Sunday, July 8, 2012
Friday, July 6, 2012
Unemployment Continues
The reports again seem dire. The unemployment is still listed at 8.2% and we are entering the mid summer season. Labor Day is the semi official start of the campaign and we still have no leadership. So here we go with the data:
As usual we start with the Romer Curve. By now we should have had a rip roaring economy. In fact the difference between doing nothing and the Stimulus would almost begin to be negligible. But we know the truth. Clueless.
The above are her errors. One can see the ever growing disparity between reality and what she predicted. Will anyone ever admit this fact? Doubtful.
Now we have the percent of population employed as the denominator. We can see it has actually dropped a nit. Thus real unemployment has gone up! Not remained constant. namely they have taken people out of the workforce again! Otherwise we would have seen 8.4% or more.
This is the data on the gap. We are growing marginally.
But the above is the telling curve. We have a growing potential workforce based upon the green line. Namely each month new potential workers enter the potential workforce. Thus just to stand still we must add 150,000-180,000 new jobs a month. That just keeps us at 8.2%. But we are adding far fewer, thus the negative gap, the red line, shows we are negative for the past two months.
As I have said before, I believe we may have already entered another recession. The GDP will be of interest but it is for Q2 only.
As I have said before, I believe we may have already entered another recession. The GDP will be of interest but it is for Q2 only.
STOP and GO and Cancer Cell Proliferation
In a recent paper by Solimini et al the authors discuss the
concepts of STOP and GO genes and carcinogenesis[1]. The paper reports on some
extensive experimental results focusing on the issue of proliferation and the
loss of certain sets of gene sites, the STP and GO sites.
The authors begin by discussing the current concepts of
changes in oncogenes and tumor suppressor genes, some of the key pathway
elements that we examine in analyzing intracellular pathway dynamics. They
state:
Cancer progression is directed by alterations in
oncogenes and tumor suppressor genes (TSGs) that provide a competitive advantage
to increase proliferation, survival, and metastasis. The cancer genome is
riddled with amplifications, deletions, rearrangements, point mutations, loss
of heterozygosity (LOH), and epigenetic changes that collectively result in
tumorigenesis.
How these changes contribute to the disease is a central
question in cancer biology. In his “two-hit hypothesis,”
Knudson proposed that two mutations in the same gene are required for
tumorigenesis, indicating a recessive disease. In addition, there are now
several examples of haploinsufficient TSGs .
Current models do not explain the recent observation that
hemizygous recurrent deletions are found in most tumors. Whether multiple genes
within such regions contribute to the tumorigenic phenotype remains to be elucidated…
The last sentence regarding the inability to explain the
presence of hemizygous deletions under the current model is the main driver for
this effort. Thus they argue and demonstrate experimentally that:
Tumors exhibit numerous recurrent hemizygous focal
deletions that contain no known tumor suppressors and are poorly understood. To
investigate whether these regions contribute to tumorigenesis, we searched
genetically for genes with cancer-relevant properties within these hemizygous
deletions.
We identified STOP and GO genes, which negatively and
positively regulate proliferation, respectively.
STOP genes include many known tumor suppressors, whereas
GO genes are enriched for essential genes.
Analysis of their chromosomal distribution revealed that
recurring deletions preferentially over-represent STOP genes and under-represent
GO genes.
We propose a hypothesis called the cancer gene
island model, whereby gene islands encompassing high densities of STOP
genes and low densities of GO genes are hemizygously deleted to maximize
proliferative fitness through cumulative haploinsufficiencies.
Because hundreds to thousands of genes are hemizygously deleted
per tumor, this mechanism may help to drive tumorigenesis across many cancer
types.
This is an intriguing hypothesis. It adds more pieces to an
already complex puzzle. The Cancer Gene Island, CGI, hypothesis seems to
indicate the complex changes in multiple gene sites. In particular there was a
deletion of the STOP genes in preference to the GO genes. Unfortunately there
did not seem to be a mechanism for these deletions, however the experimental
evidence does indicate the phenomenon.
In their experimental analysis they have observed certain in
vitro results which compel their hypothesis. They state:
This in silico analysis suggests that the loss of a
single copy of GO genes has a negative impact on cellular fitness. To
independently test this hypothesis, we turned to the other arm of our screen
that identified candidate GO genes whose depletion limits proliferation and
survival. Because both normal and cancer cells are dependent on these essential
GO genes, we analyzed data from proliferation screens on HMECs, one normal
prostate epithelial cell line, and seven breast or prostate cancer cell lines
They provide an interesting pathway model as shown below (as
mofified, and also not that they have short hairpin RNAs (shRNAs)).
They conclude as follows:
The enrichment for genes localized to deletions suggests
that we have identified dozens of new TSGs in recurrent deletions. We have also
likely identified more TSGs outside of these regions because the STOP gene set
is (i) enriched for known TSGs, many of which are not found in recurrent
deletions, and (ii) enriched for genes that undergo somatic loss-of-function
mutation.
Finally, this work suggests that cells possess a substantial
number of genes that restrain proliferation in vitro, which could be
inactivated to promote clonal expansion during tumorigenesis in addition to the
traditional driver genes currently known. Given the prevalence of multiple,
large, recurring hemizygous deletions encompassing skewed distributions of
growth control genes in tumors, we propose that the elimination of cancer gene
islands that optimize fitness through cumulative haplo-insufficiencies may play
an important role in driving tumorigenesis, with implications for the way in
which we think about cancer evolution.
As with many such works this raises as many questions as it
seems to answer. However the control or lack thereof of proliferation and the
cell cycle is a critical issue in carcinogenesis.
[1] Solimini, N., et al, Recurrent Hemizygous Deletions in
Cancers May Optimize Proliferative Potential, Science, 6 JULY 2012 VOL 337, p
104.
The End of the Dark Ages
I read a wonderful book by Richter on the monastery at Bobbio, Lombardy, from the early Seventh to the late Eighth centuries. I present it below. But the conclusion which may be drawn is that with the wealth of documents in the Library and the growth of them one could readily deduce that the "Dark Ages" was an artifact of the Renaissance man. In fact the total lack of any comments by Gibbon in his diatribe against Catholics totally ignores this.
Bobbio, by Richter, is an exceptionally well written presentation of the history of the monastery founded by Columbanus in the early 7th century. Richter provides a history of the three hundred years, from early 600s through the late 800s and deals directly with the original sources in a smooth and accessible manner. His writing style is clear and fluid and he provides the history of Bobbio in the context of the surrounding historical settings. It is in many ways an academic tour de force. Richter takes a some what complex set of issues from the 7th through 9th centuries, using the original sources, and makes them flow and readable. As I will comment upon, having some solid secondary school Latin is always a help but not a necessity.
Bobbio was in Lombard territory when founded by Columbanus and at the time the Lombards were Arian Christians, simply they did not believe in the Trinity or the divinity of Christ. Columbanus had been "expelled" from the Merovingian territories, most likely due to his battles with Queen Brunhilda, and having left Frankish lands he settled here. It is then the tale of this monastery from the time of Columbanus that Richter so admirably tells.
The book is concise, some 188 pages, and it is structured to basically follow the history. The first three chapters present the time of Columbanus and his immediate legacy. Richter interspersed his text with excerpts from the originals in 7th century Latin (it starts on p 19 with the writ of exemption). This is actually more useful than most would expect. I found that my Latin, French, and Italian were adequate to handle the inserts but at the same time reading them does provide a sense of how the language was halfway between Cicero and the Scholastics. One can see the mild local differences and the structure is evolving but the inclusion is quite helpful.
Richter does cover the key points concerning Bobbio, especially it exemption from control by the local bishop, which I assume in the 7th century was less of an issue than in the 9th. Furthermore the text, in the first three chapters, is focused on Bobbio and much less of Columbanus. There have been several recent works on Columbanus, none as scholarly as Richter, but it would possibly have been useful if Richter had provided a bit more background from his perspective on Columbanus.
Chapter 4 talks of the Scriptorium in the 7th century. This is a wonderful chapter and it details both the documents from that time and the ones from earlier upon which the documents were overwritten. The discussion on p 73 of the overwriting on Ulfila's Gothic translation of the Bible is intriguing. It would be interesting to hear more just of that discovery alone. The discussion here is quite complete and does set out the controversies and attempts to resolve them. What is interesting and a lingering question is that we see the strong and driving influence and competence of the Irish monks but one wonders just how they came by this. This was not a task of Richter but after reading the volume in toto is screams for an answer.
Chapter 5 speaks somewhat of the century where there were recorded abbots. The discussion on pp 92-93 is of interest in that it presents the potential lingering Irish influence. One of the questions that is not addressed to any significant degree was the openness of the abbey. The Frankish abbeys were allegedly open to lay people, and to some degree they were seen as institutions of learning, not just classic closed abbeys like those of the Benedictines. If this were the case, and given the extent of the Scriptorium in non-religious content, one may wonder.
Chapter 7 discusses the changes during the era of Charlemagne. Chapter 8 presents the economy of the monastery. There is exceptionally complete detail which is presented in a fresh and clear manner.
Chapter 9 was of most interest to me. It was the Library in detail in the 9th century. On pp 154-156 is a details presentation of the key contents and the mix of documents is intriguing. This Chapter by itself if of substantial value.
The remaining chapters provide additional detail and especially the details regarding the movement of the remains of Columbanus.
This book is superbly researched, is readable while being academically of the highest caliber. This provides a well done addition not only to the works regarding Columbanus but also to the early Middle Ages.
For anyone interested in this period, no matter where in Europe the interest may be, this is a highly recommended work.
Bobbio, by Richter, is an exceptionally well written presentation of the history of the monastery founded by Columbanus in the early 7th century. Richter provides a history of the three hundred years, from early 600s through the late 800s and deals directly with the original sources in a smooth and accessible manner. His writing style is clear and fluid and he provides the history of Bobbio in the context of the surrounding historical settings. It is in many ways an academic tour de force. Richter takes a some what complex set of issues from the 7th through 9th centuries, using the original sources, and makes them flow and readable. As I will comment upon, having some solid secondary school Latin is always a help but not a necessity.
Bobbio was in Lombard territory when founded by Columbanus and at the time the Lombards were Arian Christians, simply they did not believe in the Trinity or the divinity of Christ. Columbanus had been "expelled" from the Merovingian territories, most likely due to his battles with Queen Brunhilda, and having left Frankish lands he settled here. It is then the tale of this monastery from the time of Columbanus that Richter so admirably tells.
The book is concise, some 188 pages, and it is structured to basically follow the history. The first three chapters present the time of Columbanus and his immediate legacy. Richter interspersed his text with excerpts from the originals in 7th century Latin (it starts on p 19 with the writ of exemption). This is actually more useful than most would expect. I found that my Latin, French, and Italian were adequate to handle the inserts but at the same time reading them does provide a sense of how the language was halfway between Cicero and the Scholastics. One can see the mild local differences and the structure is evolving but the inclusion is quite helpful.
Richter does cover the key points concerning Bobbio, especially it exemption from control by the local bishop, which I assume in the 7th century was less of an issue than in the 9th. Furthermore the text, in the first three chapters, is focused on Bobbio and much less of Columbanus. There have been several recent works on Columbanus, none as scholarly as Richter, but it would possibly have been useful if Richter had provided a bit more background from his perspective on Columbanus.
Chapter 4 talks of the Scriptorium in the 7th century. This is a wonderful chapter and it details both the documents from that time and the ones from earlier upon which the documents were overwritten. The discussion on p 73 of the overwriting on Ulfila's Gothic translation of the Bible is intriguing. It would be interesting to hear more just of that discovery alone. The discussion here is quite complete and does set out the controversies and attempts to resolve them. What is interesting and a lingering question is that we see the strong and driving influence and competence of the Irish monks but one wonders just how they came by this. This was not a task of Richter but after reading the volume in toto is screams for an answer.
Chapter 5 speaks somewhat of the century where there were recorded abbots. The discussion on pp 92-93 is of interest in that it presents the potential lingering Irish influence. One of the questions that is not addressed to any significant degree was the openness of the abbey. The Frankish abbeys were allegedly open to lay people, and to some degree they were seen as institutions of learning, not just classic closed abbeys like those of the Benedictines. If this were the case, and given the extent of the Scriptorium in non-religious content, one may wonder.
Chapter 7 discusses the changes during the era of Charlemagne. Chapter 8 presents the economy of the monastery. There is exceptionally complete detail which is presented in a fresh and clear manner.
Chapter 9 was of most interest to me. It was the Library in detail in the 9th century. On pp 154-156 is a details presentation of the key contents and the mix of documents is intriguing. This Chapter by itself if of substantial value.
The remaining chapters provide additional detail and especially the details regarding the movement of the remains of Columbanus.
This book is superbly researched, is readable while being academically of the highest caliber. This provides a well done addition not only to the works regarding Columbanus but also to the early Middle Ages.
For anyone interested in this period, no matter where in Europe the interest may be, this is a highly recommended work.
Thursday, July 5, 2012
It's 100F and I Just Feel Like Reading the Canadians
I never met Frances Woolley but I have a student or two in her University town. But here I am in my air conditioned office trying to bang out a few more pages on pathway dynamics of melanoma and its control when I see Frances and warts. Any excuse to get away from BRAF, MEK, p53, and PTEN. Go to warts. I am staring at the wart on my right hand, been there I think 50 years, yes Frances, they may never go away. I never found it a social stigma, but then again here I am typing this silly response.
So I guess when it gets a bit on the warm side up North they get to opine on those things that truly have meaning in life, warts. Now also having had the opportunity to have studied medicine, I know of lots of different warts. Warts in places that we never want to think of, rough warts, flat warts, itchy warts, just lots of warts. How to treat warts, first a small number may actually be a malignancy, but a very small number. Most are just, well, there. Some come and go, then there is the plantar wart on the bottom of your foot, may be uncomfortable, but is always a tough one to get rid of.
So is this a medical problem? I don't have a license so I can only speak from personal experience, not providing any medical advice, but well, it is akin to acne, do we go to a physician to get our acne fixed, well sixty years ago we did not, we just washed out faces with lye soap, probably why we look this way now!
But Frances did make my afternoon. As she says:
Or perhaps a Saturday Night Live skit on a wart charity, the Wart Foundation. Perhaps that is also why so many US comedians are from Canada. Happy summer to all! Keep it up, it is to peak 105F on the morrow! What about this global warming stuff, perhaps there may be something there as well.
So I guess when it gets a bit on the warm side up North they get to opine on those things that truly have meaning in life, warts. Now also having had the opportunity to have studied medicine, I know of lots of different warts. Warts in places that we never want to think of, rough warts, flat warts, itchy warts, just lots of warts. How to treat warts, first a small number may actually be a malignancy, but a very small number. Most are just, well, there. Some come and go, then there is the plantar wart on the bottom of your foot, may be uncomfortable, but is always a tough one to get rid of.
So is this a medical problem? I don't have a license so I can only speak from personal experience, not providing any medical advice, but well, it is akin to acne, do we go to a physician to get our acne fixed, well sixty years ago we did not, we just washed out faces with lye soap, probably why we look this way now!
But Frances did make my afternoon. As she says:
Sometimes, when others fail to act, private charities step in. Think,
for example, of the Bill and Melinda Gates Foundation's work on malaria.
Unfortunately verucca vulgaris has failed to attract
charitable donations, research dollars and high profile advocates. It's
harder to raise funds for ugly animals than for beautiful ones; chronic
problems like poverty attract relatively fewer donations than dramatic
events like tsunamis. Donors get excited about saving lives, or making
dramatic improvements in people's existence. Consequently, private funds
for wart research are lacking.
Or perhaps a Saturday Night Live skit on a wart charity, the Wart Foundation. Perhaps that is also why so many US comedians are from Canada. Happy summer to all! Keep it up, it is to peak 105F on the morrow! What about this global warming stuff, perhaps there may be something there as well.
The Cost of Getting Information
Nick Rowe wrote a spot on piece regarding JSTOR. He clearly was using this as a metaphor for many other things so I thought I would throw in my two pieces, shilling, pence, whatever. Here goes.
1. Microsoft: If you think you have problems with JSTOR try and figure out what is wrong with your operating system if you have to go to Microsoft. The only way to find out how Microsoft works is to use Google. Does that tell you something.
2. MIT: Now I am not an economist, but I have a pile of degrees from MIT in EECS, that means computer science. Now MIT decided to put on this on line open course. I wrote about my travails, but for clarity I used to be in charge of the course many decades ago. Has not really changed much so I thought I would give it a whack. Now like Nick I have a real life, namely I do other stuff besides trying to find out how the software works. Thus when I came upon a question which required me to enter an equation, there being no directions on how to do so, and after 5 or 6 tries, I said to myself, this is not me, it is them. I stopped, and apparently so did 119,000 other people. Tell you something? To me yes, to the MIT programmer whiz, no, it was my stupid fault. Well there went a few years of alumni donations. If Google had designed the interface then when I ran into an entry problem they would have nicely directed me to directions, example, user groups, emails, whatever. I would have solved the problem near instantly. Not MIT, too much like Microsoft. Was I ever that bad?
3. Google: Now that is the way to do things. If you make a mistake they suggest how to solve it, then they try again, it is never your fault, they try again. Now that is truly Google's future if they recognize it. Why is Google this way? The answer may be quite interesting.
4. Open Access: I just gave up peer review publications. You see when you get over seventy you keep wondering if there will be enough time to get through a review cycle. Also, the only thing you really do is make some up and coming Associate Prof happy that they got you to dot or cross something. Thus open access, open access everything. As for peer reviews, send me an email, yell, scream, even use that old device called a phone, and I have video if you insist on using facial responses.
Thus, as usual, Nick has keen insight into the obvious. I have learned that "if all else fails listen to the customer" is a powerful aphorism with a great deal of insight. Google listens, Microsoft does not, nor did MIT in its first attempt. JSTOR may be just an artifact of an older generation, like a FAX machine, just kick it once and a while Nick, it will make you happy!
1. Microsoft: If you think you have problems with JSTOR try and figure out what is wrong with your operating system if you have to go to Microsoft. The only way to find out how Microsoft works is to use Google. Does that tell you something.
2. MIT: Now I am not an economist, but I have a pile of degrees from MIT in EECS, that means computer science. Now MIT decided to put on this on line open course. I wrote about my travails, but for clarity I used to be in charge of the course many decades ago. Has not really changed much so I thought I would give it a whack. Now like Nick I have a real life, namely I do other stuff besides trying to find out how the software works. Thus when I came upon a question which required me to enter an equation, there being no directions on how to do so, and after 5 or 6 tries, I said to myself, this is not me, it is them. I stopped, and apparently so did 119,000 other people. Tell you something? To me yes, to the MIT programmer whiz, no, it was my stupid fault. Well there went a few years of alumni donations. If Google had designed the interface then when I ran into an entry problem they would have nicely directed me to directions, example, user groups, emails, whatever. I would have solved the problem near instantly. Not MIT, too much like Microsoft. Was I ever that bad?
3. Google: Now that is the way to do things. If you make a mistake they suggest how to solve it, then they try again, it is never your fault, they try again. Now that is truly Google's future if they recognize it. Why is Google this way? The answer may be quite interesting.
4. Open Access: I just gave up peer review publications. You see when you get over seventy you keep wondering if there will be enough time to get through a review cycle. Also, the only thing you really do is make some up and coming Associate Prof happy that they got you to dot or cross something. Thus open access, open access everything. As for peer reviews, send me an email, yell, scream, even use that old device called a phone, and I have video if you insist on using facial responses.
Thus, as usual, Nick has keen insight into the obvious. I have learned that "if all else fails listen to the customer" is a powerful aphorism with a great deal of insight. Google listens, Microsoft does not, nor did MIT in its first attempt. JSTOR may be just an artifact of an older generation, like a FAX machine, just kick it once and a while Nick, it will make you happy!
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