May 23, 2013 ? A new tension gauge tether (TGT) laboratory method developed at the University of Illinois at Urbana-Champaign has broad applications for research into stem cells, cancer, infectious disease, and immunology.
Cells in the human body do not function in isolation. Living cells rely on communication with their environment -- neighboring cells and the surrounding matrix -- to activate a wide range of cellular functions, including reproduction of new cells, differentiation of stem cells into distinct cell types, cell adhesion, and migration of white blood cells to fight bodily infections. This cellular communication occurs on the molecular level and it is reciprocal: a cell receives cues from and also transmits function-activating cues to its neighbors.
The mechanics of this type of cellular interaction have been studied extensively: receptors extending through the cell membrane are activated when they form a bond to specific molecules. Now for the first time, University of Illinois biophysicists at the Center for the Physics of Living Cells and the Institute for Genomic Biology have measured the molecular force required to mechanically transmit function-regulating signals within a cell.
The new laboratory method, named the tension gauge tether (TGT) approach, developed by Taekjip Ha with postdoctoral researcher Xuefeng Wang, and reported in the May 24, 2013, issue of the journal Science, has made it possible to detect and measure the mechanics of the single-molecule interaction by which human cell receptors are activated. The researchers used integrin, a cell membrane receptor protein that is activated when it bonds to a ligand molecule.
In the TGT approach, Ha and Wang repurposed DNA strands, using them as tethers for ligand molecules, to test the tension required to activate cell adhesion through integrin. The integrin bonds to the tethered ligand, and adhesion is activated only if the DNA tether does not rupture.
Taking advantage of the geometric characteristics of DNA's double helix form, the researchers were able to tune the strands to rupture at discrete tension levels: by varying the attachment points along the DNA strands, the force required for rupture was either low (unzipping the helix), high (shearing the strands), or intermediary (combination of unzipping and shearing).
"If you went fishing and a fish broke your 30-lb fishing line but not the 40-lb one, you would know that its strength was in the range of 30?-40 pounds," explained Wang. "Here we applied the same strategy to measure the molecular tension applied by cells (the fish). Mammalian cells apply a force to activate cell membrane proteins called integrins which mediate cell adhesion. We immobilized ligand molecules (the bait) on a surface through molecular tethers (the fishing line) with defined tension tolerances, tunable from 10 pico Newton (pN) to 60 pN). After integrin-ligand binding, cells apply a force on the bonds, and we compare this force to the molecular tether strength by observing cell adhesion status."
Since single-molecule interactions are difficult to monitor, the researchers observed the receptor-regulated cellular function, to gauge whether the integrin was activated. Ha and Wang discovered that integrin experiences a well-defined "quantum of force," about 40 pico-Newton (pN), to activate cell's adhesion to a surface.
"We observed that mammalian cells adhere on the culture surface with 43 pN tension tolerance of ligands, but not on 33 pN surface. Therefore we deduced that single molecular tension is around 40 pN on integrin cell-membrane receptors during cell adhesion," Wang added.
"This is a very exciting result," commented Ha, an Edward William and Jane Marr Gutgsell Endowed Professor at Illinois. "With the ability to define the single molecular forces required to make living cells behave as desired, we may be one step closer to a remedy for certain hard-to-cure diseases. We know that the behavior of cancer cells and stem cells can be controlled by how stiff or soft their environments are. Understanding and manipulating molecular conversation through defined forces has huge implications for the development of future medical interventions. We expect the TGT approach will have broad applications in laboratory studies of cell differentiation, cancer metastasis, as well as immunology and infectious disease."
This research was funded by the National Science Foundation through the Physics Frontiers Center Program (0822613). In addition to his appointment at the University of Illinois, Taekjip Ha is an investigator with the Howard Hughes Medical Institute.
May 23, 2013 ? Even while being dragged to its destruction inside a cell, a cancer-promoting growth factor receptor fires away, sending signals that thwart the development of tumor-suppressing microRNAs (miRNAs) before it's dissolved, researchers reported in an early online publication at Nature.
Under conditions of oxygen starvation often encountered by tumors, the epidermal growth factor receptor (EGFR) gums up the cell's miRNA-processing machinery, an international team led by scientists at The University of Texas MD Anderson Cancer Center discovered.
"So when hypoxia stresses a cell, signaling by EGFR prevents immature miRNAs from growing up to fight cancer," said senior author Mien-Chie Hung, Ph.D., professor and chair of MD Anderson's Department of Molecular and Cellular Oncology and holder of the Ruth Legett Jones Distinguished Chair.
The group's findings point to a potential new prognostic marker for breast cancer, Hung noted, but also provide the first evidence of a growth factor signaling pathway regulating miRNA maturation.
"Inside of a cell, you have signal induction, in this case through EGFR, and you also have a protein complex that processes precursors into mature miRNA to perform a function. They didn't appear to talk to each other, it's as if one speaks English and the other Chinese," Hung said. "This is the first paper to show how they communicate."
The scientists established the relationship in cell line experiments, confirmed it in a mouse model and human breast cancer samples, then found that it reduced breast cancer patient survival in a review of 125 cases.
A new cancer-promoting role identified for EGFR
EGFR penetrates the cell membrane to receive signals from growth factors outside of the cell. After a growth factor binds to it, EGFR conveys the signal into the cell by attaching phosphate groups to other proteins, often acting as a molecular "on switch."
In many cancers, EGFR is overexpressed or dysfunctional, constantly sending signals to cells to divide. Hung and colleagues found that EGFR also fuels cancer progression by stifling tumor-suppressing miRNAs.
As a tumor grows, large portions of its interior can become starved for oxygen (hypoxia) for lack of adequate blood vessels. This stress suffocates many tumor cells, but the few that endure become highly malignant, resist treatment and are most likely to spread, Hung said.
Anti-angiogenesis drugs designed to kill tumors by blocking their ability to spin webs of supportive blood vessels often succeed at first, Hung said, but then fail against the more malignant cells that survive hypoxia.
When hypoxia hits, EGFR gets active and gets eaten
Low-oxygen conditions cause EGFR overexpression. EGFR also is pulled into the cell interior, captured in cavities called vesicles and eventually fed into lysosomes, a membrane-enclosed organelle loaded with enzymes to dissolve proteins.
It was known that EGFR continues to signal even while caught in the vesicles, which actually prolongs its activation. Hung and colleagues found that EGFR signals to a key protein in miRNA processing called argonaute 2, or AGO2.
AGO2 connects with two other proteins called Dicer and TRBP to form a complex that processes microRNA precursors into mature miRNAs, which regulate gene expression after messenger RNA has been expressed but before it's translated into a protein.
Oncoprotein-regulating miRNAs don't grow up
The scientists found that EGFR attaches phosphate groups to AGO2, which in turn weakens AGO2's ability to connect with Dicer to produce mature microRNAs. EGFR's effect is stronger during oxygen starvation than under normal conditions.
The team identified a number of specific miRNAs affected by EGFR, most of which have been reported to have tumor suppressor characteristics. The miRNAs regulated by phosphorylated AGO2, including miR-31, miR-192 and miR-193a-5p, also shared a long-loop structure in their precursors that miRNAs unaffected by AGO2 phosphorylation lack.
Hypoxic environments around tumors promote metastasis by helping cells evade programmed cell death. Hung and colleagues showed that EGFR-mediated AGO2 phosphorylation blocks cell death and enhances invasiveness under hypoxia.
Experiments in a mouse model of breast cancer confirmed that expression of EGFR and the presence of phosphorylated AGO2 increase during tumor progression under oxygen-starved conditions.
EGFR-AGO2 connection found in human breast tumors; reduces survival
The hypoxia-EGFR-AGO2 connection was strong in tumor samples from 128 breast cancer patients, but it was low or absent in normal breast tissue. In 125 breast cancer cases analyzed by the team, half of 62 patients with high levels of phosphorylated AGO2 survived to 48 months and beyond. Median survival had not been reached for the 63 patients in the low-level group, but 78 percent had survived to 48 months.
"One can imagine other receptors for platelet-derived growth factor and insulin-like growth factor also regulating miRNAs, perhaps by regulating Dicer or TBRP," Hung said. "This is a turning-point paper; it will induce lots of new questions for scientists to pursue."
[unable to retrieve full-text content]Some populations of roaches have evolved a highly effective strategy to avoid sweet-tasting poison baits, researchers say.
Contact: Marcus Neitzert marcus.neitzert@dzne.de 49-228-433-02271 Helmholtz Association of German Research Centres
A new animal model gives insights into mechanisms of Parkinson's disease pathogenesis
This news release is available in German.
In Parkinson's disease, the protein "alpha-synuclein" aggregates and accumulates within neurons. Specific areas of the brain become progressively affected as the disease develops and advances. The mechanism underlying this pathological progression is poorly understood but could result from spreading of the protein (or abnormal forms of it) along nerve projections connecting lower to upper brain regions. Scientists at the German Center for Neurodegenerative Diseases (DZNE) in Bonn have developed a novel experimental model that reproduces for the first time this pattern of alpha-synuclein brain spreading and provides important clues on the mechanisms underlying this pathological process. They triggered the production of human alpha-synuclein in the lower rat brain and were able to trace the spreading of this protein toward higher brain regions. The new experimental paradigm could promote the development of ways to halt or slow down disease development in humans. The research team headed by Prof. Donato Di Monte presents these results in the scientific journal "EMBO Molecular Medicine".
Parkinson's disease is a disorder of the nervous system. It typically manifests itself with motor disturbances, such as an uncontrollable trembling of the limbs, as well as non-motor symptoms, including sleep disorders and depression.
At the present, no cure exists for Parkinson's disease, although symptomatic intervention, including treatment with dopamine agonists, can alleviate patients' motor impairment. Parkinson's is the second most common neurodegenerative disorder, after Alzheimer's disease; it is estimated that 100,000 to 300,000 patients are affected by Parkinson's disease in Germany alone.
In a small percentage of cases, Parkinson's disease is due to genetic abnormalities carried within families. For the vast majority of patients, however, the cause of the disease remains unknown; the development of this sporadic form of the disease is likely promoted by both environmental and genetic risk factors. An intriguing characteristic of the brain of patients with sporadic Parkinson's disease is the progressive accumulation of intraneuronal inclusions that were first described by a German neurologist, Friedrich Lewy, and are therefore called Lewy bodies.
"A major discovery in the late 90's was that Lewy bodies are formed when the protein alpha-synuclein becomes aggregated," says Di Monte. "Since then, it was also found that aggregates of alpha-synuclein are progressively accumulated within the patients' brains during the course of the disease".
Pathology studies from human brains show that the deposits usually start forming in the lower part of the brain, in an area named "medulla oblongata". In subsequent disease stages, alpha-synuclein aggregates are observed in progressively higher (more rostral) brain regions, including the midbrain and cortical areas.
"This spreading appears to follow a typical pattern based on anatomical connections between regions of the brain," says the neuroscientist. "For this reason, it has been hypothesized that alpha-synuclein or abnormal forms of it can be transferred between two interconnected neurons and hence migrate throughout the brain. But until now, there was no way of targeting the medulla oblongata to reproduce this spreading of alpha-synuclein in the laboratory. It is also unclear what conditions could trigger the inter-neuronal passage of the protein or its aggregates. We have now developed a new experimental paradigm which enables investigations on these fundamental issues."
From the neck into the brain
The researchers' concept is based on reproducing alpha-synuclein spreading in rats: for this, they transferred the blueprint of the human form of alpha-synuclein into the rat brain. The blueprint was transported by specifically engineered viral particles that the scientists injected into nerve fibres in the neck of the animals. The genetic code for the protein passed along these fibres into the medulla oblongata, where transfected rat neurons began producing high quantities of human alpha-synuclein.
"We have good reasons to believe that the medulla oblongata is a primary site of early disease development. This is why we wanted to activate production of alpha-synuclein specifically in this part of the brain. The medulla oblongata is difficult to reach via surgical procedures. For this reason, we injected the viral particles into the vagus nerve. This is a long nerve stretching from the abdomen via the neck to the medulla oblongata. The nerve consequently served as an entrance into the brain and, in particular, the medulla oblongata," Di Monte explains.
A migrating protein
The researchers monitored the production and localization of human alpha-synuclein in rats' brains over a period of four and a half months after injection of the viral particles. As predicted, the exogenous protein was synthesized only within neurons of the medulla oblongata connected to the vagus nerve. Starting at two months, however, human alpha-synuclein was observed also in brain areas more and more distant from the medulla oblongata (see figure). Caudo-rostral spreading involved inter-neuronal passage of the protein along specific nerve tracts and was accompanied by morphological alterations (such as swellings) of the neuronal projections taking up human alpha-synuclein.
The study, sponsored in part by the Blanche A. Paul Foundation, bears a number of critical implications. It reproduces a pattern of protein propagation that resembles the progressive spreading of pathological alpha-synuclein in Parkinson's disease. As importantly, the process of protein transmission was triggered by overproduction of alpha-synuclein within a specific brain region.
"Overproduction of alpha-synuclein accompanies a variety of conditions, such as aging, neuronal injury or genetic polymorphisms, that could promote the development of Parkinson's disease." concludes Di Monte. "Thus, our results suggest a mechanistic link between disease risk factors, enhanced levels of alpha-synuclein, spreading of the protein and its pathological accumulation."
Insight into the early stages of Parkinson's
The new model mimics events that likely occur in the early stages of alpha-synuclein pathology in the absence of overt behavioural (in rats) or clinical (in patients) manifestations. "It will therefore become a valuable tool to investigate early mechanisms of disease pathogenesis that could be targeted for therapeutic intervention. Early intervention would have a greater probability to prevent or halt the spreading of pathology and progression of the disease," says Di Monte.
###
The German Center for Neurodegenerative Diseases (DZNE) investigates the causes of diseases of the nervous system and develops strategies for prevention, treatment and care. It is an institution of the Helmholtz Association of German Research Centres with sites in Berlin, Bonn, Dresden, Gttingen, Magdeburg, Munich, Rostock/Greifswald, Tbingen and Witten. Website: http://www.dzne.de/en
Original publication
"Caudo-rostral Brain Spreading of ?-Synuclein through Vagal Connections", Ayse Ulusoy, Raffaella Rusconi, Blanca I. Prez-Revuelta, Ruth E. Musgrove, Michael Helwig, Bettina Winzen-Reichert, Donato A. Di Monte EMBO Molecular Medicine (2013), DOI: 10.1002/emmm.201302475 - http://onlinelibrary.wiley.com/doi/10.1002/emmm.201302475/abstract
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Contact: Marcus Neitzert marcus.neitzert@dzne.de 49-228-433-02271 Helmholtz Association of German Research Centres
A new animal model gives insights into mechanisms of Parkinson's disease pathogenesis
This news release is available in German.
In Parkinson's disease, the protein "alpha-synuclein" aggregates and accumulates within neurons. Specific areas of the brain become progressively affected as the disease develops and advances. The mechanism underlying this pathological progression is poorly understood but could result from spreading of the protein (or abnormal forms of it) along nerve projections connecting lower to upper brain regions. Scientists at the German Center for Neurodegenerative Diseases (DZNE) in Bonn have developed a novel experimental model that reproduces for the first time this pattern of alpha-synuclein brain spreading and provides important clues on the mechanisms underlying this pathological process. They triggered the production of human alpha-synuclein in the lower rat brain and were able to trace the spreading of this protein toward higher brain regions. The new experimental paradigm could promote the development of ways to halt or slow down disease development in humans. The research team headed by Prof. Donato Di Monte presents these results in the scientific journal "EMBO Molecular Medicine".
Parkinson's disease is a disorder of the nervous system. It typically manifests itself with motor disturbances, such as an uncontrollable trembling of the limbs, as well as non-motor symptoms, including sleep disorders and depression.
At the present, no cure exists for Parkinson's disease, although symptomatic intervention, including treatment with dopamine agonists, can alleviate patients' motor impairment. Parkinson's is the second most common neurodegenerative disorder, after Alzheimer's disease; it is estimated that 100,000 to 300,000 patients are affected by Parkinson's disease in Germany alone.
In a small percentage of cases, Parkinson's disease is due to genetic abnormalities carried within families. For the vast majority of patients, however, the cause of the disease remains unknown; the development of this sporadic form of the disease is likely promoted by both environmental and genetic risk factors. An intriguing characteristic of the brain of patients with sporadic Parkinson's disease is the progressive accumulation of intraneuronal inclusions that were first described by a German neurologist, Friedrich Lewy, and are therefore called Lewy bodies.
"A major discovery in the late 90's was that Lewy bodies are formed when the protein alpha-synuclein becomes aggregated," says Di Monte. "Since then, it was also found that aggregates of alpha-synuclein are progressively accumulated within the patients' brains during the course of the disease".
Pathology studies from human brains show that the deposits usually start forming in the lower part of the brain, in an area named "medulla oblongata". In subsequent disease stages, alpha-synuclein aggregates are observed in progressively higher (more rostral) brain regions, including the midbrain and cortical areas.
"This spreading appears to follow a typical pattern based on anatomical connections between regions of the brain," says the neuroscientist. "For this reason, it has been hypothesized that alpha-synuclein or abnormal forms of it can be transferred between two interconnected neurons and hence migrate throughout the brain. But until now, there was no way of targeting the medulla oblongata to reproduce this spreading of alpha-synuclein in the laboratory. It is also unclear what conditions could trigger the inter-neuronal passage of the protein or its aggregates. We have now developed a new experimental paradigm which enables investigations on these fundamental issues."
From the neck into the brain
The researchers' concept is based on reproducing alpha-synuclein spreading in rats: for this, they transferred the blueprint of the human form of alpha-synuclein into the rat brain. The blueprint was transported by specifically engineered viral particles that the scientists injected into nerve fibres in the neck of the animals. The genetic code for the protein passed along these fibres into the medulla oblongata, where transfected rat neurons began producing high quantities of human alpha-synuclein.
"We have good reasons to believe that the medulla oblongata is a primary site of early disease development. This is why we wanted to activate production of alpha-synuclein specifically in this part of the brain. The medulla oblongata is difficult to reach via surgical procedures. For this reason, we injected the viral particles into the vagus nerve. This is a long nerve stretching from the abdomen via the neck to the medulla oblongata. The nerve consequently served as an entrance into the brain and, in particular, the medulla oblongata," Di Monte explains.
A migrating protein
The researchers monitored the production and localization of human alpha-synuclein in rats' brains over a period of four and a half months after injection of the viral particles. As predicted, the exogenous protein was synthesized only within neurons of the medulla oblongata connected to the vagus nerve. Starting at two months, however, human alpha-synuclein was observed also in brain areas more and more distant from the medulla oblongata (see figure). Caudo-rostral spreading involved inter-neuronal passage of the protein along specific nerve tracts and was accompanied by morphological alterations (such as swellings) of the neuronal projections taking up human alpha-synuclein.
The study, sponsored in part by the Blanche A. Paul Foundation, bears a number of critical implications. It reproduces a pattern of protein propagation that resembles the progressive spreading of pathological alpha-synuclein in Parkinson's disease. As importantly, the process of protein transmission was triggered by overproduction of alpha-synuclein within a specific brain region.
"Overproduction of alpha-synuclein accompanies a variety of conditions, such as aging, neuronal injury or genetic polymorphisms, that could promote the development of Parkinson's disease." concludes Di Monte. "Thus, our results suggest a mechanistic link between disease risk factors, enhanced levels of alpha-synuclein, spreading of the protein and its pathological accumulation."
Insight into the early stages of Parkinson's
The new model mimics events that likely occur in the early stages of alpha-synuclein pathology in the absence of overt behavioural (in rats) or clinical (in patients) manifestations. "It will therefore become a valuable tool to investigate early mechanisms of disease pathogenesis that could be targeted for therapeutic intervention. Early intervention would have a greater probability to prevent or halt the spreading of pathology and progression of the disease," says Di Monte.
###
The German Center for Neurodegenerative Diseases (DZNE) investigates the causes of diseases of the nervous system and develops strategies for prevention, treatment and care. It is an institution of the Helmholtz Association of German Research Centres with sites in Berlin, Bonn, Dresden, Gttingen, Magdeburg, Munich, Rostock/Greifswald, Tbingen and Witten. Website: http://www.dzne.de/en
Original publication
"Caudo-rostral Brain Spreading of ?-Synuclein through Vagal Connections", Ayse Ulusoy, Raffaella Rusconi, Blanca I. Prez-Revuelta, Ruth E. Musgrove, Michael Helwig, Bettina Winzen-Reichert, Donato A. Di Monte EMBO Molecular Medicine (2013), DOI: 10.1002/emmm.201302475 - http://onlinelibrary.wiley.com/doi/10.1002/emmm.201302475/abstract
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AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.
This undated publicity image released by Fox shows employees of Velocity Merchant Services (VMS) in Downers Grove, Ill., in a scene from the reality workplace series, "Does Someone Have to Go?" The network will begin airing a nonfiction show where employees of small businesses are compelled to rat out underperforming colleagues and put their jobs at risk. The series premieres Thursday, May 23 at 8 p.m. EST on Fox. (AP Photo/Fox
This undated publicity image released by Fox shows employees of Velocity Merchant Services (VMS) in Downers Grove, Ill., in a scene from the reality workplace series, "Does Someone Have to Go?" The network will begin airing a nonfiction show where employees of small businesses are compelled to rat out underperforming colleagues and put their jobs at risk. The series premieres Thursday, May 23 at 8 p.m. EST on Fox. (AP Photo/Fox
NEW YORK (AP) ? This time "you're fired" is more than a Donald Trump catchphrase. Fox is turning the firing of real people from real jobs into prime-time entertainment starting this week.
The network on Thursday will begin airing "Does Someone Have to Go?" a series where cameras go into small businesses and employees are compelled to rat out underperforming colleagues. At the end, they choose one co-worker to recommend for firing.
"This is the thing they promise to do in retreats but nobody really does it," said Mike Darnell, executive in charge of alternative programming for Fox.
Darnell and Fox have pushed the boundaries of reality TV since it was first recognized as a genre, from the highs of "American Idol" to the lows of "Who Wants to Marry a Multimillionaire?" He said he sees "Does Someone Have to Go?" as a new direction for a programming form dominated by singing and dancing competitions.
It's a revamped version of a show, then called "Someone's Gotta Go," that Fox had been working on with the Endemol production company four years ago. In its initial incarnation, employees were given the power to determine who should be laid off within companies that needed to shrink for economic reasons. The show drew awful advance publicity ? one magazine called it a step toward public executions ? and never aired.
"The network decided the heat was too intense given the economic climate," Darnell said. "We never lost our affinity for the idea."
Along with the softer name, the new version takes the economy out of it; productivity and personality are at the roots of employment decisions. A firing isn't necessarily mandated ? probation or options like anger management counseling are considered. Within the three companies profiled for the six episodes, Darnell said that people are fired.
Thursday's first episode focuses on Velocity Merchant Services, a company based in the Chicago suburbs that sells credit card processing machines. Sixteen employees participate, and the show quickly labels them: the procrastinator, the motor mouth, the jerk, the slacker and the tattle-tale.
Each employee is interviewed on camera talking about colleagues, then everyone is called into a conference room to see what the others said. They are also told each other's salaries, before voting on three of their colleagues that most deserve firing, a process that reduces one woman to tears.
Then, in the ultimate reality show twist, the 16 employees are brought into a conference room where the video screen shows portraits of each of them. One by one, a picture is removed, until only the three "losers" remain onscreen. One is the mother of company founder Dema Barakat, judged by her colleagues to be a management mole who is paid too much.
Next week: choosing who among the three get to keep their jobs.
The show's executive producer, Cris Abrego, said it is "absolutely not cruel. It's not like a random firing ... It really is a process of them proving their value to the company."
Why would a company put itself through this? Publicity is alluring, particularly for a small firm, and a show like "Undercover Boss" on CBS has proven beneficial to many companies that have participated, said Geoff Wilson, president and CEO of 352 Media Group, a digital marketing agency based in Gainesville, Fla., that seriously considered being part of the show. Producers offered to pay the company $25,000 to participate and would spruce up the office to make it more camera-friendly. Each employee who agreed to be part of it would be paid $1,500. Producers would contribute $10,000 toward a severance package for anyone fired, he said.
Velocity, or VMS, is a family-run company that had hit a plateau, said Danoush Khairkhah, CEO and Barakat's husband. Its biggest problems were with personalities, not with business, he said.
"Opportunity knocks only several times in your life," Khairkhah said.
He was interested to see how his employees would perform when given the chance to take issues into their own hands. They knew what they were getting into, he said, although they didn't know specifically they would see film of colleagues criticizing them or learn their salaries.
"It's not bad to sit there and hear what your colleagues think of you," he said. "How many times in your life does someone sit you down and say, 'Here are the things I don't like about you?' That's great. Now you can correct them and go on the right path. Some people can, and some people crumble when they hear negative things."
Things have improved at VMS since the show was filmed over five days last December, he said. Employees are taking more initiative and aren't afraid to speak up about problems. Khairkhah and his employees haven't seen the show yet. They plan a party Thursday night to all watch it together.
He does have some concerns after seeing commercials promoting the show.
"No one wants to see a commercial about your business saying 'toxic office,'" he said. "If it was toxic, we wouldn't be here 15 years. When I saw that I was kind of shocked. But I understand this is show business and they've got to build up drama."
352 Media Group was very close to participating, Wilson said. Most of his employees wanted to, although there was a vocal minority. He was told the show was called "Office Life," he said, but noticed a clause in the contract that gave producers the right to change the title if they wanted.
Hmmmm. That made him suspicious.
"I wouldn't say the producers lied to us," he said. "I would say that they creatively represented the facts." (Abrego said that dealings with the companies have been "100 percent above board.")
After Wilson turned Endemol down, producers sent him a copy of a show pilot to see what it was like and offer advice. He breathed a sigh of relief; his company depends on teams working well together and a public airing of dirty laundry would have been devastating, he said.
"I am unbelievably happy that our sixth sense told us to stay away from this," Wilson said.
___
EDITOR'S NOTE ? David Bauder can be reached at dbauder(at)ap.org or on Twitter (at)dbauder. His work can be found at http:bigstory.ap.org/content/david-bauder.
In a few years, men will be able to communicate more effectively through a machine than face to face. Sounds obvious today. But in 1968, a full year before ARPANET made its first connection? It was downright clairvoyant.
Sometimes a vision of the future can be so accurate that it's hard for those of us living in the future to understand what made it visionary in the first place. In the late 1960s the human side of networked computing wasn't a given. Few people looked at the hulking machines of the time and thought that they'd be great dating facilitators some day. The ARPANET was created for resource sharing between academics and other serious-minded people. In their early days, these networks weren't seen as a tool for something like ordering a pizza or sharing cat GIFs with someone halfway around the world.
Connecting People
The human element?the idea of average people interacting with computers, but more importantly with other people ? was not a front-of-mind concern for the people who laid the foundation of the internet as we know it. Which is what makes a 1968 paper that predicted the extent of that human element so special.
The paper was written by J.C.R. Licklider and Robert Taylor, illustrated by Rowland B. Wilson, and appeared in the April 1968 issue of Science and Technology. The article includes some of the most amazingly accurate predictions for what networked computing would eventually allow. Granted, amazingly accurate with a retro-futuristic twist that keeps it firmly a product of its time.
Take the light-pen. The top image shows off a late-'60s light-pen and rather presciently imagines how computer-augmented romance might take off. The computer, we see, improves the man's drawing in such a way as to make his proposal less repugnant. The self-correcting stylus may not exist yet, but OkCupid and other digital matchmakers are a mainstay of our digital lives.
The article rather boldly predicts that the computerized networks of the future will be even more important for communication than the "printing press and the picture tube"?another idea not taken for granted in 1968:
Creative, interactive communication requires a plastic or moldable medium that can be modeled, a dynamic medium in which premises will flow into consequences, and above all a common medium that can be contributed to and experimented with by all.
Such a medium is at hand?the programmed digital computer. Its presence can change the nature and value of communication even more profoundly than did the printing press and the picture tube, for, as we shall show, a well-programmed computer can provide direct access both to informational resources and to the processes for making use of the resources.
The paper predicts that the person-to-person interaction that a networked computer system allows for will not only build relationships between individuals, but will build communities.
What will on-line interactive communities be like? In most fields they will consist of geographically separated members, sometimes grouped in small clusters and sometimes working individually. They will be communities not of common location, but of common interest. In each field, the overall community of interest will be large enough to support a comprehensive system of field-oriented programs and data.
Google Now, Back Then
The article even hints at the veritable Internet of Things (which ostensibly justifies the high cost of gadgetry, or "data-gathering instruments"):
In each geographical sector, the total number of users?summed over all the fields of interest?will be large enough to support extensive general purpose information processing and storage facilities. All of these will be interconnected by telecommunications channels. The whole will constitute a labile network of networks?ever-changing in both content and configuration.
What will go on inside? Eventually, every informational transaction of sufficient consequence to warrant the cost. Each secretary?s typewriter, each data-gathering instrument, conceivably each dictation microphone, will feed into the network.
The idea of technology as a buffer is certainly an appealing one. And in theory, things like email can provide us with that buffer. When it comes down to it, you only have to check your email when you want to, and no one is forcing you to respond. This kind of brush-off, of course, is a little harder to do when an insurance salesman physically knocks on your door.
Licklider and Taylor called their futuristic buffer tool OLIVER, a kind of individualized automated personal assistant used by everyone. OLIVER acts intelligently, learning what should be prioritized for its user.
A very important part of each man?s interaction with his on-line community will be mediated by his OLIVER. The acronym OLIVER honors Oliver Selfridge, originator of the concept. An OLIVER is, or will be when there is one, an ?on-line interactive vicarious expediter and responder,? a complex of computer programs and data that resides within the network and acts on behalf of its principal, taking care of many minor matters that do not require his personal attention and buffering him from the demanding world. ?You are describing a secretary,? you will say. But no! Secretaries will have OLIVERS.
At your command, your OLIVER will take notes (or refrain from taking notes) on what you do, what you read, what you buy and where you buy it. It will know who your friends are, your mere acquaintances. It will know your value structure, who is prestigious in your eyes, for whom you will do what with what priority, and who can have access to which of your personal files. It will know your organization?s rules pertaining to proprietary information and the government?s rules relating to security classification.
Some parts of your OLIVER program will be common with parts of other people?s OLIVERS; other parts will be custom-made for you, or by you, or will have developed idiosyncrasies through ?learning? based on its experience in your service.
In an age of telegrams and phone calls, the authors imagined computer networking as a fantastic replacement for inefficiencies. Even business trips, they insisted, would be a thing of the past.
You will not send a letter or a telegram; you will simply identify the people whose files should be linked to yours and the parts to which they should be linked-and perhaps specify a coefficient of urgency. You will seldom make a telephone call; you will ask the network to link your consoles together.
You will seldom make a purely business trip, because linking consoles will be so much more efficient. When you do visit another person with the object of intellectual communication, you and he will sit at a two-place console and interact as much through it as face to face. If our extrapolation from Doug Engelbart?s meeting proves correct, you will spend much more time in computer-facilitated teleconferences and much less en route to meetings.
If OLIVER and the paper's other online efficiencies sound familiar, it's because they're basically the endgame of Google Now and Siri: Technology that knows you so well, it does your thinking?and in some cases, living?for you.
A Digital Utopia
In the end, Licklider and Taylor predict that all of this interconnectedness will make us happier and even make unemployment a thing of the past. Their vision of everyone sitting at a console, working "through the network" is stunningly accurate for an information-driven society that fifty years ago would've looked far less tech-obsessed.
When people do their informational work ?at the console? and ?through the network,? telecommunication will be as natural an extension of individual work as face-to-face communication is now. The impact of that fact, and of the marked facilitation of the communicative process, will be very great?both on the individual and on society.
First, life will be happier for the on-line individual because the people with whom one interacts most strongly will be selected more by commonality of interests and goals than by accidents of proximity. Second, communication will be more effective and productive, and therefore more enjoyable. Third, much communication and interaction will be with programs and programmed models, which will be (a) highly responsive, (b) supplementary to one?s own capabilities, rather than competitive, and (c) capable of representing progressively more complex ideas without necessarily displaying all the levels of their structure at the same time-and which will therefore be both challenging and rewarding. And, fourth, there will be plenty of opportunity for everyone (who can afford a console) to find his calling, for the whole world of information, with all its fields and disciplines, will be open to him?with programs ready to guide him or to help him explore.
The primary question, they insist, is whether everyone can afford to be online. Once that hurdle is surpassed, the impact of this brave new world on society as a whole will be positive:
For the society, the impact will be good or bad, depending mainly on the question: Will ?to be on line? be a privilege or a right? If only a favored segment of the population gets a chance to enjoy the advantage of ?intelligence amplification,? the network may exaggerate the discontinuity in the spectrum of intellectual opportunity.
On the other hand, if the network idea should prove to do for education what a few have envisioned in hope, if not in concrete detailed plan, and if all minds should prove to be responsive, surely the boon to humankind would be beyond measure.
The article is a fascinating explanation of networked computing tech written mere months before the internet's first sputtering breaths. Again, many of their predictions don't read as terribly futuristic to those of us here typing away in the early 21st century. But that's precisely what makes them so astounding.
You can read the entire paper online [pdf]. Many thanks to Morten Bay for sending this article my way.
Spain's Sergio Garcia at a Press Conference during the PRO/AM tournament at the Wentworth Club, Surrey, England, Wednesday May 22, 2013. Tiger Woods says the "fried chicken" comment from Sergio Garcia was hurtful and inappropriate. Two weeks after they verbally sparred at The Players Championship, Woods say it's time to move on. Garcia was at a European Tour awards dinner Tuesday night when he was jokingly asked if he would have Woods over for dinner during the U.S. Open. The Spaniard replied, "We'll have him round every night. We will serve fried chicken." (AP Photo/Adam Davy/PA ) UNITED KINGDOM OUT PHOTOGRAPH
Spain's Sergio Garcia at a Press Conference during the PRO/AM tournament at the Wentworth Club, Surrey, England, Wednesday May 22, 2013. Tiger Woods says the "fried chicken" comment from Sergio Garcia was hurtful and inappropriate. Two weeks after they verbally sparred at The Players Championship, Woods say it's time to move on. Garcia was at a European Tour awards dinner Tuesday night when he was jokingly asked if he would have Woods over for dinner during the U.S. Open. The Spaniard replied, "We'll have him round every night. We will serve fried chicken." (AP Photo/Adam Davy/PA ) UNITED KINGDOM OUT PHOTOGRAPH
FILE - At left, in a May 5, 2013 file photo, Sergio Garcia grimaces during The Players Championshop golf tournament in Ponte Vedra Beach, Fla. At right, in a March 25, 2013 file photo, Tiger Woods walks to the 16th green during the final round of the Arnold Palmer Invitational golf tournament in Orlando, Fla. Woods and Garcia don't like each other, and are making no attempt to disguise their feelings. (AP Photo/File)
FILE - In this June 16, 2002 file photo, Sergio Garcia, left, and Tiger Woods talk on the 11th hole while waiting for play to resume after a rain delay during the final round of the U.S. Open Golf Championship in Farmingdale, N.Y. Garcia was at a European Tour awards dinner Tuesday night, May 21, 2013 when he was jokingly asked if he would have Woods over for dinner during the U.S. Open. The Spaniard replied, "We'll have him round every night. We will serve fried chicken." Woods took to Twitter on Wednesday, May 22, 2013 and said the comment wasn't silly, rather it was wrong and hurtful. (AP Photo/Dave Martin, File)
VIRGINIA WATER, England (AP) ? Sergio Garcia apologized to Tiger Woods on Wednesday for saying he would have "fried chicken" at dinner with his rival, a comment that Woods described as hurtful and inappropriate.
"I want to send an unreserved apology. I did not want to offend anyone," Garcia said Wednesday. "My answer was totally stupid and out of place."
Garcia was at a European Tour awards dinner Tuesday night when he was jokingly asked if he would have Woods over for dinner during the U.S. Open. The two players had been verbally sparring since The Players Championship nearly two weeks ago.
"We'll have him round every night," Garcia replied. "We will serve fried chicken."
The remark took the golfers' differences into ugly territory, reminiscent of when Fuzzy Zoeller made a similar comment about Woods after he won the 1997 Masters, becoming the first player of black heritage to win a major.
"The comment that was made wasn't silly. It was wrong, hurtful and clearly inappropriate," Woods said in a series of tweets. "I'm confident that there is real regret the remark was made. The Players ended nearly two weeks ago and it's long past time to move and talk about golf."
For once, both players agreed.
Garcia held an impromptu news conference at the BMW PGA Championship to elaborate on a statement he sent out Tuesday night through the European Tour.
"I want to also apologize to my Ryder Cup teammates who were there last night for taking the shine away from a wonderful event, and finally and foremost, I want to apologize to Tiger to anyone I could have offended. I felt very sick about it and feel really bad, and just hope to settle things down and move on."
Garcia said he called Mark Steinberg, Woods' agent at Excel Sports, because he doesn't have a phone number for the world's No. 1 player.
The Spaniard said his comment about fried chicken was not intended as a racist remark.
"It was a funny question and I wanted it to be a funny answer in reply," he said. "I started to get a sick feeling straight after the dinner and I felt so bad I thought my heart was going to come out of my body. I felt bad about (it) all day."
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Public release date: 24-May-2013
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