The Fanboy Nation: The Evolution Of Comic Books

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The Fanboy Nation

The Evolution Of Comics In The Last Century

I was standing outside my tower, sucking on a cigarette and reading Frank Miller's The Dark Knight Returns. It's a comic book, or more specifically a graphic novel, collecting the four issue run from the late 80's that looked at the bleak future of Gotham City. In the story Batman comes out of retirement after 0 years. Now a 50 something year old man battling with alcoholism, Batman faces a city that has outlawed costumed vigilantes and has been transformed into a desolate pit of crime and deviance.

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A fellow student walked out the door and I grunted an acknowledgement of his presence. A few minutes passed, and as Batman tried to rally together a hopeless gang called the "mutants" this guy snickers at me and says, "comic books are for eight year olds." I looked him in the eye, fighting the urge to strangle him, and asked him what the last book he read was. "Reading? Man, who the hell reads books in their spare time?" I took a final drag on my cigarette, flicked it at his $10 shoes, gave him the finger and stormed inside.

It infuriates me when people think of comics as "kid's stuff", ignorant to the fact that comic books have become much more than Archie having to choose between Betty and Veronica. I've read and collected comic books for years, and have a very unhealthy affection for them. In school I've had to read "classics" like Of Mice and Men, A Tale Of Two Cities, and The Odyssey. It's taken me ages to read books like that and usually I just haven't enjoyed them. Comics are entirely different, though. I read Paul Dini and Alex Ross's 500+ page epic, Earth X, in one sitting. It amazed me, the details of this story. The way it reflected American culture, and attacked sensitive issues, all the while containing a totally enjoyable superhero yarn. It boggles my mind that people refuse to believe in comics as literature. So, this paper is going to have a dual-purpose; I'll research and detail the evolution of comic books into literature, and ask the question, just for the sake of proving it, "are comics just for kids?"

I started my research in my dorm room, going through my boxes of comics and selecting tales that I thought were noteworthy. I read through them over the course of a few hours, and then headed to the library to see what I could dig up on comic books. Digging through the second floor stacks on literature, I came a cross a musty section that housed books on comics. In a book that resembled the monolith from 001 A Space Odyssey I found data critical to my quest. To my surprise social commentary had been tried in comic books as far back as the early 100's. In 110 George Herriman began featuring his creation, Krazy Kat in The New York American. Herriman often used his comic as a social critique by locating Krazy Kats identity almost exclusively in an overtly ideological naïve nature. During his adventures, numerous characters joined Krazy Kat. Herriman used these companions to expose the false consciousness of his fellow Americans through ignorance of their habits, often "pointing out the pretensions and mis-recognitions necessary for the maintenance of everyday life"(Sabin, 5). More than any other aspect of his character, this naïve nature fixes Krazy as an individual. Like the background scenes of "Coconino County" where he lives, Krazys gender and race shifted, at random sometimes, but more often according to his social situation. Herriman penned his opinions about the socially constructed nature of categories like race and gender, as well as categories such as class, age, ethnicity, and occupation, into such a deep allegory, however, that few readers noticed them. Herriman caught heat for his comic, though, when his flagship character began dating the transgender rodent, Ignatz Mouse. Despite constant battles with publishers, though, Herriman's creation went the distance and remained a successful strip for nearly thirty years. (Sabin, -6)

It surprises me that issues like those that Herriman dealt with would be raised as far back as 110. Back then America was a much more conservative country, and to think that someone would have the gall to discuss transgender relations or age, race, class, or occupation strains is really quite amazing. I think Herriman was way ahead of his time. He belonged in the 60's with Robert Crumb and his classic feline STD cocktail, Fritz The Cat.

I read about Krazy Kat standing in the book stacks, and decided to grab some more books and go sit down. I picked up a couple of volumes of the International Journal Of Comic Art, A book on comic book culture, a book (mentioned above) on the history of comics through 1 and a coffee table book on Underground comics. Satisfied and weighed down by 40 lbs of books I proceeded to a secluded table.

Before I got into the maturing process of comic book tales, I wanted to make myself comfortable with the evolution of the industry. Sabin's book was a great resource. The industry after Krazy Kat came along was booming, and more creators began emerging from the woodwork. The attitude taken by many artists was "The World Is Our Oyster"(Sabin, 7), and their success mirrored that statement. In January of 1 "Tarzan Of The Apes", a pulp favorite began enjoying huge success as a daily newspaper strip. The positive reaction made way for an even bigger hit, "Plainclothes Tracy"(later became "Dick Tracy"), created by Chester Gould. "Tracy" was the crime-noir tale of a yellow trench coat-clad cop with a very diverse rogues gallery. Tracy's rogue's gallery was the subject of controversy for the first two years of it's publication, as the villains were based on actual mobsters, criminals, and crooked cops. Despite the setbacks, Gould's comic stayed put, and is published to this day in The Chicago Tribune.(Sabin, 7)

1 rolled around and the Ledger Syndicate chose to collect and publish a small amount of Sunday comics on Seven by Nine inch plates, an idea hit upon by two printer employees. The idea was met with praise, and set the wheels ago in the minds of Sales Manager Harry L. Wildenberg and salesman Max C. Gaines of the Eastern Color Printing Company (Goldweber, 88). The two businessmen theorized that if these plates could work, then two of these plates could fit on a tabloid page and produce a 7 ½ by 10-inch book when folded. With the idea in hand, on February 7th, 1, pages of newspaper reprints including "Mutt and Jeff", "Joe Palooka", and "The Reg'lar Fellas", were gathered and Funnies On Parade was created, the very first page publication that resembled today's comic books. Looking to test their product, 10,000 copies were produced and given out as premiums by Proctor & Gamble. Funnies On Parade was an instant success, and sold out within two weeks (Sabin, 1).

This is obviously where the idea was given birth, transferring newspaper reprints into collections. Herrimann's Krazy Kat obviously gave everyone else the go-ahead to give their ideas a go. I would guess that the mindset was "well, if this guy made it with stories as inane as "Krazy Kat " then maybe we can make it too!" Another thing I was thinking of had to do with Tarzan. My thinking is this if Tarzan was created today, if he was redone, I think we'd find his relationships with primates a little different. Realistically, if monkeys raised a boy, he would have a natural urge, at some point, to experiment sexually with his hairy brothers and sisters. When did the rest of the creators make the leap into mature subject matter?

The next two years saw comic books skyrocket to new heights of success, and in 15 they took an interesting turn. In February of '5, Major Malcolm Wheeler-Nicholson, an ex-cavalry officer and pulp writer published the tabloid-sized anthology title New Fun Comics #1 through National Allied Publications (later named DC comics)(Wright, 5). It was the first comic to contain new material, rather than reprints of Sunday cartoons. Much of it was written by Wheeler-Nicholson himself. Considering that the other early titles were successes because of recognizable characters, this was quite a risk. New Fun Comics #6 contained the first work of Jerry Siegel and Joe Shuster, the later creations of Superman, in comics. After the sixth issue, the title became More Fun, and after the eighth issue converted to 8"X11", standard size for modern comics. With this size change, it became the first comic book of "standard-size" to publish new material and continued on until 14. Wheeler-Nicholson had redefined the comic field forever.

In 17, though, Wheeler-Nicholson, after having financial trouble launching his third title, was forced to take on one of his printers, to whom he owed money. Harry Donnefield was the man's name and with Wheeler-Nicholson he helped found Detective Comics and their first new title, the company's third, was Detective Comics #1, launched in March of 17. The new title concentrated solely on crime and suspense stories, instead of the usual varied themes, and is the title that would later launch Batman and Superman. The initials of the company eventually became the new name. The DC imprint continues to this day and has the longest uninterrupted run of any imprint. Despite the company's success, Wheeler-Nicholson was still having financial difficulty, and late in the year, sold his remaining interest to Harry Donenfield. (Wright, 14)

With the success of DC, even after the untimely demise of its president, new creators were jumping on board left and right. One young man, named Joe Siegel, presented DC with a new idea; a costumed crime fighter, on a quest to uphold "Truth, Justice and the American Way." (Wright, 15) The idea was turned down without much thought, and dismissed. Siegel worked on his idea, against the odds, and returned to DC two months later. This time his proposal was much more detailed, and he presented the heads of the company with Superman, who was "more powerful than a locomotive, could leap tall buildings in a single bound, and soar higher than the eagles." (Goulart, 86) Though still skeptical, DC accepted Siegel's proposal and took him on board. Superman made his first appearance in Action Comics #1, and was an overnight success. Legions of fans flocked to the newsstands to see what all the fuss was about, and within two weeks the title had sold over 175,000 copies. (Sabin, 86) Superman remains DC's flagship character, and still enjoys the same (if not more) success that he did in his debut.

So now we have Superman, ever the Boy Scout, and a true symbol of American Freedom and prosperity. He was clean-cut, fair, polite, a "Dapper-Dan" stereotype. But Superman was hardly the type of hero to give the industry a more mature, dark side. He did make comics more popular, but reinforced the fact that comics were simple, safe and basically just for kids. I took the obvious next step, Superman's mirror image, and the yin to his yang, Batman. Batman was set in a darker, more depraved world. Criminals of a strange and sadistic nature overran his city of Gotham. Put simply, Batman was a more mature and grim character. I think this is where comics began to mature a little, and became just a smidge less kid friendly.

. Inspired by Da Vinci's drawings of flying machines, Kane tried a number of names before settling on Batman. Bird-Man, Eagle-Man and Hawk-Man were all names that Kane had tossed aside. (Wright, 140) Da Vinci, once again, inspired the name, this time with his quote "remember that your bird should have no other model than the bat." Batman was an independent masked vigilante who, after a mugger killed his parents, turned to crime fighting to exact vengeance on all those who broke the law. He was a loner and Kane exploited this by having Batman work under the cover of darkness and outside the law. (Sabin, 0) His costume was designed to be so awesome that it would throw fear and respect into all villains that crossed the batman's path.

Batman had no superpowers, and fans were mainly turned on by the exciting, dangerous stories, which most collectors agree, were better than Superman's. (Richards, interview) Kane also had a new and different art style that combined cinematic angles and use of light and darkness to create a unique fantasy world. The twisted, dark villains in Batman's quest for vengeance were unlike anything seen previously. Batman made his first appearance in Detective Comics #7. and the following spring he debuted in his own title, Batman #1. This book featured the first appearances of The Joker, and Catwoman, maniacal villains that relied more on psychological terror to intrigue fans.

Psychological terror! How's that for mature reading? The fact that the majority of DC readers preferred Batman to Superman is a clue to me that people were definitely ready for the more mature subject matter. But with my knowledge that Marvel comics played a pretty decent role in the maturing of the comic book industry I decided to move into a new direction.

By the early 60's, DC superheroes were waning, almost wiped off the map entirely, not helped by prices from 1 to 15 cents from most publishers. Marvel was still doing well, however, and the fledgling company had captured the majority of the market. Marvel had marked its territory as the leader in the comic book industry, with intriguing storylines and characters that were deep. Spider-Man, for example was a teenager with problems like acne, girls, school bullies, etc. and when he gained amazing powers did his troubles fade away? Oh no! They just got worse. How was a mild-mannered teenager to handle a dual identity on top of everything else? Readers ate the stuff up.

Marvel's "new formula"(Sabin, 55), as some authors have called it, has been included in almost all the comic history books I've picked up. Apparently it was new to comics to have readers connecting with characters like Peter Parker the bookworm, the dysfunctional family ties of the Fantastic Four, and the inner turmoil of the incredible hulk. This is something, in all my years of collecting, that I haven't heard about, but while DC ushered in the modern day superhero it was Marvel who took the truly revolutionary leap, making the characters more than just four colour muscle bound clowns.

The 60's came and went, and Marvel upped the ante several times. 167 saw the first death of a core character as Spider-Man's girlfriend, Gwen Stacy, was murdered by an arch nemesis. Readers were shocked, as they had come to love Gwen since her introduction 4 years prior. Harry Osborn, the son of Marvel villain The Green Goblin, started abusing LSD behind the backs of his friends. Iron Man, a founding member of The Avengers, was revealed to be struggling with Alcoholism. These all had noticeable effects on not only the stories, but the readers as well. Parents wrote in like mad, disgusted that Marvel was printing material about alcohol, drugs and death. Marvel stood their ground though, and advised parents to check out the comics before their kids read them. (Sabin, 148)

This is interesting, because rarely will a media company back down from the threat of public outcry. Marvel didn't give in though, in this situation, and continued to occasionally print stories that were controversial in a medium that was still considered by the masses as "kid's stuff." Comic books were maturing in the sense that a few characters were going through abstract experiences, or some stories were being told on a more intellectual level. There wasn't anything up yet that would totally change the way comic book tales were weaved.

It was during the mid-80's that DC changed the comic book medium as a whole, and made its triumphant return to the forefront of corporate comic success. DC signed on a young unknown Englishman, named Frank Miller to pen a Batman tale. Instead of the "blah" that the 80's was pumping out, DC got an absolute goldmine.(Kidd, 01) Batman The Dark Knight Returns took place in the future and dealt with an elderly Bruce Wayne coming out of superhero retirement and putting on the mantle of the Bat one last time.

"The Dark Knight Returns was about a Bruce Wayne who couldnt cope. Too young to cope with middle age and retirement, he became Batman again. Then, finding himself too old to cope as Batman - the young Batman - Bruce Wayne was forced to find a third way. Leave both Bruce Wayne and Batman behind, go underground, and become something...else." (Kidd 0)

This Batman was a tougher, less merciful vigilante than any variation, ever, on The Dark Knight. Miller also portrayed some classic DC characters in a different light, as Superman was no longer the Boy Scout he had once been, but was being pushed around by the corrupted American government. The Green Arrow, another character from the early days of DC, had lost an arm (yet still managed to handle a bow masterfully) and to top it off, a teenage girl had replaced Robin, The Boy Wonder, Batman's sidekick. In the span of four months this title generated more sales for DC than any project beforehand. (Kidd, 0)

Also in 186, DC created a comic book limited series called Watchmen. This 1 issue series dealt with a society on the brink of economical breakdown, where real people did have superpowers. The Watchmen were a group of vigilantes that were forced to stop their actions by the government after a police strike. Years later the come out of retirement to help prevent the breakdown of a collapsing society and to solve the murder mystery of one of their former teammates. The book took some serious risks as it dealt with such issues as rape, politics and foreign policies; issues that were very sensitive at the time, especially in a comic book. (Vachss, 1)

I read Watchmen. It was amazing. If there's a Citizen Kane of comic books, it's definitely Watchmen. It. Is. Huge. It's huge in scope, cast, drama, scale and action. The story jumps all over the timeline of these characters. Their past, their present and their futures are all told throughout this book, which on the surface is a murder mystery, but in reality is a totally revolutionary work of art. This book, in my opinion, should be taught in classrooms around the world. The way Moore weaves the histories of some of these characters, along with the horror of the cold war and the nuclear arms race, is incredible. Everything is set in the parallel world of Earths past. America won Vietnam and never reconciled their differences with the Soviet Union. Superheroes saved lives, and then were subsequently outlawed when they became too unpredictable, too dangerous. Now, everything is at stake as the world races towards nuclear Armageddon, and one lone vigilante superhero tries to solve one last case, one that will have far reaching consequences if he does. I feel slightly ashamed writing this, but Watchmen goes beyond what even The Dark Knight Returns accomplished.

With the release of Watchmen and The Dark Knight Returns comics were unquestionably able to dance in the realm of literature and were obviously maturing, as the aforementioned books were targeted towards a group of readers older than 17(Vachss 8).

Other publishers soon caught wind of DC's success and took chances of their own. Marvel comics hired a fledgling artist named Todd McFarlane to take over writing and art duties on their number one seller, "Amazing Spider-Man." McFarlane had a very dark, brooding style to his art, which spilled over into his stories. Spider Man became more of a grim vigilante than a wisecracking web-slinger. Sales skyrocketed as word of McFarlane's talent spread and soon Marvel was ready to turn over a brand new Spider Man book to McFarlane, over which he was allowed full creative control. McFarlane stayed with Marvel for years working primarily on Spider Man, but also giving his touch to characters like The Incredible Hulk and The Punisher. After his stay at Marvel, Todd joined a group of rogue creators, artists, editors and writers to form an independent comic book publishing house called Image. (Goulart, 167)

It's odd to hear Image called an independent company, as they've grown into something huge, and are the third ranking comic book company (sales wise) behind Marvel and DC. As for McFarlane, I never cared for his work after he left Marvel, but I must give credit where credit is due; he kept the mature and intelligent side of comics alive into the 0's.

Marvel was publishing a good number of books every month that were grim, gritty and intelligent. DC had taken what Miller and Moore did for them and ran with it, keeping their stories as realistic as possible, and always intelligent. Then, in 1, a new publisher sprung up, and did something that no mainstream publisher had done to date; they only published comics for readers over 17. Their name was Vertigo and their goal was to shock, offend and educate as many people as possible.

While many writers that worked for Vertigo created some amazing stuff, the most important of all was Neil Gaiman. Gaiman was a scholar to the end. His creation was entitled Sandman and was the most intelligent, graceful and literary work in comic books since Watchmen.

"Neil Gaiman's Sandman series contains some of the most horrifying scenes ever depicted in comic books. Tortures, rapes, mutilation, maiming, hopeless people are poisoned, lacerated, incinerated, even shredded. The ultimate effect of the books, though, is that of kindness, acceptance, consolation, mercy and redemption. Sandman deals with the relationships of stories and dreams. They can be compared to works like The Tempest and A Midsummer Nights Dream. Also, Gaiman includes homage and passages to and from Shakespeare, like issues 1-1 which parallel Love Labour's Lost" (Goldweber, 78)

Upon reading Goldweber's review of Sandman I realized that my question had been answered, my point had been proven, my quest was over. If comic books can be compared, no, become literature, as Neil Gaiman, Frank Miller and Alan Moore did, then they must have evolved into a more mature art form, and there's no way that comic books are purely "kids stuff" anymore. Sure, anyone could draw the latter conclusion from the 17+ requirements on some comics, but you could argue that the age restriction isn't just to protect kids from seeing violence and sex, its to mark a comic book as higher-level reading.

And that's what comic books have become higher level reading. Sure you can still pick up an issue of Lady Death if you simply want a half-nude, top-heavy woman hacking people to pieces with a sword, or you can still pick up Thundercats if you simply want to relive some of the 80's through some weird nostalgic perversion, but if you want to stimulate your mind there's nothing better to take in than any number of comics from any number of publishers. The characters have come a long way and so has the industry. What were once 4 panel cartoon strips in the Sunday newspapers are now full color page glossy, expansive, engaging, and sometimes classic pieces of literature. And that's why I can stand up loud and proud and say "I'm a comic book geek and I'm damn proud!."

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Scenarios

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What are scenarios?

Scenarios are stories about the future.

Scenarios are images of the future, projected from multiple perspectives on the present and the past. These images intertwine the unpredictable with elements of relative certainty in coherent stories.

Scenarios are a set of organised ways for us to dream effectively about our own future. (P. Schwartz, 11, p. 4)

Scenarios help to perceive different futures in the present. They illuminate the future, but they do not predict it. This is very important to keep in mind.

The best scenarios arent necessarily those that come true; they are the ones that subvert expectations, providing deep insights into the changes happening all around us. The better scenarios are, the more they penetrate into the deepest possible understanding of the present. (P. Mc Corduck and N. Ramsey, 16, p.18)

Scenarios are a tool for ordering ones perceptions about alternative future environments, in which decisions might be played out. (P. Schwartz, 11)

History

The use of scenarios as a tool for strategic decision making has its roots in the military. The U.S. Air Force used scenarios in war games. During and after WOII, scenario thinking was taken up by the RAND corporation a research institute in the U.S.A. http//www.rand.org. Herman Kahn further developed the scenario method at the Hudson Institute http//www.hudson.org, which he established after his resignation from RAND. In his famous book The Year 000 (167), Kahn reworked scenarios to a tool for business strategy. From the 160s onward, scenarios found their way into the corporate world.

Shell was one of the first corporations, which started and continued to use scenarios. Theres a famous story about Pierre Wack and Ted Newland, who introduced and used scenarios to warn Shells executives for a possible dramatic rise in oil prices. Therewith, successfully preparing Shell for the oil-crisis of 17. Both were members of the Group Planning division of Shell out of which originated Global Business Network (GBN) http//www.gbn.org. GBN is a network of - so called- remarkable people and corporate members. GBN functions as an international think-tank and consultancy firm. One of its leading figures is Peter Schwartz who wrote one of the most famous books about scenario thinking and its history The Art of the Longview (11)

Nowadays the scenario method is used in a wide variety of fields and professions. Not just for business strategy, but also in conflict mediation projects - among others in South Africa http//www.gbn.org/ and Colombia http//www.gbn.org/ for policy preparing processes as in this Dutch example http//www.minvenw.nl/, for the analysis of the future of countries http//www.gbn.org/, for the analysis of the future of social issues, such as education, and for the film script of Deep Impact http//www.movie-page.com/18/deep_impact.htm.

METHOD

HOW TO

The Scenario Method

The scenario method is a tool for coherent thinking about the future. Scenarios are developed in order to provide deeper understanding of present options for actions - and their consequences - in the light of possible future environments.

Nobody can predict, therefore one should not try. The only relevant discussions about the future are those where we succeed from shifting from the question whether some-thing will happen to the question What do we do if it happens? (A. de Geus)

Note Scenarios are not predictions of the future.

The scenario method is based on the assumption that the future is unpredictable.

In order to prepare for future possibilities it is necessary to consider uncertainties and make them part of your reasoning. This is in contrast with forecasts, which aim at finding the right future. Forecasts neglect uncertainty and thus often fail when they are needed most, namely when sudden unforeseen changes occur.

The world around us in infinitely complex. The scenario method aims at structurally incorporating uncertainty in our thinking, through the reduction of complexity to manageable proportions without ignoring alternatives by oversimplifying it. Using the form of stories to develop a number of consistent pathways into the future does this.

Scenarios are made in order to increase understanding of current options in the light of possible futures. (P.M. Schütte)

How do you do it?

Why and What?

Before you start, you will have to ask yourself a number of questions. The most important of which is

·Why do I/we want to make scenarios?

·What do I/we hope to achieve with it? [Finding a balance between content & process]

·What are the objectives

·Who is the self in relation to which we are composing scenarios?

Once you've answered these questions, you will have to think about the design of your scenario project. Who to involve, etc. Once you have done this, too. It's time to get going.

Rules of Thumb

First of all, there are a three 'rules of thumb' to which scenarios must conform they must be relevant, novel and substantial.

Scope

Scenarios focus mainly on the 'contextual' environment , a number of categories have been distinguished to which cover most of what is going on in the world, as a guidance for your research. Furthermore, scenarios deal with possible futures, and not with probable or desirable ones.

Horizons

Scenario horizon

Before you start you should determine a horizon year, in which your scenarios take place. You usually try to put the horizon year as far away as possible. It should not be so far away, that it is virtually impossible to say anything sensible about what could happen. In other words, we are not writing science fiction. On the other hand, in order to stretch the mind and include some 'out of the box' thinking, one should get out of the 'comfort zone' (period of time, about which we feel confident as to what will most probably happen). Therefore it is necessary to go as far into the future as you can.

Strategy horizon

If you are going to develop strategic options by using scenario thinking, you should also determine a strategic horizon year. This is usually not so far ahead. Strategy focuses on concrete actions you can take in the near future. You will have to evaluate and revise your strategy frequently to check whether you are still on the right track.

Research research_proc.htm

Every scenario project starts by doing research. Naturally, the amount and scope of which will depend on your time and resources.

Scenario building blocks

The future consists of predetermined elements and uncertainties. Also called driving forces.

Scenario Framework

Once you have gathered al your data and transformed them into clusters, you create a Scenario structuring space. In this space you place all the clusters according to impact and predictable outcome. Once you have done this you consider the driving forces in the outmost corner bottom right and infer two main driving forces, which are independent of each other, to form the axes of the scenario matrix.

It is very important that the driving forces on the axes are as independent as possible of each other. The axes form the framework in which your scenarios will take place. They should leave as much space as possible to contain developments without becoming hollow phrases. If they are dependent on each other you will actually have only one axe of the matrix covered, since a development on the one will have a consequence for developments on the other.

Following this you will have to determine the extreme outcomes of each axe.

And finally you should come up with a name for each of the four scenarios. A good name for a scenario is very important. It should be a concept or a short sentence, which is easy to remember and captures the content of the scenario. (Convergence)

Creating the story

Summarising Scheme for scenario construction

New insights

Revised scenarios

GO TO THE FORUM

Finding a balance between Content & Process

Scenarios can help with

·Surmounting blind spots

·Understanding whats happening around you

·Articulating important questions

·Increasing awareness of insufficient connection

·Clarifying strategic options

·Articulating strategy

·Solving problems

·Directing mental models towards action

Some Rules of Thumb for Effective Scenarios

Relevant

·Illuminate current issues

·Respond to certain circumstances

·Link to current mental models (link naar mental models pagina)

Novel

·Contain new ideas or perceived old ideas

·Challenge existing mental models and strategies

·Provide fresh perspectives

Substantial

·Improve understanding of the present

·Be well researched

·Be internally consisten

Scope I

The scenario method distinguishes three levels of analysis the self, the transactional environment and the factual environment.

Click here for an example of a Corporation as the self.

The first level of analysis is the self. This is the starting point from which you look into future. The basic question here is How will possible future events influence the self? The self can be you as a person, an organisation, a village, a family, or even a nation state. The self is the level in which you have most direct influence in comparison to the other levels.

The second level; the transactional environment (link naar transactional environment) is the environment directly surrounding and interacting with the self. In case the self is you as a person, then your family and friends would be part of the transactional environment. When the self is a village, then the region and nation state, of which that village is part, will be placed in the transactional environment. In the case of a company as the self, the transactional environment will be formed by all the stakeholders of that company, such as shareholders, clients, suppliers and so on. At this level elements can still influence each other, but less so and often more indirectly than on the level of the self. This is the level of actors.

The third level is the contextual environment. This level contains the rest of the world which influences the self, but which the self cannot influence very easily or at all (in case of the weather for instance). At this level the world presents itself as facts to the self, since it can do little to change it. It is the context in which we live. This context might include technological developments, such as the spread of Internet. Furthermore, this level contains larger and often slowly changing structures in society, such as ecological changes, the development of nation states or the capitalist system on which most of the worlds economies are based. This is the level of factors.

Note Scenarios are stories about the third level. They explore the world around us as it presents itself to us and influences our scope of action. By using scenarios to make sense of this world you try to look from the outside to the inside. In other words, the movement of thought goes from a broad view of the context to a more focused view of the self.

Scope II

Another way of categorising the scope we deal with using scenarios is

PESTE

Which stands for the

·Political environment

·Economical environment

·Social environment

·Technological environment

·Ecological environment

By exploring important developments in all these categories you will be able to cover a large part of what is going on in the world. Of course these categories are not so neatly divided as they seem to be in this model. Most developments can be placed in two or more categories. Most importantly, these categories are interconnected and interactive. It is this dynamic relationship, which offers useful information. The scenario method tries to capture the complex dynamics of these interactions in the scenario stories.

Scope III

Yet another way of categorising the scope of scenarios concerns

POSSIBLE, PROBABLE & DESIREABLE Futures

Scenarios deal with POSSIBLE futures. If you want to find out about the PROBABILITY of certain future developments you will have to use other methods of analysis. The reason scenarios deal with POSSIBLE futures instead of PROBABLE ones is because the scenario method aims at thinking structurally about uncertainties. In order to be able to do so, it is important to take into account as many possibilities as you can. Therewith developing a feel for the complexity of the world around you. By looking for PROBABILITIES youll have to give priority to a number of possibilities, therewith reducing the number of uncertainties. Basically, using the scenario method is diametrically opposed to searching for PROBABLE futures, which you do using forecasting methods.

Note Because, the human mind can handle only a number of possibilities at the same time, the scenario method prescribes the creation of three or mostly four scenarios. The stories should structurally differ from each other in terms of content. This is the reason why it is not advisable to create two scenarios, because they will tend to become opposites of the same spectrum. For example, in one scenario all will go well, and in the other all will go wrong. You end up with an Utopia and a Worse case scenario. Even when writing three scenarios one should be careful to avoid Utopia, Worst case & The Avarage between them.

The Research process

Focus

The research process, with which each scenario study starts, aims at an analysis of the present and the past. This analysis focuses on

·Speed of change

·Cause and effect and other relations

·Driving forces

·What's already in the pipeline?

·What can still be influenced, or what is uncertain?

Mental Models

Mental models refer to our perceptions of the world. Our 'image of reality'. Scenario's aim to stretch these mental models. In order to do so, a self-reflecting attitude is very important throughout the scenario process.

Brainstorming and Clustering ideas

In the scenario research process you will have to look for driving forces forces which propel change in the world. In order to find these driving forces it is useful to start with a brainstorm. You don't want to overlook things thus you try to get as many ideas on the table as possible (divergence). Because too many loose ideas are unworkable the next step will be to group ideas in clusters by combining them into a smaller number of broader concepts, which can be related to each other (convergence). While forming and studying these clusters, you should be able to detect the driving forces of the system you are dealing with.

Interviews

A good way of gathering information and ideas is interviewing people. Try to interview people from diverse backgrounds, whom are related to the area of the issue concerned. (divergence)

After you have been through the whole process of creating scenarios, it is usually a good idea to invite some interesting people over to get their opinion on the subject. You can digest their reaction into the scenarios to enrich them.

Scenario Building Blocks

Driving Forces. Predetermined Elements & Critical Uncertainties

In the research process you will have to look for driving forces forces which propel change in the world. In order to find these driving forces it is useful to cluster ideas and combine them into a smaller number of broader concepts, which can be related to each other. While forming and studying these clusters, you should be able to detect the driving forces of the system you are dealing with.

Kees van der Heijden defines a driving force as 'a variable which has a relatively high level of explanatory power in relation to the data displayed in the cluster.' Driving forces can be placed in a continuum from predetermined elements to critical uncertainties. They are usually outside our direct personal control. A number of examples of driving forces are political or economical trends, technological developments or large-scale environmental degradation. (scope I and scope II) It is very important to recognise and understand the driving forces and the impact they have on the question you are dealing with.

Both predetermined elements and critical uncertainties are closely related. Initial uncertainty is not the same as indeterminacy; understanding of underlying structures can contain uncertainty. Furthermore, by questioning assumptions about perceived predetermined elements they might turn out not to be as predetermined as they seemed and the other way around. This process of questioning might lead you to change your 'mental map' of reality. Or at least, your will be able to consider your actions in advance for, when something you never thought would happen, does occur.

Driving forces are the building blocks of scenarios. They help to structure the exploration of the future.

Scenario Building Process

Creating the story

A SCENARIO IS

AN ARCHETYPE OF THE PAST

+

AN INTERPRETATION OF THE PRESENT

+

AN INTERNALLY CONSISTENT STORY DESCRIBING A ROAD FROM THE PRESENT TO A FUTURE.

In order to write a scenario, as described above, you need the following elements

·Driving forces or 'scenario building blocks' Behaviour over time from key variables

·An end-situation This is a description of what the future will look like in the horizon year. It is the end of the story.

·A key event This is an event or happening, which gives impetus to the story. The key event gives a major impulse to the changes, which are about to take place in the scenario. Key events mark the beginning of a process or a change of direction; therefore, it is useful to start the scenario with a key event.

·The plot or storyline(s) This is the internally consistent development from the present to the future.

Directing mental models towards action

What is

Scenario Planning?

Scenarios are specially constructed stories about the future. Each scenario represents a distinct, plausible world. The purpose of scenario planning is not to predict the future; but rather, to show how different forces can manipulate the future in different directions. It is very important to realize this, for this procedure helps to identify these forces if and when they happen. The utility of scenario planning lies in its ability to anticipate the future. When this is accomplished, the ability to better respond to future events is increased.

How to write scenarios...

First, we needed identify the focal issue or decision. Of course, we could simply tell stories of what we think may happen in the future, but our task was to narrow the scenarios down to a specific issue. Only then could we build, expand, and learn from our scenarios, enabling us to make better decisions. We found that sometimes the questions can be quite broad (e.g. What will be the future of technology in banking?) or quite specific (e.g. How will technology change and reshape the physical structure of present-day financial institutions?).

We then had to identify the primary driving forces of today to predict the events of tomorrow. These forces are detailed in the sidebar to the left. Scenarios are not necessarily good or bad; they are, in fact, a potpourri of circumstances and events.

It [scenario planning] can prepare us in the same way that it prepares corporate executives it helps us understand the uncertainties that lie before us, and what they might mean. It helps us rehearse our responses to those possible futures. And it helps us spot them as they begin to unfold. (Wilkinson, Scenarios Special Wired Edition, January 16 )

Please note that this sample paper on scenarios is for your review only. In order to eliminate any of the plagiarism issues, it is highly recommended that you do not use it for you own writing purposes. In case you experience difficulties with writing a well structured and accurately composed paper on scenarios, we are here to assist you. Your cheap custom college paper on scenarios will be written from scratch, so you do not have to worry about its originality.

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Gap junctions

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1.0 INTRODUCTION

During the course of evolution of single cells to multicellular organisms, new genes and functions were developed to assure coordinated regulation of cellular processes within these more complex entities. In multi-cellular organisms a delicate balance of regulatory and integrative mechanisms has to be achieved in order to maintain a relatively stable internal environment in the face of variations in the external conditions. This state of equilibrium, termed homeostasis, is controlled by three major communication processes 1) extracellular communication, ) intracellular communi-cation, and ) intercellular communication. The integrated control of these three communication routes permits an organism to proliferate, to differentiate, to undergo apoptosis (programmed cell death) and to adapt/respond to stimuli (Trosko and Ruch, 18).

It has been suggested that the gain in ability of more complex organisms to regulate cell growth, differentiation and apoptosis is directly related to the appearance of intercellular communication. This notion is supported by several studies that have shown that this type of communication is severely impaired in cancers, which often exhibit behavior characteristic of a single-cellular organism. Processess typical to these organisms such as uncontrolled cell proliferation, inability to terminally differentiate and an altered apoptosis rate are often found in cancerous cells (Trosko and Ruch, 18). Besides growth control, intercellular communication plays an essential role in a variety of physiological processes including electrical coupling, tissue response to hormones, and regulation of embryonic development.

The diversity and the vital character of these functions for the survival of an organism clearly demonstrate the importance of understanding the mechanisms involved in the control of intercellular signaling. Intercellular communication is mediated through the gap junction communication channel, which has become one of the focal points of the research in the field with a particular emphasis on the regulatory aspects of gap-junctional intercellular communication (GJIC). The insight gained from these studies can lead to the development of new therapeutic approaches to a variety of patho-physiological states caused by abnormal intercellular communication.

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1.1 The Gap Junction Communication Channel

1.1.1Gap Junctions

Gap junctions are sites between adjoining cells that allow for direct intercellular passage of molecules smaller than 1 kDa. These channels are relatively non-specific and the observed selectivity is based mainly on molecular size, allowing the passive diffusion of small molecules and ions such as water, cAMP, sugars, nucleotides, amino acids, fatty acids, small peptides and drugs, but blocking the transfer of proteins, complex lipids, polysaccharides, nucleic acids and other large molecules. Recent studies have challenged the apparent non-specificity of GJs hinting at more complex regulatory mechanisms behind the control of GJ permeability to certain compounds. Gap junctions are found in almost all multicellular organisms of the animal kingdom, both invertebrates and vertebrates, and in almost all tissues with the exception of a few terminally differentiated cells such as erythrocytes, lymphocytes, skeletal muscle and adipocytes (Kumar and Gilula, 16).

An integral membrane protein called a connexin is the main structural unit of the gap junction channel (Fig. 1, A). Connexins comprise a multi-gene family with at least twenty mammalian connexin genes discovered to date. The expression of a particular connexin type is strictly correlated with the cell type and tissue in which it is found. Gap junctions have a relatively simple molecular organization they display a hierarchy of assembly with six connexin subunits forming an integral complex called a connexon (Fig. 1, B). The connexons from the plasma membrane of the neighboring cells align and interact to form the gap junction channel (Fig. 1C). In turn, gap junctions cluster in specific regions resulting in the formation of gap junction plaques (Fig. 1D).

Figure 1. The Structure of a Gap Junction. Schematic model of gap junction showing the arrangement of six connexin subunits to form a connexon, which contains the central channel connecting the cytoplasm of the two adjoining cells.

All connexins appear to have the same topology in the plasma membrane with the polypeptide spanning the lipid bilayer four times, with both N- and C- termini located in the cytoplasm. One of the four transmembrane domains, M, is amphipatic in nature and contributes to the lining of the channel. The two extracellular loops (E1 and E) (Fig. 1A) negotiate the docking of the two opposing connexons by facilitating the initial interactions between them. Each loop contains a characteristic arrangement of three cysteine residues that are thought to enhance the rigidity of these extracellular segments necessary for the docking of the two connexons and formation of a gap junction. The intracellular loop between the transmembrane domains M and M as well as the C-terminus exhibit the greatest variability among different connexins and therefore are believed to be important for regulation of the protein (Kumar and Gilula, 16).

The X-ray crystallographic study of a recombinant gap junction membrane channel lacking its C-terminus has revealed that the outer diameter of a GJ within a membrane has a diameter of ~ 70 Å with the intercellular portion of the channel narrowing to ~ 50 Å (Unger et al., 1). The vertical cross-section of the interior of the channel disclosed that its diameter narrows down from ~ 40 Å to ~ 15 Å within its transmembrane region in proceeding from the cytoplasmic to the extracellular portion of the bilayer. The channel widens again to ~ 5 Å within its extracellular section. Taking into account the contributions from the amino acids side chains, the narrowest diameter of the GJ is about 5 Å (Unger et al., 1).

1.1. Assembly and Degradation

Similarly to other integral membrane proteins, "connexins are synthesized at the endoplasmic reticulum (ER) membrane in a typical process that involves a signal recognition particle, an integral signal anchor sequence, docking of the nascent-chain/ribosome complex to the translocon, and cotranslational integration of the connexin polypeptides into the ER membrane" (Falk, 000). The final topological organization of the connexins is attained at the level of their ER membrane integration (Falk et al., 14; Ahmad et al., 1; Diez et al., 1). The exact location at which connexin oligomerization takes place has not been clarified. Several studies have reported that connexins are assembled into oligomers within specialized region of the ER (George et al., 18, 1), either the intermediate compartment or ER-Golgi Intermediate Compartment (Schweizer et al., 10). However, other studies in NRK and CHO cell lines suggested that oligomerization of endogenously expressed Cx4 takes place after exit from the ER in late Golgi membranes (Musil and Goodenough, 1). These observations strongly suggest that the process is likely cell - type specific. Connexins are trafficked to the plasma membrane by a consecutive series of vesicle fusion and budding from the ER through the Golgi apparatus by following the general secretory pathway (Musil and Goodenough, 11). The process of targeting connexons to the plasma membrane is not currently understood but two general models have been proposed. The first involves the direct transport of the connexon to the GJ site whereas the other entails an indirect transport of the connexon by lateral movement within the plasma membrane towards the gap junction site following its insertion at a distant location (Falk, 000). Once localized into the plasma membrane, the connexons from the neighboring cells dock with each other via interactions of their connexin subunit extracellular loop domains forming a complete GJ channel. GJ channels in turn aggregate to form GJ plaques. The formation of plaques is assisted by calcium-dependent cell-adhesion molecules such as E-cadherins (Laird et al., 15; Laird 16). The cytoskeletal proteins ZO-1 and --spectrin have also been reported to play a role in this process (Toyofuku et al., 18).

The degradation and turnover of gap junctions are the least understood aspects of connexin processing within the cells. The turnover of connexins is relatively fast compared to other integral membrane proteins with the reported half-lives in the range of 1 h for Cx4 and Cx45 in cultured cells or tissues (Beardslee et al., 18; Saffitz et al., 000) contrasted with 17 100 h for integral membrane proteins measured in hepatocytes (Chu and Doyle, 185). The current evidence suggests that gap junctions are removed from the membrane by internalization of entire channels within large fragments of GJ plaques (Severs et al., 18). The subsequent degradation process involves both lysosomal as well as proteasomal pathways (Laing and Beyer, 15; Laing et al., 17; Laird, 16; Rahman et al., 1; Musil et al., 000).

1.1. Gap Junctions and Their Role in Human Diseases

Gap junctions play an essential role in a number of diverse physiological processes. Charcot-Marie-Tooth (CMTX) disease was the first pathology associated with a connexin. This progressive neuropathy results from myelin disruption and axonal degeneration of peripheral nerves and is caused by a mutation in Cx (Martin et al., 000). This connexin has a wide tissue distribution and is one of the major GJ proteins in liver as well as in oligodendrocytes. The fact that a mutation in Cx results in only a mild neuropathy suggests that connexins can compensate for the loss of other connexins in different tissues. Other diseases associated with mutations in various connexins include dominant and recessive hearing loss (Cx6, Cx1, Cx0), dominant epidermal disease (Cx1, Cx0., Cx0), dominant skin disease caused by abnormalities in keratinization, cataracts (Cx46, Cx50), and abnormal cardiac development (Cx4) (Table 1) (Bennett, 14; Kelsell et al., 001). Aberrant regulation of GJIC has been implicated in several types of neoplasia (Andrade-Rozental et al., 000). The majority of tumors express less connexin, have fewer gap junctions and exhibit a decrease in GJIC (Cesen-Cummings et al., 18; Yamasaki, 10).

Table 1. Human diseases associated with mutations in connexin genes (adapted from Kelsell et al., 001)

Connexin (gene)Human disorder

Cx (GJB1)X-linked Charcot-Marie-Tooth Disease neuropathy often associated with hearing loss

Cx6 (GJB)Dominant and recessive non-syndromic moderate-profound sensorineural hearing lossDominant epidermal disease (palmoplantar keratoderma) and Vohwinkel's syndrome

Cx1 (GJB)Recessive non-syndromic moderate-profound sensorineural hearing lossDominant non-syndromic high frequency hearing lossDominant skin disease (Erythrokeratoderma variabilis)Dominant sensorineural hearing loss and neuropathy

Cx0. (GJB4)Dominant skin disease (Erythrokeratoderma variabilis)

Cx0 (GJB6)Dominant hearing lossClouston's hidrotic ectodermal dysplasia skin disease (palmo-plantar keratoderma), hair loss, nail defects and often mental deficiency

Cx4 (GJA1)Association with visceroatrial heterotaxy

Cx46 (GJA)Cx50 (GJA8)Dominant zonular pulverant cataract

1. REGULATION OF GAP JUNCTIONS

1..1 General Aspects of GJ Regulation

GJ regulation is a complex process that can be achieved by a broad range of mechanisms that can generally be categorized into two major groups. The first category includes all the processes that affect the formation and levels of GJs starting with Cx gene expression through translation, oligomerization into connexons, transport to the membrane, assembly into GJ and plaques, gating and finally degradation. The impaired GJIC caused by down-regulation of Cx in certain types of neoplasia is illustrative of this type of regulatory mechanisms. The second group includes all the modes of regulation that do not alter the cellular levels of GJ but affect its functionality, which is directly related to the fluctuation of the channel between the 'open' and 'closed' states. This GJ gating can be effected by a variety of exogenous and endogenous factors including extracellular soluble factors (mitogens, hormones, anesthetics and drugs) and biomolecules (oncogenes, growth factors, tumor promoters) (Berthoud et al., 000; Evans and Boitano, 001). These agents can exert their GJIC modulatory action either directly by introducing structural modifications to the channels, or indirectly for example by perturbing the lipidic environment in the vicinity of the channel and thus affecting its conformation (Hossain and Boynton, 000). The majority of GJIC modulators act by initiating complex signaling pathways leading to the activation of various kinases, phosphatases and adaptor proteins.

1.. Regulation of Gap Junctions by Phosphorylation of Connexins

Most connexins (including Cx1, Cx, Cx7, Cx40, Cx4, Cx45, Cx46, Cx50, and Cx56) contain protein kinase "consensus phosphorylation sequences" and have been demonstrated to be phosphoproteins (Lampe and Lau, 000). The majority of the phosphorylation events occur on the C-terminal cytoplasmic tail, which has been shown to be important for regulation (Fig. ). It is interesting to note that the Cx4 truncated mutant that lacks a C-terminal retains its ability to form functional channels in Xenopus oocytes or SKHep1 cells, albeit with altered permeability and electrophysiological properties compared with those of a wild type Cx4 channel (Fishman et al., 11; Dunham et al., 1). A Cx mutant that is truncated at its C-terminal has been linked to CMTX disease (Rabadan-Diehl et al., 14). The above examples emphasize the important regulatory role of the C-terminal domain in channel gating and possibly in the rates of connexin transport, assembly and turnover.

A variety of protein kinase modulators have been applied to investigate the effects of phosphorylation on gap junction function, revealing that phosphorylation events are connexin and cell-type specific. However, some general trends have been observed across different connexins. For example, compounds that increase levels of intracellular cAMP tend to enhance GJIC. This observation has been attributed to increased rates of connexin transcription, increased levels of connexin RNA or protein (Darrow et al., 16), changes in connexin phosphorylation status (Traub et al., 187), as well as changes in Cx4 transport (Atkinson et al., 15) and GJ conductance (Spray et al., 11; Jongsma et al., 000). On the other hand, agents that activate PKC such as phorbol esters generally diminish GJIC. Staurosporine, a protein kinase inhibitor, has been shown to increase GJIC in SKHep cells expressing Cx4, whereas okadaic

Figure . A schematic representation of the primary structure of rat Cx4. Phosphorylation sites in Cx4 targeted by V-Src, MAP kinase and PKC are indicated.

(Borrowed from Lampe et al., 000)

acid, a phosphatase inhibitor, has had the opposite effect on GJIC (Moreno et al., 14). These studies taken together demonstrate that phosphorylation is an important regulatory mechanism for GJ function. However, the signaling pathways responsible for these observations have not yet been fully deciphered.

1..Phosphorylation of Cx4

Cx4 is the most common connexin expressed across a broad range of cell lines and tissues. The phosphorylation of Cx4 can have both an inhibitory and stimulatory effect on GJIC. The primary sites of Cx4 phosphorylation are multiple serine residues (1 residues) on its C-terminal domain (Fig. ). The extent of phosphorylation on threonine residues is significantly smaller (Kanemitsu et al., 17). Cx4 phosphorylation on tyrosine has been reported only in cells expressing oncoproteins such as v-Src or v-Fps (Kurata and Lau, 14). The protein kinases PKC, MAP kinase and pp60src were shown to phosphorylate Cx4 (Lau et al., 000). Many other protein kinases could also be involved in Cx4 phosphorylation.

Cx4 extracted from untreated mammalian cells and separated by SDS-PAGE can generally be resolved into several bands corresponding to its different isoforms. Typically observed are a nonphosphorylated (NP ~ 4 kD) form that migrates faster on the gel and two slower bands that correspond to the most common phosphoisoforms (P1 and P, ~44 kD and ~46 kDa respectively), which have been shown to be phospho-rylated mainly on serine residues (Musil and Goodenough, 11). However, neither the protein kinase(s) isoforms responsible for these phosphorylations nor their target sites in untreated cells have been identified.

1...1 Phosphorylation of Cx4 During Its Life Cycle

Phosphorylation events have been associated with the localization of Cx4 to the plasma membrane as well as with aggregation of connexons into GJ plaques, pointing to the possible role of this post-translational modification in the regulation of Cx4 transport and/or the assembly or disassembly of GJs (Musil and Goodenough, 11). Phosphorylation has been demonstrated to occur as soon as 15 min after Cx4 synthesis in cultured fibroblast cells, clearly showing that it can occur before the protein's arrival at the membrane (Crow et al., 10). The fact that a nonphosphorylated form of Cx4 can be detected at the membrane suggests that either these early phosphorylations are transient in nature or that dephosphorylation occurs at the membrane (Musil and Goodenough, 11). Although Cx4 does not have to be phosphorylated in order to be localized to the membrane, Cx4 present in GJ plaques has been found to be phosphorylated almost exclusively to its P form and selectively resistant to solubilization by Triton X-100 (Musil and Goodenough, 11). However, it is not known if these phosphorylation(s) play a role in the formation and stabilization of GJs in plaques.

1...Phosphorylation of Cx4 by PKC and PKA

The stimulation of PKC by the short exposure to phorbol ester TPA results in a marked decrease in GJIC, as indicated by a reduction in dye transfer in different cell types (Rivedal and Opsahl, 001). PKC can phosphorylate Cx4 on S68 and S7 in vitro (Saez et al., 17; Lampe et al., 000). It has also been shown that S68 is a major site of phosphorylation in vivo (Lampe et al., 000). The cells expressing the site-directed mutant S68A were resistant to dye transfer inhibition by TPA. Examination of the channel conductance in cells treated with TPA has further supported the notion that the PKC-mediated phosphorylation of S68 in Cx4 is involved in the mechanism of GJIC inhibition by TPA since the S68A mutant (unlike wild-type Cx4) showed no decrease in the full open conductance state of GJ channels (Lampe et al., 000). PKA does not appear to phosphorylate Cx4 in vitro. However, compounds that stimulate an increase in cAMP levels generally enhance Cx4 intracellular levels. Additionally, studies in which PKA or PKC were introduced into L cells transfected with either wild type or S64P mutant Cx4 cDNA have implied that both kinases may play a complex role in GJIC regulation (Britz-Cunningham et al., 15).

1... Phosphorylation of Cx4 by Tyrosine Protein Kinases

Both EGF and PDGF receptor tyrosine kinase activation through ligand binding negatively affected GJIC causing a rapid inhibition of dye transfer and a significant increase in the phosphorylation of Cx4 on serine residues (Kanemitsu and Lau, 1; Hossain et al., 18). The effect of EGF receptor on Cx4 GJIC was shown to rely on activation of MAP kinase but not to be related to PKC activity (Kanemitsu and Lau, 1). MAP kinase seems to phosphorylate Cx4 directly in EGF-treated cells by targeting Ser55, Ser7, and Ser8 residues (Warn-Cramer et al., 16; 18). A triple mutant of these three residues formed functional GJs but was not affected by MAP kinase in response to EGF-stimulation (Warn-Cramer et al., 18). Evidence supporting the role of MAP kinase in the regulation of GJIC also comes from experiments in which purified MAP kinase was demonstrated to phosphorylate Cx4 channels reconstituted into liposomes and to induce a decrease in their conductance (Kim et al., 1).

The inhibition of GJIC by activation of the PDGF receptor involves more complex mechanisms and is less understood. The process appears to depend on both PKC and MAPK activity and may be regulated by other signaling pathways in addition to Cx4 phosphorylation (Hossain et al., 18; 1a; 1b). The potential sites of serine phosphorylation following stimulation of the PDGF receptor, the effective downstream serine protein kinase(s), and potential other regulatory protein(s) have not been determined.

Activation of non-receptor cytoplasmic kinases, such as pp60src, potentiates phosphorylation of Cx4 on tyrosine residues, resulting in a marked inhibitory effect on GJIC. The v-Src tyrosine kinase seems to phosphorylate Cx4 directly in vitro and in vivo (Loo et al., 15). Cx4 has been shown to interact directly with v-Src tyrosine kinase through the interactions between phosphotyrosine sites and proline-rich regions on Cx4 and the SH and SH domains on v-Src respectively (Kanemitsu et al., 17). Phosphorylation of Y65 and possibly Y47 may play a role in the observed impairment of GJIC. The current body of evidence strongly supports the importance of the Y65 residue in this process as a Y65F mutant was not able to associate with the activated pp60src kinase in Xenopus oocytes although it formed functional channels.

Another model of GJIC disruption by v-Src kinase has been recently proposed based on findings that are in direct conflict with the above mentioned results. In these studies, the activation of v-Src affected a Y65F mutant by decreasing junctional conductance in Xenopus oocytes (Zhou et al., 1). Additionally, the ability of v-Src to inhibit GJIC was eliminated by a treatment with the MEK inhibitor, PD805, implying that phosphorylation on a serine rather than a tyrosine residue can be of significance (Zhou et al., 1). MAP kinase may be a potential enzyme through which v-Src exerts its action although further studies are needed to clarify the mechanisms involved (Zhou et al., 1).

1...4Dephosphorylation of Connexins by Protein Phosphatases

The role of protein phosphatases in the regulation of gap junctions is only beginning to emerge. The recent studies of selective inhibition of different classes of protein phosphatases in stimulated cells have highlighted the importance of these enzymes in the regulatory nature of the connexin phosphorylation-dephosphorylation cycle. Okadaic acid, an inhibitor of protein phosphatases PP1 and PPA, has been reported to stimulate the phosphorylation of Cx4 in cultured rat myocytes, a process affecting GJ communication as indicated by an accompanying decrease in the unitary channel conductance (Moreno et al., 14). In another study the treatment of EGF-stimulated rat liver epithelial cells with okadaic acid slowed down the recommencement of GJIC and the dephosphorylation of Cx4 (Lau et al., 1). Similarly, the usually observed dephosphorylation of Cx4 upon treatment with 18-glycyrrhetinic acid was prevented in the presence of okadaic acid (Guan et al., 17).

The inhibitors of PPB protein phosphatases exhibited properties similar to those of PP1 and PPA classes in that they retarded the restoration of GJIC and prevented the dephosphorylation of Cx4 in cells treated with TPA (Cruciani et al., 1). However, only PPB class inhibitors were able to induce the above effect in cells that were subjected to hypoxia (Li et al., 000). Although the above evidence strongly supports the function of protein phosphatases in GJIC control, little is known about the exact identity of the enzymes involved. In addition, most of the studies to date have examined the impact of phosphatase inhibition in stimulated cells. The insight into the role of phosphatases in GJIC regulation in untreated cells is lacking mostly due to the fact that phosphatase inhibitors such as okadaic acid failed to alter GJIC in several unstimulated cell lines (Lau et al., 1; Guan et al., 17; Saez et al., 1). This implies a more subtle level of control that protein phosphatases maintain on GJIC regulation in unstimulated cells. It is also reasonable to expect that the mechanisms of phosphatase function in the regulatory process are cell type specific.

In summary, the following aspects of the role of the Cx phosphorylation/ dephosphorylation in the regulation of GJIC have been established (Lampe and Lau, 000)

1.After the arrival of a connexon at the plasma membrane, Cx phosphorylation is not always essential for the formation of a functional GJ channel,

.phosphorylation of specifc residues (Ser or Tyr) reduces GJIC, implicating the "gating" of GJ channels,

.phosphorylation may facilitate protein-protein interactions important for Cx regulation,

4.phosphorylation is important for Cx processing, i.e. trafficking, assembly and/or turnover,

5.dephosphorylation by protein phosphatases may be important for modulating the effects induced by phosphorylation.

Please note that this sample paper on gap junctions is for your review only. In order to eliminate any of the plagiarism issues, it is highly recommended that you do not use it for you own writing purposes. In case you experience difficulties with writing a well structured and accurately composed paper on gap junctions, we are here to assist you. Your cheap custom research papers on gap junctions will be written from scratch, so you do not have to worry about its originality.

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Short story by H.G Wells

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The little shop was not paying. The realisation came insensibly. Winslow was not the man for definite addition and subtraction and sudden discovery. He became aware of the truth in his mind gradually, as though it had always been there. A lot of facts had converged and led him there. There was that line of cretonnes - four half-pieces - untouched, save for half a yard sold to cover a stool. There were those shirtings at 4/4 d. - Bandersnatch, in the Broadway, was selling them at /4 d. - under cost, in fact. (Surely Bandersnatch might let a man live!) Those servants caps, a selling line, needed replenishing, and that brought back the memory of Winslows sole wholesale dealers, Helter, Skelter, & Grab. Why! how about their account?

Winslow stood with a big green box open on the counter before him when he thought of it. His pale grey eyes grew a little rounder; his pale, straggling moustache twitched. He had been drifting along, day after day. He went round to the ramshackle cash-desk in the corner - it was Winslows weakness to sell his goods over the counter, give his customers a duplicate bill, and then dodge into the desk to receive the money, as though he doubted his own honesty. His lank forefinger, with the prominent joints, ran down the bright little calendar (Clacks Cottons last for All Time). One - two - three; three weeks an a day! said Winslow, staring. March! Only three weeks and a day. It cant be.

Tea, dear, said Mrs. Winslow, opening the door with the glass window and the white blind that communicated with the parlour.

One minute, said Winslow, and began unlocking the desk.

An irritable old gentleman, very hot and red about the face, and in a heavy fur-lined coat, came in noisily. Mrs. Winslow vanished.

Ugh! said the old gentleman. Pocket-handkerchief.

Yes, sir, said Winslow. About what price

Ugh! said the old gentleman. Poggit-handker-chief, quig!

Winslow began to feel flustered. He produced two boxes.

These sir - began Winslow.

Sheed tin! said the old gentleman, clutching the stiffness of the linen. Wad to blow my pose - not haggit about.

A cotton one, praps, sir? said Winslow.

How much? said the old gentleman over the handkerchief.

Sevenpence, sir. Theres nothing more I can show you? No ties, braces?

Damn! said the old gentleman, fumbling in his ticket-pocket, and finally producing half a crown. Winslow looked round for his metallic duplicate-book which he kept in various fixtures, according to circumstances, and then he caught the old gentlemans eye. He went straight to the desk at once and got the change, with an entire disregard of the routine of the shop.

Winslow was always more or less excited by a customer. But the open desk reminded him of his trouble. It did not come back to him all at once. He heard a finger-nail softly tapping on the glass, and, looking up, saw Minnies eyes over the blind. It seemed like retreat opening. He shut and locked the desk, and went into the back room to tea.

But he was preoccupied. Three weeks and a day! He took unusually large bites of his bread and butter, and stared hard at the little pot of jam. He answered Minnies conversational advances distractedly. The shadow of Helter, Skelter, & Grab lay upon the tea-table. He was struggling with this new idea of failure, the tangible realisation that was taking shape and substance, condensing, as it were, out of the misty uneasiness of many days. At present it was simply one concrete fact; there were thirty-nine pounds left in the bank, and that day three weeks Messrs. Helter, Skelter, & Grab, those enterprising outfitters of young men, would demand their eighty pounds.

After tea there was a customer or so - small purchases some muslin and buckram, dress-protectors, tape, and a pair of Lisle hose. Then, knowing that Black Care was lurking in the dusky corners of the shop, he lit the three lamps early and set to refolding his cotton prints, the most vigorous and least meditative proceeding of which he could think. He could see Minnies shadow in the other room as she moved about the table. She was busy turning an old dress. He had a walk after supper, looked in at the Y.M.C.A., but found no one to talk to, and finally went to bed. Minnie was already there. And there, too, waiting for him, nudging him gently, until about midnight he was hopelessly awake, sat Black Care.

He had had one or two nights lately in that company, but this was much worse. First came Messrs. Helter, Skelter, and Grab, and their demand for eighty pounds - an enormous sum when your original capital was only a hundred and seventy. They camped, as it were, before him, sat down and beleaguered him. He clutched feebly at the circumambient darkness for expedients. Suppose he had a sale, sold things for almost anything? He tried to imagine a sale miraculously successful in some unexpected manner, and midly profitable, in spite of reductions below cost. Then Bandersnatch Limited, 101, 10, 10, 105, 106, 107 Broadway, joined the siege, a long caterpillar of frontage, a battery of shop fronts, wherein things were sold at a farthing above cost. How could he fight such an establishment? Besides, what had he to sell? He began to review his resources. What taking line was there to bait the sale? Then straightway came those pieces of cretonne, yellow and black, with a bluish-green flower; those discredited skirtings, prints without buoyancy, skirmishing haberdashery, some despairful four-button gloves by an inferior maker - a hopeless crew. And that was his force against Bandersnatch, Helter, Skelter, & Grab, and the pitiless world behind them. Whatever had made him think a mortal would buy such things? Why had he bought this and neglected that? He suddenly realised the intensity of his hatred for Helter, Skelter, & Grabs salesman. Then he drove towards an agony of self-reproach. He had spent too much on that cash-desk. What real need was there of a desk? He saw his vanity of that desk in a lurid glow of self-discovery. And the lamps? Five pounds! Then suddenly, with what was almost physical pain, he remembered the rent.

He groaned and turned over. And there, dim in the darkness, was the hummock of Mrs. Winslows shoulder. That set him off in another direction. He became acutely sensible of Minnies want of feeling. Here he was, worried to death about business, and she sleeping like a little child. He regretted having married, with that infinite bitterness that only comes to the human heart in the small hours of the morning. That hummock of white seemed absolutely without helpfulness, a burden, a responsibility. What fools men were to marry! Minnies inert repose irritated him so much that he was almost provoked to wake her up and tell her that they were Ruined. She would have to go back to her uncle; her uncle had always been against him and as for his own future, Winslow was exceedingly uncertain. A shop assistant who has once set up for himself finds the utmost difficulty in getting into a situation again. He began to figure himself crib-hunting once more, going from this wholesale house to that, writing innumerable letters. How he hated writing letters! Sir, - Referring to your advertisement in the Christian World. He beheld an infinite vista of discomfort and disappointment, ending - in a gulf.

He dressed, yawning, and went down to open the shop. He felt tired before the day began. As he carried the shutters in, he kept asking himself what good he was doing. The end was inevitable, whether he bothered or not. The clear daylight smote into the place, and showed how old and rough and splintered was the floor, how shabby the second-hand counter, how hopeless the whole enterprise. He had been dreaming these past six months of a bright shop, of a happy couple, of a modest but comely profit flowing in. He had suddenly awakened from his dream. The braid that bound his decent black coat - it was a trifle loose - caught against the catch of the shop door, and was torn away. This suddenly turned his wretchedness to wrath. He stood quivering for a moment, then, with a spiteful clutch, tore the braid looser, and went in to Minnie.

Here, he said, with infinite reproach; look here! You might look after a chap a bit.

I didnt see it was torn, said Minnie.

You never do, said Winslow, with gross injustice, until things are too late.

Minnie looked suddenly at his face. Ill sew it now, Sid, if you like.

Lets have breakfast first, said Winslow, and do things at their proper time.

He was preoccupied at breakfast, and Minnie watched him anxiously. His only remark was to declare his egg a bad one. It wasnt; it was flavoury, - being one of those at fifteen a shilling,- but quite nice. He pushed it away from him, and then, having eaten a slice of bread and butter, admitted himself in the wrong by resuming the egg.

Sid, said Minnie, as he stood up to go into the shop again, youre not well.

Im well enough. He looked at her as though he hated her.

Then theres something else the matter. You arent angry with me, Sid, are you, about that braid? Do tell me whats the matter. You were just like this at tea yesterday, and at supper-time. It wasnt the braid then.

And Im likely to be.

She looked interrogation. Oh, what is the matter? she said.

It was too good a chance to miss, and he brought the evil news out with dramatic force. Matter? he said. 1 done my best, and here we are. Thats the matter! If I cant pay Helter, Skelter, & Grab eighty pounds, this day three weeks -- Pause. We shall be sold up! Sold up! Thats the matter, Min! SOLD UP!

Oh, Sid! began Minnie.

He slammed the door. For the moment he felt relieved of at least half his misery. He began dusting boxes that did not require dusting, and then reblocked a cretonne already faultlessly blocked. He was in a state of grim wretchedness; a martyr under the harrow of fate. At any rate, it should not be said he failed for want of industry. And how he had planned and contrived and worked! All to this end! He felt horrible doubts. Providence and Bandersnatch - surely they were incompatible! Perhaps he was being tried? That sent him off upon a new tack, a very comforting one. The martyr pose, the gold-in-the-furnace attitude, lasted all the morning.

At dinner - potato pie - he looked up suddenly, and saw Minnies face regarding him. Pale she looked, and a little red about the eyes. Something caught him suddenly with a queer effect upon his throat. All his thoughts seemed to wheel round into quite a new direction.

He pushed back his plate and stared at her blankly. Then he got up, went round the table to her - she staring at him. He dropped on his knees beside her without a word. Oh, Minnie! he said, and suddenly she knew it was peace, and put her arms about him, as he began to sob and weep.

He cried like a little boy, slobbering on her shoulder that he was a knave to have married her and brought her to this, that he hadnt the wits to be trusted with a penny, that it was all his fault; that he had hoped so - ending in a howl. And she, crying gently herself, patting his shoulders, said ssh! softly to his noisy weeping, and so soothed the outbreak. Then suddenly the crazy bell upon the shop door began, and Winslow had to jump to his feet, and be a man again.

After that scene they talked it over at tea, at supper, in bed, at every possible interval in between, solemnly - quite inconclusively - with set faces and eyes for the most part staring in front of them - and yet with a certain mutual comfort. What to do I dont know, was Winslows main proposition. Minnie tried to take a cheerful view of service - with a probable baby. But she found she needed all her courage. And her uncle would help her again, perhaps, just at the critical time. It didnt do for folks to be too proud. Besides, something might happen, a favourite formula with her.

One hopeful line was to anticipate a sudden afflux of customers. Perhaps, said Minnie, you might get together fifty. They know you well enough to trust you a bit. They debated that point. Once the possibility of Helter, Skelter, & Grab giving credit was admitted, it was pleasant to begin sweating the acceptable minimum. For some half-hour tea the second day after Winslows discoveries they were quite cheerful again, laughing even at their terrific fears. Even twenty pounds to go on with might be considered enough. Then in some mysterious way the pleasant prospect of Messrs. Helter, Skelter, & Grab tempering the wind to the shorn retailer vanished - vanished absolutely, and Winslow found himself again in the pit of despair.

He began looking about at the furniture, and wondering idly what, it would fetch. The chiffonier was good, anyhow, and there were Minnies old plates that her mother used to have. Then he began to think of desperate expedients for putting off the evil day. He had heard somewhere of Bills of Sale - there was to his ears something comfortingly substantial in the phrase. Then, why not Go to the Money-Lenders?

One cheering thing happened on Thursday afternoon a little girl came in with a pattern of print, and he was able to match it. He had not been able to match anything out of his meagre stock before. He went in and told Minnie. The incident is mentioned lest the reader should imagine it was uniform despair with him.

The next morning, and the next, after the discovery, Winslow opened shop late. When one has been awake most of the night, and has no hope, what is the good of getting up punctually? But as he went into the dark shop on Friday he saw something lying on the floor, something lit by the bright light that came under the ill-fitting door - a black oblong. He stooped and picked up an envelope with a deep mourning edge. It was addressed to his wife. Clearly a death in her family - perhaps her uncle. He knew the man too well to have expectations. And they would have to get mourning and go to the funeral. The brutal cruelty of people dying! He saw it all in a flash - he always visualised his thoughts. Black trousers to get, black crape, black gloves - none in stock - the railway fares, the shop closed for the day.

Im afraid theres bad news, Minnie, he said.

She was kneeling before the fireplace, blowing the fire. She had her housemaids gloves on and the old country sun-bonnet she wore of a morning, to keep the dust out of her hair. She turned, saw the envelope, gave a gasp, and pressed two bloodless lips together.

Im afraid its uncle, she said, holding the letter and staring with eyes wide open into Winslows face. Its a strange hand!

The postmarks Hull, said Winslow.

The postmarks Hull.

Minnie opened the letter slowly, drew it out, hesitated, turned it over, saw the signature. Its Mr. Speight!

What does he say? said Winslow. Minnie began to read. Oh! she screamed. She dropped the letter, collapsed into a crouching heap, her hands covering her eyes. Winslow snatched at it. A most terrible accident has occurred, he read; Melchiors chimney fell down yesterday evening right on the top of your uncles house, and every living soul was killed - your uncle, your cousin Mary, Will and Ned, and the girl - every one of them, and smashed - you would hardly know them. Im writing to you to break the news before you see it in the papers --The letter fluttered from Winslows fingers. He put out his hand against the mantel to steady himself.

All of them dead! Then he saw, as in a vision, a row of seven cottages, each let at seven shillings a week, a timber yard, two villas, and the ruins - still marketable - of the avuncular residence. He tried to feel a sense of loss and could not. They were sure to have been left to Minnies aunt. All dead! 7x7x5 / 0 began insensibly to work itself out in his mind, but discipline was ever weak in his mental arithmetic; figures kept moving from one line to another, like children playing at Widdy, Widdy Way. Was it two hundred pounds about - or one hundred pounds? Presently he picked up the letter again, and finished reading it. You being the next of kin, said Mr. Speight.

How awful! said Minnie in a horror-struck whisper, and looking up at last. Winslow stared back at her, shaking his head solemnly. There were a thousand things running through his mind, but none that, even to his dull sense, seemed appropriate as a remark. It was the Lords will, he said at last.

It seems so very, very terrible, said Minnie; auntie, dear auntie - Ted - poor, dear uncle --

It was the Lords will, Minnie, said Winslow, with infinite feeling. A long silence.

Yes, said Minnie, very slowly, staring thoughtfully at the crackling black paper in the grate. The fire had gone out. Yes, perhaps it was the Lords will.

They looked gravely at one another. Each would have been terribly shocked at any mention of the property by the other. She turned to the dark fireplace and began tearing up an old newspaper slowly. Whatever our losses may be, the worlds work still waits for us. Win-slow gave a deep sigh and walked in a hushed manner towards the front door. As he opened it, a flood of sunlight came streaming into the dark shadows of the closed shop. Bandersnatch, Helter, Skelter, & Grab had vanished out of his mind like the mists before the rising sun.

Presently he was carrying in the shutters, and in the briskest way, the fire in the kitchen was crackling exhilaratingly, with a little saucepan walloping above it, for Minnie was boiling two eggs, - one for herself this morning, as well as one for him, - and Minnie herself was audible, laying breakfast with the greatest eclat. The blow was a sudden and terrible one - but it behoves us to face such things bravely in this sad, unaccountable world. It was quite midday before either of them mentioned the cottages.

Ar hun o bryd mae'r cwmni yn mynd yn gret. Ar gyfartaledd mae pob berson syn mynd i fewn i siop mam yn gwario £.6. Mae hwn yn 0c lan ar cyfartaledd 001.Mae'r siop yn cyflwng dda ac mae popeth yn dda yn yr siop. Ond fel pob siop neu weithdu mae ambell i stwr yn ddigwydd rhwng y staff. Yn siopiau arall fel Porth Tywyn a Sospan mae'r siopiau yn colli arian.

Maer wybodaeth yn cael ei storio ar cyfrifiadiron y swyddfa ym Mharc Trostre. Maer cwmni yn rhedeg rhyw fath o rhaglen syn edrych fel rhyw addapiwyd o Microsoft Excel™ achos mae rhyw fath o taemlen ar y chwith or screen a wedyn rhyw fath o rhaglen scanio. Gallwch cael wybodaeth allan or rhaglen trwy teipio mewn eich cynnyrch ac maen wilio am y preisiau, dyddiau cynnyrch a fath o fwyd.

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Does dim lawer o broblemmau yn y rhaglen. Yn unrhyw perygl fawr fel pob cwmni yw cael Virus.

Gall hwnnw ddinistrio'r cyfrifiaduron ac rhan pwysig y cwmni.

Dydu Jenkins ddim yn ddefnyddio llawer o hysbysebion. Y prif hysbyseb yw yn y Llanelli star. Does ddim angen llawer o hysbysebion ar Jenkins achos mae ffordd arall o hysbysu am ddim. Yn siml, maer person sy'n prynnu'r cynnyrch yn ddweud wrth ei ffrindiau ac wedyn mae'r ffrind yn ddweud wrth ffrind ac yn y blaen. Mae hwn yn ddigwydd hefyd am bron pob siop on mae'n ddigwydd yn aml am pobyddion, siopiau bwyd cyflym (e.e Cheinis a siop sglodion) ac ambell i waith siopiau fawr fel Tesco™ a ASDA™.

Hefyd, mae Siopiau Jenkins yn rhoi bwrddiau ddu tu allan yr siop ble allair weithwyr rhoi cynygion fel ( pasty am £1).

Does ddim hysbysebion teledu, radio neu ddim byd,dim ond streion rhwng y pobl, y papur Llanelli Star™ ar fwrdd du.

Mae cyfrifiaduron yn bwysig yn fusnes pwysig. Os ysgrifennai person wybodaeth ar papur ac ar ol amser fach collwyd y papur, beth wna y person, ysgrifennu'r waith allan eto?. Ond ar cyfrifiaduron gall neu mwy o pobl cael y wybodaeth ar nifer fawr o cyfrifiaduron ac wedyn, gall y person tynnu lan y wybodaeth achos maen hawdd i safio. Hefyd, gall person safior waith ar ddisc a cadwr waith yn cyfrifiadur adref.

Hefyd ar papur maen galed i creu graffiau, maen cymeryd rhy gormod o amser, ond ar cyfrifiaduron, maen hawdd, gallwch creu graffiau yn bron ddim amser. Gallwch gywiro waith yn hawdd ar cyfrifiadur ond mae hi'n gymlaeth ar pap

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Beth rwy am wneud yn y brosiect. Rwy am...

-Creu prosiect syn ddangos wybodaeth dda enghlyn ar fusnes David Jenkins Ltd.

-Ddefnyddio popeth sydd ar gael ac am creu prosiect lliwgar, diddorol ac prosiect sy'n mynd i ennill marciau.

-Gadael i'r darllenydd wybod popeth am y fusnes.

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-Helpu i creu system bresennol well a help hysbysebu'r cwmni yn well.

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