Friday, September 23, 2016

"ANOTHER DAY, ANOTHER DREAM"



Hope Springs Eternal!

He leaned into the curtains to see who was there. The crowds were milling around. Some taking to their seats, others standing and observing others, still others wanting to be noticed cast their eyes hither and yon for recognition. The porcelain white skinned women gowned and beautified hovered on the arms of their escorts while some with their noses pitched slightly higher walked alone. Their aloneness a symbol of their success as men gathered around them, showering them with cheek to cheek fake kisses. These, he thought were the famously rich people and he, an off the street hobo had been cast to play a part in the play. This was going to be the answers to his prayers. Who knows, he thought, I might be able to mingle with them someday. His prayers had been answered.



The crowd stilled in their seats. The lights dimmed. A trumpet sounded and then all was abuzz with stagehands, actors and set mobility. He was told as he had rehearsed many times now to appear in his native clothing of the smelly rags that had seen the street water, rain water and other unnatural fluids dried and permanently stained on the brown threadbare cloak. His face unshaven with a dark stubble and his mind was set to memorize the few words he was supposed to speak. He went over and over them in his mind, half reciting to himself and to the walls and curtains around him.




Time speeded and slowed as he watched with admiration, the efficiency and alacrity of the stagehands changing the set to keep the spectators mesmerized to the underlying theme of the play. The lights brightened, then dimmed and then brightened again in cycles to keep the spectators memorized by the mirage. The actors laughed, cried, showed anger and disgust and it all appeared real. He was transfixed. From his eyes that had seen a stainless steel pen fall from the pocket of a man on a fast gallop on the street, late for work, he had called out to him as he retrieved it from the street corner for him, the man had turned, looked at him and the offering and shook his head after seeing his pen clasped in dirty hands and walked on, to now in front of these wealthy and important people, all under the same majestic canopy. He still had the pen. He considered it his good fortune, since it was the same afternoon, when another well dressed man had asked him if he would be interested to play a part in a play for money.

The curtain was lit up once again as the intermission ended and the shuffling crowd gathered in their seats. The middle act created the scene of playful elegance and chivalry on stage.

He could hear his breathing and the faint whistle of years long exposure to the pollutants from the automobile exhausts as he sat begging for food on the street corners. The fume had taken some toll on his bronchioles. He was unable to walk the entire street without stopping and catching his breath. His pulse quickened as the play continued to hurtle towards the end and the gasps and muted sounds of disbelief in this suspended disbelief echoed through the large auditorium. He could from his perch see the two mezzanines filled with awestruck spectators watched spellbound as his moment of fame approached.

His moment had come. He walked on to the stage, the bright lights dimmed and he shuffled on the staged street corner where he was meant to stand. The streetlamp overhead on the spot lit the floor brightly encircling him in its lumens. All else was dark. He could not see beyond the first row of the spectators. He shuffled to the spot near the lamp and leaned against it for a few seconds as he and been told. He looked down on the floor and picked up a coin placed strategically for him to acquire. He rubbed the coin against his ragged clothes and uttered the words he had memorized.

“Another day, another dream.” As he pocketed the coin, he collapsed on the stage floor. The streetlamp light dimmed to dark. He got up as the stagehands scurried past him.

The stage brightened and the an actor took center stage, To the last syllable of recorded time, “And all our yesterdays have lighted fools the way to dusty death. Out, out, brief candle!
Life’s but a walking shadow, a poor player that struts and frets his hour upon the stage and then is heard no more. It is a tale told by an idiot, full of sound and fury, signifying nothing.” 

A thunderous ovation broke out as the crimson gilded curtain came down and swallowed the stage. He felt his heart swell with pride. His moment in life had come.

The man who had asked him to play the part appeared from nowhere, “Thank you. You were great,” he says. He hands him two hundred dollar bills. “This should help you,” as he looks back towards someone unseen, “Joe” he points out to a stagehand, “could you please walk him to where he has to go.” And he was gone.

Back out on the cold street, he watches the limousines gorging themselves with people covered in satins and silks as the parade of the beautiful people leaves the theater. Soon the normal late night bustle begins to take over and he is left staring at the marquee.


He realizes, he is the idiot. His minute of glory was to bring a real wretched down trodden from the street to magnify the imagery and pretense of the play. The rich and famous were back clinking glasses in some expensive restaurants or brick lined carpeted homes pretending to diminish the evils of poverty in society as they absolved themselves off their guilty pleasures. “Did you see that poor wretched person in the end. He was so real!” they would claim. “Nah! he was a high paid actor! its Broadway after all, dear.” “Either case,” a slightly corpulent gentleman confided, “don’t look at me, I empty my pockets to all the beggars on the street every day.” Alas discussing the wretched  distilled away the humor in the air and made everyone uneasy and restless.

“Yeah John,” the young financial district upstart chimed, “only with quarters and nickels?” The fat man ignored the slant, “Hey, doesn't anyone know the borough politician, I think having beggars lowers the real estate values and doesn’t look good either.” A general consensus of nodding heads followed. Silence broke out for a while. Someone argued about taxes and the conversation shifted to vacation homes, yachts and airplanes.

A muted repentance of hypocrisy, well, is still hypocrisy.

Sunday, September 11, 2016

PHYSICIAN SUICIDE



PHYSICIAN SUICIDE
&

The misshapen chaos of well seeming forms

Were I a soldier in an infinite army of like minded individuals, I might march to the same beat, move the limbs in the slow and sculpted movement of experienced sinews, hold my head in the temperate form paralleling the majesty of the uniform, sing to the tunes of the collective, view the world from the same pulpit as the preacher and file away the dreams of my youth in the forbidden corners of my imprisoned personal vanity. All semblance of me buried in the form of a single line made of the infinite numbers of similar dots.

But I am not a wanton of simplistic pleasures of agreeability or contextually. I am not the victim of the mind that seeks to swim in the collective tank. I am the unum that desires to seek the fortunes of knowledge, not the pecuniary one but the enlightened angel that hides behind the soft covers of group think beast.

The misshapen chaos of the well seeming forms have come to haunt us. They disguise in the costumes so appealing and seemingly enduring that the lust for the luster and desire for the hues overpowers the senses. These chaotic circles envelope us in our entirety casting a stranglehold on our imagination, our essence, our individuality and our thoughts.

Such is the price we pay for these well seeming forms that caress and cajole our minds. A price too steep, I think, that threatens our very humanity.

Does the calculated mind that oversees such calamity not understand the consequence of its actions? I dare say, it does not. For even as it displeases, it continues to erect newer barriers and rings of confusion around the substance of those well meaning forms. The barriers get higher and higher as their depth gets deeper and deeper, becoming fortresses within fortresses all encased in the realm of meaning well.

Forms such as these, so cruel to the touch that they freeze the fingers, which probe. So dense that they repel the thought that dares and so vicious that they resort to violence against the mind that wonders, captivatingly ossifying any inkling that might threaten them.


These forms take human lives in the form of suicide. Physician suicides. Doctor losses arising from the untimely frost on the wisest minds that roam. These forms bury the architecture of experiential wisdom under the guise of “think not, do,” a form so beguiling that baser natures cannot repudiate. So what if a few die, so what if the many don't get what they should, in the end there is no readiness.

The chaos that ensues destroys the very foundation of the structure that once stood for health and happiness guarded by the wiser angels amongst us. Now the ruins spread like a conflagration, destroying everything but leaving behind a trail of embers; the charred remains of a once polite and very human loving thought.

Physicians take their own lives, mentally shattered from the compressive force of bureaucracy that claims other’s safety by erecting maze upon maze of uncertainty and demand. The maze so clever that exits are all but closed after the entry. Only the solid wall of policies, regulations and mandates exist as you run through the maze, constantly reaching dead ends that never seem to end. Retracing steps to see where one went wrong only to find another dead end. In these hurdles, faced with the never ceasing complexity of the demands, the mind gives up. The center ceases to fathom and cannot hold together the psyche made so fragile by the fear that grinds at the root of every measured step taken. No one is the wiser of the scars that never felt the wound. it seems that no one cares.

When 300-400 physicians commit suicide and female physicians have a 250-400% increased risk of suicides as compared to females in other professions, and 9.4% of the final year medical students are dazed and lost to this monster annually, something is terribly wrong! Something rots at the core of this accelerating phenomenon.

Medicine is complex, Medical care is an art and less of a science than what is believed in the current reductionist society, so tempered with the lust of prediction and probability. The demise of good medical care is near and continues to collapse at the periphery under the erected weighty barriers and threatens one day soon to collapse the center as well. It is humanity’s Hadrian wall.

What resurfaces from this creative destruction is a future of disembodied humans, of virtual machines, of deprivation and an unimaginable lust for the shiny object that will fail to define the better angels of our humanity.

“Virtue itself turns vice, being misapplied
And vice sometimes by action dignified”

Am I a nihilist? I often wonder. But the recent past has been accelerating at breakneck speed for me to be otherwise. We have arrived at the misshapen chaos that no one seems to understand all erected on the foundation of well seeming forms!


Wednesday, September 7, 2016

THE ECONOMIC SUBSTRATE

The Ultimate Substrate of Economic Health is embodied in what happens to any life. How the person takes care of himself or herself, how the family and society support that person. Overtime it appears that we in the western world have devolved from personal responsibility to blaming every pitfall on others. Some use it to benefit themselves, others use it to absolve themselves of guilt. The pattern remains the same. The cycle renews and has renewed for many generations, ultimately to be replaced by a new cycle.

One cycle appears to be coming to an end and where the next cycle begins is anyone’s guess?


The fundamentals define our future. In this complex world of finance in the United States, there are 320 million players who have an intimate stake in the outcome. The young ones who will create a new future, the middle aged who are functioning on maintaining the current paradigm and the elderly who hope to remain comfortable in their waning years.

The complex colorful origami is still made of paper in the end and fundamentals still matter for any outcome.

So here is a short rendering of the forces that are currently in play that create our economic futures. This by no means is a dystopian future, nor is it a utopian Shangdi-La. It is.

Where the future might lead is another Mind Map yet to come…but will come!


Please comment… it will make for a better conversation. 

Monday, September 5, 2016

IMAGINE

Imagine if you will, you are lying on a field of grass in an open meadow, the declining sun casting its golden hue that you are not aware of, except with the brightness cast on the cloaked retina. Imagine the thoughts of the preceding days clashing within the mind. Imagine that some thoughts cling on to others, like glue, while others fall away in a dried heap. Imagine further that the links between the glued thoughts grow firm and attract others together. Imagine the smell of the grass wafts in like a catalyst opening bonds and closing others between those thoughts. Those inaccessible thoughts stacked into layers of consciousness can suddenly be accessed by the prudence of a relational dynamic insight. Imagine all that and what do you suppose would happen?



Some have solved problems while buoyed by water, others have allowed the miseries of an industrial London to form the basis of classic literature while still others have surprised themselves after being trapped in a hopeless spiral of confusion and colliding thoughts with an answer while resting or awakening from a deep sleep. 



To say that every idea or innovation comes from such bonding would be erroneous. Not having experienced such a transformative explosion of thought confluence or not having entertained any weighty matters or simply having being confined to the empiricism of reductive thoughts, it is difficult to imagine, such a concept. As one such mathematician named Evariste Galois claimed, “Science progresses by a series of combinations where chance plays not even the smallest of parts.” Unfortunate for Galois, he died at the age of 21 in a duel, never recognized by his contemporaries including Poisson for the genius within. Imagine had he lived…there would have been more time, more reflection, more layers of contextual content and more eurekas?

The wonders of free thought is the wonder of finding solutions. After working on a problem over many days trying to find if a straight line that did not meet the vertices of a triangle could not intersect the sides of that triangle, Roland Dobrushin determined he could not solve the problem, because he did not understand “the straight line.” He won the mathematic prize with that comment. Imagine that, stepping down the rungs of the ladder into the deep, dark hole and finding no light replied as he did. All answers seemed to lead to the “mystery within Euclid’s geometry.”



The question then arises, “Does knowledge flow downwards, or does it boil up from the depths?” It is a question long forgotten by the modern minds. Knowledge to them is a series of concatenations inspired by "their applied wisdom." This follows in such things as curricula where Chapter One precedes Chapter Two and after Chapter Twenty the student is no wiser for it. The teacher reads the written words, answers the questions contained from the instructor cheat sheets and the student grades are graphed on the Gaussian curve. From outlier to outlier, no one steps back to understand the motive behind the year spent. What was Hazard Ratio or the Regression Line supposed to represent? What made Galois go on a duel the night before, fearing his death, pen his thoughts and experiments and send to his friend? What was Archimedes’ “Eureka” moment and what significance did it have for whom and why? 



As the candle extinguishes and the hand that holds the pen losses it’s grip, ink falls on the paper below creating the ink-splotch, the morning sun might reveal an answer to the problems from the splotch itself and another “Eureka” moment arrives. Such are the moments that explode from the merger of ideas when the mind is freed from conjecture. As Friedrich August KekulĂ© von Stradonitz found out that the ring structure of benzene came to him in a dream where a snake was eating its own tail or Newton seeing an apple fall discovered gravity, are examples of those eureka moments that defy plod through a problem mechanism, and arriving at the truth, redefines the need for cerebral lateralization to conjure up links in the peace of rest.

Gavin Weightman in “Eureka; how invention happens” states, “But time and again, even in the twentieth century, those innovations which have transformed our lives have been pioneered not by the big guns of established industries or the laboratories of the most brilliant scientists but by a few visionaries who had the temerity to imagine they could make the impossible possible.”



Modern day educating is about “crossing the Ts and dotting the Is.” The mind is never encouraged to expand the horizons of understanding. The written word is forced as the crucible of knowledge. One wonders even to this day how those that create and innovate do so given the mountains of busywork in learning?

The answer comes from the few who have expanded the largest spheres of knowledge and understanding; Steve Jobs (Apple), Bill Gates (Microsoft), Mark Zuckerberg (Facebook), Michael Dell (Dell Computer), Julian Assange (Wikileaks Founder) and Evan Williams (Twitter). Most times it is the slow boil of an idea that curriculum cannot address, which becomes the new paradigm. Other times it is an experiment that succeeds accidentally at a scale not fathomed and still other times it is the ingenuity of cobbling up parts to make and distribute hardware from a dorm that breaks the mold. Indeed, as Johann Heinrich Pestalozzi wondered; the heart, gives the sense of union, the mind, a sense of reflection and the hand, work through action, sequentially and concurrently as they conspire to create innovations and advance human thought. All imagined! All inductive! All creations, sans curriculum! 


Imagine what you can do with an idle moment of thought?


Wednesday, August 31, 2016

Its the ECONOMY Stupid!

Its the ECONOMY Stupid!
Its the ECONOMY Stupid!
Its the ECONOMY Stupid!

Dissecting the innards of the largest economy in the world is like David battling against a 100 Goliaths! But in the quiet peaceful doldrums of summer, one can sit down under the shade of a tree, let the breezes fill the space and cajole the mind into contemplation.

My take on the Quantitative Easing and its impact on the economy and how the experts continue to make it worse by injecting more of their unwanted and un-needed help. The Too Big to Fail concept has burdened the citizenry in ways that we have not fully felt yet, except in the slow drip of job losses. Although the unemployment remains at 4.9% and one has to ask about those 95 million sitting on their hands as well as how does one count and keep a straight face...but then I digress. Indeed at the end of the day the unfunded liability can be defaulted on and the Debt can be defaulted on and what will be left is a Third World Global Order...to the delight of some!

Wall Street continues to sell stocks at higher highs due to the cheap money available for stock buybacks, but at what costs...CAPEX? The future? main Street struggles to keep people employed, but demand decreases because the consumer is tapped out. If 70% of the economy is fueled by the consumer in the U.S. and 40% of the U.S. consumer fuels the world economy, a tapped out U.S. consumer with limited discretionary income and no job is not the answer anymore.

While Regulations continue to place a stranglehold on businesses the art of negotiating the Policy world costs more than $2 Trillion. The Impact of Regulatory Costs on Small Firms article from Small Business Association written in 2010 placed the cost at $1.75 Trillion.
Take a look at this Mind Map below. The arrows point to the influencer of the influenced. The tentacles of the FED's Quantitive Easing Trap continues to unfold and affect the Economy in ways that were never imagined. Of course the expert economists will find fault to protect their turf, but for us simple people with limited knowledge, this is a good place to start.


If you have opinions please convey them…it will make for a robust discussion. Thank you!


Friday, August 26, 2016

"WHAT WILL IT TAKE?"



In the matter of writing, exclamation points are used for varying degrees of expressions. Sometime we mean, “look how horrible!” and other times we think, “Can you believe it!” But each exclamation point has a story to tell. Some saucy, some sticky, some plain vanilla wonderful. Sometime with exclamation points, we want to invite the attention of another to come in and enter our thoughts - a difficult proposition indeed. But what about the curly exclamation point that we call the question mark? Where does that take us? And therein lies a tale…

“What will it take?” The answer to that question is not easily available. The answer seems hidden in the last missing page of a well worn mystery novel. Conjuring up ideas of how to answer a question like that one takes skill and wading into an ocean of emotions. Indeed what would it take to fix a problem like Joe’s?

Joe, you see has a medical riddle. He carries a truant gene that seems to create the mischief in his cells. Joe is painfully aware of this for he has been told of the same after three surgeries and countless therapeutic endeavors to salvage his life. He is safe for now. Content at working his daily dose of living as a salesperson in a shoe store. He is on a constant follow up with his oncologist and each visit is marked with the growing fear of the inevitable. He has learned to avoid the downer thoughts but the fog of uncertainty keeps visiting him in times of repose. He is a truly wonderful gentleman. His once blond hair is now gone replaced by a shaved head. his physique is equally diminished after many bouts under the scalpel and chemicals. A once brawny physique, which he claimed he had, is now replaced with the scrawny shadow of the former self that I see. Yet he claims he sees life in a better light now. He walks daily, communes with nature and has a smile that would brighten any dull cloudy day. Faced with the prospects of a hazy future, he has learned the art of living and the wonders of the limits of survival that each one of us take for granted. He is working on a doctorate in psychology. He already has one in physics.

“What will it take?” he asks again. “We shall see Joe, we are working on it.”

“Sorry Sir, but Joe’s plan does not approve the PET/MRI scan without further information and a certified letter from the oncologist.” The tinny voice speaks from the Insurer never-never-land. “But I am the oncologist!”

“We still need documentation Sir.”

“We have received the documentation, but the test is still denied.” a different de-empathized voice responds a week later.


“But I certified the reasoning for the test.”

“Would you like to speak with the supervisor?”

“Sure!”

After the click and the muzak that invites frustration another click and a human voice arrives, “May I help you?”

I am looking for an approval for a PET/MRI scan based on the certified documentation I sent earlier.”

“Could you briefly explain the issue. That will help greatly.”

A ten minute explanation later, we are running in circles.

“Are you a physician?”

“No sir, I am a Registered Nurse.”

“May I speak with physician in your department.”

“Surely.” And the shifting sounds on the telephone cease momentarily and then the infernal muzak comes back to haunt.

“Hello, may I help you?”

“Are you a doctor?”

“Yes, my name is Jane Blah, Blah.”

“I am looking for an approval for a PET/MRI scan.”

“Um, I looked at the records you provided and I am sorry but based on the data, I cannot approve the test.”

“Are you an oncologist?”

“No, I am a pediatrician.”

“Do you have any training in oncology?”

“No.”

“Then how can you deny this request?”

“We have criteria for best practices based on the Choosing Wisely programs and we adhere to that. Besides, we are constantly reviewing the established criteria.”

“Oh! Okay. Do you mind giving me your full name, your position at this Insurance company and your official phone number?”

“Sure, why?

“I will send that information to my attorney and ask the patient to hire an attorney as well so that the future is not as murky for his survival or for an unnecessary litigation. While you adhere to your criteria, a patient's future is at stake that your have promised to help mitigate their financial health needs through premiums. I am sure you will prevail!” The sarcasm and irony was not lost on the receiver.

“There is no need for that!” The voice on the other end has some degree of angst now.

“There is a need for this, when you arbitrarily try to make decisions based on your esteemed guidelines without consideration of your client’s needs.”

“Let me see what I can do.”

The phone goes dead.


And therein lies a tale to ponder upon! This exclamation point has many meanings but only a few very clear expressions!

Thursday, August 11, 2016

CANCER CELL CYCLE & the CDK INHIBITORS



Interesting thing about medicine is that knowledge never seems to end. It comes in waves as brilliant folk look upon failures and success with a critical eye and not through the lens of judgment. For both adding to success and learning from failure ultimately defines progress.


We have known about the cell cycle for quite a long time. Lets look upon the cell as it divides from one into two. Such division is required for the growth and well being of the human body. Cyclins are a very Important part of Cell Division and growth!


In short a Cell must go through the cycle of acquiring various agencies of proteins and enzymes before it can divide into two. Cells are in a continuous state of growth and replication. The stages move from G1 —> S —> G2 —> M and back to —>G1

(G1 = Initial state)

(S = Synthesis phase where the cell synthesizes various needed agencies within)

(G2 = Bulking up stage and acquired various agencies)

(M = Mitosis stage or the actual act of division)

There is a G0 cell phase which is interdependent on the G1 phase. G0 cells are quiet but functional, and not surging through the cell cycle. They can recruited into the cycle when need arises.

Chemotherapeutic drugs affect the cells cycle in various stages. eg. Vinca alkaloids and Taxanes in the M phase and the Alkylating agents in the G1 - S phase etc.



We shall focus on the G1 - S Phase inhibitors where most of the mischief seems to take place.

When an external mitogenic stimulus is received, in oncogenesis (tumorogenesis) at the G1 phase, the D1 Cyclins merge with the CDK4 and CDK6 to create a D:CDK4/CDK6 complex. 

(D1 Cyclins + CDK4/CDK6 = D:CDK4/CDK6)



The D:CDK4/CDK6 complex phosphorylates the Retinoblastoma protein (pRb). pRb is a well known tumor suppressor. Thus phosphorylation of the pRb leads to its inactivation. 

The pRb has the unique characteristics of sequestering the E2F family of transcription factors. This inactivation of the pRb leads to release of the E2F family of transcription factors that drive the wayward cancer cell from the G1 through to the S phase.


Although this might seem straightforward and simplistic, let us not forget that there are various Negative feedback loops available to protect us fragile humans. These are the INK family of p16 protein which is encoded by the CDKN2A gene and the CIP/KIP family of p21 and p27 proteins. Provocation by the TGF-beta signaling mechanism via the SMAD3/4 pathway, which leads to expression of the p16 and KIP family of p21 and 27 proteins that act as suppressors of the Cyclin D1 complex formation. Some of the initiators of these negative feedback loos are basic cell senescence and the release of various molecules that trigger the cell growth cessation


The "Ts" suggest blockade and Arrows mean throughput!

The magic being that p16 binds with the CDK4 and CDK6 and prevents them from creating the D:CDK4/CDK6 complex. This binding prevents the cell from going into the next phase of the cell cycle and ultimate division.



Most of the data on the Cycle Dependent Inhibitor activity was determined in Breast Cancer research where the Estrogen Receptor positive cases became resistant to the Anti-estrogenic compounds.

Several drugs have been manufactured as CDK inhibitors. The lead one is Pablociclib, that received FDA approval in Hormone positive Breast Cancer.


Pablociclib by itself was essentially useless as a therapeutic option. But in ER+, HER2- Breast cancer cases that had developed resistance to the antiestrogens, Pablociclib when given with Letrazole there was a substantially higher PFS of 26.1 months versus 7.5 months in (PALOMA-1 trial). PALOMA-2 trial (using Pablociclib + Fulvestrant) confirmed the PALOMA-1 trial data. The dose limiting toxicity, as one might expect, is based on the Neutropenia and Diarrhea. Both organs Bone marrow and the GI tract have fairly robust cell replication. The toxicity seems to have been addressed modestly well with another D:CDK4/CDK6 Inhibitor, Abemaciclib. And Abemaciclib crosses the blood-brain barrier to impact the brain metastatic disease as well. Corroborative data are not yet available on the brain metastatic activity at present.

Lest one thinks that these Inhibitors only work on Breast Cancer, you might not know that animal trials with mice suggest otherwise. Activity is noted in the laboratory in Melanoma, Colorectal Cancer and Non Small Cell Lung Cancer as well. Trials are or will shortly be in progress to prove efficacy in the various malignancies.

The problems that still need to be addressed are whether these “Ciclibs” can be used with chemotherapeutic agents, since both impact the cell cycle dynamics. And whether the combination might reduce the effects of one another. And equally whether they can be used with the Immune check-point Inhibitors (Anti PD-1 and PD-L1) since the growth and proliferation of the T Reg cells is dependent on the Cell Cycle also.
Time, Hard work and Good Basic plus Clinical Research will tell the tale.

Meantime, we have seem to have another arrow in our quiver.

Online References:

1. http://cancerdiscovery.aacrjournals.org/content/6/4/353.full

2. https://genomebiology.biomedcentral.com/articles/10.1186/gb4184

3. http://genesdev.cshlp.org/content/13/12/1501.full

4. http://ac.els-cdn.com/0092867495903852/1-s2.0-0092867495903852-main.pdf?_tid=0e3f1db2-5d7a-11e6-b269-00000aab0f6b&acdnat=1470669128_f251eeee9fd0e65f46702003f67c90e4