangilinan anew Allen Durham still determined to help Meralco win 1st PBA title LATEST STORIES Tim Cone, Ginebra set their sights on elusive All-Filipino crown Don’t miss out on the latest news and information. Gretchen Barretto’s daughter Dominique graduates magna cum laude from California college Japeth Aguilar embraces role, gets rewarded with Finals MVP plum Ginebra beats Meralco again to capture PBA Governors’ Cup title UAAP: Ateneo avenges opening game loss, trips UP View commentslast_img read more

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  • LOOK: Ateneo vs UP UAAP Season 81 Finals schedule

    first_imgLights inside SMX hall flicker as Duterte rants vs Ayala, Pangilinan anew Carpio hits red carpet treatment for China Coast Guard PLAY LIST 02:14Carpio hits red carpet treatment for China Coast Guard02:56NCRPO pledges to donate P3.5 million to victims of Taal eruption00:56Heavy rain brings some relief in Australia02:37Calm moments allow Taal folks some respite03:23Negosyo sa Tagaytay City, bagsak sa pag-aalboroto ng Bulkang Taal01:13Christian Standhardinger wins PBA Best Player award LATEST STORIES After winning title, time for LA Tenorio to give back to Batangas folk Ginebra beats Meralco again to capture PBA Governors’ Cup title Gretchen Barretto’s daughter Dominique graduates magna cum laude from California college Don’t miss out on the latest news and information. The Blue Eagles are shooting for back-to-back UAAP titles while the the Fighting Maroons hope to cap off their inspired run with a long-awaited crown.The full schedule of the finals series below:FEATURED STORIESSPORTSGinebra beats Meralco again to capture PBA Governors’ Cup titleSPORTSJapeth Aguilar wins 1st PBA Finals MVP award for GinebraSPORTSGolden State Warriors sign Lee to multiyear contract, bring back Chriss For the complete collegiate sports coverage including scores, schedules and stories, visit Inquirer Varsity. Lights inside SMX hall flicker as Duterte rants vs Ayala, Pangilinan anew ‘Mia’: Rom-com with a cause a career-boosting showcase for Coleen Garcia No.13 lucky for Orlando Bloom The UAAP Season 81 men’s basketball finals between Ateneo and University of the Philippines begin this weekend.The best-of-three affair will kick off on Saturday at Mall of Asia Arena.ADVERTISEMENT MOST READ Sports Related Videospowered by AdSparcRead Next Nadine Lustre’s phone stolen in Brazil ‘I love you forever’: Heartbroken Sean Manganti bids Adamson goodbye Japeth Aguilar embraces role, gets rewarded with Finals MVP plum View commentslast_img read more

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  • City Council approves 75 Street service project

    first_imgThis project will include the construction and installation of road pavement, curbs, gutters, storm mains and catch basins, sidewalks, driveways and overall boulevard restoration.As part of the city’s Community Charter, a local area service project may not move forward if over 50 per cent of the property owners disapprove. They must also hold ownership of over 50 per cent of the assessed value.This requires time to allow for the submission of petition, but as of Wednesday March 18, 2015 at 4:30 p.m., the city only received opposition from 36.5 per cent of property owners – representing 38.5 per cent of the assessed value.- Advertisement -There are 82 property owners affected by this project – with all parcels being assessed at just under $16.7 million.The city plans to pay for their portion of the project through Fair Share funds, while residents have two methods of payment to choose from; either through one lump sum payment at the end of the project or through their taxes over the next 20 years.Construction is slated to begin in the spring.Advertisementlast_img read more

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  • Van Gaal ‘amazed’ by Man United’s defeat at Swansea

    first_imgManchester United manager Louis van Gaal admitted he was “amazed” his side slumped to a 2-1 defeat at Swansea, while the Red Devils were also left to lament a fresh injury blow to striker Robin van Persie.The Dutch striker returned to the starting line-up having sat out of last week’s FA Cup victory over Preston with injury, but he left the Liberty Stadium on crutches as United slipped to fourth place following Arsenal’s win at Crystal Palace.Van Gaal’s men took a first-half lead through Ander Herrera but Ki Sung-yueng equalised within two minutes and Bafetimbi Gomis gave the hosts victory when he deflected Jonjo Shelvey’s 73rd minute strike past David de Gea.Gomis’ goal secured Swansea’s first-ever league double over United after the Welsh club’s 2-1 win at Old Trafford on the opening day of the season, but Van Gaal felt what was only his side’s second defeat in 20 games in all competitions was undeserved on the balance of play.Statistics showed United had 12 shots compared to Swansea’s eight, but Van Gaal’s men managed only three on target compared to the home team’s six.“It is always frustrating when you lose and you are the dominating team, your disappointment is much bigger because of that,” United manager Van Gaal said.“In the first half it was an equal game as I counted as many chances for Swansea as we had.“That was not a big difference, but in the second half it was a big difference.“Swansea had a chance in the first minute of the second half and after that we dominated the game.“Every two minutes we had a chance but we were not effective.”Van Gaal also bemoaned the nature of Swansea’s winner when Gomis unknowingly got in the way of Shelvey’s powerful effort.“They had one counter, the shot deviated, maybe also in an offside position from Gomis, and it was a goal,” he said.“Nevertheless we dominated the game even with ten men when Robin van Persie could not run any more after his injury and I had three substitutes on the field.“It is amazing we have lost and we have lost only to Southampton in 19 games before this, but you have to pick yourself up and continue.” Manchester United manager Louis van Gaal 1last_img read more

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  • LAUSD pays for fliers backing mayor’s plan

    first_imgLos Angeles Unified officials have sent thousands of fliers urging parents and teachers to let Mayor Antonio Villaraigosa manage some district schools in what critics decried Monday as a biased campaign that misuses taxpayer funds. The district paid for the fliers and automated calls to remind parents about today’s vote at seven schools, but critics say the information is essentially an advocacy campaign for the mayor’s Partnership for Los Angeles Schools. One flier obtained by the Daily News from the district’s innovation division lists the benefits of a yes vote to join the partnership but makes no mention of any potential drawbacks. “Any time a government official or the government itself has a stake in the outcome of an election, it’s unfair to use public money to influence that election,” said Tim Bittle, director of legal affairs for the Howard Jarvis Taxpayers Association. AD Quality Auto 360p 720p 1080p Top articles1/5READ MOREWhicker: Clemson demonstrates that it’s tough to knock out the champ“It sure sounds like the mayor has a stake in the outcome of this election, because if he can persuade the parents and the teachers to approve this plan and then he pulls off some positive reform, it’s going to be a publicity opportunity for him and his quest perhaps for higher office.” But Kathi Littmann, executive director of the LAUSD’s innovation division, said her office is working with the mayor to develop the reform effort and did a thorough job informing communities about the issues in a limited amount of time. The district and the mayor’s nonprofit partnership will tally costs of the campaign later this month, but Littmann said district funds are being used appropriately because students – not the mayor – will ultimately benefit. “I think what would have been irresponsible was to ask the community to make a decision without having the information,” Littmann said. “It’s an LAUSD initiative and to not put out that information would have violated everything the (innovation) division is about – which is informed decision-making at the school-site level. “We put lots of information out there of what this is and what it’s not.” Littmann said each school was responsible for generating the content of the automated calls to parents, so what some may have said is unclear. Officials at the Mayor’s Office said the partnership had no connection to the fliers that were issued, and that the $200,000 in community outreach efforts was funded by grants. School board member Julie Korenstein said she has not seen the fliers, and that the board has not been involved in decisions with the mayor’s partnership. But she said voters should know all the facts – including that the mayor’s schools will not be under the local district’s jurisdiction anymore. “I’m not exactly sure why L.A. Unified is putting up the money to sell this,” she said. “I don’t know if this board … would have been wanting the superintendent to spend taxpayer money this way because we never had that discussion. “I might want my money to go to books and supplies for the classroom rather than putting out fliers trying to sell an unknown entity to people.” The push comes as the partnership and the district have agreed to give Villaraigosa a role overseeing at least two groups of underperforming schools starting in the 2008-09 school year. But teachers and parents at the school have to agree, so today those at Santee, Jordan and Roosevelt high schools will vote on the plan. Teachers and parents at Hollenbeck, Stevenson, Gompers and Markam middle schools also will vote. The district hopes to announce the results Wednesday, assessing support for the mayor’s plan through a majority vote – 50percent plus one – of parents and certificated staffers. For the latest school news, go to www.insidesocal.com/education.160Want local news?Sign up for the Localist and stay informed Something went wrong. Please try again.subscribeCongratulations! You’re all set!last_img read more

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  • KNIFE-WIELDING THUG IN HORRIFIC ATTACK ON PUBLICAN GIVEN COMMUNITY SERVICE

    first_imgA well-known Co Donegal publican who was stabbed in the back by a thug during a vicious attack looked visibly shaken after the thug was given 240 hours community service.Martin Coyle shook his head and left Letterkenny Circuit Court as John Gibbons – who was facing two Section 3 assault charges – was given a non-custodial sentence.Mr Coyle, who runs the Village Inn in Kerrykeel, could be seen shaking his head. His wife Laura, who was also attacked was visibly upset. Details of the shocking incident on October 7, 2010, were relayed to the sentencing hearing today by prosecuting counsel Patricia McLaughlin and the guard who investigated it Garda Ken Dempsey.John Gibbons and his brother Joe – who wasn’t before the court and is on the run outside the jurisdiction – had been drinking all day following the death of their grandmother.Around 9pm their mother Frances Gibbons had called the bar to order takeaway food for the wake.A short time later Mr Coyle was informed that Joe Gibbons wanted to see him outside.The court heard Joe Gibbons charged at Mr Coyle, shouting ‘Right me and you down to the car park’.Mr Coyle said he then saw John Gibbons – who had been barred from the premises – joining the attack.Blows rained down from both men on the defenceless publican who ran back into the bar and into the kitchen area. His wife Laura was also hit.“I continued to try to protect myself,” said Mr Coyle in his statement.“I was pushed up against a steel table, I was slightly bent over – I remember taking a blow in the lower back and that must have been when I was stabbed.”(Mr Coyle didn’t know at the time that he had been stabbed; the wound was found by Gda Dempsey when he arrived at the scene, the court heard).The attack didn’t stop there however, said Ms McLaughlin.John Gibbons hit Mr Coyle again, and then attempted to headbutt Laura Coyle.Gda Dempsey said he later recovered a steak knife which he believed had been used to stab Mr Coyle.CCTV footage from the premises confirmed the detail of the attack given by numerous witnesses.The Gibbons had fled the scene. John Gibbons was arrested two days later.Mr Coyle asked that his victim impact statement was not be read to today’s court. However it emerged he had to stop living at the bar for a time after the incident.Gda Dempsey detailed John Gibbons’ previous convictions, six in all including one for a previous Section 3 assault.In mitigation, defence barrister Peter Nolan said John Gibbons, who is now 26, had not come to Garda attention since the attack.Gibbons then went into the dock and looking towards the Coyles, said: “I am sorry for what happened; it shouldn’t have happened.”In a lengthy summing up Judge John O’Hagan said he knew Kerrykeel,“It is a beautiful little village and there are lovely people in it,” he said.He said Mr Coyle was a law-abiding and hard-working citizen trying his best to make a living in hard times.“What was done on this particular night was absolutely disgraceful,” said Judge O’Hagan.He said the Coyles had been actually preparing food for the Gibbons family after a funeral.“Having injured Mr Coyle they just left him there like a piece of meat. They were full of drink,” said the judge.“That’s a great example to be giving to your now five year old daughter and your partner who is a hard working woman who is doing her best,” the judge told Gibbons.“We’ve had no explanation as to why this altercation took place at all.”Judge O’Hagan said again that 90% of cases he hears are drink-fuelled Section 3 assaults.He said such behaviour was now taking place at weddings, first communions, confirmation “and now I’m told at wakes and funerals.”“The fact is that this was an errand of mercy for the funeral and it was turned into this theatre of assault,” said the judge.He said there were mitigating factors; Gibbons had pleaded guilty saving the expense of a trial and an ordeal of giving evidence for the Coyles.“I cannot be seen to take revenge, I can punish, but I cannot take revenge,” he said.“People think that prisons are hotels; they are not. I am advised that I should look at an alternative remedy. The options open to me are Custodial sentence, a Suspended sentence or Community Service.“Community Service does not avoid the words imprisonment; it is a substitute for imprisonment and it is not to be taken as someone getting off. It is to persuade people not to offend again.”He said he understood the Coyles may not be happy with the sentence but community service was the appropriate sentence.“It is on his record for his life,” said the judgeHe jailed John Gibbons for 3 years on each count, but substituted 240 hours instead of prison. The sentences were concurrent.The Coyles were visibly upset as they left the court.Gibbons went outside, smoked a cigarette and laughed and joked with a friend as he left the court building.KNIFE-WIELDING THUG IN HORRIFIC ATTACK ON PUBLICAN GIVEN COMMUNITY SERVICE was last modified: January 31st, 2013 by BrendaShare this:Click to share on Facebook (Opens in new window)Click to share on Twitter (Opens in new window)Click to share on LinkedIn (Opens in new window)Click to share on Reddit (Opens in new window)Click to share on Pocket (Opens in new window)Click to share on Telegram (Opens in new window)Click to share on WhatsApp (Opens in new window)Click to share on Skype (Opens in new window)Click to print (Opens in new window) Tags:KERRYKEELKNIFE-WIELDING THUG IN HORRIFIC ATTACK ON PUBLICAN GIVEN COMMUNITY SERVICEThe Village Innlast_img read more

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  • Orange Line wasn’t as juicy as it seemed

    first_imgIn my car, I could leave my apartment at 8:30 and still be at work by 9 a.m. Not on the bus. In all, the 13.6-mile trip from apartment to office would take about an hour and five minutes, including walking to and from the stations and waiting for a bus to arrive. That’s 20 minutes longer than the drive takes in the worst traffic, and nearly 45 minutes longer than the drive on an average day. Sure, I was saving money on gas – and as gas prices climbed, so did the savings. But the bus extended my day by more than an hour. I was getting less sleep in the mornings and I’m spending less time with my fianc e in the evenings. Why does it take the bus 45 minutes to travel 13.6 miles on a deserted road? It seems to defy the laws of physics. I grew up in New York, where public transportation gives commuters the ability to get anywhere in the city – and usually quicker than by car. That combination is what makes public transportation successful. If the Orange Line could do one of those two, maybe I’d still be riding it. It fails on both counts. My Great Orange Line Experiment faded in February and March. I found myself making excuses to drive home instead of taking the bus – I had something large to carry, or I had an assignment to be at the next morning. When it came time to buy my April bus pass, I realized there was no point. I wasn’t taking the bus enough to make it worthwhile. Instead, now I sleep a little later in the morning, get home a little earlier in the evening, and connect my iPod to my car stereo to listen to Bruce Springsteen. josh.kleinbaum@dailynews.com (818) 713-3669160Want local news?Sign up for the Localist and stay informed Something went wrong. Please try again.subscribeCongratulations! You’re all set! AD Quality Auto 360p 720p 1080p Top articles1/5READ MORE11 theater productions to see in Southern California this week, Dec. 27-Jan. 2I’d start the day with a nice walk and finish the day the same way. On the bus, I’d see interesting people, have time to read a newspaper or book, or listen to Bruce Springsteen on my iPod. The honeymoon lasted less than a month. After a few minor accidents in the Orange Line’s opening weeks, MTA and city officials panicked – a panic surely fueled by media coverage of each Orange Line fender-bender, and assertions by opponents of the busway that the dangers they’d predicted had come true. In a knee-jerk reaction, MTA officials ordered the Orange Line buses to slow down through all intersections. It made no sense. Slowing down the drivers frequently made them miss the next green light. Two or three such stops could add 10 minutes to the trip. Suddenly, my 7:45 a.m. wake-up was too late. I’d leave my apartment at 8:20, be on the bus by 8:30, get off the bus at 9:15 and be at work by 9:25 – 25 minutes late. When I bought a Metro pass in December, two months after the Orange Line opened, I was ready to become a public-transit champion. Six months later, I’ve retreated to the friendly confines of my Ford Focus. I’d always been frustrated by Los Angeles’ dearth of viable public transportation, so taking the Orange Line seemed like the perfect solution: I could help the environment, save money and skip the stress of the Ventura Freeway during rush hour. My Valley Village apartment is just a short walk from the busway’s stop at Laurel Canyon Boulevard. The Daily News’ office is a short walk from the Orange Line’s last stop on Owensmouth Avenue in Woodland Hills. last_img read more

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  • Man City receive huge boost as they look to keep wonderkid

    first_img REPLY Manchester City have been given a huge boost in their attempts to keep wonderkid Phil Foden after Juventus withdrew their interest, according to reports in Italy.The 18-year-old has played 11 times in the Premier League and impressed when called upon by Pep Guardiola. shining huge blow Latest Football Stories Oxlade-Chamberlain suffers another setback as Klopp confirms serious injury ADVICE However, with his current contract dwindling down, a number of elite clubs are monitoring his situation.Juventus were said to be one of the frontrunners and reports have suggested that they were lining up an audacious offer to lure the teenager to Italy.But Calciomercato has reported that the Turin giants have decided against offering Foden a deal because they do not want to damage their strong relationship with the Premier League champions. Top nine Premier League free transfers of the decade MONEY Manchester City wonderkid Phil Foden. Berahino hits back at b******t Johnson criticism – ‘I was in a dark place at Stoke’ Every time Ally McCoist lost it on air in 2019, including funny XI reactions Where Ancelotti ranks with every Premier League boss for trophies won center_img no dice REVEALED REVEALED Forbes list reveals how much Mayweather, Ronaldo and Messi earned this decade Ronaldo warned Lukaku how hard scoring goals in Serie A would be before Inter move Son ban confirmed as Tottenham fail with appeal to overturn red card Premier League Team of the Season so far, including Liverpool and Leicester stars Which teams do the best on Boxing Day in the Premier League era? RANKED BEST OF They may not get the chance to anyway, with Foden understood to be close to agreeing a bumper six-year deal at the Etihad. 1last_img read more

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  • Study leads to preservation zone

    first_img “As you go through some of these neighborhoods, you begin to appreciate the care people have for the homes and it would be a shame to see these neighborhoods torn down to make room for two- and three-story mansions,” Cordaro said. “This gives a sense of history to how the city developed and it’s important to send a message we care about our neighborhoods.” The official designation could pave the way for similar efforts in several other areas of the Valley that have expressed interest in having similar zones, including the Balboa Highlands in Granada Hills and Stonehurst in Shadow Hills. Rick Orlov, (213) 978-0390rick.orlov@dailynews.com 160Want local news?Sign up for the Localist and stay informed Something went wrong. Please try again.subscribeCongratulations! You’re all set! AD Quality Auto 360p 720p 1080p Top articles1/5READ MOREWalnut’s Malik Khouzam voted Southern California Boys Athlete of the Week With the designation, a board will be created to oversee renovations, tear-downs and replacements of any of the homes, which include a mixture of bungalows, Craftsman and other styles. Residents are protective of their neighborhood and want to see it remain as it was developed nearly 80 years ago. Cardenas said there were only a handful of residents concerned about the impact such a designation would have on their ability to sell their homes in the future. “We know there are some people with questions and who are upset and we hope to show them they don’t have to worry about it,” said Cardenas, whose district encompasses the proposed historic zone and who used to sell real estate in Van Nuys. Jamie Cordaro, president of the Van Nuys Neighborhood Council, said his group supported the designation. A landmark Van Nuys neighborhood known for its unique homes has become the first area in the San Fernando Valley to receive protection against new development. The Los Angeles City Council, after years of study, agreed this week to create a Historic Overlay Protection Zone for the area around the Van Nuys Civic Center. “We’ve been trying to get this through from before I came on council,” Councilman Tony Cardenas, who took over the effort started by former Councilwoman Cindy Miscikowski, said Friday. “This is a special neighborhood and it will give residents the protections they want and also preserve an area that is important to the city.” last_img read more

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  • Elaborate Quality Control Governs the Cell’s Protein-Folding Factory

    first_imgIf it weren’t for quality control in our cells, we’d be dead.  That’s the gist of an amazing Insight article in the Dec. 18 issue of Nature.1  “Aberrant proteins are extremely harmful to cells,” the authors begin.  How harmful?  Here is a short list of diseases that can result from improperly folded proteins or failures in the quality control systems that direct their formation: Creutzfeldt-Jakob disease, Alzheimer’s disease, and other degenerative diseases, scurvy, cystic fibrosis and more.  In fact, serious defects in protein assembly are probably never seen, because they could prevent an organism from getting past the first cell division in the embryo.  The only way a cell can live and grow is with the assistance of a host of traffic controllers, regulators, monitors, ushers, transporters, inspectors, security guards and emergency technicians maintaining the complex processes of protein assembly.  Success must be ensured constantly, 24 x 7, that despite a flurry of activity, must maintain a state of dynamic equilibrium, called homeostasis.    Each cell in the body is like a city of interrelated factories made up of protein machines and structures operating under strict regulations, built on coded instructions.  One of the most important factories is the protein folding system, which ensures that newly-sequenced proteins coming out of ribosomes are folded into their correct (native) shapes.  Proteins are made up of amino acids, usually hundreds of them, that are first sequentially assembled in ribosomes, based on templates sent from the DNA code.  Then, they are folded into specific, complex three-dimensional shapes that perform numerous and diverse functions in the cell (see 06/13/02 and 05/31/02 headlines.)  Protein folding is assisted by enzymes whimsically called chaperones (see 05/05/03 headline) but is also checked and rechecked by numerous other quality control systems (see 09/09/02 headline).    In the current paper in Nature, the authors have unveiled more of the complexity in the quality controls governing protein folding.  Some of the folding occurs in networked subway tunnels that run throughout the cell, called the endoplasmic reticulum (ER).  Before getting into the ER, some proteins already begin their folding with assistance from certain chaperones.  The authors explain, “In mammalian cells, proteins are translocated into the ER … where they start to fold co-translationally [i.e., while they are en route into the ER].  Folding is completed post-translationally, and, generally, individual subunits have folded before assembly and oligomerization [the joining together of multiple chains] take place.  Sequential interactions with distinct chaperones are required for each of these steps.”  (Emphasis added in all quotations.)  The job is completed inside the ER, and the finished protein “tool” is then sent on its way to work.  But that is just the tip of a huge iceberg made up of a multitude of processes – hardware and software – that work together to ensure success.    In the following examples from the article, entitled “Quality control in the endoplasmic reticulum protein factory,” don’t worry about unfamiliar technical terms.  Just try to keep track of how many different players are involved in the team of factory workers dedicated to one job: folding a single protein.  And keep in mind that each team player is itself a protein, built with the same quality control.  You can almost envision little factory workers, each skilled at their specific tasks, alert and knowing just what to do, but it’s all done with chemicals!  Be patient in these extended quotes, because the awe is in the details. Redox regulation:  A sensitive chemical balance is maintained between reducing and oxidizing (redox) conditions along the protein’s pathway through the folding factory.  “The redox gradient between the ER and the cytosol seems to be important for intercompartmental signalling, particularly in the integrated response to oxidative stress, in which adaptive responses emanating from different compartments are coordinated.  And redox reactions with opposite electron fluxes must take place in the ER to mediate formation, isomerization and reduction of disulphides.  The wealth of redox assistants allows these fluxes to be separate, and channels electron transport through specific protein�protein interactions.”Location specificity:  “Although most folding factors in the ER are ubiquitously expressed throughout the body, some are tissue-type specific or cell-type specific, and probably fulfil a particular synthetic task….  For example, efficient collagen production requires the expression of hsp47, whereas a tissue-specific protein-disulphide-isomerase-like protein, PDIp, is produced in the pancreas and probably permits the massive secretion of digestive enzymes.”Bridge builders:  Junctions called disulphide bridges are common in protein folds, and these, although weak, are carefully maintained by a host of enzymes called oxidoreductases: “The impressive number of oxidoreductases in the ER suggests that catalysis and regulation of disulphide-bond formation is crucial for folding.  Energywise, in most cases, the contribution of a disulphide bond is hardly more than that of a single hydrogen bond [i.e., quite weak], yet, without disulphide bonds, native conformations are not obtained.  Disulphide bonds cannot force a folding protein into a given conformation: in the sampling of conformations during folding in the ER, native and non-native disulphide cross-links are transiently formed [i.e., correct and incorrect links form and break easily, and must be guided].  Continuous activity of oxidoreductases probably ensures that these covalent links remain flexible until folding is completed.”Correct fold recognition:  Even though a string of amino acids could conceivably fold in large number of ways, like a Rubik’s cube, somehow the chaperones are able to tell a correct (native) fold from an incorrect one.  “Besides providing a unique folding environment, the ER has a crucial quality-control role.  How does it discriminate between native and non-native proteins?  The answer to this question depends primarily on ER chaperones.  When folding or assembly intermediates expose hydrophobic [i.e., water-avoiding] surfaces, unpaired cysteines or immature glycans, ER-resident chaperones or oxidoreductases interact with them, and as a consequence they are retained in the ER or retrieved from the Golgi complex [see 11/12/01 headline].  By forming multimolecular complexes, folding factors in the ER may provide matrices that couple retention to folding and assembly.  Immature proteins may also form aggregates that are excluded from vesicles exiting from the ER” [i.e., such that they are not ejected before they are ready].Fail-safe inspection:  A protein needs to pass multiple layers of monitoring: “All proteins are subjected to a ‘primary’ quality control that monitors their architectural design through ubiquitous folding sensors (Table 1).  ‘Secondary’ quality-control mechanisms rely instead on cell-specific factors and facilitate export of individual proteins or classes of proteins…. the ER is the main test bench where molecules destined for the extracellular space are scrutinized for their potential toxicity.”Feedback regulation:  The ER not only does quality control, but sends messages back to the nucleus to regulate the production of more chaperones: “The reasons for having a quality-control system in the ER are easy to understand where protein folding and function are concerned, especially in multicellular organisms where development relies on the fidelity of protein secretion.  Quality control can also regulate the transport or the activity of certain proteins during differentiation or in response to stress or metabolic requirements.”Waste control:  When a protein cannot be folded after repeated attempts, more assistants are on hand to ensure proper dismantling and recycling: “Mutations or unbalanced subunit synthesis make folding or assembly � and hence exit from the ER � impossible.  To maintain homeostasis [dynamic equilibrium], terminally misfolded molecules are ‘retrotranslocated’ or ‘dislocated’ across the ER membrane to be degraded by cytosolic proteasomes” [organelles equipped to break up badly-folded proteins and recycle their parts].Time limits:  Somehow, the cell knows when a protein has had enough time to shape up or ship out:  “A fascinating problem is how molecules that have not been given the time to fold (and therefore are unfolded) are discriminated from those that have failed to fold after many attempts (misfolded), and must therefore be disposed of.  One way of timing glycoprotein quality control involves the sequential processing of N-glycans and in particular mannose trimming in the ER.  It remains to be seen how substrates are eventually targeted to the retrotranslocation channels, how these are opened, and to what extent proteins must be unfolded to negotiate dislocation.”Workforce regulation:  Like a company’s human resources department that responds to managers’ calls for more workers, the cell keeps track of how many chaperones are available, and sends out “help wanted” ads to the nucleus.  “To maintain the efficiency of quality-control mechanisms in diverse physiological conditions, living cells have evolved regulatory circuits that monitor the levels of available chaperones.  This is true for both the cytosol and the ER, and compartment-specific responses clearly exist that selectively restore optimal levels of the desired folding factors.”Emergency squads:  The authors provide two examples of rapid-response traffic control teams: “The accumulation of aberrant proteins in the cytosol triggers the heat-shock response, resulting in de novo synthesis of hsp70 and other cytosolic chaperones.  But if aberrant proteins accumulate in the ER, cells activate a different response, the unfolded protein response (UPR), which leads to the coordinated synthesis of ER-resident chaperones and enzymes.”Failure consequences:  The authors give an example of what can go wrong when the system gets swamped, starved, or sent defective parts: “Physiologically, ER stress (a condition in which the folding machinery in the ER cannot cope with its protein load) can be caused by synthesis of mutated or orphan proteins, absence of cofactors (an example being scurvy, in which collagen cannot fold because of the lack of vitamin C), or a drastic increase in otherwise normal cargo proteins.”Unified response to varied inputs:  A variety of signals can lead to the same Unfolded Protein Response (UPR) pathway: “How do the diverse unfolded or misfolded proteins that accumulate in the ER provoke the same pathway?  The unifying concept is that BiP and other primary quality-control factors maintain the stress sensors in the ER in the inactive state, so that chaperone insufficiency triggers UPR whatever the nature of the cargo.”Meltdown regulation:  What happens when the damage is so great, that further operation of the factory would be dangerous?  Three independent controls make sure an orderly shutdown occurs (apoptosis, or cell death: see 04/09/02 headline).  “The mammalian ER sensors, Ire1, PERK and ATF6, guarantee a tripartite response with synergic strategies.  By phosphorylating eIF2alpha, PERK transiently attenuates translation, limiting protein load.  ATF6 drives the transcriptional upregulation of many ER-resident proteins and folding assistants.  Ire1 activates XBP-1, which in turn induces transcription of factors that facilitate ER-associated degradation (ERAD).  The two-step activation of XBP-1 (transcriptionally induced by ATF6 and post-transcriptionally regulated by Ire1) guarantees the proper timing of the UPR [unfolded protein response] attempts to fold proteins precede the decision to degrade them.  If the response fails to clear the ER, apoptosis is induced through several pathways.”  The authors explain that “The UPR is multi-faceted and regulates proteins involved in quality control, ERAD and many aspects of the secretory pathway.”Balancing act:  The quality control mechanisms walk a tightrope, with serious consequences for falling off:  “Quality control must be a balance between retaining and degrading potentially harmful products and not preventing export of biologically active proteins.  CFTR mutants in cystic fibrosis illustrate an overzealous quality control, where biologically active mutants cannot leave the ER.  In this case, relaxing the quality control could cure the patient.  But disease can also originate from defective degradation.  If the rate of synthesis of a protein exceeds the combined rates of folding and degradation, a fraction of it will accumulate intracellularly.”  Misfolded proteins have to make it across the ER membrane in time, and get degraded by the proteasome in time, or else aggregations (aggresomes) can build up inside or outside the ER.  These are implicated in a number of “ER storage diseases.”The authors put this all into perspective: “Over the past few years, much has been learned about how proteins are handled by the ER folding and quality-control machineries, and some of this knowledge has begun to be translated to industry and to the clinic.  Yet, many questions remain….”  They hope that further elucidation of these complex, coordinated systems will allow drug designers to target faulty elements that cause degenerative diseases, or induce apoptosis in tumors to make them self-destruct.  Clearly, though, in spite of the complexity already described, much remains to be learned about cell quality control.1Robert Sitia and Ineke Braakman, “Quality control in the endoplasmic reticulum protein factory,” Nature 426, 891 – 894 (18 December 2003); doi:10.1038/nature02262.If you endured the heavy reading in the above paragraphs, you were undoubtedly rewarded with a sense of how incomprehensibly amazing and mind-boggling a living cell is.  Think of it: all this activity is going on right now in every cell in your body.  The authors describe it in typical scientific jargon, but sprinkled here and there are hints of their own wonder and fascination at how all this quality control works.  Who could help but to be awe-struck at the choreography and efficiency of so many coordinated parts?  No human enterprise comes close.    Only twice do the authors mention evolution just in passing, and in both cases, they merely assume it rather than explain it.  The first reference almost argues against it: “A certain degree of freedom from quality control is essential for the evolution of proteins.  However, it comes at a price for multicellular organisms.  Indeed, many proteins that cause systemic amyloidosis [clumping, runaway misfolding] … can adopt more than one conformation and can undergo uncontrolled aggregation outside of the cells.”  This means that mutations have a hard time getting past the guards, and even when they do, the consequences could be catastrophic.  How then, could evolution ever get a beneficial mutation past the controls, without mucking up the whole works or triggering the cell-death alarm?  Don’t look for an explanation from these authors.  If there was ever a need for more examples of irreducible complexity, this is surely a contender.    This afternoon, after reading this scientific paper, I was sitting in a fast food restaurant eating a hamburger and looking out the window at a sunset.  I paused for a moment to think about how many tiny miracles of sophisticated, coordinated interaction were going on inside my body to make possible the enjoyment of tasting food and seeing a beautiful sky.  If more people knew just a fraction of this information, and really thought about it with any common sense at all, they would be impelled to acknowledge that an all-wise Creator with superior intelligence must exist.  The beauty and balance of all these systems should move us to fear Him and want to know Him.  A big part of the problem in society is that so few individuals have any vague idea of what is required to allow them to do something as routine as eating a hamburger, talking with a friend, or looking at the colors in the sky.    Scientific papers are difficult for most people to read, requiring understanding of specialized vocabulary and abstract concepts.  O, that more talented people could translate this information into everyday terms, and visualize it for more to see, that it might rekindle their sense of wonder.  Do you have such talent?  Has this article struck a chord with you?  Would you think and pray about how you might make this kind of worship-inducing information accessible to children and adults alike?  Some possibilities come to mind: radio, print, audio-visual media, film, tracts, church bulletins, classroom teaching, educational games and role playing, computer animations… did you get any ideas while reading?  If this kind of amazing information excites you, how could you make it accessible to those in your sphere of influence?  If you have an inspiration, write in and share it.    Our perception of our lives and the world around us is often far too simplistic.  Science should be, like James Joule said, a worshipful quest.  He felt the study of nature and nature’s laws was “essentially a holy undertaking,” and of “great importance and absolute necessity in the education of youth.”  He said, “After the knowledge of, and obedience to, the will of God, the next aim must be to know something of His attributes of wisdom, power and goodness as evidenced by His handiwork…. It is evident that an acquaintance with natural laws means no less than an acquaintance with the mind of God therein expressed.”  Let’s hear a hearty Amen.  Take a moment to thank God for quality control that keeps your machinery humming.(Visited 42 times, 1 visits today)FacebookTwitterPinterestSave分享0last_img read more

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