Are you a data / social platform expert? A global educational publisher, based in London, is looking to appoint a Data and Platforms Manager within the marketing department of their ELT Division.
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This is a global role which will be highly influential and will steer the marketing CRM to deliver improved responses and stronger customer relationships.
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The successful candidate will develop strategies for ELT data and marketing platforms; lead virtual teams in implementation; work closely with colleagues and stakeholders; maximise the value of current data sources; represent the department in the implementation of Salesforce.com worldwide to ensure compatibility with ELT global needs and to be involved in senior management meetings including contributing your expertise to the wider global business. In short, you will be the champion of the use of data, marketing platforms, CRM and social strategies, selling the vision, enthusing colleagues and driving progress.
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The ideal candidate will have demonstrable expertise with CRM and social platform technology and good understanding of agile development techniques. A strategic thinker, you will be able to prioritise competing demands and will have a high degree of influencing and leadership skills. You will have expertise in Project Management ? Prince 2 would be desirable - and are likely to have a degree in a business or technology related subject.
To apply for this position, please contact Abigail Barclayat Inspired Selection publishing recruitment agency (email: a.barclay@inspiredselection.com). Please provide a CV and your current salary details in your application. To view all current opportunities available via Inspired Selection, please visit our website at www.inspiredselection.com.
Inspired Selection operates an Equal Opportunities policy.? We treat all employees and job applicants fairly and equally regardless of their sex, sexual orientation, marital status, race, colour, nationality, ethnic or national origin, religion, age, disability or union membership status.?
Sony has officially launched the?Xperia Z Ultra, the company?s latest smartphones in the Xperia series.?Sony?unveiled?the Z Ultra last month and it went on sale in India online last week.?The Xperia Z Ultra has a 6.44-inch?(1920 x 1080 pixels)?Triluminos Display with?with X-Reality engine, powered by 2.2 GHz quad-core Snapdragon 800 processor and runs on Android 4.2 (Jelly Bean). It has a 8-megapixel rear camera with Sony Exmor RS?sensor, 1080p video recording and a 2-megapixel front-facing camera.
It has IP55 / IP58 rating for dust and water resistance. It has pen input that recognizes input from a pen or pencil since it has handwriting recognition software . It is the?world?s slimmest Full HD 1080p smartphone?? at just 6.5 mm thick.
It comes bundled with Sony media apps such as Sony Music music and the Sony LIV video streaming app. Sony has partnered with Gameloft to offer Asphalt 7 game that comes per-installed in the device.
Sony Xperia Z Ultra specifications
6.4 inch (1920 x 1080 pixels)?Triluminos Display with X-Reality for Mobiles
The Sony Xperia Z Ultra is priced at an MRP of Rs. 46990. We already know that the MOP (Best Buy price) of the device is?Rs. 44,990. The Xperia Z Ultra comes in?black, white and purple colors and would be available across India from August 2nd.?Check out our?Xperia Z Ultra hands-on.
[unable to retrieve full-text content]Researchers have identified the mechanism behind a plague of LED light bulbs: a flaw called "efficiency droop" that causes LEDs to lose up to 20 percent of their efficiency as they are subjected to greater electrical currents.
San Francisco-based mobile payment startup Square started swiping credit cards in Japan two months ago. Bloom Energy Corp. is about to start selling its power-generating Bloom Boxes in Japan.
Advocates of U.S.-Japan business ties are hoping to build on these relatively isolated but promising expansions by fostering more startup activity. That's both in the form of home-grown Japanese entrepreneurship and by encouraging more American startups to jump into the market.
The Japanese startup cheerleaders include some serious Silicon Valley venture capital muscle.
?The Japanese economy has been flat for a very long time,? said Draper Fisher Jurvetson co-founder Tim Draper at the 2013 Japan Innovation Awards held Friday by the Japan Society of Northern California and Stanford?s U.S. Asia Technology Management Center at Stanford University. ?Now is the time for the entrepreneurs to soar.?
Japan?s economy remains sluggish, especially compared to neighboring China?s recent explosive growth, with even optimistic outlooks for Japan forecasting decades more of GDP stagnation. But on top of Bloom Energy and Square, incubators have started popping up in tech-savvy Japanese cities, according to University of Pennsylvania research.
Draper himself has also helped establish the Draper Nexus venture capital firm, with offices in Silicon Valley and Tokyo dedicated to funding Japanese entrepreneurs. The firm is part of DFJ?s international network of independent venture firms.
For Bloom Energy CEO KR Sridhar, whose company was honored with an award at the event Friday, the big Bloom opening in Japan came just last week.
Lauren Hepler covers economic development, sports, and hospitality for the Silicon Valley Business Journal. She can be reached at 408.299.1820
It's been a tough year for Toyota, which hoped to boost its sales numbers with the rugged Toyota Tundra.
For a vehicle with a payload capacity of 2,000 pounds and the ability to tow a 10,000-pound trailer, the 2014 Toyota Tundra will be expected to do some heavy lifting -- and not just on the job site.
It?s been an unusually tough year for Toyota, both here and abroad. While the maker revealed Friday that it had narrowly retained its global sales lead, the gap between the Japanese giant and rival General Motors markedly narrowed and while GM gained 4 percent for the first six months of 2013, Toyota was down 1.2 percent.
It hasn?t helped to be caught up in an ongoing political dispute between China and Japan that even saw rioters burn a Toyota dealership. But the maker has also had some unexpected setbacks in what has long been its most profitable market, the U.S., where two key lines, the midsize Camry and the Prius hybrid ?family,? suffered unanticipated sales declines. Meanwhile, the outgoing Toyota Tundra pickup has failed to take advantage of the revival of the U.S. truck market, the fastest-growing segment in the industry this year.
?Toyota will be perfectly positioned to take advantage of that growth,? once it launches a major update of the Tundra next month, predicted Bill Fay, the head of the flagship Toyota division for the U.S. market, during a media drive of the new pickup. He expects a 30 percent jump in sales next year. In a market dominated by Detroit, that?s little more than an after-thought.
Read more: Ford Hangs Out Help Wanted Sign but Where are All the Applicants?
When the outgoing Tundra was introduced in 2007, many analysts had big expectations for the new truck. So did Toyota, which built a dedicated factory in San Antonio, Texas to handle production. But after initially topping 200,000, sales quickly plunged. While much of that was the result of the overall crash in pickup demand during the recession, Fay admits the truck has lagged the segment?s revival.
And it?s not the only product challenge the maker is facing. The Camry, which has been the nation?s best-selling passenger car for more than a decade, suffered a 2 percent decline during the first half of the year even as the rest of the market surged. Meanwhile, the Prius, itself the long-dominant hybrid model, was off 5 percent between January and June.
Fay downplayed both problems, though he acknowledged both of Toyota?s key models are facing tougher competition. Ford, in fact, has made a successful point of targeting the various Prius models with an assortment of its own gas-electric models, including the Fusion Hybrid and C-Max Hybrid, which set sales records for the first half.
The Japanese maker has had to respond by cutting prices on the Camry and by ramping up incentives on both the midsize sedan and the various Prius hybrids. But it can afford to do so, noted analyst George Peterson, chief analyst with AutoPacific, Inc., noting that the weakened yen has given the Japanese maker more cash to play with.
Read more: VW, GM Top Latest JD Power Survey of "Surprised, Delighted" Car Buyers
While Toyota has been increasing incentives selectively, it still has some of the lowest givebacks in the market, an average $1,660 per vehicle in June, according to TrueCar.com, compared to $2,537 for the industry overall.
And Fay suggested Toyota could further rein in that spending with the launch of four new models in 2014, a list that includes not just the Tundra but an all-new version of the Corolla, the 800-pound gorilla in the compact sedan segment.
Read more: Chevy Impala Wins Respect, Endorsement from Consumer Reports
But analyst Peterson says Toyota has other worries that aren?t so easy to dismiss. The maker has been lagging in recent AutoPacific studies that focus on not only quality, reliability and dependability ? traditional Toyota strengths ? but also on the factors that surprise and delight consumers.
That was echoed by the results of the new J.D. Power APEAL study which also focuses on what the industry calls ?things-gone-right? factors. While Volkswagen and Chevrolet led the industry, the Toyota brand landed fifth from the bottom. Perhaps equally disconcerting, GM also topped the more traditional J.D. Power Initial Quality Survey last month, handily outperforming Toyota.
?The competition isn?t standing still,? said Peterson. ?Toyota has been building acceptable appliances for decades. Now they have to make products that are exciting and sexy.?
Read more: Mini Vision Concept Offers Hint of All New Microcar Coming Later this Year
Indeed, the newly redesigned Toyota Avalon was supposed to be a prime example of what Toyota could do, underscoring the oft-stated goal of CEO Akio Toyoda to put more ?passion? into the brand. But that isn?t as easy as it might seem, as Toyota was reminded when influential Consumer Reports magazine ranked the new Chevrolet Impala tops in the full-size sedan segment, besting the new Avalon.
There are other challenges facing Toyota. For one thing, caution analysts, it has become almost wedded to the Baby Boom generation and is struggling to attract younger, hipper buyers. That was supposed to be the role of Scion. The ?brand-within-a-brand? has clearly been bringing in younger blood ? but despite scoring a hit with the new FR-S sports car, overall Scion sales have fallen sharply the last several years and Toyota is struggling to come up with a rescue strategy.
Read more: Acura Set to Reveal Running Prototype of Reborn NSX Supercar
Despite the challenges, Toyota brand boss Fay insisted he?s ?pleased with the position we?re in? going into the 2014 model-year.
And, indeed, the maker remains a significant force to be reckoned with, echoed analyst Peterson, noting that his research finds Toyota?s reputation has fully recovered from the hits it took during the unintended acceleration scandal of a few years back.
That said, Peterson and other observers warn that despite its size and power, the Japanese giant has some significant and mounting challenges ahead ? enough to strain even a heavy lifter like the new Toyota Tundra.
June 28, 2013 ? A new study from researchers at Uppsala University and University of Havana uses mathematic modeling and experiments on ants to show that a group is capable of developing flexible resource management strategies and characteristic responses of its own.
The results are now published in Physical Review Letters.
Group-living animals are led to regulate their activity and to make decisions on how to manage resources, under the action of a variety of environmental stimuli and of their intrinsic interactions. The latter are typically cooperative, in the sense that the activity of a single animal increases nonlinearly with the number of already active ones.
The researchers monitored experimentally and using mathematical modeling the activity profile of food-searching ants in a natural environment. The number of ants entering in or exiting the nest was recorded as well as the local temperature over several days.
The study shows that the group is capable of developing flexible resource management strategies and characteristic responses of its own. This is achieved by operating in an aperiodic fashion close to a regime of chaos, where nonlinearity is especially pronounced and offers the group more options than just following passively the day/night temperature cycle.
Furthermore, the group bursts into its foraging activity rapidly and subsequently relaxes to the inactive mode more slowly. This flexible behavior is reminiscent of "free will" in the sense that groups' activities are not totally constrained by the environment but on the contrary constitute new, emerging modes of behavior not encoded in the external stimuli or in the activity rhythms of the individuals within the group.
"Our results are likely to account for a wide range of temporal rhythms observed across the animal kingdom as well as in human societies," says Stamatios Nicolis, researcher at the Department of Mathematics, who lead the study.
"For instance, signal processing in the brain typically leads to complex patterns of electrical activity as witnessed by the electroencephalogram whose aperiodic, chaotic-looking structure is not a simple replica of the signal but reflects instead the ability of the brain to store vast amounts information and to process them selectively depending on the circumstances," says Stamatios Nicolis.
June 26, 2013 ? Most efforts at improving solar cells have focused on increasing the efficiency of their energy conversion, or on lowering the cost of manufacturing. But now MIT researchers are opening another avenue for improvement, aiming to produce the thinnest and most lightweight solar panels possible.
Such panels, which have the potential to surpass any substance other than reactor-grade uranium in terms of energy produced per pound of material, could be made from stacked sheets of one-molecule-thick materials such as graphene or molybdenum disulfide.
Jeffrey Grossman, the Carl Richard Soderberg Associate Professor of Power Engineering at MIT, says the new approach "pushes towards the ultimate power conversion possible from a material" for solar power. Grossman is the senior author of a new paper describing this approach, published in the journal Nano Letters.
Although scientists have devoted considerable attention in recent years to the potential of two-dimensional materials such as graphene, Grossman says, there has been little study of their potential for solar applications. It turns out, he says, "they're not only OK, but it's amazing how well they do."
Using two layers of such atom-thick materials, Grossman says, his team has predicted solar cells with 1 to 2 percent efficiency in converting sunlight to electricity, That's low compared to the 15 to 20 percent efficiency of standard silicon solar cells, he says, but it's achieved using material that is thousands of times thinner and lighter than tissue paper. The two-layer solar cell is only 1 nanometer thick, while typical silicon solar cells can be hundreds of thousands of times that. The stacking of several of these two-dimensional layers could boost the efficiency significantly.
"Stacking a few layers could allow for higher efficiency, one that competes with other well-established solar cell technologies," says Marco Bernardi, a postdoc in MIT's Department of Materials Science who was the lead author of the paper. Maurizia Palummo, a senior researcher at the University of Rome visiting MIT through the MISTI Italy program, was also a co-author.
For applications where weight is a crucial factor -- such as in spacecraft, aviation or for use in remote areas of the developing world where transportation costs are significant -- such lightweight cells could already have great potential, Bernardi says.
Pound for pound, he says, the new solar cells produce up to 1,000 times more power than conventional photovoltaics. At about one nanometer (billionth of a meter) in thickness, "It's 20 to 50 times thinner than the thinnest solar cell that can be made today," Grossman adds. "You couldn't make a solar cell any thinner."
This slenderness is not only advantageous in shipping, but also in ease of mounting solar panels. About half the cost of today's panels is in support structures, installation, wiring and control systems, expenses that could be reduced through the use of lighter structures.
In addition, the material itself is much less expensive than the highly purified silicon used for standard solar cells -- and because the sheets are so thin, they require only minuscule amounts of the raw materials.
John Hart, an assistant professor of mechanical engineering, chemical engineering and art and design at the University of Michigan, says, "This is an exciting new approach to designing solar cells, and moreover an impressive example of how complementary nanostructured materials can be engineered to create new energy devices." Hart, who will be joining the MIT faculty this summer but had no involvement in this research, adds that, "I expect the mechanical flexibility and robustness of these thin layers would also be attractive."
The MIT team's work so far to demonstrate the potential of atom-thick materials for solar generation is "just the start," Grossman says. For one thing, molybdenum disulfide and molybdenum diselenide, the materials used in this work, are just two of many 2-D materials whose potential could be studied, to say nothing of different combinations of materials sandwiched together. "There's a whole zoo of these materials that can be explored," Grossman says. "My hope is that this work sets the stage for people to think about these materials in a new way."
While no large-scale methods of producing molybdenum disulfide and molybdenum diselenide exist at this point, this is an active area of research. Manufacturability is "an essential question," Grossman says, "but I think it's a solvable problem."
An additional advantage of such materials is their long-term stability, even in open air; other solar-cell materials must be protected under heavy and expensive layers of glass. "It's essentially stable in air, under ultraviolet light, and in moisture," Grossman says. "It's very robust."
The work so far has been based on computer modeling of the materials, Grossman says, adding that his group is now trying to produce such devices. "I think this is the tip of the iceberg in terms of utilizing 2-D materials for clean energy" he says.
This work was supported by the MIT Energy Initiative.
Communications minister Stephen Conroy has announced he has resigned in the wake of last night?s Labor leadership coup against Julia Gillard.
Senator Conroy?s office this morning confirmed the minister has stepped down announcing the news on Twitter.
?Can confirm Conroy has resigned. Keep supporting Labor & the #NBN, most important infrastructure in our country?s history #auspol,? his office tweeted.
Conroy has been a controversial and somewhat combative communications minister who spearheaded Labor?s NBN policy and led the media reform debate in March, which ultimately saw the legislation scrapped under fierce opposition from the media industry.
The Daily Telegraph is reporting former arts minister Simon Crean is tipped to be the new communications minister.
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There are sure lots of variants of roasting to choose from. It is encouraging to find out the quantity of Indianapolis area coffee shops which can be either roasting their own pinto beans or acquiring them from local roasters. At now, the golden beans, called pergamino, have to be hulled, which is done by machine.
However, could I do this, there is a certain a higher level understanding I (and now we) must have with regard to sustainable coffee and its ecological significance. where to buy pure green coffee bean. Still within their original state, green beans are weighed and placed into a coffee roasting machine. But none have shown the dramatic results on this new study.
Other reports have linked caffeine to weight loss and a reduced chance of metabolic syndrome. Shade grown/shade-grown pinto beans: traditional espresso beans that are shade grown (with a canopy of trees). Bjava Coffee and Tea, at 56th and Lafayette, is among the most recent coffee shops to begin roasting their beans on site.
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Include it in in your taste or coffee, you'll feel lighter. Is there a coffee antioxidant? So what about coffee shops in the past, did they exist, did they survive?
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All Critics (125) | Top Critics (29) | Fresh (116) | Rotten (9)
The harmonies they strike in this reality-inspired charmer are sweetly sublime.
You could drive an Abrams tank through the film's plot holes, but you'll likely be too busy enjoying yourself to bother.
"The Sapphires" feels like a movie you've already seen, but it's nonetheless thoroughly enjoyable, like a pop song that's no less infectious when you know every word.
"The Sapphires" sparkles with sass and Motown soul.
Sapphires is hardly a cinematic diamond mine. But this Commitments-style mashup of music and melodrama manages to entertain without demanding too much of its audience.
Quite possibly the least original movie you'll see this summer -- and one of the most enjoyable.
The mood is so charming and the music so inspiring that you continually cut it a break.
By-the-numbers in every sense of the word, the film tracks a tried-and-true sort of triumph while featuring renditions of soul classics so bursting with energy and joy you won't care that the originality meter is leaning on empty.
Even when it seems contrived The Sapphires is a feel-good movie in the most positive meaning of that term, thanks to the Motown music and O'Dowd's cheeky charm. Like the Four Tops, I loved every sugar pie, honey bunch moment. I can't help myself.
Unfortunately, it has been turned into a routine and uninspiring movie, following a tired, old formula the entire way.
A surefire crowdpleaser with all the ingredients for the type of little-movie-that-could sleeper success that Harvey Weinstein has nurtured in years and award seasons past.
You've seen this story before, but never pulled off with so much joie de vivre.
They can put a song across just like the Dreamgirls. What's not to like?
Exuberant but fairly formulaic.
Doesn't always mix its anti-prejudice message and its feel-good nostalgia with complete smoothness. But despite some ragged edges it provides a reasonably good time.
Director Wayne Blair -- another veteran of the stage show -- finds his footing during the film's many musical numbers.
Despite the prosaic plot and reserved approach taken by Blair, Briggs, and Thompson, it's tough to get cynical about such a warmhearted picture that strives to tell so uplifting a story.
A movie with enough melody and camaraderie to cover up its lack of originality.
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The selling exhibition ?Shuimo Water Ink: Chinese Contemporary Ink Paintings,? curated by Mee-Seen Loong at Sotheby?s in New York, demonstrated once again the versatility and power of art made with the simplest of materials and the most refined and complex techniques. The works ranged from soaring, meticulous Song-style landscapes to confrontational abstractions achieved with the single thrust of a large, wet brush. But the show had less to do with traditional, scholarly self-effacement or Modernist iconoclasm, and more to do with acts of personal expression.
For example, color is used in non-traditional ways in Li Huayi?s Whispering Pine, Reaching to the Clouds (2012), a vast white-to-grey mountain landscape depicted from a vertiginous angle, with the twisting pine of the title ?colorized.? Whereas the tree executed in blacks and grey would naturally attract the eye, the addition of color adds a touch of surprise to the work, much louder than a whisper.
Color was not used in the dense, convoluted, near-terrifying landscapes of Tai Xiangzhou. Tai?s lengthy calligraphic colophons, in skillful regular script, demonstrate the artist?s respect for his classical heritage. At the other extreme, color bursts across the comical expressionist works of Li Jin, with their overt social criticism.
Abstraction in a traditional mode might describe the works of American born Arnold Chang?in which elements familiar in Chinese landscape painting appear to be distorted and displaced in a fresh and modern way?yet his scrolls still bear the stamp of the refined scholar-intellectual. Similarly, Liu Dan?s large?Silent Mountains, Meandering Paths?(2013) delights and disarms the eye with its ambiguous confusion and blending of clouds and mountains.
Scholarly fondness for the grotesque is stretched to the limits by Zeng Xiaojun, whose?Wild Spirit Screen?(2012) is a haunting depiction of a psychedelic, surrealistic plant form?an uprooted tree of sorts with stark intertwined branches, odd root systems, unnatural growths and spooky crevices. Call it Chinese Gothic, if you please.
In technical terms, the collages by the Master of the Water, Pine and Stone Retreat, are unique in this exhibition in a couple of ways. First, the inscriptions are in English, the native language of the British artist. Second, the subject matter?or more precisely, the ink on the paper?is applied in the form of collage. The Master first paints traditional landscape elements on ?cloud-dragon paper? and then cuts out sections of this material to paste on the finished work. The trompe l?oeil effect is entirely convincing. In?The Eight Sainted Staves?(2012), eight separate scrolls each depict a walking stick accompanied by a long text in a faux-literary Chinese style about the artist?s encounter with the ?Chisel-Immortal,? the artisan to whom the artist attributes the creation of the staves. With (British) tongue firmly in (Chinese) cheek, these works raise intriguing questions about Chinese art and identity.
?Water Ink,? one of Sotheby?s first selling exhibitions of Asian art, set off a small controversy over the issue of a major auction house stepping on the toes of individual galleries and dealers with fewer resources. But there are more factors than the obvious commercial ones at play here, and it is hoped that the incident will remain a storm in an inkpot.
One of the most important themes of this year?s D: Dive Into Mobile conference is that mobile is about more than just apps that solve our first-world problems. To understand what ?global mobile? means, consider the example of Asia Kamukama, who spoke Monday afternoon in the first of three ?Global Voices? sessions.
Kamukama is the co-founder of the Maendeleo Foundation, with the goal of ?promoting information communications technology in rural Uganda? and in places that otherwise would have limited or no access to computers.
About 57 percent of Uganda has access to electrical power, Kamukama said, but only 15 percent can afford it nationwide. In rural areas, that number drops to 2 percent.
And that?s the problem: Having the technology is one thing, but powering it is another. Maendeleo has incorporated solar panels in its classrooms since it began in 2007, but Kamukama said their low-cost desktops had a rough time being ported around with the panels in a specially modified RAV4.
?Sometimes we would drive about 400 kilometers with five desktops, and halfway through, they would die, full of dust,? she said.
So Maendeleo hooked up with Intel and began using its (also low-power) Classmate PCs. A month of testing with the same solar panels and SUV were successful enough, Kamukama said, that Maendeleo bought 15 of them.
The Maendeleo Foundation has consequently been able to give 28,000 people their first taste of tech, Kamukama said, and plans to expand the schools? programs into remote libraries are under way. She said those library partnerships would help keep Ugandans interested in and engaged with computers after her group drives away.
Paul Krugman: Missing Deflation: "Keynesians have, over all, had a very good track record in this economic crisis?. One area where things haven?t worked out as expected, however, is on the deflation front?. One possibility was that there wasn?t as much slack in the economy as we thought, that a lot of the problem was structural?. Another possibility? was that downward nominal wage rigidity could explain why the fairly rapid falls in inflation seen in previous slumps weren?t happening?. [N]ow we have two new analyses, by Hobijn and Daly at a Boston Fed conference, and in the IMF?s new World Economic Outlook, both of which strongly suggest that the issue isn?t structural unemployment, it?s low responsiveness of inflation to unemployment when inflation is low to begin with?. This does say that there is little risk of accelerating inflation. Indeed, Hobijn and Daly suggest that there?s a 'pent-up demand for wage cuts' that will probably push inflation lower even if the economy is recovering. Central banks and other policy makers will be making a terrible mistake if they look at low, stable inflation and pat themselves on the back for a job well done. Low, stable inflation, it turns out, is entirely consistent with catastrophic economic mismanagement. Notice how Keynesians responded to the partial failure of a prediction: by asking what they got wrong, and how their model of the world needed to be adjusted. This, of course, shows what fools we are: everyone on the other side of these debates knows that you respond to mistakes by never acknowledging them, and doubling down on whatever you originally claimed."
Tim Taylor: The Stock of Federal Investment: "The total stock of physical capital from federal investment is worth $3.2 trillion in 2013, according to the budget estimates, which look both at investment and at depreciation over time. About 30% of that is defense-related. About 20% is direct federal spending on projects like water and power. The remaining half or so is capital financed by federal grants, and about two-thirds of that ($1.1 trillion) is related to transportation. The total stock of research and development capital from federal investment is $1.6 trillion in 2013. One way to divide that up is that about 40% is related to national defense, and 60% is not. Another way to divide it up is that about half is basic research, and the other half is applied research. The total stock of education and training from federal investment is estimated at $2.2 trillion in 2013, with about three-quarters of that being K-12 education, and the rest being higher education. I'm sure that the calculations behind these estimates can be critiqued on many grounds, but just taking them at face value, it's thought-provoking that the stock of physical capital investment is less than the sum of the education and R&D capital."
Bernanke: Low-Income Communities Struggle Despite Recovery | Alan Blinder: A Good Grade for a Responsible Budget | Robin Harding: Boston Fed: Labour force participation | Eric Rosengren: Fed Mandate Argues for Aggressive Stimulus | Ezra Klein: From ?Mad Men? to a Mad Congress | Austin Frakt: Penn LDI : The economics of community rating and the individual mandate | Enrico Moretti: Unemployment benefits should encourage geographic mobility | Brad Plumer: Here?s why 10.4 million American workers are still in poverty | Greg Anrig: Beyond the Education Wars: Evidence That Collaboration Builds Effective Schools | David Hilfiker: Flowers for Algernon | James Fallows: Ten Years Ago: The Mohammed al-Dura Case | Buiter?s manifesto on a new eurozone world order, post-Cyprus: Citi chief economist Willem Buiter sketches the new face of creditor rights in the eurozone, reveals the hole in the heart of the EU's crisis resolution plans, and forecasts more debt restructuring in Cyprus | Stephen Gandel: The 10 stages of Jamie Dimon's blubbering London Whale grief |
Authorities have arrested 46-year old Eric Williams for making a "terroristic threat" after searching his home.? Williams is the former justice of the peace in? Kaufman County, Texas, a position he lost last year when the District Attorney's office convicted him of theft. NBC's Lester Holt reports.
By Matthew DeLuca, Staff Writer, NBC News
A former justice of the peace in the North Texas county where a district attorney and his wife were found dead in their home in March has been arrested and charged with making a ?terroristic threat,? authorities said Saturday.
Eric Lyle Williams, 46, was arrested and booked into the Kaufman County Jail in the predawn hours Saturday, according to jail records. Williams was arraigned Saturday morning and charged with one count of making a terroristic threat and two counts of insufficient bond.
It was not clear to whom the threat was directed.
Williams was being held on $3 million bond, the Kaufman County Sheriff?s Department said.
Authorities continue to investigate the deaths of District Attorney Mike McLelland and his wife Cynthia, who were discovered fatally shot March 30 in the small town of Forney. Investigators also continue to probe the death a month earlier of Assistant District Attorney Mark Hasse.
Williams has not been named as a suspect in any of the deaths.
Local, state, and federal law enforcement officers conducted a search of Williams? home on Friday. An affidavit underlying the search warrant has been ordered sealed, sheriff's department spokesman Lt. Justin Lewis said.
And Saturday night, NBCDFW.com reported that agents were searching a self-storage facility?in the town of Seagoville but wouldn't say whether the activity was part of the McLelland and Hasse cases. Agents could be seen searching a car found in a unit there, NBCDFW.com reported.
Williams was kicked out of office and had his law license suspended after being convicted of theft. He is appealing his conviction.
Williams? attorney David Sergi release a statement on Friday saying that his client ?has cooperated with law enforcement and vigorously denies any and all allegations.?
Williams said that he had nothing to do with the McLelland?s death and denied owning a gun in an interview earlier this month with NBC affiliate KXAS.
?If I was in their shoes, I would want to talk to me,? Williams said at the time. ?In the investigators? mind, they want to check with me to do their process of elimination.?
Williams said in the interview that he had given investigators his cellphone after being contacted by them hours after the McLellands? bodies were found.
?I?ve cooperated with law enforcement,? Williams said in April. ?I certainly wish them the best in bringing justice to this incredibly egregious act.?
The Associated Press contributed to this report.
Related:?
This story was originally published on Sat Apr 13, 2013 11:43 AM EDT
TIP! You shouldn?t trash bedroom doors simply because of some dirt. Remove your door from the frame, and sand it down until the bare wood is exposed.
Working with friends and family can make the most onerous home improvement job more fun. Make it into a weekend project and work together to get the job done. Think of all the money you?re saving doing the job yourselves. All the tips here will help you get your project in order so that you can get a running start.
TIP! Using high-gloss paint on your shutters and front door will make your house look more attractive. Homes that are made of light colored brick are a perfect candidate for a deep tone on the front door.
If a lock is having problems, you can change out the entire thing or look to change out only the cylinder. This part actually does the locking. If you have lost your house key, you can change the cylinder without having to change whole lock. If you want the door to look better or want added security, just go ahead and replace the whole unit.
TIP! If you shorten the hose on your dryer, you can save money on energy. The first step is removing the dryer hose and cleaning it.
Switching out doorknobs adds a modern feel and can boost your home?s safety too. This kind of a project generally takes less than an hour to do. All you need to start is a screwdriver. Go to the closest hardware store and find a knob you like.
TIP! Before you start enjoying your backyard this summer, it is a good idea to evaluate the condition of your deck. There could be rotting wood that needs to be fixed.
You may need permission to complete large projects like digging a pool. If you aren?t aware of local regulations or you don?t undertake structural property changes, try hiring pros to help you assess items to avoid extra costs or fines later.
TIP! When was your home painted last? A paint job is a quick, easy and fairly affordable way to make your house look much better. Brightening up dingy, outdated siding can give you that fresh new look you are craving.
To catch potential problems before they get out of control, just take a short walk through your house on a monthly basis, looking for things that could use some improvement. Identifying air leaks is one such example. Sealing and insulating the leaks is a quick and simple repair that will reduce your heating bill.
TIP! Check the adequacy of your deck?s water resistance by wetting it down some after hot weather. If the water is soaked up by the wood, you must treat the wood with a water repellent product.
You need to include some dry days into your painting projects. Success only comes when you keep this in mind. Days of high humidity increase the time it takes for your painting project to dry. By painting on drier days, you will reduce the time between coats. This will make your project go much faster.
TIP! Have you thought about putting vinyl siding on your home? Vinyl siding will help to increase the value of your home. As much as eighty percent of the cost can be recovered upon selling the home.
Try a decorative paint finish on your walls for a unique look for your room. Applying the same color paint in both a glossy and flat finish to your walls offers an attractive appearance that has a lot of rich texture. Put two flat paint coats on the wall, then stencil on glossy paint in unique designs. Interest will be piqued by the glossy paint.
TIP! You should always be sure to cover your floors before you start to paint a room. It can be hard to clean paint from hardwood or carpeted floors.
If you?re in the home improvement mindset, look into checking your air conditioner filters. Your HVAC system will function less efficiently with clogged, dirty filters. Your air conditioner uses more energy to keep the house cool when it works harder. This means higher electricity bills.
TIP! When you?re doing significant interior painting, it?s absolutely vital to put down drop cloths. (Old sheets can work in a pinch.
You need to think about more than cost when you are looking for contractors to help out your home improvement. There are other things you need to consider like the time line, labor cost, warranties, and how long the company has been in business. Factor all that into your decision.
TIP! Use a water heater blanket to increase the efficiency of this appliance. Such blankets successfully trap heat that would otherwise be lost, reducing the energy required to heat your water.
Try to reuse what you can, for the environment, and for your pocketbook. Why not paint your cabinet for a fresh, new look? Replace the handles and knobs, too. Try painting instead of replacing to freshen up a room.
TIP! You can get a lot of enjoyment out of doing home improvement projects yourself. Staying positive will make them even more so.
When you buy supplies for home improvement, get some safety equipment too. This includes steel-toed boots, hard hats, safety glasses, and gloves. If you get hurt during your project, you?re going to be kicking yourself. Wear the equipment throughout the project.
TIP! The best home improvement projects are sown from a single bright idea. Talk to interior designers to learn about some modern ideas.
Developing a solid plan makes it easier to succeed at home improvement. When you do your home improvement project with a friend, you will enjoy the task and share happy memories. It is sure to be rewarding to look at what you have accomplished and consider what you have saved.
SAN FRANCISCO (AP) ? A tour bus carrying visitors from Yosemite National Park was traveling at an unsafe speed when the driver lost control and crashed on a mountain road, leaving 16 people injured, the California Highway Patrol said Sunday.
The bus was about six miles outside of the south entrance of the park when it went off Highway 41, a winding mountain road when it crashed about 6 p.m. Saturday. It came to a stop when it hit a tree, CHP Officer Scott Jobinger said.
Fifteen passengers and a tour guide suffered minor to moderate injuries.
"At this point the cause was the bus was traveling at unsafe speed and went off the road," Jobinger said. He said the accident remained under investigation to determine if other factors played a role.
CHP Sgt. Edward Greene told the Fresno Bee that the impact of the crash caused several passengers to be thrown to the driver's side of the bus, with the bus stopping when it hit the tree.
"If the tree wasn't there to stop the bus, it would have continued down the ravine," Greene said.
The 15 injured passengers, described as mostly elderly, and a tour guide were taken to local hospitals for treatment.
Four of the injured were treated at Community Regional Medical Center, and four were treated at Clovis Community Medical Center, said Jennifer Avila-Allen, a spokeswoman for the hospitals. All but one at Community Regional had been released, she said. The conditions of the others, taken to a different hospital, were not known.
The bus was towed to an impound yard where it will be inspected to see if any mechanical problems may have contributed to the crash, Jobinger said.
The bus driver, identified as Changefeng Liu, 49, of Fremont, Calif., was the only person on the bus who was not hurt. He has not been arrested, and alcohol is not believed to be a factor in the crash.
Investigators have not determined the exact speed of the bus at the time it went off the roadway, but the scenic highway has sharp curves where the speed limits drop to 35 miles per hour, Jobinger said.
The bus is operated by Seven Happiness Tour & Charter, a Burlingame, Calif.-based company that specializes in providing tours to the Chinese-American community, said Charles Wu, who works at the company and answered the phone at its headquarters Sunday. He said the owner would not be available to comment until Monday.
"Most of them (passengers) were Chinese people from the Bay Area," Wu said.
Wu said he had not talked to the bus driver since the crash and have few details about the incident, but said Liu had worked for the company for about six years.
Liu could not be reached for comment.
The tour bus company, which operates six motor coaches and six mini-buses or vans, has not had any crashes in the last 24 months, according to records with the Federal Motor Carrier Safety Administration.
Apr. 12, 2013 ? Large helpers (nannies) in a cichlid fish allow the dominant male and female to reduce their personal contribution to their offspring and territory, according to new research published today in Functional Ecology.
By removing the large helper for 30 days -- which corresponds to one breeding cycle in this species -- a team from the University of Bristol and the University of Bern (Switzerland) studied the investment strategies of the dominant pair and the survival of their brood, while checking for immigration of new helpers.
Dr Rick Bruintjes, NERC Science & Business Marine Renewable Energy Fellow at the University of Bristol described: "In the cichlid Julidochromis ornatus, one large male helper spends almost all of his time close to the breeding shelter, whereas the dominant pair is only around half of their time. By removing the large helper we found that one day after removal the dominants increased territorial duties, however, seven days after removal the initial higher investment was back to pre-removal levels."
Senior statistician Dr Dik Heg from the University of Bern said: "Already after seven days, 36 per cent of the removal groups had a new large subordinate immigrant. Only with a new immigrant large helper did dominants relax their territorial duties, showcasing the benefit of having a large subordinate for the dominant pair."
MSc Zina Heg-Bachar, research assistant at the University of Bern, explained: "Removal of the nanny did not change survival rates of fry and small fish, most likely because the parents and/or the new nanny compensated for the absence of the original nanny."
This study shows the importance of large helpers in allowing the dominant pair to reduce their personal contribution to their offspring. Moreover, it highlights the importance of immigration of new helpers to relieve dominants from carrying out parental behaviours in cooperative breeding systems.
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Journal Reference:
Rick Bruintjes, Zina Heg-Bachar and Dik Heg. Subordinate removal affects parental investment, but not offspring survival in a cooperative cichlid. Functional Ecology, 2013
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Disclaimer: Views expressed in this article do not necessarily reflect those of ScienceDaily or its staff.
Uber CEO Travis Kalanick just wrapped up a press phone call where he discussed the policy paper that the company released earlier this morning. The apper stated that Uber would be rolling out ridesharing services in cities where it had received "tacit approval" in the sense that regulators didn't crack down on other services. To kick things off, Kalanick noted that ridesharing is kind of a loose term, so he specified that he means "non-licensed drivers who are providing transportation services for compensation." He said Uber has been staying away from that business, because of the "extreme regulatory risk": "Believe it or not, that was at a level that we were just not comfortable with." (The "believe or not" refers to the fact that Uber has certainly seemed willing to fight other regulatory battles.)
In a recent survey of Atlanta and other U.S. mobile device users, BYOD Insight 2013: A Cisco partner network study, findings revealed surprising information regarding the number of people that use their smartphones for work. The survey highlighted several different issues, but what stood out was the vast difference between the number of workers who use their mobile devices for work and the number of workers who are compensated for doing business on their own devices. Companies are accustomed well-established work requirements like clothes and automobiles and computers, but like any new technologies in the workplace, personally owned mobile devices are creating issues with usage.
Should mobile devices, like smartphones and tablets be treated like clothing, cars or computers? They are all used for work in one way or another, cost money, and their use can leave the business vulnerable to a lawsuit. And for each of the three items, there are usually company policies that define how they should be used. The policies and laws for clothes and vehicles are well established, and there usually is no debate about them.
The policies around smartphones, however, are varied among all companies, and as they currently stand, also leave businesses wide open to lawsuits and penalties. ?Thus, it is worth considering these potential issues and taking steps to prevent them.
Clothes are important. A lawyer needs to wear a suit, a construction worker steel toed shoes, and soldiers wear uniforms. In order to have the job, a well-established policy is that the worker has to pay for the clothes themselves. Lawsuits aren?t very common due to clothing policies; there is the small possibility of one from a workplace safety violation, for example, someone not wearing steel-toed shoes in a construction zone, but it is unlikely.
Automobiles are similar to clothes in the establishment of policy and procedure. If a worker needs a vehicle to get their job done, they will be either provided with one, or compensated by the company. There might be an issue with a worker getting involved in an accident, and in almost all cases any financial issues arising from it are covered by insurance.
Computers are necessary to get things done at work. When the devices were owned and provided by the company, it was very clear who paid for them. The big change in the last few years is that consumer and mobile devices have become more powerful and useful than the desktop-bound devices of the past. As the results of the survey show, 90 percent of workers use their personal mobile devices for work, and only 8 percent of workers are getting any kind of compensation or stipend for those same devices.? It might be time for employers to accommodate to these changes in the workplace, but are they ready to do so?
This change in device usage can be a problem for several reasons. The first is the workplace expectation that users have access to mobile devices and can be reached in an urgent situation. That is all well and good, but once that expectation is set, it can lead to issues and questions. If a supervisor needs to reach an employee and calls their cellphone, does the worker need to answer? If the worker sets up the mobile device to access email, do they need to respond? If the company does not provide the phone and does not pay for it at all, probably not. ?And the question of who pays for it can be up for debate.
For highly paid professionals, the additional expense of a mobile device is minor, especially when compared to the increased efficiency they get. The ability to answer an email quickly, update a calendar, and hold conversations while being out and about adds literally hours of productivity to their day. They will pay for and use the devices whether the company pays for them or not. Compared to the cost of a good suit, the mobile device cost is minor.
Hourly employees, however, are the people affected by this change the most, and might be justifiably disgruntled. When they use their smartphone to navigate, take pictures, talk to someone while looking through the warehouse, or make reports from a job site using their own phone, they are paying for it out of their own pocket. Adding up the amount of hours they use their phone and comparing it to the cost of service, they could be paying somewhere between $50 and $150. For someone making $15 per hour, that is a big cost.
The managers of a company might say that the workers don?t have to use their own smartphones to get their work done, and they might be right, but these changes happen quickly. It is better to stay one step ahead of the potential issues, create a policy, and treat their employees like they would want to be treated themselves. The quickest and easiest thing to do might be to add a small mobile phone stipend to every employee?s paycheck for when they use their own phones to do work.
And instead of lagging behind the trend, companies may be able to increase the productivity of their entire organization by encouraging and promoting mobile device usage in all aspects of work: help pay for devices, hold training classes to show people how to make the most effective use of their devices, and have someone test different apps and keep people up to date on which ones work well.
Technology continues to evolve and the number of workers using their own devices to get work done will only continue to increase as time passes. The combination of features available on smartphones and the personal devices of the future ensure that people will use their own devices in the workplace. To prevent frustration and lawsuits, companies should look at how these devices are being used today and make sure they have a policy that addresses reality. To truly gain a competitive advantage, companies can embrace smartphones, help pay for them, and promote their use.
Author: Rolf Versluis
Twitter:?@adcapnet LinkedIn:?Rolf Versluis LinkedIn Facebook:?Adcap Network Systems Facebook Page
VELIKA IVANCA, Serbia (AP) ? A 60-year-old veteran gunned down 13 people in Serbia, including a baby, in a pre-dawn house-to-house rampage Tuesday before trying to kill himself and his wife, police and hospital officials said.
The man, identified as Ljubisa Bogdanovic, used a handgun in the shooting spree at five houses in Velika Ivanca, a village 50 kilometers (30 miles) southeast of Belgrade, emergency hospital spokeswomanNada Macura said. The dead included six women, several of them his relatives.
Residents of the village described the suspect as a nice quiet man. They said he first killed his son before leaving the house and then began shooting his neighbors, some of whom were still asleep.
"He knocked on the doors and as they were opened he just fired a shot," said resident Radovan Radosavljevic. "He was a good neighbor and anyone would open their doors to him. I don't know what happened."
Neighbor Milovan Kostadinovic said the suspected killer was caught by a police patrol while on the way to his house.
"If they didn't stop him, he would have wiped us all out," Kostadinovic said, standing in front of his two-story, red tile- roofed house ? one of a dozen modest homes that make up the village, which is located on a lush green hill covered with fruit trees. "He shot himself when police stopped him."
Serbian police chief Milorad Veljovic said 12 people were killed immediately between 5 a.m. and 5:30 a.m., and one person died in a Belgrade hospital. The man and his wife were both severely injured by the shootings and another person was also injured, the hospital spokeswoman said.
"We are all caught by surprise," Veljovic told reporters. "Most of the victims were shot while asleep."
He said the motive for the killings Tuesday was unclear.
The suspect had lost his job last year and fought as a Serb volunteer soldier in the war in Croatia in 1992, the police chief said. Villagers said Bogdanovic fought in Vukovar, the eastern Croatian town that was destroyed in a massive Serbian-led army offensive ? the scene of the worst bloodshed during Croatia's 1991-95 war for independence.
Macura, the hospital spokeswoman, said the shooter had no known history of mental illness. Stanica Kostadinovic, another neighbor, said the man's father had hanged himself when he was a young boy and his uncle had a history of mental illness.
Although such shootings are rare in Serbia, weapons are readily available, mostly from the 1990s wars in the Balkans. Initial reports said the suspect had a license for the handgun.
Serbian Prime Minister Ivica Dacic said Tuesday the killings should serve as a warning that the government should pay more attention to gun control laws and other social problems facing the Balkan country, which is still reeling from the wars in the 1990s.
Police blocked off the village while forensic teams and investigators in white protective robes took evidence from homes where the shootings took place.
Serbia's last big shooting spree occurred in 2007, when a 39-year-old man gunned down nine people and injured two others in an eastern village.
Whether you're digging into a long gaming session or just looking for a better way to video chat on your PC, a headset with a microphone can go a long way. If you don't want to plop down the cash for one, you can add one to your existing over-the-ear headphones yourself.
This particular mod uses a pair of cheap Monoprice 8323 headphones, but you could probably perform the process on any set of cans (though the more expensive your headphones, the less we'd recommend breaking them open). You'll need a bit of electronics experience to make this work, and the instructions aren't incredibly detailed, but if you know what you're doing they're pretty easy to follow. When you're done, you'll have a cheap gaming headset with a completely detachable microphone.
Of course, if you really want the features a good headset can offer, check out our roundup of the five best gaming headsets. Hit the link for the full set of instructions.
I did a detachable mic boom mod for my cheap Monoprice 8323 headphones | Reddit
New vaccine-design approach targets HIV and other fast-mutating virusesPublic release date: 28-Mar-2013 [ | E-mail | Share ]
Contact: Mika Ono mikaono@scripps.edu 858-784-2052 Scripps Research Institute
LA JOLLA, CA March 28, 2013 A team led by scientists from The Scripps Research Institute (TSRI) and the International AIDS Vaccine Initiative (IAVI) has unveiled a new technique for vaccine design that could be particularly useful against HIV and other fast-changing viruses.
The report, which appears March 28, 2013, in Science Express, the early online edition of the journal Science, offers a step toward solving what has been one of the central problems of modern vaccine design: how to stimulate the immune system to produce the right kind of antibody response to protect against a wide range of viral strains. The researchers demonstrated their new technique by engineering an immunogen (substance that induces immunity) that has promise to reliably initiate an otherwise rare response effective against many types of HIV.
"We're hoping to test this immunogen soon in mice engineered to produce human antibodies, and eventually in humans," said team leader William R. Schief, who is an associate professor of immunology and member of the IAVI Neutralizing Antibody Center at TSRI.
Seeking a Better Way
For highly variable viruses such as HIV and influenza, vaccine researchers want to elicit antibodies that protect against most or all viral strainsnot just a few strains, as seasonal flu vaccines currently on the market. Vaccine researchers have identified several of these broadly neutralizing antibodies from long-term HIV-positive survivors, harvesting antibody-producing B cells from blood samples and then sifting through them to identify those that produce antibodies capable of neutralizing multiple strains of HIV. Such broadly neutralizing antibodies typically work by blocking crucial functional sites on a virus that are conserved among different strains despite high mutation elsewhere.
However, even with these powerful broadly neutralizing antibodies in hand, scientists need to find a way to elicit their production in the body through a vaccine. "For example, to elicit broadly neutralizing antibodies called VRC01-class antibodies that neutralize 90 percent of known HIV strains, you could try using the HIV envelope protein as your immunogen," said Schief, "but you run into the problem that the envelope protein doesn't bind with any detectable affinity to the B cells needed to launch a broadly neutralizing antibody response."
To reliably initiate that VRC01-class antibody response, Schief and his colleagues therefore sought to develop a new method for designing vaccine immunogens.
From Weak to Strong
Joseph Jardine, a TSRI graduate student in the Schief laboratory, evaluated the genes of VRC01-producing B cells in order to deduce the identities of the less mature B cellsknown as germline B cellsfrom which they originate. Germline B cells are major targets of modern viral vaccines, because it is the initial stimulation of these B cells and their antibodies that leads to a long-term antibody response.
In response to vaccination, germline B cells could, in principle, mature into the desired VRC01-producing B cellsbut natural HIV proteins fail to bind or stimulate these germline B cells so they cannot get the process started. The team thus set out to design an artificial immunogen that would be successful at achieving this.
Jardine used a protein modeling software suite called Rosetta to improve the binding of VRC01 germline B cell antibodies to HIV's envelope protein. "We asked Rosetta to look for mutations on the side of the HIV envelope protein that would help it bind tightly to our germline antibodies," he said.
Rosetta identified dozens of mutations that could help improve binding to germline antibodies. Jardine then generated libraries that contained all possible combinations of beneficial mutations, resulting in millions of mutants, and screened them using techniques called yeast surface display and FACS. This combination of computational prediction and directed evolution successfully produced a few mutant envelope proteins with high affinity for germline VRC01-class antibodies.
Jardine then focused on making a minimal immunogenmuch smaller than HIV envelopeand so continued development using the "engineered outer domain (eOD)" previously developed by Po-Ssu Huang in the Schief lab while Schief was at the University of Washington. Several iterative rounds of design and selection using a panel of germline antibodies produced a final, optimized immunogena construct they called eOD-GT6.
A Closer Look
To get a better look at eOD-GT6 and its interaction with germline antibodies, the team turned to the laboratory of Ian A. Wilson, chair of the Department of Integrative Structural and Computational Biology and a member of the IAVI Neutralizing Antibody Center at TSRI.
Jean-Philippe Julien, a senior research associate in the Wilson laboratory, determined the 3D atomic structure of the designed immunogen using X-ray crystallographyand, in an unusual feat, also determined the crystal structure of a germline VRC01 antibody, plus the structure of the immunogen and antibody bound together.
"We wanted to know whether eOD-GT6 looked the way we anticipated and whether it bound to the antibody in the way that we predictedand in both cases the answer was 'yes'," said Julien. "We also were able to identify the key mutations that conferred its reactivity with germline VRC01 antibodies."
Mimicking a Virus
Vaccine researchers know that such an immunogen typically does better at stimulating an antibody response when it is presented not as a single copy but in a closely spaced cluster of multiple copies, and with only its antibody-binding end exposed. "We wanted it to look like a virus," said Sergey Menis, a visiting graduate student in the Schief laboratory.
Menis therefore devised a tiny virus-mimicking particle made from 60 copies of an obscure bacterial enzyme and coated it with 60 copies of eOD-GT6. The particle worked well at activating VRC01 germline B cells and even mature B cells in the lab dish, whereas single-copy eOD-GT6 did not.
"Essentially it's a self-assembling nanoparticle that presents the immunogen in a properly oriented way," Menis said. "We're hoping that this approach can be used not just for an HIV vaccine but for many other vaccines, too."
The next step for the eOD-GT6 immunogen project, said Schief, is to test its ability to stimulate an antibody response in lab animals that are themselves engineered to produce human germline antibodies. The difficulty with testing immunogens that target human germline antibodies is that animals typically used for vaccine testing cannot make those same antibodies. So the team is collaborating with other researchers who are engineering mice to produce human germline antibodies. After that, he hopes to learn how to drive the response, from the activation of the germline B cells all the way to the production of mature, broadly neutralizing VRC01-class antibodies, using a series of designed immunogens.
Schief also hopes they will be able to test their germline-targeting approach in humans sooner rather than later, noting "it will be really important to find out if this works in a human being."
###
The first authors of the paper, "Rational HIV immunogen design to target specific germline B cell receptors," were Jardine, Julien and Menis. Co-authors were Takayuki Ota and Devin Sok of the Nemazee and Burton laboratories at TSRI, respectively; Travis Nieusma of the Ward laboratory at TSRI; John Mathison of the Ulevitch laboratory at TSRI; Oleksandr Kalyuzhniy and Skye MacPherson, researchers in the Schief laboratory from IAVI and TSRI, respectively; Po-Ssu Huang and David Baker of the University of Washington, Seattle; Andrew McGuire and Leonidas Stamatatos of the Seattle Biomedical Research Institute; and TSRI principal investigators Andrew B. Ward, David Nemazee, Ian A. Wilson, and Dennis R. Burton, who is also head of the IAVI Neutralizing Center at TSRI.
The project was funded in part by IAVI; the National Institutes of Health (AI84817, AI081625 and AI33292); and the Ragon Institute.
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New vaccine-design approach targets HIV and other fast-mutating virusesPublic release date: 28-Mar-2013 [ | E-mail | Share ]
Contact: Mika Ono mikaono@scripps.edu 858-784-2052 Scripps Research Institute
LA JOLLA, CA March 28, 2013 A team led by scientists from The Scripps Research Institute (TSRI) and the International AIDS Vaccine Initiative (IAVI) has unveiled a new technique for vaccine design that could be particularly useful against HIV and other fast-changing viruses.
The report, which appears March 28, 2013, in Science Express, the early online edition of the journal Science, offers a step toward solving what has been one of the central problems of modern vaccine design: how to stimulate the immune system to produce the right kind of antibody response to protect against a wide range of viral strains. The researchers demonstrated their new technique by engineering an immunogen (substance that induces immunity) that has promise to reliably initiate an otherwise rare response effective against many types of HIV.
"We're hoping to test this immunogen soon in mice engineered to produce human antibodies, and eventually in humans," said team leader William R. Schief, who is an associate professor of immunology and member of the IAVI Neutralizing Antibody Center at TSRI.
Seeking a Better Way
For highly variable viruses such as HIV and influenza, vaccine researchers want to elicit antibodies that protect against most or all viral strainsnot just a few strains, as seasonal flu vaccines currently on the market. Vaccine researchers have identified several of these broadly neutralizing antibodies from long-term HIV-positive survivors, harvesting antibody-producing B cells from blood samples and then sifting through them to identify those that produce antibodies capable of neutralizing multiple strains of HIV. Such broadly neutralizing antibodies typically work by blocking crucial functional sites on a virus that are conserved among different strains despite high mutation elsewhere.
However, even with these powerful broadly neutralizing antibodies in hand, scientists need to find a way to elicit their production in the body through a vaccine. "For example, to elicit broadly neutralizing antibodies called VRC01-class antibodies that neutralize 90 percent of known HIV strains, you could try using the HIV envelope protein as your immunogen," said Schief, "but you run into the problem that the envelope protein doesn't bind with any detectable affinity to the B cells needed to launch a broadly neutralizing antibody response."
To reliably initiate that VRC01-class antibody response, Schief and his colleagues therefore sought to develop a new method for designing vaccine immunogens.
From Weak to Strong
Joseph Jardine, a TSRI graduate student in the Schief laboratory, evaluated the genes of VRC01-producing B cells in order to deduce the identities of the less mature B cellsknown as germline B cellsfrom which they originate. Germline B cells are major targets of modern viral vaccines, because it is the initial stimulation of these B cells and their antibodies that leads to a long-term antibody response.
In response to vaccination, germline B cells could, in principle, mature into the desired VRC01-producing B cellsbut natural HIV proteins fail to bind or stimulate these germline B cells so they cannot get the process started. The team thus set out to design an artificial immunogen that would be successful at achieving this.
Jardine used a protein modeling software suite called Rosetta to improve the binding of VRC01 germline B cell antibodies to HIV's envelope protein. "We asked Rosetta to look for mutations on the side of the HIV envelope protein that would help it bind tightly to our germline antibodies," he said.
Rosetta identified dozens of mutations that could help improve binding to germline antibodies. Jardine then generated libraries that contained all possible combinations of beneficial mutations, resulting in millions of mutants, and screened them using techniques called yeast surface display and FACS. This combination of computational prediction and directed evolution successfully produced a few mutant envelope proteins with high affinity for germline VRC01-class antibodies.
Jardine then focused on making a minimal immunogenmuch smaller than HIV envelopeand so continued development using the "engineered outer domain (eOD)" previously developed by Po-Ssu Huang in the Schief lab while Schief was at the University of Washington. Several iterative rounds of design and selection using a panel of germline antibodies produced a final, optimized immunogena construct they called eOD-GT6.
A Closer Look
To get a better look at eOD-GT6 and its interaction with germline antibodies, the team turned to the laboratory of Ian A. Wilson, chair of the Department of Integrative Structural and Computational Biology and a member of the IAVI Neutralizing Antibody Center at TSRI.
Jean-Philippe Julien, a senior research associate in the Wilson laboratory, determined the 3D atomic structure of the designed immunogen using X-ray crystallographyand, in an unusual feat, also determined the crystal structure of a germline VRC01 antibody, plus the structure of the immunogen and antibody bound together.
"We wanted to know whether eOD-GT6 looked the way we anticipated and whether it bound to the antibody in the way that we predictedand in both cases the answer was 'yes'," said Julien. "We also were able to identify the key mutations that conferred its reactivity with germline VRC01 antibodies."
Mimicking a Virus
Vaccine researchers know that such an immunogen typically does better at stimulating an antibody response when it is presented not as a single copy but in a closely spaced cluster of multiple copies, and with only its antibody-binding end exposed. "We wanted it to look like a virus," said Sergey Menis, a visiting graduate student in the Schief laboratory.
Menis therefore devised a tiny virus-mimicking particle made from 60 copies of an obscure bacterial enzyme and coated it with 60 copies of eOD-GT6. The particle worked well at activating VRC01 germline B cells and even mature B cells in the lab dish, whereas single-copy eOD-GT6 did not.
"Essentially it's a self-assembling nanoparticle that presents the immunogen in a properly oriented way," Menis said. "We're hoping that this approach can be used not just for an HIV vaccine but for many other vaccines, too."
The next step for the eOD-GT6 immunogen project, said Schief, is to test its ability to stimulate an antibody response in lab animals that are themselves engineered to produce human germline antibodies. The difficulty with testing immunogens that target human germline antibodies is that animals typically used for vaccine testing cannot make those same antibodies. So the team is collaborating with other researchers who are engineering mice to produce human germline antibodies. After that, he hopes to learn how to drive the response, from the activation of the germline B cells all the way to the production of mature, broadly neutralizing VRC01-class antibodies, using a series of designed immunogens.
Schief also hopes they will be able to test their germline-targeting approach in humans sooner rather than later, noting "it will be really important to find out if this works in a human being."
###
The first authors of the paper, "Rational HIV immunogen design to target specific germline B cell receptors," were Jardine, Julien and Menis. Co-authors were Takayuki Ota and Devin Sok of the Nemazee and Burton laboratories at TSRI, respectively; Travis Nieusma of the Ward laboratory at TSRI; John Mathison of the Ulevitch laboratory at TSRI; Oleksandr Kalyuzhniy and Skye MacPherson, researchers in the Schief laboratory from IAVI and TSRI, respectively; Po-Ssu Huang and David Baker of the University of Washington, Seattle; Andrew McGuire and Leonidas Stamatatos of the Seattle Biomedical Research Institute; and TSRI principal investigators Andrew B. Ward, David Nemazee, Ian A. Wilson, and Dennis R. Burton, who is also head of the IAVI Neutralizing Center at TSRI.
The project was funded in part by IAVI; the National Institutes of Health (AI84817, AI081625 and AI33292); and the Ragon Institute.
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Public release date: 28-Mar-2013
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