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text:
Daily Labor Report ®
Employees during a walkout at Activision Blizzard offices in Irvine, Calif., on July 28, 2021.
Photographer: Bing Guan/Bloomberg
Activision Investors Join Calls Seeking Tech Culture Change (1)
By Maeve Allsup
Aug. 6, 2021, 8:45 AM; Updated: Aug. 7, 2021, 12:45 AM
Securities suit says company hid California investigation
Future shareholder litigation could spur workplace changes
Activist shareholders, who have used litigation to force businesses to address issues of workplace discrimination and harassment, are eyeing a new target: the video game industry.
A federal securities fraud claim from an Activision Blizzard Inc. shareholder claimed the company kept investors in the dark about a California state investigation into its alleged "frat boy" culture. And on Friday, the video game giant was hit with a shareholder derivative suit filed in California state court, seeking changes to internal policies and practices.
The lawsuits are the latest challenge to the video-game giant. Lawyers and industry watchers said such suits could be an effective tool to address persistent questions about workplace culture at Activision and in the broader gaming world, as investors take notice of the financial and public relations fallout from toxic employment practices.
Other companies including Alphabet Inc., Pinterest Inc., and Victoria's Secret parent L Brands Inc., have faced lawsuits filed by shareholders over workplace culture and claims of harassment or bias.
"These shareholder suits are the ones that are really starting to change things in corporate America," said San Diego attorney Frank Bottini. "They can have incredibly important, concrete results and really be a catalyst for change at a company or in an industry."
Shareholder advocacy and engagement is "exploding these days," according to Michael Connor, executive director of the Open Media and Information Companies Initiative, a group focused on shareholder engagement and corporate accountability.
"There are much larger numbers of investors who are willing to both engage with the companies directly and certainly support shareholder proposals," he said.
Activision Lawsuits
The federal complaint filed on Aug. 3from the Activision investor alleges that after a lawsuit from the California Department of Fair Employment and Housing detailing claims of workplace harassment came to light on July 21, the company's stock price plunged, leading to a "precipitous decline in the market value."
The Friday derivative complaint alleges Activision Blizzard now has a reputation as a hostile work environment for women, and faces serious financial consequences and restrictions on its operations. It seeks to force the company to take actions to reform corporate governance and internal procedures.
Both complaints cite the California DFEH lawsuit, which followed an investigation that lasted over two years. That announcement sparked employee action, with Activision workers staging a walkout and over 2,000 current and former employees signing a petition supporting the agency suit.
Video game industry workers, similar to those in other industries, are often restricted from litigation and public statements by mandatory arbitration and non-disclosure agreements.
Former Activision Blizzard employees told Bloomberg Law those agreements, combined with a culture of secrecy around releasing new games, prevented employees from speaking out about alleged harassment.
That makes shareholder litigation important, Bottini said. Investors don't sign the same arbitration agreements or gag orders, and can step up and file lawsuits when employees can't, he added. But he cautioned that change through litigation can come slowly.
The stock-drop suit was filed the same day the company held its latest earnings call. Analysts questioned the company over the suits and the impact they would have on the company's productivity, product pipeline, and worker morale.
Jen Oneal, who was named one of the company's new "coleaders" after Blizzard President J. Allen Brack announced he was leaving the company, said she was seeing "great progress."
"There's a lot of work ahead of us but the passion and productivity are already here," said Oneal.
The company also hired law firm Wilmer Cutler Pickering Hale and Dorr to investigate its culture. Activision CEO Bobby Kotick told employees in a July 28 statement that the review would "ensure that we have and maintain best practices to promote a respectful and inclusive workplace."
Asked about the Aug. 3 investor suit, an Activision Blizzard spokesperson said the company engages with shareholders and works to be responsive to their "interests and concerns with respect to our executive compensation, corporate governance practices, human capital management, and any other matters of importance."
The company did not immediately respond to a request for comment on the derivative shareholder action.
Shareholder Pressure
Molly Bowen, an attorney at Cohen Milstein, said there are two primary tracks investors looking to force change can pursue in court. Securities fraud claims, such as the first suit against Blizzard, filed in federal court are ultimately aimed at recovering harm caused to investors by alleged misconduct, while shareholder derivative suits have the goal of remedying harm caused by leadership for the benefit of the company.
The derivative suit against Google parent Alphabet, which alleged executives failed to prevent sexual harassment, ended in a $310 million settlement and pledges by the company to address diversity and gender equality issues.
Courts have a high bar for such suits, Bottini said, requiring plaintiffs' lawyers to conduct a thorough investigation to be able to allege that company officers breached their duties. That process could involve requests for non-public company documents, such as emails or minutes from board of directors meetings, and can often include side litigation to force companies to comply with those requests.
"If you file a derivative case without getting those documents and doing an investigation, it's likely the case would be dismissed," said Bottini, who added that his firm, Bottini & Bottini, is also investigating a derivative suit..
New Precedent
Shareholder lawsuits seeking remedies related to workplace discrimination and harassment are relatively new, and the law in this area has moved quickly, Bowen said.
"Shareholders have a really important role to play in remedying these wrongs, but I don't know if that's how people thought about it even just eight years ago," she said.
Attorney Louise Renne, who has represented shareholders in similar litigation, called lawsuits focused on equity and diversity issues in the workplace a fairly new phenomenon, citing Alphabet's July 2020 settlement as a landmark moment.
Shareholders seeking changes in other companies should use that settlement as a template, Renne said.
As part of the settlement, Alphabet pledged to expand diversity efforts, and created an independent audit board to oversee issues of harassment.
Alphabet didn't respond to Bloomberg Law's request for comment.
In the case of L Brands, the company has a pending settlement to end shareholder lawsuits alleging a culture of sexual harassment. The settlement would see the company spend $90 million on workplace changes, including ending the use of non-disclosure agreements.
Pinterest is also facing shareholder derivative lawsuits that allege a culture of discrimination and bias against female executives.
Connor at Open MIC said shareholder suits could bring changes to workplace culture in the gaming industry.
"I don't think there's any question that there's more litigation coming," he said.
—With assistance from Paige Smith
(Updates throughout to add information about derivative suit filed Aug. 6.)
To contact the reporter on this story: Maeve Allsup in San Francisco at mallsup@bloomberglaw.com
To contact the editors responsible for this story: Meghashyam Mali at mmali@bloombergindustry.com; Andrew Childers at achilders@bloomberglaw.com
Maeve Allsup
Proposed Shareholder Class Action
California DFEH Complaint
Activision, Battling Workplace Controversy, Beats Estimates (1)
Aug. 3, 2021, 8:21 PM
Blizzard President Departs as Game Maker Faces Labor Lawsuit (5)
Activision Blizzard Hid Harassment Probe, Investor Suit Says (2)
Activision Hires Wilmer for Internal Probe as Workers Howl (1)
Activision 'Frat Boy' Suit Jolts Effort to Change Gaming Culture
Activision Blizzard Sued Over 'Frat Boy' Culture, Harassment (1)
Cohen Milstein
Bottini & Bottini
shareholder proposals
shareholder suits
employee morale
work slowdowns and stoppages
Activision Blizzard Inc
L Brands Inc

redpajama_set_name: RedPajamaCommonCrawl


text:
A lifelong love of flight inspires Japanese aviation engineer Jiro Horikoshi, whose storied career includes the creation of the A-6M World War II fighter plane.
Genre: Animation, Biography, Drama, History, Romance, War
Director: Hayao Miyazaki
Actors: Hideaki Anno, Hidetoshi Nishijima, Keiko Takeshita, Masahiko Nishimura, Miori Takimoto, Morio Kazama, Stephen Alpert
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A Shaun the Sheep Movie: Farmageddon
When an alien with amazing powers crash-lands near Mossy Bottom Farm, Shaun the Sheep goes on a mission to shepherd the intergalactic visitor home before a sinister organization can capture…
Country: Belgium, France, UK, USA
Genre: Adventure, Animation, Comedy, Family, Fantasy, Science Fiction
When the evil mayor of Oakton decides to bulldoze Liberty Park and build a dangerous amusement park in its place, Surly Squirrel and his ragtag group of animal friends need…
Lego Scooby-Doo!: Haunted Hollywood
Oooh Hollywood! The glitz, the glam…the Headless Horseman?! Join your favorite K-9 sleuth, Scooby-Doo, along with Shaggy and the Mystery Inc. gang as they find themselves in a tinsel-town twist!…
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Welcome to Hotel Transylvania, Dracula's lavish five-stake resort, where monsters and their families can live it up and no humans are allowed. One special weekend, Dracula has invited all his…
The Stolen Princess: Ruslan and Ludmila
This wonderful story happened in the age of valiant knights, beautiful princesses, and battling sorcerers. Ruslan, a wandering artist dreaming to become a knight, met beautiful Mila and fell in…
Genre: Animation, Comedy, Family, Fantasy
The Croods is a prehistoric comedy adventure that follows the world's first family as they embark on a journey of a lifetime when the cave that has always shielded them…
Genre: Action, Adventure, Animation, Comedy, Family, Fantasy
Red Shoes and the Seven Dwarfs
Princes who have been turned into Dwarfs seek the red shoes of a lady in order to break the spell, although it will not be easy.
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Madagascar 3: Europe's Most Wanted
Animal pals Alex, Marty, Melman, and Gloria are still trying to make it back to New York's Central Park Zoo. They are forced to take a detour to Europe to…
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Batman vs. Teenage Mutant Ninja Turtles
Batman, Batgirl and Robin forge an alliance with the Teenage Mutant Ninja Turtles to fight against the Turtles' sworn enemy, The Shredder, who has apparently teamed up with Ra's Al…
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Dory is reunited with her friends Nemo and Marlin in the search for answers about her past. What can she remember? Who are her parents? And where did she learn…
Scooby-Doo! and Kiss: Rock and Roll Mystery
Get ready to Rock! Scooby-Doo and the Mystery Inc. Gang team up with the one and only KISS in this all-new, out-of-this-world adventure! We join the Gang at Kiss World…
Genre: Animation, Comedy, Family, Music, Mystery, Science Fiction
Legend of the Guardians: The Owls of Ga'Hoole
Soren, a young barn owl, is kidnapped by owls of St. Aggie's, ostensibly an orphanage, where owlets are brainwashed into becoming soldiers. He and his new friends escape to the…
Genre: Action, Adventure, Animation, Family, Fantasy, Mystery, Thriller, War
Trailer: The Wind Rises


Tzoumaz, Valais is situated in the heart of preserved and generous natural surroundings for mountain holiday lovers with a wide range of family and sporty activities. Available are themed trails, mountain biking and scooting, tennis courts, swimming pool and play areas to enjoy during the summer sun. Also on offer are culture of the region, tasting of local products and the wealth of the alpine heritage.
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Smart inverters are key to building a flexible grid solution
By SPW | August 6, 2018
By Lior Handelsman, founder and VP of marketing and product strategy of SolarEdge
Our energy world is undergoing a radical transformation as we change the way we consume and generate energy. Renewables, including solar, while currently contributing only 2% of world electricity consumption, are becoming an increasingly larger portion of the energy equation making up 70% of new capacity in 2017. At the same time, a large number of traditional coal-based power plants are being retired which means renewables occupy a larger portion of the production capacity, rendering the grid less stable and predictable than when running on 24/7 fossil fuel consumption. As our energy generation is transitioning, so too are our consumption patterns as more people embrace the entrance of IoT devices, smart homes and electric vehicles. This means that the electric grid requires new flexible solutions to support this new era of energy generation and production. In order to implement a flexible grid, there are a number of factors that need to be considered.
Through the aforementioned transformation, overall energy generation based on solar energy will more closely follow the PV bell curve versus the duck curve which is solely based on energy demand. This will have a number of effects on how energy is managed at the macro level. Since solar energy is intermittent and consumption patterns differ from production patterns, the base load needs to instantly ramp up and down. Since this ramping up and down is particularly burdensome on the grid, there needs to be a means to shift demand and supply patterns so they are more aligned throughout the day. This is because some of the peak energy demand times are not at the same time as standard PV generation. It will be the role of distributed battery storage and water heaters to ensure that energy is available during the times it is most needed and used. Equally, consumption patterns will shift according to the time of PV production, thanks to smart energy management. This includes household loads and EV charging. Given the large diversity of different loads and distributed energy resources, any solution designed to support the grid will need to support a very diverse load mix in order to offer maximum flexibility.
Any deployed solution for grid management needs to offer affordable control configuration. Just as much of the world is moving from hardware-based control to cloud-based for cost savings, so too should any grid management tool. Hardware or on-premise solutions have many hidden costs beyond the original cost of the hardware itself, such as installation, maintenance, upgrades/replacements and additional data links. The main costs with cloud-based solutions are incurred from the initial licensing fees and any setup or integration charges. The cost-effectiveness of cloud-based solutions compared to local-control systems accelerates the adoption rate of new technology and improves its ROI, which will enable the grid to catch up to the new energy reality.
Inexpensive, available and reliable communication is an additional key requirement for any type of grid solution to be able to communicate and control all distributed energy resources (DERs) like solar PV systems, storage, EV chargers and more. The most common communication methods for DERs are ethernet and cellular network. The prices of both broadband and mobile data are declining while their coverage and reliability are improving. With this strong communication infrastructure in place, any grid solution should leverage these communication networks. Also key in terms of communication is the ability to communicate with a variety of different types of systems, interfaces and protocols. This type of interoperability is key for integrating PV, EVs, batteries, thermostats, sensors, switches, capacitors and water heaters into one control platform.
Just as machine learning, partial autonomy and artificial intelligence are becoming a larger part of our everyday lives, so too should they be integrated into energy control platforms. Advanced analytics and machine learning can help plan for more flexibility and increase predictability to enable PV generation and load forecasting. In addition, there are certain types of events that need a fast frequency response and require local autonomy or grid-edge computing. When controlled by platforms with partial autonomy, our grid can become increasingly efficient, flexible and smart.
While a distributed grid can offer more security, especially against a physical attack, it can also allow for additional access posts. This coupled with cloud-based systems requires a new level of cyber protection. Cyber security needs to be implemented at all levels — inverter, IoT, server and platform — in order to protect the grid. The flexibility of any given solution must not compromise its security.
There are already a number of flexible grid services solutions available in the market. However, many of these solutions are missing one of the key links between this high-level solution and its implementation — the solar inverter. The PV inverter should serve as the linchpin that connects all of the distributed energy resources with any grid platform. Smart inverters are well positioned to provide the required systematic flexibility, such as grid sensing, smart energy management, cellular/ethernet communications, and advanced computing and memory capabilities. With PV inverters being the link to a smarter grid, it is reasonable to assume that their progress will lead the evolution of the entire grid.
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To dream of being an alumni represents completion and a sense of pride or accomplishment. If you dream of being an alumni of a school that you did not attend in real life, then it indicates that you are dealing with past regrets. You are wondering how your life would be had you made different choices.


Informal full-length portrait of William D. Shepherd, involved in the Shepherd case, looking toward the camera, walking with an unidentified man on a wet sidewalk in front of a building in Chicago, Illinois, dark exposure. An elevated train track is visible in the background. Signs for the Hummel Light and Fixture Co. store and a cafeteria are visible in the background.


Lottery by title, character and design is a sport of chance, right? The answer is not as clear a yes as you would want o naturally think. This is simply because more than the years, some issues have been noticed and these issues can be called the character of lotteries that has developed over time. And what they give is to display a sample of how successful lottery numbers and how people who the winnings have played out. And there are some hanging similarities with all types of lotteries which has remained constant. Now this is not to say that they have or can be rigged but it would do the ardent lottery participant some good if they get to know these things and see if they can use them simply because it can improve there chances of successful the next lottery they get involved in.
The 1 who succeed may not always be pretty intelligent, however, he should be a person who is good at studying. If you want to succeed, do maintain in mind to have a condition of studying mind.
The economy has taken a toll on a large percentage of People in america. People have not only lost their work, their dream houses, their cars, their worldly positions, but their desires have also been shattered. So how do you remain good when you have lost everything?
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The History of a Movement, Part II: Raising the Stenciling Stakes
By Charles Komanoff
It's time for Part 2!
Amid the bloodiest year in Mayor de Blasio's Vision Zero, Streetsblog continues its seven-part series focusing on a key strand in the movement for livable safe streets, written by a central figure in that movement, Charles Komanoff. A former head of Transportation Alternatives, Komanoff 25 years ago launched a highly effective public awareness campaign calling out the daily carnage on New York City streets. Under the name "Right Of Way," his group brought the brutal reality of pedestrian and cyclist deaths to the public eye in the form of high-visibility street actions (including one arrest). Part I, which ran on Monday, opened in December 1996. This installment focuses on initial media coverage of the movement.
Photo: Peter Meitzler
Right Of Way's December 1996 street stenciling kicked off a monthly routine: Comb the papers for accounts of fatal crashes. Gather somewhere and affix precut two-inch stencil letters and numerals onto cardboard. Load up the bike trailer and pedal into the night. Spray, shoot, move on. Out by 8 p.m., home by 11.
The tempo quickened with the arrival of spring, as the stenciling surfaced in a few neighborhood papers. Most of us were publicity-shy, but not Harris Silver, who originated the stenciling idea and produced the image that became flatso. Harris reached out to Clyde Haberman, a New York Times newsman who disdained city cyclists, but seemed attuned to pedestrians' vulnerability to cars. Haberman profiled us in his April 25, 1997 column, Why the Streets Aren't Safe: The Drivers.
His piece led, fittingly, with our stenciling of Jie Zhang:
Jie Zhang's fate comes to mind because of a grim tribute that some pedestrian advocates paid her the other night at the site where she was hit. In orange paint, they sprayed the outline of a human body on the sidewalk, with her name, date of death and the words "killed by automobile" below.
Haberman continued:
That same night, these urban guerrillas on bikes went around Manhattan similarly marking the places where nine other people were killed by motorists. They have been on this campaign for several months. Their defacing of public property is illegal, but they justify it as answering to a higher call. While that may be debatable, it is hard to argue when they call New Yorkers on foot an embattled species.
Just as we wanted it. We were "urban guerrillas on bikes" but also "pedestrian advocates" acting on behalf of "New Yorkers on foot." The placement was perfect, too: leading the B section of the establishment organ that ignored pedestrian imperilment — except when the culprits were bicycle-riders.
A few weeks later, the driver of a long-haul commuter bus ran over an NYPD auxiliary lieutenant, a crash covered by the Times as Volunteer Killed on a Street She Protected. The crash, while tragic, had an element of providence: The deceased, Alberta Kenney, was neighbor and friend to Bette Dewing, kvetchmeister columnist for the Upper East Side paper, Our Town.
Memorial for Antonia Monge. Photo: Peter Meitzler
Cyclists had sparred with Dewing for years, branding her ragtag group, Pedestrians First, an antibike front that ignored killer drivers. After Kenney was killed, we routed our next memorial ride to First Avenue and 81st Street, where Dewing gamely held Kenney's stencil in place as we painted. Thus commenced Dewing's shift from foe to ally. We would stencil together again, in 2003 and 2014.
Then, in July, Rachel Fruchter, age 57, a living embodiment of intersectional health care as ob-gyn teacher, researcher, caregiver and advocate for underserved communities, was killed when a van driver, operating illegally in Prospect Park on a weekend morning, sped into her bicycle. The night photo of our memorial image, by stenciler Peter Meitzler, haunts me to this day.
Dr. Fruchter's death sparked a vigil in Prospect Park, where speakers angrily juxtaposed her lifetime of good deeds with the multitude of failings by NYPD and the Parks Department — car entitlement that allowed the van to be driven out of bounds and operated negligently. (My remarks were published later that year in the UK 'zine Bike Culture.) At another vigil a few days later, in City Hall Park, her adult son eloquently expressed his own fury.
Memorial for Rachel Fruchter. Photo: Peter Meitzler
We had the exhilarating sense that our stenciling project was beginning to evoke a movement confronting "traffic violence" as such. Drivers were privileged, unaccountable and deadly. We were fighting back.
When NY Post columnist Andrea Peyser attempted to make a cause célèbre from a delivery cyclist's fatal crash into a 68-year-old pedestrian on an Upper West Side sidewalk — the city's first deadly bike-ped collision in several years — one of our founding members, Michael Smith, composed a lacerating account of an eerily similar incident a few weeks later in which a motorist drove onto a sidewalk in East Meadow, Long Island, killing a 68-year-old cyclist.
And when Brooklyn Council Member Noach Dear vowed to block a proposed bike lane through his district, we not only lambasted his parochialism in a Daily News op-ed, Bikes Are Safe, It's Cars That Kill; we stenciled 15 memorials to pedestrians run over by drivers in his Borough Park redoubt. (Shortly after, we would learn that Dear's district had the most pedestrian fatalities of any Brooklyn council district.)
That Borough Park foray was made possible through our Freedom of Information Law request for state DMV crash reports of 1994-1997 pedestrian and cyclist fatalities in New York City. At $20 a pop, the nearly one thousand records would have cost us $20,000, but for the free service offered to elected officials. My Council member, Kathryn Freed, proffered the request on our behalf. (A later, supplemental request was tendered by then-Council Member Anthony Weiner, whose brother had been killed by a reckless driver outside Washington, DC.)
Within a month we had several boxes stuffed with 947 computer printouts. Each fatality was represented by a photocopy of its NYPD MV-104a "accident" report along with DMV's coded distillation indicating proximate cause and, for a minority of cases, legal outcomes. Amazed, we found ourselves with a treasure trove, one we could plumb to determine not just who was being "killed by automobile" in New York City, but how and why.
Come back on Friday for Part III of the series, which focuses on broadening the movement and the message beyond the base.
Filed Under: Carnage, Charles Komanoff, DOT, NYPD, Street Safety, Traffic Enforcement, Promoted
Viral Video of W. Va. Reporter Struck by Pick-Up Driver on Live TV Should be a Watershed Moment
History of a Movement, Part V: Things Fall Apart
By Charles Komanoff	| Dec 15, 2021
Today's installment focuses on how reality — and the system — fought back.
The History of a Movement, Postscript: Notes on This Series
Here's a final roundup of details from Charles Komanoff's provocative series on the early street safety movement.
The History of a Movement, Part VI: Remembrance and Hope
In this penultimate chapter, one former Right of Way volunteer says, "I was very fortunate to have had that experience — utterly convinced, beyond the least shadow of a doubt, that we were doing the right thing."
The History of a Movement, Part III: The Death of Dante Curry
"After marking a hundred streets with strangers' names and body outlines, we were making a memorial to someone with whom we had a tangible, almost intimate connection. A child." Our seven-part series continues...
The History of a Movement, Part IV: 'Killed By Automobile'
Today's episode focuses on never-before seen crash data that Charles Komanoff and his team compiled into the book, "Killed By Automobile."
The History of a Movement, Part I: Hazmat Suits and Street Memorials
By Charles Komanoff	| Dec 6, 2021
Today, as we confront the bloodiest year in Mayor de Blasio's Vision Zero, Streetsblog begins a seven-part series focusing on a key strand in the movement for livable safe streets, written by a central figure in that movement, Charles Komanoff.


Makeup Table With Lights - Round Outdoor Ottomans and Sofa. marvel bean bag chair. navy blue couch. 36 inch bathroom vanity.
Published at Sunday, December 30th 2018, 21:52:38 PM. Modern By Brechtje Arnold. Buying a sofa is a major investment, and there is no reason you shouldn't be able to enjoy what you buy. No one needs the frustration and shopper's regret that comes from a hasty and ill thought out purchase. A good salesperson will understand and help you find the one that is best suited to your needs.
Published at Sunday, December 30th 2018, 21:49:21 PM. Midcentury By Carlene Albrecht. Sofas are big, so where they´re placed can have a big impact on the traffic flow in the room. People should never have to awkwardly step around items in order to pass through a room. Nor should there be any tripping hazards. It's important to make sure that there are a couple of feet between the coffee table and sofa, and between the sofa and any chairs. Create a clear path so people can walk from one end of the room to the other without difficulty.
Published at Sunday, December 30th 2018, 21:49:17 PM. Industrial By Drika Baumann. One of the biggest furniture investments you´ll make is a sofa. Sofas cost a lot of money, they take up a lot of space, and they´re where you and your family will likely spend a lot of time. So make sure you know what you're doing before you go out and buy one. Check out these sofa do's and don't to make sure you get the best sofa for your investment.
Published at Sunday, December 30th 2018, 21:49:14 PM. Sofa By Edelmira Beck. If you'd like to recreate this look exactly, the paint used was Montana Colors' Greyhound Brown, but you could also use spray paint specially formulated for painting vinyl (pleather) and fabric. I know from experience that it works great. And if any of you do start spray painting your furniture, be sure to tell us all about it! Meri leaves us with these wise words of advice that apply to projects large and small: "Wear a mask when you spray paint."
Published at Sunday, December 30th 2018, 21:16:23 PM. Traditional By Edwige Becker. No codes to be found? If your couch-buying needs aren't urgent, consider waiting for a major sale. These events are often centered around major holidays or long weekends and can dramatically decrease the price you pay. Stores frequently hold smaller sales, too: once you've got all the details picked out, consider pausing your purchase and checking the site´s homepage on a daily basis. You may just find a fantastic deal.
Published at Sunday, December 30th 2018, 21:16:20 PM. Modern By Emma Frank. A queen size sleeper sofa can easily seat three, and can provide a comfortable bed for two people. It will measure approximately 84 inches wide and be about 90 inches long when the bed is opened up. If the sleeper is going to be used every night for sleeping, a full-size sleeper sofa is what you need even if you have a tiny space. An adult might find a twin-sized sleeper too small and restricting for everyday use, and, in a pinch, a full-size sleeper can even sleep two. But again if two people are going to use it regularly, the full sized sleeper might not be very comfortable or spacious enough.
Published at Sunday, December 30th 2018, 21:16:16 PM. Midcentury By Ferdinanda Berger. A coffee table should be chosen in a proper proportion for the size of the room and the sofa in front of which it stands. A large square room would look strange with a small, delicate oval glass-topped coffee table, just as a small room would be cramped with a large, heavy, dark-painted square coffee table.


As world leaders descend on the United Nations this weekend, former President Bill Clinton will be taking them to East Africa through virtual reality. Viewers with special goggles will be able to follow Clinton's travels in eight minutes.
Two days ago, I found myself facing Bill Clinton, listening to the former U.S. president talk passionately about the work he and his foundation, the Clinton Global Initiative, have been doing in Africa.
In a seven-minute movie, viewers with special goggles will be able to follow Clinton's travels. Footage was captured last spring with 360-degree cameras. What you see through the goggles changes as you move your head left, right and even up or down.
The goal of a virtual-reality film shown during the September annual meeting of the Clinton Global Initiative was to "drive collaborative action," according to Bryan Mochizuki, its director of marketing.
Does development need virtual reality?


Everyone is someone's child, even a serial killer. How did the relationships between the world's most notorious serial killers and their mothers turn them into psychopathic murderers? In this unnerving and shocking series each episode explores a different killer's disturbing childhood, their unnatural maternal relationships and the devastating impact of 'Mother'. Presented by crime journalist, Donal MacIntyre, Murderers & Their Mothers is the new series that explores the most infamous and abhorrent crimes of the twentieth century's serial killers, by stepping back to the childhoods that moulded these men.


text:
'''VOLTTRON platform™ messaging header name constants.'''

__author__ = 'Brandon Carpenter <brandon.carpenter@pnnl.gov>'
__copyright__ = 'Copyright (c) 2016, Battelle Memorial Institute'
__license__ = 'FreeBSD'

CONTENT_TYPE = type('ContentTypeStr', (str,),
                    {'JSON': 'application/json',
                     'PLAIN_TEXT': 'text/plain'})('Content-Type')

DATE = 'Date'

TIMESTAMP = 'TimeStamp'

FROM = 'From'
TO = 'To'

REQUESTER_ID = 'requesterID'
COOKIE = 'Cookie'

class Headers(dict):
    '''Case-insensitive dictionary for HTTP-like headers.'''

    class Key(str):
        def __new__(cls, value):
            string = str(value)
            obj = str.__new__(cls, string.lower())
            obj._orig = string
            return obj
        def __str__(self):
            return self._orig
        def __repr__(self):
            return repr(self._orig)

    def __init__(self, *args, **kwargs):
        Key = self.__class__.Key
        obj = super(Headers, self).__init__(((Key(key), value)
               for key, value in dict(*args, **kwargs).iteritems()))
    def __contains__(self, key):
        return super(Headers, self).__contains__(str(key).lower())
    def get(self, key, default=None):
        return super(Headers, self).get(str(key).lower(), default)
    def __getitem__(self, key):
        return super(Headers, self).__getitem__(str(key).lower())
    def __setitem__(self, key, value):
        super(Headers, self).__setitem__(self.__class__.Key(key), value)
    def __delitem__(self, key):
        super(Headers, self).__delitem__(str(key).lower())
    def copy(self):
        return Headers(super(Headers, self).copy())
    @property
    def dict(self):
        '''Return a dictionary with originally-cased keys.'''
        return {str(k): v for k, v in self.iteritems()}
    def setdefault(self, key, value):
        return super(Headers, self).setdefault(self.__class__.Key(key), value)
    def update(self, *args, **kwargs):
        Key = self.__class__.Key
        obj = super(Headers, self).update(((Key(key), value)
               for key, value in dict(*args, **kwargs).iteritems()))
    def __repr__(self):
        return '%s(%s)' % (self.__class__.__name__,
                           super(Headers, self).__repr__())

redpajama_set_name: RedPajamaGithub


J. S. Harris, C. Lin, W. Martin, F. Sugihwo, M. Larson, and B. Paldus, "Micromachined tunable optoelectronic devices for spectroscopic applications," in Advanced Semiconductor Lasers and Their Applications, L. Hollberg and R. Lang, eds., Vol. 31 of OSA Trends in Optics and Photonics (Optical Society of America, 1999), paper 130.
Micromachined tunable optoelectronic devices can be used to improve spectroscopic measurements. The standing wave enhancement effect in Fabry-Perot cavities can be used to increase sensitivity. The size and cost of semiconductor micromachined devices make them an attractive alternative to conventional tabletop spectroscopy setups. Recent advances in micromachined tunable optoelectronic devices and their application to spectroscopy are described.


When we published our previous two Fintech Influencers to Follow lists in 2017 and 2016, they were popular among influencers and anyone interested in innovative thinking in financial services.
With the publication of our 2018 list, some things feel different. Influencer outreach and engagement strategies are of interest to more individual leaders and businesses, and yet, the idea of the influencer list has come under some criticism, largely among the influencers themselves.
Below the list, you will find FAQs about influencer lists in general and how this list was compiled.
If influencer lists are useful, why do some people dislike them?
The idea of the influencer list has come under attack over the past year and there are some reasons that might explain this.
Influencer lists are no longer a novel concept. As more lists have appeared, there has been a decrease in their quality, many published primarily as click bait. There are also more people referencing (and perhaps, in some cases, even overplaying) their ranking on influencer lists as a bona fide credential, while others question the legitimacy of the predominantly quantitative social networking criteria used for most of these lists.
All of this has led to some public criticisms of influencer lists, notably JP Nicols' infographic and Ron Shevlin's [Fintech Influencers Lists Have Jumped the Shark], to name but two, as well as many private Twitter DM conversations.
To be fair, neither Nicols nor Shevlin fundamentally disagree with the concept of influencer ranking. Rather, they argue that influence is hard to measure and people tend to make too much of appearing and ranking on lists – with which I generally agree.
However, I think it's a mistake to dismiss influencer lists because of any of these arguments. I have written a previous defence of influencer lists and argued for why we should not throw the baby out with the bathwater.
It goes without saying (yet, I'm saying it) that influence is a far more complex and nuanced concept than something that can be reduced to social media follower counts and engagement statistics. Many real-world influencers are not online, or not as active online as others. And to a degree, in some cases a significant one, online visibility is about "gaming the system" successfully.
People who have cultivated good reputations with large online audiences have leveraged the online system to the benefit of their online visibility. They have attracted relatively larger numbers of followers or followers who themselves have large audiences, who read their content and share it with others. Their influence and reach are indeed focused online, and in some cases limited to the online sphere, but it's still a form of influence.
No. When influencer lists get published, every person on the list wants to see where they are ranked. While this is a natural, human response, it would be a mistake to conclude that ranking is the most important aspect of any list.
A good influencer list is a starting point for discovery and engagement. It has the advantage of limiting the universe of possible people to whom you should be paying attention to the hundred or so that may be of greatest value.
Event planners can find potential speakers for events.
Business leaders in fintech startups can network with other industry leaders.
Influencers themselves can increase their visibility, reach and influence by being recognized on a list.
Influencer outreach and engagement is, in my opinion, the antidote to declining organic reach in social networks. Try sharing a post or publishing an article on LinkedIn or Facebook and see how many views you get this year – far less than a year or two ago.
Of course, you can do more paid promotion and advertising as a way to attract attention online – that's precisely what the social networks want you to do. But, as powerful as paid media can be at the right time and in the right place, it is far better at winning clicks and eyeballs than hearts and minds. If you want engagement and influence, you need to work through the gatekeepers to your target audiences – the influencers.
As in previous years, this list was developed using a commercially available social media analytics tool (Little Bird, now part of Sprinklr) which offers a powerful engine for crunching large volumes of social media data. The software compiles a list of online influencers that frequently communicate on topics related to "fintech" and then looks at the inter-relationships among these accounts. The software scores influencers in a variety of ways, however this list is based on the "insider rank" which compiles a large list of people actively engaged in online discussions of fintech and ranks accounts based on the most followed insider. Obviously, using a different scoring criterion would results in a different ranking.
Pingback: Greetings! Check out a review about DeNet from our adviser Simon Сocking! It`s truly comprehensive!


text:
COVER STORY | IN THE NEWS | STAGE MATTERS
TALK OF THE TABLE | THE HUM | CALENDAR
A Life in the Theater
by WILLIAM S. KOWINSKI
In my sixth column (with hardly a negative word in the previous five) and after glowing notices of four shows, last week I wrote what I frankly dreaded: a negative review.
I wasn't bothered by the prospect of letters to the editor (though I recall none for the "positive" pieces). I had my say here, and others have theirs in the letters section. The dialogue is part of the point.
But I know how hard people work to create theater. I've been involved in it since my third grade class put on the first play I wrote. In fourth grade I had my first and only rep company, when I wrote scripts for my Cub Scout den, and we blew away the other dens and their knot-tying demonstrations for the Pack prize every month. I wrote, acted and directed in college, and I've seen my scripts produced occasionally since. I've been a dramaturge and otherwise involved as a participant or close observer of professional, college and community productions. I love the process. So I wasn't looking forward to the inevitable hurt feelings.
Besides, Charlie can say anything he wants about films in his column, but Steve Martin doesn't live here.
I also know that producers, directors and actors on the North Coast, as elsewhere, themselves make qualitative judgments, which can be quite harsh. They just don't often make them in public, and sign their names. Judgments are part of the process. Dealing with them is part of the job.
Some may feel that community theater should essentially be immune from criticism, but those theaters still charge admission and ask for contributions. Evaluation is a reasonable element, as it is for the artistic growth of the theaters themselves. Producers know that they are competing for audience with other entertainment, including available versions of the plays they're producing, just as theater artists learn from excellent productions, and are inspired by them.
As for my credentials, I offer this additional information: Like a lot of small town working class or lower-middle class kids, I didn't see live theater as a child, but I've since seen hundreds of plays in at least 15 different cities and towns, from the back of New York restaurants to Broadway, and from the Guthrie in Minneapolis to summer barn theater in central Pennsylvania, and at the Changing Scene in Denver, which was down an alley past a dumpster and an old washing machine.
That's in addition to plays at all North Coast venues in the past nine years. Although I've written on theater for three newspapers and several national magazines, most of the time nobody was paying me to go. These gigs did provide the opportunity to talk at length with Jason Robards Jr., August Wilson and many younger theater professionals.
But that doesn't mean I'm the expert, or I can't be wrong. Responses are individual. What I say doesn't prevent anyone from going to a show, nor should it deter anyone from feeling justified in enjoying it. But if I'm not honest, what's the point?
Other things being equal, I'd rather not write about something I don't like. That's not always possible, and in last week's case I felt strongly about the play itself. I've seen Shakespeare's plays at every level and every sort of venue they're performed, up to and including Kevin Kline as Hamlet, and Glenda Jackson as Lady Macbeth. I don't expect New York or regional theater gloss at a community theater. I am also dismayed by seeing a production there I'd expect to see in a high school, where the purpose is quite different.
I don't believe, as some do, that community theaters aren't capable of doing decent Shakespeare. But these plays probably require more time, attention and directed energies than other productions, and the best actors and directors in the community. The community deserves this. Great plays are great opportunities.
In my columns here so far, I've deliberately highlighted the particular pleasures of live performance, and of the process of creating it. My subtext has been that in addition to movies, music and other forms of art and entertainment, stage matters.
My hope is to encourage a thriving theater community. But healthy theater requires self-criticism and self-analysis, and ever-greater aspiration. My contribution is to add information and context, and describe my responses. All I'm finally doing is adding to the discussion, while providing something I hope is worth reading. I feel a responsibility to the community and to the participants, but also to my editors, readers and to the plays themselves, and the life and future of the theater. I try to balance those responsibilities.
Correction to a factual error in last week's column: The performance of As You Like It I attended last Friday was not its official opening night, which for this play was Thursday (whereas for the last NCRT production, the Thursday production I saw was apparently a preview, and Friday the official opening.) My response was so strong that it was unlikely to be changed by a more enthusiastic audience of families and friends, or another hour or two of misery. I might also point out that since I wrote about the production as a whole, I mentioned no names.
Comments? Write a letter!
© Copyright 2006, North Coast Journal, Inc.


Some of the pioneers who started or attended the first World's Championship were: Carroll Shelby, Tom Tierney, H. Allen Smith, Wick Fowler, Dave Witts, Bill Neale, Frank X. Tolbert, Father Duffy, Ormly Gumfudgin, and Bill Doner to name a few. It was a shoot-out between Wick Fowler and H. Allen Smith. There were three judges; Hallie Stilwell, Floyd Schneider and Dave Witts. Hallie voted for H. Allen, Floyd voted for Wick. Dave Witts, the self- proclaimed mayor of Terlingua and third judge, spat out both samples and declared his taste buds were ruined! He called it a draw and declared a moratorium for one year.
In a 4-quart pot, brown meat in oil or butter or in a blend of the two.
Simmer 2-3 hours with the lid on.


So on Sunday my family celebrated Thanksgiving. We shared a big turkey with some guests.
So many different dishes (thanks Eugenio for the turkey aha!) Everything to fill your stomach!
Yesterday I had a day off. My family decided to take Asli & I to the National Historic Park of Nova Scotia. It's called Kejimkujik. We learned about the First Nations and enjoyed the landscapes.
How to tell you that my eyes were shining?


text:
Spermophagus turanicus is een keversoort uit de familie bladkevers (Chrysomelidae). De wetenschappelijke naam van de soort werd in 1957 gepubliceerd door Lukjanovitsch & Ter-Minassian.

turanicus

redpajama_set_name: RedPajamaWikipedia


We offer designs for Quick Curb Appeal, Shady Gardens, Easy Edibles, Balcony Gardening and more for easy gardening solutions!
View our Annual Catalogue for featured plants as well as seasonal gardening tips, preserving natural resources and water gardening.
Get inspired! Let the custom designers at Sheridan Nurseries help you create a container garden masterpiece for any season or style.
View our brochure to learn simple tips and options for going green with your outdoor living and gardening.


text:
Who Was Dr. Gonstead?
5 Components of the Gonstead System
Gonstead Chiropractic
Corrective Exercises
Lifestyle Coaching
Carpal Tunnel Pain?
Carpal Tunnel Syndrome is a painful condition that happens when the median nerve in your wrist is compressed by swelling, often due to an underlying medical condition. It is one of the most common conditions affecting the nerves. Traditionally there were few options to deal with this problem and those available, such as surgery and medication, were invasive and expensive. Fortunately, chiropractors in South Milwaukee have success treating Carpal Tunnel Syndrome with a more conservative and gentle approach. If you are wondering whether your wrist pain is caused by Carpal Tunnel Syndrome, and want more details on the alternative treatments available from South Milwaukee chiropractors, then read on.
Carpal Tunnel in South Milwaukee
Carpal Tunnel Syndrome is usually accompanied by sensations of burning, pain, tingling, or swelling in the palm of the hands and extends into the first three fingers and the thumb. Occasionally people also report a feeling of swelling in the hand even when no swelling is present. Patients commonly experience weakness in the affected hand and have difficulty with picking up small objects. This condition can have a major impact on a person's lifestyle and in some sever cases, if left untreated, the damage to the median nerve can cause permanent loss of movement in the hand.
What is the Cause of Carpal Tunnel Syndrome?
The pain experienced with Carpal Tunnel Syndrome is a result of the swelling and misalignment of tissues and bone which then press on the nerve. Often there is an underlying problem. Some patients have had an obvious injury, a stress or break to the wrist, that causes the symptoms to develop.
The most common cause is related to occupations that involve the long term use of vibrating instruments and the repetitive use of the hands and wrist. At other times, this issue seems to develop out of nowhere. Metabolic disorders involving the pituitary and thyroid gland can be a contributing factor to the unexplained development of Carpal Tunnel Syndrome, as can pregnancy and obesity. More commonly, Carpal Tunnel Syndrome, that develops in one or both wrists without a clear cause, is the result of a nerve irritation stemming from the spine.
How is Carpal Tunnel Treated?
Traditionally, Carpal Tunnel treatment has been limited to decompression surgeries, physiotherapy, and prescription medicines. Due to the fact that these options often fail to deal with the underlying problem, they may only provide short-term relief and, at times, can prove completely ineffective. When left untreated, or when unsuccessfully treated, people are forced to adapt their lifestyles to accommodate this debilitating issue. This may include quitting one's job and needing help with basic everyday living.
Fortunately, many people in South Milwaukee are finding long-term relief from Carpal Tunnel Syndrome through chiropractic treatment. Chiropractic medicine is a non-invasive alternative that seeks out and deals with the underlying cause of Carpal Tunnel Syndrome. A chiropractor will perform an evaluation of your condition and formulate an individualized treatment plan that will work to correct nerve interference in the spine and restore you to an optimal state of health. If you are noticing any signs of Carpal Tunnel Syndrome do not hesitate to call our team at South Shore Family Chiropractic today for a consultation.
By Appointment 9:00am - 11:00am
South Shore Family Chiropractic
1113 College Avenue Suite A
South Milwaukee, WI 53172
TOP-NOTCH CARE
"South Shore Family Chiropractic has gotten me through some tough injuries while playing college athletics, and continues to help me live a pain free life!!"
-LINDSAY J
"I felt like someone really cared about my well being. I was just not a number. Thank you for the kindness everyone showed."
-MARGE O
GREAT CHIROPRACTOR
"I didn't feel rushed. Dr Scheuing took his time and asked a lot of questions to understand what my problems were. He explained everything he was going to do before he did them."
-DAWN E
You can follow South Shore Family Chiropractic on these social platforms.


text:
Q: Create a linked list from space separated input I am trying to make a linked list from space separated integer input.
Input:

*

*Number of nodes

*Space separated input

int main()
{
    int n;
    cout<<"Enter number of nodes";
    cin>>n;
    cout<<"\nEnter data"<<endl;
    int temp;
    lNode *head = NULL;
    while(cin>>temp)
    {
        CreateLinkedList(&head,temp);
    }
    PrintLinkedList(head);

    return 0;
}

Here I am not getting how to limit the user input to the number of nodes which he has given as first input. Is there any other way to get user input?

A: You can ask the input as a string:
string line;
getline(cin, line);

Then you can separate the entered numbers in the line using stringstream so you should include the sstream library (eg. #include <sstream>):
stringstream ss(line);
int number;

while(ss >> number) {
    ... do whatever you want to do with the number here ...
}

redpajama_set_name: RedPajamaStackExchange


text:
Getting a handle on liquids: automation solutions for drug discovery
23 December 2019 , By Helen Stewart-Miller and Thomas Hope , Winter 2019/20
Posted in Archive, Enabling Technologies | Tagged ADME / Tox, AI / data analytics / healthtech / informatics, Analysis, Assay development & optimisation, Assay development optimisation & technology, Automation / robotics, Business, Cellular & Molecular biology, Cellular assays, Drug development, Drug discovery, Enabling technologies, Gene Editing, Genomics, High Content Screening, High Throughput screening, Immunology, Lead discovery, Lead optimisation, Protein chemistry / Proteomics, Screening, Target validation, Toxicology
By Helen Stewart-Miller and Thomas Hope
The accurate and precise measurement of liquids and the transport of exact volumes between vessels, or from one instrument to another, are processes that constitute the very essence of research.
However, while this simple requirement for the meticulous handling of liquids has been ever-present in laboratories the world over, there has been dramatic evolution in the techniques and equipment used to perform such tasks, from the humble Pasteur pipette to today's automated liquid handling instruments. This article focuses on the latest developments in automated liquid handling for drug discovery, and the current trends that are shaping the industry, such as lowvolume handling and miniaturisation, before looking ahead to the next steps that will lead to tomorrow's breakthroughs.
The need for high accuracy and high throughput in the search for new drug candidates has driven the development from manual methods towards automated liquid handling. Automation provides the throughput and consistency required to screen huge numbers of samples as rapidly as possible, leaving human hands free for less repetitive and more creative tasks, such as designing experiments and data analysis.
"Automated liquid handling addresses a multitude of high-throughput screening (HTS) challenges," said Kevin Truempi, Product Manager of Automation Solutions at Agilent. "There is an ever-growing demand to screen and collect more data over multiple timepoints, vastly increasing the sample count for processing and analysis. Automated liquid handling systems are crucial for generating reproducible data at high throughput for improved downstream analysis."
When implemented correctly, automation is unsurpassable in terms of its ability to increase throughput capacity compared to what is possible by hand. By shortening screening time and improving the reliability and reproducibility of data, decisions can be made more quickly and with greater confidence, which can ultimately lead to significant cost savings. As Carola Schmidt, Global Director of Automated Solutions, Applied Genomics at PerkinElmer, explained: "Standardisation of drug discovery workflows by automating the liquid handling processes offers the highest return on investment in terms of the reduction of human error and accuracy improvement."
The challenge for automated liquid handling in drug discovery is adapting to complex, physiologically- relevant assays. It is the systems that address this specific need that have the potential to deliver the most significant reductions in costs and timelines while enabling drug discovery companies to explore a much broader part of the available chemical space. "Libraries of millions of compounds in buffer solutions are required for screening. Utilising automation to prepare these samples quickly and accurately allows scientists to optimise their results, as well as their time," said Harry Forsyth, Regional Sales Manager at Analytik Jena. This speeds up hit generation and hit-to-lead processes, which in turn increases the probability of generating promising clinical candidates.
The evolution of automation in drug discovery
Automation has been a part of drug discovery for decades, but recent years have seen major advances in liquid handling technologies. One notable trend has been that instrument manufacturers are continuously striving to achieve more with less, bringing about benefits in terms of affordability. Today, even laboratories with relatively small budgets can purchase equipment capable of performing tasks that were once the preserve of much larger and more expensive systems. "Systems are generally smaller in footprint and easier to use," noted Joby Jenkins, Director of Product Strategy at SPT Labtech, "and as a result, companies of all sizes can reap the benefits of automation without the need for huge financial and infrastructure investments."
This drive for optimisation has also led to the design of instruments with greater flexibility to suit a broader range of applications, ensuring a rapid return on investment. "The use of automated liquid handling systems now goes well beyond HTS," commented Dr Rémi Magnan, Associate Director of Cellomics and Proteomics at Tecan. "Instruments are now providing solutions for compound management, assay development and ADME-Tox (Absorption, Distribution, Metabolism, Excretion and Toxicity) studies and immunogenicity screens." Liquid handling solutions are also addressing the increasing number of cell-based assays, phenotypic screens and functional genomics/CRISPR screens to identify a better quality of hit from a physiologically-relevant test system.
Software is another area undergoing unprecedented change. Previously, engineers with specialist knowledge were required to program most of the earliest examples of automated liquid handling instruments. Today, instruments are equipped with intuitive, user-friendly interfaces, enabling laboratory personnel to carry out programming tasks, without the need for expertise in coding or robotics.
Factors to consider when implementing automated liquid handling
As the automation of liquid handling expands to cover every aspect of drug discovery, the range of available instrumentation is also growing, with systems to suit every application, laboratory space and budget. Identifying the right automated liquid handling instrument for a specific screening strategy can, therefore, feel like a daunting task. However, the process can be simplified by first considering three key factors, namely: reliability, media viscosity and software.
"The importance of reliability cannot be underestimated, not only of the instrument hardware itself, but also its fundamental dispensing mechanism. Both can be overlooked by end-users who are influenced by throughput, volume range, or price," said Joby Jenkins at SPT Labtech. "Automated liquid handlers must deliver day-in, day-out and guarantee as much up time as possible. Furthermore, as volumes will inevitably decrease to reduce cost and increase throughput, the reliability of low-volume dispensing across a variety of liquid types becomes ever more critical to avoid compromising data integrity."
Fortunately, instrument manufacturers have made great strides in this regard in recent years, but it is important that potential buyers check the availability and responsiveness of the product support offered by suppliers, along with the general maintenance requirements of instruments.
For PerkinElmer's Carola Schmidt, one of the most important issues pertains to media viscosity: "Different media have different viscosities. If not accounted for, viscosity variation can reduce pipetting accuracy. Every time a medium is incorporated into an HTS workflow, pipetting accuracy should be validated. Without validation, the actual media volumes pipetted can be inexact, leading to unreliable results. Such inaccuracies can easily harm an institution's scientific reputation."
The third factor that is vital to the successful implementation of an automated liquid handling system is software, which needs to be sufficiently user-friendly to enable the novice user to perform basic operations, while still allowing those with the expertise to access more advanced features and tools. "Most HTS systems need automated liquid handlers to be fully integrated with multiple devices, such as acoustic dispensers, high-content imagers and readers. This can make data tracking and structuring throughout the whole workflow a major challenge. There is, therefore, a growing need for software infrastructure that can assist users with data handling to facilitate data exploration," noted Dr Rémi Magnan at Tecan.
The miniaturisation of HTS workflows
Miniaturisation is one of the main current trends in drug discovery. Harry Forsyth at Analytik Jena explained: "Lab space is at a premium in today's environment, with the cost per square foot increasing rapidly every year, especially in the major technology hubs. This means that scientists are searching for instrumentation that provides optimal performance but takes up the smallest possible amount of space. Our FeliX liquid handling platform is designed to address this need, providing an excellent solution for researchers looking to optimise their laboratory space. In addition, the FeliX system is open and modular, so it can be combined with multiple systems, robotic arms, stackers, hotels and many other components, creating an HTS solution tailored specifically to our customers' needs."
An additional benefit of miniaturisation for HTS workflows is that it allows laboratories to increase their throughput (ultra HTS), productivity and efficiency. More samples can be processed within the same footprint while requiring less samples and lower reagent volumes. "Cost savings are realised through the reduction in the volume of reagents needed in the workflow," commented Carola Schmidt. This is a particularly important issue because the reagents that are increasingly used in drug discovery are becoming more expensive and are often only available in very limited amounts. Without miniaturisation, the large-scale screening of these precious reagents may simply be impossible. But reducing the demand of these reagents is not the only benefit here. "Miniaturisation also reduces the amount of biohazard and plastic waste, which has significant environmental benefits, as well as cost savings," added Schmidt.
Overcoming new challenges with miniaturisation
The drive for miniaturisation brings new challenges for liquid handling, and instrument manufacturers are adopting a variety of approaches to solve the issues. The first of these is achieving consistent and precise liquid handling with volumes in the nanolitre range or lower, which presents difficulties such as overcoming static forces that can prevent proper dispensing into recipient wells.
"There are several products designed to address the issue of precise liquid handling at low volumes," commented Kevin Truempi at Agilent. "Our Agilent Bravo is a screening workhorse that delivers precise liquid handling for 96- to 1536-well plates. The instrument is equipped with positive displacement syringes for very precise pipetting. Furthermore, the software controlling the robot includes a state-of-the-art scheduler that enables timed incubations to be carried out, which are a requirement for many screening assays today."
Tecan has tackled the handling of very low volumes by harnessing HP's proven thermal inkjet technology to dispense precise volumes of liquids. "Tecan's D300e Digital Dispenser can dispense volumes as low as 11pL and up to 10μL directly from the stock solution into the assay plate. The dead volume can be as low as 2μL, which is especially important when compounds are only available in small quantities. The main application of the D300e is for assay development and target validation, where high flexibility and easy operation with little programming are paramount," explained Dr Rémi Magnan.
Analytik Jena manufactures liquid handling systems with a proven tip sealing technology that enables users to perform high precision HTS with volumes in the sub-microliter range. "Our tip sealing technology works by applying a uniform pressure that partially embeds the top of each tip into a silicone mat, making an airtight seal. This also ensures uniform tip length for enhanced pipetting performance and liquid transfers into dry or highdensity microplates," said Harry Forsyth at Analytik Jena.
In short, many of the challenges of low-volume automated liquid handling come down to reliability – for HTS results to be valid, the accuracy and repeatability of dispensing are essential. For example, an error of +/-200nL can be fairly insignificant (1%) in a 20μL dispense. However, for a 1μL dispense, a volumetric error of the same magnitude translates into a huge 20% error. "Add to this the need to handle more challenging reagents as assays get ever more complex, and it becomes difficult for liquid handlers to perform at the levels required by screeners to give robust data," said Joby Jenkins at SPT Labtech.
SPT Labtech addresses this issue of low volume dispense reliability with direct piston-driven positive displacement technology. This approach eliminates the reliance on valves, pumps, pressure, air and system liquid displacement to provide highly reliable and accurate dispensing, irrespective of liquid viscosity, surface tension or environmental conditions.
Advancing tomorrow's HTS workflows
While miniaturisation and low-volume handling are the dominant trends today, given the rapid advance of technology, manufacturers must ensure their instruments have the flexibility to adapt to ever-changing requirements. For example, PerkinElmer has identified the need for increased standardisation, a development that will become ever more important as the prevalence of collaborative multicentre studies continues to grow. Although these diffuse networks play a vital role in advancing drug discovery research, they can present difficulties due to laboratory-specific differences in workflows.
"The incorporation of automated liquid handlers into HTS workflows dramatically improves lab standardisation with automated sample tracking and Laboratory Information Management Systems (LIMS) integration. PerkinElmer's liquid handling workstations facilitate sample tracking by incorporating automated barcode scanning into every step of sample processing. Samples are placed into a PerkinElmer automation solution where they are scanned by the barcode reader, which communicates with the LIMS and then processed according to predefined work orders, allowing labs to import data into management systems easily," commented PerkinElmer's Carola Schmidt.
In a similar vein, Agilent offers automated plate barcode labelling and sealing with its BenchCel Workstations. "All our automation products can be interfaced with LIMS and can output pre-configured email user notifications, tracking sample and progress to minimise manual entries and idle time," noted Kevin Truempi at Agilent.
There is a growing tendency for HTS workflows to include more and more integration of thirdparty devices. For such systems to operate effectively, good communication between these devices and the liquid handler is vital. Tecan's latest generation liquid handler, Fluent®, has been designed to provide a high degree of flexibility to accommodate the integration of a broad range of third-party devices. Tecan's specialty integration solution, Labwerx™, allows users to integrate a number of modules and devices with the automated liquid handler, allowing complex customised systems to be built to accommodate the needs of modern HTS workflows.
The ever-increasing complexity of screening assays in the drug discovery field has started to shift the focus away from speed-based performance towards data integrity and system-based flexibility. "The ordering and timing of reagent additions and general volumetric performance are critical for more involved assays, and therefore the deployment of more sophisticated liquid handling technologies will become prevalent. To address these issues, SPT Labtech's dragonfly® discovery is not only equipped with positive displacement dispensing technology but also several onboard timing- management features for time-course reagent additions, as well as per-plate incubation steps, providing tighter control without the reliance on robotic integration schedulers," said Joby Jenkins at SPT Labtech.
"Our vision is for a liquid handling technology to be used right the way through the drug discovery process – from assay development and validation through to HTS and into the lead optimisation stages – eliminating transition pain points and ensuring that screening data is as robust as possible. This was not an option with earlier instrumentation, but the next generation of low-volume liquid handlers, such as dragonfly® discovery, are enabling users to realise this vision," added Jenkins.
Commercially-available automated liquid handling systems
The latest advances in automated liquid handling systems are driving ever-greater precision in lowvolume liquid handling and expediting HTS workflows for drug discovery.
Summarised below are some of the most innovative systems available on the market today:
Agilent Bravo automated liquid handling platform:
Agilent's Bravo is a highly-flexible automated liquid handling system that fits easily on a small benchtop or within a laminar flow hood. Positive displacement syringes allow for ultra-precise pipetting of volumes ranging from 300nL to 250μL in 96-, 384- and 1536-well microplates. Extensive protocol optimisation is possible with the platform's ability to pick up tips using a single barrel, row, column or array of barrels. The Bravo platform is designed for user-friendly interaction, which facilitates rapid and intuitive creation of automated assay protocols.
Complementing the Bravo Platform is Agilent's BenchCel Workstation, a compact, automated microplate handler to facilitate more efficient barcode labelling, sealing and centrifugation. The workstation boasts a rapid eight-second stack-toinstrument transfer time and can handle up to 60 standard SBS microplates per rack for expedited microplate set-up and management (Figure 1).
Analytik Jena CyBio FeliX:
Analytic Jena's CyBio FeliX is a fully-automatic, multi-channel pipetting system designed to optimise liquid handling protocols. With the system's unique compact design featuring 12 positions across two platforms, the
CyBio Felix offers functionality with a minimised laboratory footprint. Easily exchangeable pipetting heads and automatic liquid handling adapterchanging capabilities provide users with a highly flexible pipetting solution, and the modular design allows for easy integration with other automation systems for a complete and optimised HTS workflow (Figure 2).
PerkinElmer JANUS® G3, Sciclone® G3 and Zephyr® G3 liquid handling workstations:
Perkin-Elmer offers a comprehensive range of automated liquid handling solutions across the JANUS® G3, Sciclone® G3 and Zephyr® G3 workstation series. PerkinElmer's liquid handlers are both modular and scalable and can be modified from benchtop liquid handlers to fully-automated explorer™ G3 workstations by integrating them with other workflow components. This allows PerkinElmer to deliver flexibility in throughput, capacity and dynamic volume range, allowing customers to move from benchtop solutions to fully-automated workflow solutions as their needs change.
The JANUS® G3 series provides a selection of deck sizes and pipetting arms for flexible sample preparation. The workstation can accurately dispense volumes from 0.5μL to 5,000μL, with further customisation possible via a range of workstation accessories.
PerkinElmer's Sciclone® G3 workstation is another highly-flexible liquid handling solution, with open-deck architecture for easy incorporation of additional components and compatibility with bulk reagent modules, an on-deck microplate shaker and more.
Meanwhile, the Zephyr® G3 workstation provides a compact automated liquid handling solution ideal for the workbench. Accessible from all sides, the system allows for rapid replacement of consumables and easy reconfiguration of accessory components (Figure 3).
Tecan D300e Digital Dispenser, Fluent® and Labwerx™:
Tecan is driving assay miniaturisation with the D300e Digital Dispenser. Based on the proven thermal inkjet technology from HP Inc, it can dispense volumes from 11pL to 10μL directly from the stock solution into the assay plate. The dead volume can be as low as 2μL, helping to preserve limited supplies of reagents. The intuitive D300eControl software expedites experiment setup with the ability to copy and paste existing plate layouts directly from Microsoft Excel, and it is capable of using SLAS/ANSI format 12-1536-well plates, allowing for easy transfer of manual 96- well assays into higher density plate formats.
Tecan's latest liquid handler, Fluent®, has been built for flexibility with a modular, open design for easy configuration of each component. The system can rapidly change between 96- and 384-channel formats, and the Flexible Channel Arm™ offers a choice of air- or liquid-displacement technology. The arm can accommodate either fixed or disposable tips to accurately dispense volumes from <500nL to >5mL. In addition, Tecan Labwerx™ creates reliable customised end-to-end solutions to address laboratories' ever-changing needs (Figure 4).
SPT Labtech dragonfly® discovery automated liquid handler: SPT Labtech's newest liquid handling platform, the dragonfly® discovery, has been designed to reduce assay development time and greatly improve HTS efficiency, as well as enabling hit-to-lead and lead optimisation workflows. The easy-to-use system boasts precise non-contact dispensing across a broad dynamic range (200nL to 4mL) from up to 10 independently-controlled positive displacement disposable tips. The system also features a highly visual and easy-to-use software with in-built time-management features for automation of time point experiments, meaning tighter control and maximised walk-away time (Figure 5).
The latest advances offered by current automated liquid handling systems are benefiting a broad range of drug discovery applications, while continued enhancements are driving improvements in the precision, accuracy, speed and repeatability of workflows. In turn, these developments will have a significant impact on reducing assay development and transition to HTS times, helping to deliver dramatic reductions in drug discovery timescales. DDW
This article originally featured in the DDW Winter 2019/20 issue
Tecan's D300e dispenser as well as customised versions of Fluent® are for research use only and might not be available in your country.
Helen Stewart-Miller is Director of PR Services and Thomas Hope is a PR Account Executive at BioStrata, a life science specialist marketing agency. The company's growing team in Cambridge (UK) and Boston (US) includes a significant number of people with deep scientific experience and knowledge. The agency offers a range of services from strategy, branding and message development through to content creation, creative design, digital marketing and public relations.
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