Monday, February 22, 2016

Will Amazon Survive?

Amazon has created a level of customer expectation that seems hard for them to meet. They charge Prime customers a fee and then promise 2 day delivery but seem almost always to fall short. At least here in the Greater NYC area. I have spent some time trying to unravel their process using the USPS and think I have some detail.

The following is my best guess based upon a few hundreds of samples.

The above is a flow example. This is a case where they get a product from a third party vendor, they do not have it on hand. Often there is a delay here. The vendor connection and transport is subject to poor execution and thus begins the collapse of the two day promise.

Once Amazon "takes" possession they assign a shipping number from USPS. But apparently it is still a long time before USPS takes custody of the product. Amazon moves it to a local shipping point, one of theirs, then assigns it to some other third party transport to take it to a local Amazon site near the delivery. For us it is in Avenel in NJ.

At that point they contact the USPS for local transport. Up till that point one tracks Amazon NOT USPS apparently. I believe that USPS picks up and distributes the package to the local USPS where sometimes tracking data may be recorded. After all this is NOT UPS, it is the Government so don't expect people to follow through as expected.

Then the USPS delivers the package, hopefully, to the right address and not left in the rain, snow, or the wrong address.
This may be a low cost solution but it is highly prone to faults and failures. No longer is 2 day 2 days nor especially is next day ever next day, despite the extra fee charged.

My personal opinion is that thus whole system must be redesigned. It is a mess and will soon cost Amazon customers. In addition one may initially assume delays are due to the USPS but it appears that they do not take custody until delivered locally and that the tracking is just to keep the customer happy, albeit delayed.

There may have to be some shakeup at Amazon. Customers will not tolerate extra payments for poor service. At least I believe so.

Thursday, February 18, 2016

Where is Ockham When Needed?

It has not been since 1328 that we have seen Papal injunctions of this kind. Perhaps we should make Ockham's "Ninety Days", Opus nonaginta dierum, mandatory reading in the Vatican.

As the NY Times reports:

Inserting himself into the Republican presidential race, Pope Francis on Wednesday suggested that Donald J. Trump “is not Christian” because of the harshness of his campaign promises to deport more immigrants and force Mexico to pay for a wall along the border. “A person who thinks only about building walls, wherever they may be, and not building bridges, is not Christian,” Francis said when a reporter asked him about Mr. Trump on the papal airliner as he returned to Rome after his six-day visit to Mexico.

 As this Bishop of Rome had previously said about those with a different orientation that he could not see into their souls, so should he say about any person. This statement is a clear interference into the politics of a country and sets a dangerous precedent. It is for this reason that John Paul II was almost at the point of disbanding the Jesuits. 

There is a long and not very praiseworthy history of the Bishop of Rome wandering into politics. This may very well be another such path. Whatever a candidates views, they should be considered by the public voting, those of all religions, at least in a democracy. Papal interference is a double edged sword.

There is an excellent review by Reid at the Cornell site on the book by Tierney and Ockham. It is truly worth the read. He notes:

Tierney's treatment of Ockham on political rights is similarly original and provocative. He shows that Ockham argued that both the emperor and the pope were obliged to respect the rights of their
subjects. Ockham maintained that the emperor derived his power from the people, who "could not confer more power than it actually possessed." A provision of the canon law of corporations, Ockham continued, limited this power, holding that a governing majorityand, by extension, the emperor-could infringe on the rights of the other members only in the case of "necessary actions. The pope, furthermore, was limited by the canonistic maxim that no one was to be deprived of rights "without fault" (sine culpa), and the fundamental principle of evangelical liberty...

Definitely worth the read. Now Reid quotes Tierney in the same page:

Ockham's favorite way of proving [the restraints on papal power] was to argue that the evangelical liberty proclaimed in scripture limited papal power by safeguarding the natural and civil rights
of the pope's subjects.... Christian law was a law of liberty, indeed, "a law of perfect liberty" according to the Epistle of James. Paul too wrote of "the freedom that we have in Christ Jesus" and declared that "Where the spirit of the Lord is, there is liberty." But, if the pope could command anything not contrary to divine and natural law, then Christian law would be a law of most horrid servitude. All Christians would be made slaves of the supreme pontiff, for to command anything not forbidden by divine and natural law was precisely the kind of power that a master held over his slaves.... The proper limits to papal power were set by the liberties and temporal rights of emperors, kings, princes and other persons, rights that came to them from natural law or the law of nations or civil law.

Thus there was indeed a well understood separation of Church and State. Ockham battled John XXII who as a Canon Lawyer by training was now dealing the the Theologian. But clearly the almost century spent in Avignon was a turning point for what was formerly the Bishop of Rome. In a sense, one can agree with Tierney and see in Ockham the foundations of modern day political theory and understanding. I would further argue that the Nominalism of Ockham is also key but Tierney may not. Notwithstanding this battle spans centuries.

The End of the Set Top Box?

The FCC voted an NPRM regarding the set top box. Advocacy groups such as Public Knowledge state:

Today, the Federal Communications Commission approved a Notice of Proposed Rulemaking, requesting comment on a proposal to allow pay TV customers to access programming on the devices and apps of their choice without having to rent a set-top box from their cable provider. Public Knowledge applauds the FCC for taking such a significant step toward breaking open the stranglehold pay TV giants have over consumers.

 We have been following this for well over a decade. One Commissioner, Ajit Pai, made some interesting remarks that are worth following. He simply said; why not just get rid of the box totally? Good question. Most TV sets if not all have their own tuners, and manual controls. Almost all sets today have Internet connections. So why use a set top box if you already connect to the Internet and could have a simple APP?

That would open the system up totally. Then if you opened the CATV system, just a thought, and made it a common carrier...well you know where that goes!

Just a thought. Frankly there really is no need for the box any longer. We can manage our sets over the Internet already. So why not cable? And Pai is a lawyer at that.

Monday, February 15, 2016

5G and a Change of Paradigm

As we have been arguing for a few years now, the evolution from 4G to 5G will be significant. 5G will allow 100X the speed of 4G. But that is not the half of it. If the carriers are smart, a big if however, they can see this in a distributed mesh network, using intelligent customer based mesh routers so that coverage can be seamless and costs reduced.

In ArsTechnica there and article on the work at ATT. They state:

AT&T is collaborating with Ericsson and Intel on outdoor trials. "We expect field trials of 5G technologies to provide wireless connectivity to fixed locations in Austin before the end of this year," AT&T said. "The trials will help guide our 5G standards contributions and set the stage for widespread commercial and mobile availability once technology standards for 5G are established." LTE could remain AT&T's primary mobile network technology for a few years. AT&T said it wants to be ready to switch to 5G once the technology standards are set by 3GPP, the international standards body. 3GPP "will likely complete the first phase of that process in 2018," AT&T said.
Besides smartphone data, AT&T says 5G will be used for virtual reality, self-driving cars, robotics, smart cities, and massive sensor networks. On the back end, AT&T said it is relying heavily on network function virtualization and software-defined networking to reduce the cost of delivering data and to support new applications more quickly. AT&T is trying to ditch the "traditional model [that] relied on complex and cumbersome hardware" in favor of one that "turn[s] routers, firewalls and other network equipment into virtual functions running on commodity hardware," the company said.

The cost can be minimized by having the customer become part of the network at their cost.

The only barrier will be the carrier's greed in delimiting access to what they feel is of value. A smart carrier will see the ever expanding value in distributed access and not try to follow the CATV carriers down the road to perdition.

Theologians and Canon Lawyers

From 1324 to 1328, William of Ockham battled John XXII the ersatz Pope and factual Bishop of Avignon, not Rome just to make a point. John was the second Avignon "Pope" and he had been trained as a Canon Lawyer. This was a critical skill at the time because the Church had taken over more than just mankind's souls. The had land, managed kings, and their empires. Canon Law was, and still is, a remnant of Roman Law and the Code of Justinian. On the other hand Ockham was a Theologian. Theology was the Queen of such studies and it was Theology that could get you called a heretic, not a nice thing to happen at the time.

Ockham reviews John's writing and behold he considers John a heretic! The result is that John declares him a heretic. From that point on Ockham becomes the first real modern political science writer. He gave up Theology and started writing about mankind and who we were and how we should be ruled. He was the first in the path to Locke, Mill, and the like.

But the point is that  Ockham was a Theologian and John a Canon Lawyer. Their trades at the time were not only orthogonal but dissonant. Now reading a blog of, I guess, one of the libertarian folks at George Mason I see in it the the battle between businessman and economists. The author opines:

Such a claim is illogical, even if we assume – falsely – that Trump earned every cent of his monetary fortune honestly rather that at least some of it through government-orchestrated theft. Knowing how to run a business is not the same thing as knowing economics.  To assume that the two domains of knowledge and expertise are the same is an error equivalent to assuming that a successful NASCAR driver is thereby an expert automotive engineer.  Of course, it’s possible for a successful NASCAR driver to know something about automotive engineering, just as it’s possible for a successful business person to know something about economics.  But success at each of the former tasks (driving a race car and managing a business) is not the same thing as, and requires very little familiarity with, the latter domains of knowledge (automotive engineering and economics).

 I get it, the author does not like Trump. Well I have no horse in this race but the point is; economists are not entrepreneurs. Economists deal with theories. Economics is not a science. You cannot do an experiment. They fling around curves and equations sine any basis. Theologies at least had the Bible to work off of. There were God's word. Try and get two economists to agree on any word.

Business and entrepreneurs deal with facts. You make money or you lose money. Entrepreneurs can create value in society, economists have no chance of doing so. So unlike John and Ockham, the lawyer and the theologian, the entrepreneur and the economist really have no point of commonality. One lives in the world of personal consequences the other on preaching to people who often with due cause have no idea what they are shouting about.

Tax, Tax, Tax

Over the past seven plus years we have examined multiple proposals to "tax carbon". The academic's idea appears to be that by taxing something one uses less of it and thus since "carbon" is bad, hopefully not in the cells of our body but alas these are economists after all who most likely never took a biology course, then by taxing it there will be less of it.

Take a simple example. We tax liquor and gambling. Yep, we sure do. Have we seen its consumption decrease, no. It worked on cigarettes but there we had to tax it to oblivion, but one could also argue that it was social pressure more so.

Take the left leaning web site Project Syndicate. These folks from the left leaning policy house in DC suggest:

If, since then, each $5 increase in the oil price brought a $30 per ton decrease in the carbon tax, and each $5 decline brought a $45-per-ton increase, the result would be a $0.91 difference between the standard market price and the actual tax-inclusive consumer price last month. That increase would have raised the carbon price substantially, providing governments with revenue – reaching $375 per ton of carbon today – to apply to meeting fiscal priorities, all while cushioning the fall in gasoline prices caused by the steep decline in the price of crude. While $375 per ton is a very high price, reflecting the particularly low price of oil today, even a lower carbon price – in the range of $150-250 per ton – would be sufficient to meet international climate goals over the next decade. 

No this is not a paragraph from the new SAT. It is from two fellows who are arguing for a tax on carbon. 

The question should be; what is the problem?

Let us for the sake of brevity assume the problem is carbon emissions. Frankly I like warm weather but I guess my likes are irrelevant. Now the question should then be; how do we reduce carbon? There are two ways to answer this:

1. Economics: Tax the hell out of it.

2. Technology: Develop extraction and emission reduction mechanisms as well as non carbon emitting sources.

Now the first is easy to do if you control the economy and have no idea what else to do.

The second way is the way that took mankind out of the state of nature and into what we now call civilization. We invent things! New idea. So perhaps by not wasting time on a new App we could devote the efforts to carbon extraction. It is not really that hard, just takes focus.

So why the economics's approach. Does it solve the problem? Only at extortionary rates and only by placing the burden on those at the lower income levels. Why not for once consider the technological and stop raising taxes. And yes, the Government will just waste the money the raise any way.

Saturday, February 13, 2016

Only Part of the Story

Some five or six years ago we wrote a piece on benefits of Medicare. We showed that the fallacy issued by the Right that the Taxpayer is funding all benefits is utter nonsense, at least for a significant portion of the recipients. Recently we further showed that a significant portion, 10-15%, actually are underwriting the ACA recipients under the new programs.

So along comes what appears to be baseless assertions from the alleged Right Wing folks at Heritage.

They state:

Have senior citizens really “paid for” the Medicare and Social Security benefits they enjoy in retirement?  Many believe so. But for the vast majority, the answer is – unequivocally- No. Federal entitlement payroll taxes and general revenues finance Medicare and Social Security benefits on a “pay–as-you-go” basis, meaning today’s workers’ taxes fund today’s retirees. Workers’ taxes are not deposited in anything like a private sector “trust fund” today and “saved” for tomorrow’s benefits.

Now one must rem,ember that for Medicare:

1. One pays 3% of the Gross Income for say 45 years.

2. If one continues to be productive one not only pays an additional 3% for the rest of ones life then:

3. One pays an excess premium on Medicare. Say your salary is $200,000 then Medicare triples your monthly payment to $360 per month.

4. Then if you sell anything you get 3% tax on any capital sale

5. Then you also have to but a Medigap and Medicare Part D plan, most of which are useless anyhow, for about $4,000 pa.

Now just what is the deal here? Well it is that Medicare negotiates the rates for reimbursement. It pays what we have calculated as about 40% of the actual cost.

So when I see comments like this, comments which in my opinion are both unbalanced and lacking in factual analysis, I can say that both Left and Right are purveyors of what is less than factual. Pity!

The New Bell System is The Old Bell System

In a NY Times piece today there is a long discussion on how ATT is trying to adjust its workforce to meet the challenge from Amazon, Google, Netflix. Well good luck guys!

I had spent, on and off, about ten years in the System before and after Divestiture. Early on in NY Tel and Bell Labs. Frankly it was the most rigid environment ever. Only after doing a few dozen start up and even Corporate America the old Bell System was designed for drones.

For example, when I went to NYNEX at a dinner one night the head of HR said that the rule was that "The A students went to ATT and the Labs, the B students to Western Electric, and the C students to the Operating Companies" Furthermore in the Operating Companies you had grads from fourth rate schools like Manhattan College, I spent time there, and few if any from say Harvard or MIT (again went there too). Schools like Manhattan educated great swarms of followers, for NYC jobs, Con Ed, the Telephone Company, the Government. You learned how to separate green papers from pink ones.

Now along comes a world of competition. The Old Bell System approach is to set the walls up higher. Remember that the new ATT is really South West Bell, an Operating Company filled deliberately with all those C students.

But wait! Their competition such as Google, has A+ students from MIT and Stanford. The world is now technical, and how do we see the paper sorters competing? Not well.

So according to the Times the ATT CEO is trying to retool. Good luck. It is a 40 year task. First they cannot attract the great students. For when they do these people will report to the old C students and the smart one do no tolerate fools very well, so they will leave, and the old guard will say to themselves that the new ones were bad to begin with.

The CEO is now trying to revamp the company. The Times states:

In an ambitious corporate education program that started about two years ago, he is offering to pay for classes (at least some of them) to help employees modernize their skills. But there’s a catch: They have to take these classes on their own time and sometimes pay for them with their own money. To Mr. Stephenson, it should be an easy choice for most workers: Learn new skills or find your career choices are very limited.

Now that really makes sense. You want to educate C students on their own dime to become A+ students. Well fish without wings will have trouble flying. 

The article continues:

By 2020, Mr. Stephenson hopes AT&T will be well into its transformation into a computing company that manages all sorts of digital things: phones, satellite television and huge volumes of data, all sorted through software managed in the cloud. That can’t happen unless at least some of his work force is retrained to deal with the technology. It’s not a young group: The average tenure at AT&T is 12 years, or 22 years if you don’t count the people working in call centers. And many employees don’t have experience writing open-source software or casually analyzing terabytes of customer data.

Yes, 22 years, you have to remove the call centers. Is there a way to "train" someone to be a high techy? Not really. Never works. These people have been encultured  to be followers, paper sorters, understanding the GEI, the General Executive Instructions. Yes there is or was a "book" that you followed. For the most part he has a workforce of 220,000 chosen to do what they are told, by the book. The world has changed however.

Then there is this statement:

But Randall said his brother was not necessarily like the rest of the work force because there will always be hard, outdoor tasks for people like him. “There will be people turning screws and digging trenches. I’ll be long gone before that is over. But other guys I know in Oklahoma will do a skills pivot” with additional training, he said.

The problem is that technology will make this outdoor workforce obsolete. Strange the lack of discussion on wireless here. It is wireless that will replace lines, be they copper or fiber. 5G will be Gbps to each users from towers that can be set up in a day or actually purchased and facilitated by the customers themselves! As Tom Sawyer go the others to white wash the fence so too can a carrier get customers to create and operate their own network. That is thinking outside the box. ATT is still justifying copper lines on poles in Oklahoma. That is why Google may win, if it gets rid of that fiber business. But alas most likely it will be some other new Creative Destruction entity which will do that.

And the key risk is that if one tries to bring in better people, like Google, the existing culture will generate "antibodies" and attack and eliminate the new. Happens all the time. It is a Gresham's law applied to competence, bad employees chase out the good. Right now ATT has a somewhat monopoly in wireless along with Verizon. That is the survival hook for a while. The barrier to entry is the license. The risk there, however, is that when unlicensed bands can become more effective then the value of the license deteriorates. Things always change.

Friday, February 12, 2016

Healthcare is Getting Better?

The CBO has a report on the projections of Healthcare costs. It is worth the read. For all the "good news" from our Government, somehow CBO manages to state the obvious. Things are really not that good.

They state:

Most Americans are covered by private health insurance, which they either obtain through employment or purchase individually. Insurance premiums—the payments made to buy that coverage by enrollees or by other parties on their behalf—are high and rising. CBO and the staff of the Joint Committee on Taxation (JCT) project that in 2016, the average premium for an employment-based insurance plan will be about $6,400 for single coverage and about $15,500 for family coverage. Average premiums for coverage purchased individually (in what is called the nongroup market) are also high—but not quite as high as average employment-based premiums, mostly because nongroup coverage is less extensive and thus requires enrollees to make higher out-of-pocket payments when they receive care. Although premiums for private insurance have grown relatively slowly in recent years, they have usually grown faster than the economy as a whole and thus faster than average income. Over the period from 2005 to 2014, premiums for employment-based insurance grew by 48 percent for single coverage and by 55 percent for family coverage. CBO and JCT expect them to grow at similar rates over the next decade—by about 5 percent per year, on average, or about 2 percentage points faster than income per capita. As a result of that growth, average premiums for employment-based coverage are projected to be about $10,000 for single coverage and about $24,500 for family coverage in 2025, nearly 60 percent higher than they were in 2016.

Now combine that with the Yield Curve data we presented and we can see that with any bump of inflation the 5%  can readily go to 10% again and compounded inflation is a disaster. Furthermore we have not really insured the 20 million stated we have insured the sicker 10 million. Furthermore the insured are not paying any premiums of any consequence, they get a free ride while increased Medicare fees are somewhat making up for the difference.

But wait! The real problem is the added costs to providing Healthcare; the EHR, the EHR audits, the Quality metrics, the Quality metric audits. Not only do we have added overhead but we have added Government overseers. We will soon have fewer physicians, of a poorer quality, after all we do not want to make prior academic performance a decision metric any longer, and we will ultimately end up looking like the NHS, single payer or not.

Common Carriage, Elizabeth I, and the FCC

Common Carriage has been around now for over 500 years in English and in turn American Law. What this means simply is that there exists an entity called the carrier and you enter into a de facto agreement with them to transport your packet from point A to point B for a certain publicly published price. In return for that service as a common carrier the entity has liability only for the cost of carriage if the packet is somehow lost.

Thus if you ship a pound of gold, 16oz is you will, and at $1,200 per oz you have almost $20,000 worth of gold and the carrier charges you $5 a pound, then if it is lost you get $5 back. That is all. If however you are not a common carrier and you loose it you may be sued for both the $20K plus and consequential damages resulting therefrom.

Now in today's debate on Internet Neutrality there are three issues:

1. Wireless: Is wireless somehow protected perforce of their bought and paid for licenses? We have answered No. First the old RBOC go their free as did many of those who "won" license lotteries. Second, there is an issue of ownership versus right to use. What did the carrier get when the auction occurred, ownership or a right to use. We argue the latter.

2. Interconnection: Interconnection is the process of having one carrier deal with another. We have also argued for well over 25 years that interconnection should be mandated at zero price. The factotum of  externalities is nonsense. The French economist Tirole has argued its existence and has tried to justify the incumbents right to compensation. For anyone with a femto second of experience that is utter nonsense. Sock companies cannot charge shoe companies for interconnection!

3. Last Mile: This is the Net Neutrality argument. Namely should each entity connecting to the last mile pay the same rate for carriage as any other? Or can the carrier discriminate? I think when it comes to people we have finally agreed that its is both immoral and illegal to discriminate against anyone. If not we should start now a full policy and legal structure against any form of discrimination. When I buy a loaf of bread it should be the same as anyone else. But the ATTs, Verizon's, Comcasts see the world differently. If they do not like me for some reason they can charge more or even prevent me from buying access at any price. They want to determine what I can get. I don't want to carry the analogy too far but well one can see where this would go. They all have take advantages of Governmental, read from the people, advantages to render their services and make profits. They are or should be common carriers. They should not discriminate.

This is the issue before the FCC. The big guns and deep pockets of the incumbents are out in force. We should watch how this evolves. If it goes the wrong way they we may suffer the consequences.

Thursday, February 11, 2016

The Next Economic Collapse

The FED and our wonderful Government is taking on another collapse. Let us look at the yield curves.
We have this soon to be inverted curve. Watch the short term rates.
The above shows the spread between 10 year and 90 days. It is dropping very quickly. That is always a problem. But it is due to short term increasing while long term decreases!
The above is even more inspiring. The red line on the left is short term exploding. Watch the DOW, it is directly related. In my view Yellen is clueless, as are all economists, the Witch Doctors of the 21st Century!
The above shows the spread a bit better. What this process is doing is making those who can leverage richer and the poor schlubs who are trying to save for the future indentured servants.

This is what Sanders should focus on. It is his actions leading this train wreck!

The Illusion of Quality

The above is from NEJM and is discussed in a recent article on Quality in Health Care. As they note: 

Why has arriving at the essential measures of performance been so difficult in health care, when it seems to occur naturally in other fields? First, in health care we’ve allowed “quality” to be defined as compliance with evidence-based practice guidelines rather than as improvement in outcomes. Of the 1958 quality indicators in the National Quality Measures Clearinghouse, for example, only 139 are actual outcomes and only 32 are patient-reported outcomes. Defaulting to measurement of discrete processes is understandable, given the historical organization of health care delivery around specialty services and fee-for-service payments. 

What this is referring to is that under the new ACA, besides everything else, physicians must report on "Quality Measures", almost the totality of which are fabrications of metrics which have nothing to do with the patient's health. They are  getting messier all the time. The Government process is creating an overhead that is unsustainable, it matches Czarist Russia, with half the population working for the Czar checking on checkers etc. For example I recently was told that a certain Government agency now had statement of work reviews to check proper use of pronouns! Yes, pronouns.

The NEJM article continues:

Second, the limited outcomes measurement that has occurred has been led overwhelmingly by specialty societies. But outcomes are not strictly related to individual specialties or procedures; they reflect the overall care for a patient’s medical condition, in which multiple specialties are usually involved. What generally matters to patients are outcomes that encompass the whole cycle of care — including health status achieved (e.g., survival, functional status, quality of life); the time, complications, and suffering involved in getting care; and the sustainability of benefits achieved (e.g., time until recurrence). Specialty societies naturally focus on their constituents, often choosing measures that physicians can reliably control. The perspective expressed, for example, in a cardiology society’s statement that “outcome measures are highly desirable but often difficult to incorporate into performance measure sets because of vulnerability to influences outside the provider’s control” distances providers from the work of improving patients’ actual results and contributes to outcomes-measurement paralysis.

 The Societies try come up with metrics to meet the Government demands and game the system as well. In today's new ACA world we have physicians using useless EHR systems, they cannot communicate with each other, then they must re-certify, a process which just adds to the cost without adding to quality, creating artefactual "quality" metrics, and somewhere trying to treat a patient.

The process of medicine will soon come to a standstill. It is well above $3 trillion a year and rapidly approaching $4 trillion. These artificial measurements will not only add to the costs but detract from the care.

Wednesday, February 10, 2016

Harvard and Hell?

As the Crimson notes:

Ninety-one percent of contributions to current presidential candidates made by Harvard faculty, instructors, and researchers in 2015 went to former Secretary of State Hillary R. Clinton, according to a Crimson analysis of Federal Election Commission filings.

I guess they fear the fires of everlasting perdition?

Tuesday, February 9, 2016

Perhaps This is why MOOCs Have Problems?

I just read a note on the edX blog extolling the benefits of a MOOC in place of in person lectures. Sometimes the words can also be interpreted to demonstrate the problems more so than extol the thought of benefits.

Let me explain. First they state:

The course attracted over 7,500 students from 147 countries in its first run and was a prized specimen for researchers, data analysts and online course developers alike. By studying the dataset, correlations among different student demographics, learning patterns (e.g., clicking and seeking) and performance can be examined. An interesting finding was that students who performed best in assignments did not have high engagement in forums, probably meaning that they did not require much peer assistance in understanding the contents.

The problem is that the background and interest of the students bias the results greatly. In addition the data set is most likely in error. People report what they want to report and the reliability of anything in a MOOC is highly suspect.

They continue:

Although producing a MOOC takes more effort than face-to-face (F2F) lecturing, in Dr. Kajimoto’s point of view, the benefits outweigh the costs. As every single word in the videos has to be scripted, having a solid script helped Dr. Kajimoto realize how repetitive on-campus lectures are and how time in class can be better spent. Flipping the lectures also resulted in better activities engagement and quality of discussion, as students had much more time and motivation to prepare for tutorials. Peer pressure was also a factor as students fear lagging behind their classmates.

There is a key point in the above, namely that having a solid script helped Dr. Kajimoto realize how repetitive on-campus lectures are and how time in class can be better spent..

Repetitive is often what is needed in class. Saying or presenting a new concept once in one way often does not work. I recall again my first MOOC, if you will, a College Chemistry course on Television in 1959. 6AM and every day for 45 min. Somewhere along the way I missed the definition of a mole, not the ones on skin, but a chemical metric. So for a few weeks, not having access to anyone who knew, I wandered until I found it out. Then, back on track. The same problem befalls MOOCs today. For example a recent MOOC told you to open R, a statistical package, with 4 screens. Well try and find the other 2! It is that type of brick wall that redundant teaching, inefficient teaching if you will, eliminates.

Redundancy allows, enables, conversation and thought. If all you want to do is transfer your facts then the MOOC works, but remember that the other side may not get them. 

Thus this Blog note states a long list of problems, much more so than any benefits.

Another Set of Biomarkers


As we have noted there seems to be a never ending progression of biomarkers for PCa as well as other cancers. In this most recent one a Spanish research group (see Mengual et al) makes the following proposition:

Seven of the 42 genes evaluated (PCA3, ELF3, HIST1H2BG, MYO6, GALNT3, PHF12 and GDF15) were found to be independent predictors for discriminating patients with PCa from controls. We developed a four-gene expression signature (HIST1H2BG, SPP1, ELF3 and PCA3) with a sensitivity of 77 % and a specificity of 67 % (AUC = 0.763) for discriminating between tumor and control urines. The accuracy of PCA3 and previously reported panels of biomarkers is roughly maintained in our cohort. Our four-gene expression signature outperforms PCA3 as well as previously reported panels of biomarkers to predict PCa risk. This study suggests that a urinary biomarker panel could improve PCa detection. However, the accuracy of the panels of urinary transcripts developed to date, including our signature, is not high enough to warrant using them routinely in a clinical setting.

Admittedly we have a set of such non-invasive markers, including the 4K, which have been approved for use to ascertain patients who may have PCa versus those who do not. Let us consider the four proposed as an interesting case.

mRNA Specifics

The following Table and details discuss the four genes which they use.

Description (NCBI)
HIST1H2BG[1] (also H2B/a; H2BFA; H2B.1A)
Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. Nucleosomes consist of approximately 146 bp of DNA wrapped around a histone octamer composed of pairs of each of the four core histones (H2A, H2B, H3, and H4). The chromatin fiber is further compacted through the interaction of a linker histone, H1, with the DNA between the nucleosomes to form higher order chromatin structures. The protein has antibacterial and antifungal antimicrobial activity. This gene is intronless and encodes a replication-dependent histone that is a member of the histone H2B family. Transcripts from this gene lack polyA tails; instead, they contain a palindromic termination element. This gene is found in the large histone gene cluster on chromosome 6p22-p21.3

The protein encoded by this gene is involved in the attachment of osteoclasts to the mineralized bone matrix. The encoded protein is secreted and binds hydroxyapatite with high affinity. The osteoclast vitronectin receptor is found in the cell membrane and may be involved in the binding to this protein. This protein is also a cytokine that upregulates expression of interferon-gamma and interleukin-12.

ELF3[3] (also see Wang et al)
Aberrant regulation of the Wnt/β-catenin pathway plays important roles in colorectal carcinogenesis, with over 90% of cases of sporadic colon cancer featuring β-catenin accumulation. While ubiquitination-mediated degradation is widely accepted as a major route for β-catenin protein turnover, little is known about the regulation of β-catenin in transcriptional level. …Elf3, a member of the E-twenty-six family of transcription factors, drives β-catenin transactivation and associates with poor survival of colorectal cancer (CRC) patients. … first found recurrent amplification and upregulation of Elf3 in CRC tissues, and further Gene Set Enrichment Analysis identified significant association between Elf3 expression and activity of WNT/β-catenin pathway. Chromatin immunoprecipitation and electrophoretic mobility shift assay consistently revealed that Elf3 binds to and transactivates β-catenin promoter. Ectopic expression of Elf3 induces accumulation of β-catenin in both nucleus and cytoplasm, causing subsequent upregulation of several effector genes including c-Myc, VEGF, CCND1, MMP-7 and c-Jun. Suppressing Elf3 in CRC cells attenuates β-catenin signaling and decreases cell proliferation, migration and survival. Targeting Elf3 in xenograft tumors suppressed tumor progression in vivo. Taken together, our data identify Elf3 as a pivotal driver for β-catenin signaling in CRC, and highlight potential prognostic and therapeutic significance of Elf3 in CRC.

This gene produces a spliced, long non-coding RNA that is highly overexpressed in most types of prostate cancer cells and is used as a specific biomarker for this type of cancer. This gene is embedded in an intronic region of the prune2 gene on the opposite DNA strand. The transcript regulates prune2 levels through formation of a double-stranded RNA that undergoes adenosine deaminase actin on RNA-dependent adenosine-to-inosine RNA editing. In prostate cancer derived cells, overexpression of PCA induced downregulation of prune2, leading to decreased cell proliferation. Conversely, silencing in prostate cancer cells resulted in increased proliferation. Regulation of this gene appears to be sensitive to androgen-receptor activation, a molecular signature of prostate cancer. Alternative splicing results in multiple transcript variants.

Some additional comments are worth note.


Histones are proteins that assist the structuring of the DNA into nucleosomes. As noted by Stankiewicz et al:

Results…. argue for the significance of epigenetic mechanisms in the regulation of chronic stress. Microarray studies have revealed alterations in mRNA expression levels of seven factors involved in chromatin modification in adult male Swiss-Webster mice subjected to various stressors for five weeks.

Three transcripts that encode histones were found to be upregulated (H2afj, Hist1h2bm, and Hist1h2bg), and four were down-regulated. These four down-regulated genes encoded histones (Hist1h2bn, Hist1h2bh), a silencing factor known to recruit histone methyltransferases and deacetylases (Satb1, and a protein involved in histone acetylation (Hmgn2.

We show the relationship of H2B to the histone and nucleosome structure below:

As we have noted previously, SSP1 is secreted phosphoprotein 1, also commonly known as Osteopontin (OPN), also known as bone sialoprotein I (BSP-1 or BNSP), early T-lymphocyte activation (ETA-1), 2ar and Rickettsia resistance (Ric), is a human gene product which is also conserved in other species[5].

From Hendig et al, they state that it is a secreted, highly acidic phosphoprotein that is involved in immune cell activation, wound healing, and bone morphogenesis and plays a major role in regulating mineralization processes in various tissues. Increased   expression is often associated with pathological calcification. Furthermore, is a constitutive component of human skin and aorta, where it is localized to the elastic fiber and hypothesized to prevent calcification in the fibers?

SPP1 is a predominantly transcriptional regulated gene, and the   promoter is highly conserved among different species (22). Several polymorphisms in the   gene affect   expression and have been associated with various disorders, e.g., systemic lupus erythematosus and arteriosclerosis.

SPP1 is a SIBLING glycoprotein that was first identified in osteoblasts. OPN is an important anti-apoptotic factor in many circumstances. OPN blocks the activation-induced cell death of macrophages and T cells as well as fibroblasts and endothelial cells exposed to harmful stimuli. OPN prevents non-programmed cell death in inflammatory colitis. It has been shown that OPN drives IL-17 production; OPN is overexpressed in a variety of cancers, including lung cancer, breast cancer, colorectal cancer, stomach cancer, ovarian cancer, melanoma and mesothelioma; OPN contributes both glomerulonephritis and tubulointerstitial nephritis; and OPN is found in atheromatous plaques within arteries. Thus, manipulation of plasma OPN levels may be useful in the treatment of autoimmune diseases, cancer metastasis, osteoporosis and some forms of stress.
Research has implicated osteopontin in excessive scar-forming and a gel has been developed to inhibit its effect.


ELF3 is part of the ETS family. The ETS family of genes is positive or negative regulators of gene expression. They can up or down regulate expression. They are named for the initial gene discovered, the E26 Transforming Sequence, where E26 was the oncogene v-ets characterized in 1986 of an avian transforming virus called E26. It is also called the erythroblast transforming specific family, as discussed by Zong et al. As Watson et al note regarding this gene:

Four genes, ESE3 (EHF), ESE1 (ELF3), ESE2 (ELF5) and PDEF, were expressed at higher levels in breast cancer cells than normal epithelial cells. The expression of ELK3, ETS1 and FLI1 were reported to be reduced in breast cancer cells [114]. This pattern defined in cell lines does not absolutely correlate to that observed in tissue specimens. As noted above, ETS1 is over-expressed and PDEF protein is often reduced or lost in human breast cancer. While further studies are needed, ESE3 protein was absent in one breast cancer sample examined by IHC.


PCA3 has received a great deal of attention of late. It is a non-coding RNA and the controlling gene is located at 9q21-q22[6]. It is also called prostate cancer antigen 3 (non-protein coding). The presence of PCA3 is generally now believed to be a marker for PCa. Testing is now underway on many patients to determine if they have PCa using the PCA3 assay. Thus there is a great deal of interest in better understanding what the full networks are for PCA3 generation as well as looking at those pathways as a possible means to control PCa. We examine two recent studies in this area.

In the recent paper by Ferreira et al, they state:

Our findings suggest that the ncRNA PCA3 is involved in the control of PCa cell survival, in
part through modulating AR signaling, which may raise new possibilities of using PCA3
knockdown as an additional therapeutic strategy for PCa control.

This may be of significant merit as a new potentially useful therapeutic. Now it should be recalled that the AR pathway and the PSA generation is known as shown below[7].

Now Ferreira et al continue:

Due to the increased PCA3 expression in androgen-responsive cells compared with androgen-insensitive cells, and because AR signaling is an important pathway controlling PCa survival, we tested whether PCA3 expression was modulated by the androgen-active metabolite DHT and whether this expression pattern involved the activated AR.

Upregulation of PCA3 expression in response to LNCaP stimulation with DHT was significantly counteracted by the AR antagonist flutamide, indicating that PCA3 expression was induced by the activated AR. AR activation was further confirmed by the observation that LNCaP cells stimulated with DHT also showed AR transcriptional activity. Consistently, the entire AR target genes tested that contains canonical AR response elements (AREs) in their promoter sequences was upregulated upon DHT treatment. Although eight of the genes showed at least a 1.5-fold increase after AR activation, only two of them showed a significant increase in their expression levels. Interestingly, PCA3 upregulation upon DHT treatment has been observed previously, but no study has demonstrated the involvement of activated AR in PCA3 expression by using AR antagonists. Although our data also suggest that PCA3 is an androgen-responsive gene, the precise molecular mechanism by which PCA3 expression responds to this activation is still unknown.

One hypothesis is that activated AR can directly activate the PCA3 promoter, as has been demonstrated for the miR-101 and miR- 21 regulatory regions, which are also modulated by the activated AR. However, no consensus AREs has been identified in the 500-bp PCA3 promoter region. We further screened for consensus ARE elements in the entire PCA3 genomic region at the 5 Kb region upstream from the PCA3 transcription start site, and have so far identified no canonical element (data not shown). Nevertheless, we cannot exclude the possibility that other, noncanonical ARE elements could also promote AR binding and directly activate PCA3 expression, as has been previously described for other genes modulated by the AR activation. PCA3-upregulated expression in response to DHT treatment could also be a result of activated AR binding to the regulatory regions of other AR-responsive genes, which in turn could induce PCA3 expression. Further experiments should investigate direct AR binding to different PCA3 genomic regions, in order to answer these open questions.

Now they examined genes which are known pathway controllers of PCa. The CDKs especially control cell cycle flow.

As an approach to investigate the signal by which PCA3 controls PCa cell survival, we analyzed the transcript expression of PSA, AR, TMPRSS2, NDRG1, GREB1, FGF8, CDK1, CDK2, and PMEPA1 genes, all of which have key roles in PCa growth and progression, and are classical AR target genes.

Also highly regulated by androgens, fibroblast growth factor 8 (FGF8), cyclin-dependent kinase 1 (CDK1), cyclin-dependent kinase 2 (CDK2), and the gene regulated in breast cancer 1 (GREB1) gene products have classical stimulating roles in prostate growth and proliferation. Conversely, the PMEPA1 gene, although a direct transcriptional target of the AR, has been described as a negative regulator of cell growth in the prostate epithelium, as well as negatively regulating AR protein levels in different cell-culture models. We also observed that the AR transcription level was downregulated after PCA3 knockdown. These results accord with previously published data, which demonstrated that the AR gene is transcriptionally regulated by AR through binding to AR regulatory elements (autoregulation). However, differently from the other AR-responsive genes tested here, the ARE elements required for this process have not been found in the AR promoter or in the 5'-flanking region, but rather in AR coding sequences.

The observation that PCA3 is involved in the control by modulation of the AR target genes is a key observation. As we have shown, based upon various prior works, the change in AR is critical to the loss of any control over the PCa cells. They state:

Here we demonstrate for the first time that PCA3 is involved in the control of PCa cell survival, at least in part by modulating the transcriptional activity of AR target genes. To our knowledge, this is the first characterization of the functional role of PCA3 in PCa cells, and will not only improve the understanding of key roles of this transcript in prostate carcinogenesis, but also suggests an alternative strategy to use PCA3 as a putative specific target for PCa treatment approaches. Because PCA3 seems to be a regulator of the expression of AR target genes and PCa cell survival, treatment options aiming to downregulate PCA3, in combination with other androgen-depletion-based strategies, could potentially circumvent androgen-ablation resistance mechanisms.

In an earlier paper by Ferreira et al, they state:

The prostate cancer antigen 3 (DD3/PCA3) is a non-coding RNA (ncRNA) specifically expressed in prostate tissues and overexpressed in prostate cancer (PCa) tumors. Although widely applied as a diagnostic marker for PCa, to date nothing has described about its role in PCa biology. We used herein small interfering RNA (siRNA) in order to knockdown DD3 mRNA message as an approach to elucidate DD3 functional roles in PCa cells.

LNCaP cell line was been used herein as an in vitro model for DD3 functional assays. siRNA sequences were specifically designed for DD3 exon 4 mRNA sequences (siDD3), as well as scrambled siRNA (siScr), as negative control. LNCaP cells were transiently transfected with siDD3 or siScr and DD3 expression was analysed by real time PCR (qRT-PCR) using DD3 specific oligonucleotides. LNCaP cells transfected with siDD3 demonstrated a marked decrease in cell proliferation and viability, as compared to siScr transfected cells.

Further, LNCaP cells in which DD3 was knocked-down presented a significant increase in proportion of cells in SubG0/G1 phase of cell cycle and presenting pyknotic nuclei, indicative of cells undergoing apoptosis. In order to investigate the putative mechanisms underlying the decrease of LNCaP cell survival as a result of DD3 knockdown, we then evaluated the involvement of DD3 on androgen receptor (AR) pro-survival signaling. DD3 expression was significantly uregulated as a result of LNCaP treatment with dihydrotestosterone (DHT), the active androgen metabolite. This effect was reverted by the addition of the AR antagonist, flutamide.

Consistent to an AR activation by DHT treatment, LNCaP cells presented a significant upregulation of AR target genes. Notably, siDD3/LNCaP transfected cells significantly inhibited the expression of tested AR responsive genes. Besides, DD3 knockdown was able to counteract DHT stimulatory effects over AR target gene expression. Despite negatively modulating the transcription of AR target genes, DD3 knockdown did not alter Akt and ERK phosphorylation, suggesting that DD3 is mainly controlling the expression of signaling pathways downstream to AR activation.

In summary, our findings indicate that DD3 is a ncRNA whose expression is AR regulated and is involved on the control of PCa cell survival and proliferation, in part by modulating the AR signaling pathway and its target genes.

These findings correspond to the first description of DD3 roles on PCa cells and could provide new insights into understanding prostate carcinogenesis, besides opening new prospects to use DD3 not only as a biomarker for PCa, but also as an specific target for therapeutic approaches aiming to inhibit PCa growth by negatively modulating AR pro-survival signal and their target genes.

In this slightly earlier paper the authors focus on the PCA3 as a target and examine its pathway significance.

Other researchers have examined PCA3 as well as other markers. It is well known that the TMPRSS2:ERG fusion is often seen in PCA. As Salagierski and Schalken conclude:

In recent years advances in genetics and biotechnology have stimulated the development of noninvasive tests to detect prostate cancer. Serum and urine molecular biomarkers have been identified, of which PCA3 has already been introduced clinically. The identification of prostate cancer specific genomic aberrations, ie TMPRSS2:ERG gene fusion, might improve diagnosis and affect prostate cancer treatment. Although several recently developed markers are promising, often showing increased specificity for prostate cancer detection compared to that of prostate specific antigen, their clinical application is limited. The only 2 true prostate cancer specific biomarkers identified to date remain PCA3 and TMPRSS2:ERG gene fusion.


As with so many of these other putative markers we have here four mRNAs that seem diverse yet somehow are reflective of a diagnostic malignancy test. Clearly PCA3 is already a marker with some merit. ELF3 is also arguably as part of the ETS family in the same neighborhood as PCA3. The H2B mRNA fragment may or may not be reflective of a process. Finally SPP1 seems to be an outlier. Clearly causative linkages should be drawn here. But this is an interesting find.


1.     Auprich M, et al, Contemporary role of prostate cancer antigen 3 in the management of prostate cancer, Eur Urol. 2011 Nov; 60(5):1045-54. doi: 10.1016/j.eururo.2011.08.003. Epub 2011 Aug 25.
2.     Ferreira, L. et al, DD3/PCA3 non-coding RNA regulates prostate cancer cell survival and modulates AR signaling, Cancer Research: April 15, 2012; Volume 72, Issue 8, Supplement 1 , Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl) .
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