Monday, April 30, 2007

My Six Months Are Up!

 
I started Sandwalk six months ago. The goal was to give it six months to see how things worked out. I was told that you have to reach 1000 visits a day to be "successful" as a blogger and, as you can see, I didn't make it. But it's close—the average number of visits per day is a bit over 900.

It will take me a few days to evaluate the experiment.

The worst thing about Washington is ....

 
There's no Tim Horton's.

Everybody drinks Starbucks coffee. I don't like Starbucks and even if I did I have no idea how to order one. They seem to speak a different language. Whatever happened to "small," "medium,"and "large?"

Incidentally, the price of coffee is like the price of hotel rooms. It's outrageous but that doesn't seem to stop anyone from buying.

Everybody Should Have One of These

 
One of the most popular exhibits was the Leica booth. They set up a number of their most popular microscopes including the one shown in the photo. People gathered around drooling.

I wondered whether I could buy one so I asked the price, "three-fifty" was the answer. That's not bad. For only $350 dollars (US funds?) I'm thinking of getting one to put in my basement. Since I'm driving I don't have to worry about carrying it on a plane.

Herbert Tabor/Journal of Biological Chemistry Lectureship

 
One of the big events for ASBMB is the Herbert Tabor JBC lecture. It was held Saturday night in one of the large ballrooms. There were about one thousand people attending.

The first lecture was by Tony Hunter from The Salk Institute in California (USA). He spoke about mammalian kinases and phosphorylases with an emphasis on tyrosine kinases, which he discovered back in 1979. Tyrosine kinases are enzymes that attach phosphate groups to tyrosine residues in proteins. They are important because the phosphorylation and dephosphorylation of enzymes regulates their activity. Many of the genes that cause cancer (oncogenes) encode tyrosine kinases.

Hunter is trying to find out how many different proteins kinases there are in humans. The latest count suggests about 900 different enzymes. This is a remarkable number when you think about it. It means that 3-4% of all genes in our genome are kinases.

The second award winner was Tony Pawson from the Samuel Lunenfeld Research Institute and the University of Toronto (Ontario, Canada). I've heard Tony speak many times so I wasn't quite as attentive during his lecture. Tony discovered a number of proteins domains, notably the SH2 domain, that interact with tyrosine kinases and their target proteins. The work of the two Tony's is complementary and that's why they received this joint award.

UPDATE: I forgot to mention that there was a reception after the talks. Lots of delicious munchies and an open bar. I had a beer (or two). Most biochemists drink wine or fruit juice. It was not a wild bunch.

Monday's Molecule #24

 
Name this molecule. We need the exact name, preferably the correct one.

As usual, there's a connection between Monday's molecule and this Wednesday's Nobel Laureate. This one is dead easy. The prize (free lunch) goes to the person who correctly identifies both the molecule and the Nobel Laureate. (Previous free lunch winners are ineligible for one month from the time they first won.)

Comments will be blocked for 24 hours. Comments are now open.

Experimental Biology: Posters & Exhibits

 
Poster sessions and exhibits are a big part of any scientific meeting but at big meetings such as this one the number of posters and the number of exhibitors is so huge that they can only be accommodated in a very large convention center. The photos show the main exhibit hall in the process of being set up for posters and exhibits and what it looks like when people start viewing the posters and visiting the exhibits.

Sunday, April 29, 2007

ANCIENT SOCIETY 36 (2006)


Ancient Society

Festschrift Léon Mooren

Volume 36
2006

Selections from the Table of Contents


1 - 11 -
A Demotic Lease of Temple Land Reused in the Katochoi Archive (Louvre N 2328A)
CLARYSSE, W. & VANDORPE, K.
Abstract :
The katochoi of the Memphite Serapeum often reused the empty
spaces of demotic contracts for writing private documents such as
accounts, drafts of petitions and even literary texts. One such text is a list
of Macedonian months written in the margin of an old demotic lease of
temple land, dated to 215/214 BC. Three persons sublet to two others a
substantial area of land for which the rent has to be paid to the temple of
the god Horus of Buto. At least two of the persons involved have Greek
names and a third is a «Greek born in Egypt». One of the neighbouring
plots belonged to «the troop of the Greeks in Egypt». These Greeks, like
the katochoi half a century later, were clearly at home in two worlds.

13 - 44 -
Hunger, Not und Macht
Bemerkungen zur herrschenden Gesellshaft im ptolemäischen Ägypten
HEINEN, H.
Abstract :
An den Themen Hunger, Not und Macht können typische
Züge der herrschenden Gesellschaft des ptolemäischen Ägypten aufgezeigt
werden. Zwei Ehrendekrete stehen im Mittelpunkt dieses Aufsatzes:
das Kanopos-Dekret der ägyptischen Priester für Ptolemaios
III. und seine Gemahlin aus dem Jahre 238 v.Chr. (OGIS I 56; Bernand,
Prose I 9) sowie das thebanische Ehrendekret für den Strategos
Kallimachos von ca. 39 v.Chr. (OGIS I 194; Bernand, Prose I 46). In
beiden Fällen entscheiden die einheimischen Priester über Auswahl,
Definition und Belobigung herrschaftlicher Leistungen. Wenngleich
Sprache, Stil und Aufbau der beiden griechischen Texte sich an der
Form hellenistischer Ehrendekrete orientieren, so sind doch wesentliche
Inhalte deutlich durch ägyptischen Kult und Traditionen geprägt.
Daraus lassen sich Schlüsse auf die bemerkenswerte Position der ägyptischen
Priester innerhalb der ptolemäischen Eliten ziehen. Keine
andere hellenistische Monarchie kennt eine vergleichbare Situation.
Die detaillierte Interpretation des Ehrendekrets für Kallimachos führt
im Übrigen zu Ergebnissen, die sich in wichtigen Aspekten von dem
Bild unterscheiden, das ein Großteil der Forschung von der Stellung
dieses Mannes gezeichnet hat.

45 - 49 -
Ptolemaios V. als Harpokrates?
HUSS, W.
Abstract :
ln der vor wenigen Jahren von Renate Thomas publizierten, in
Privatbesitz befindlichen Statuette ist wahrscheinlich nicht Dionysos/Ptolemaios
IV., sondern Harpokrates/Ptolemaios V. zu sehen. Der antike
Auftraggeber der Statuette scheint in der Zeit um 200 v.Chr. im privaten
Bereich einen Gedanken nachvollzogen zu haben, den die offizielle Propaganda
vorgegeben hatte: Ptolemaios V. als Garant der Prosperität!

175 - 219 -
Kriton, stolarque au service d'Apollonios le diœcète
HAUBEN, H.
Abstract :
No less than 47 documents in the Zenon archive mention the
name Kriton. In Clarysse’s standard prosopography 34 are listed as
referring to the so-called stolarches of the dioecetes Apollonios, minister
for economic and financial affairs of Ptolemy II (285/282-246
BC) during the second half of his reign, and one of the wealthiest entrepreneurs
of his time.
The present article focuses on both the meaning of the term stolarches
(which occurs only once in the archive, viz, in P. Cairo Zen. I 59048)
and the manifold tasks, specific profile and individual career of
Kriton.
An exhaustive analysis of the Hellenistic and Roman literary, epigraphical
and papyrological sources seems to confirm the traditional
view that the stolarchia involved a (military or commercial) fleet command,
rather than a control of clothing or responsibility for equipment,
as claimed by more recent interpretations.
As commander of Apollonios’ small flotilla (obviously in charge of the
organization of river — not overseas — transport and communications)
Kriton was one of his most trusted employees as well as perhaps the
closest collaborator of the minister’s secretary (subsequently estate
manager) Zenon, especially in the years 258-256 BC, when Apollonios
and his staff were travelling around in Northern Egypt.
A study of the papyri not belonging to the core dossier of 34 texts leads
to the conclusion that, with the exception of two (PSI V 495 l. 7 and
P. Cairo Zen. III 59462), all the references to Kriton may probably
also be ascribed to the (ex-)stolarches, who, after the accession of
Ptolemy III (246) and the subsequent disappearance of the minister in
245, seems to have established himself (like his friend and former colleague
Zenon had done after his dismissal in 248/247) in the region of
Philadelphia in the Fayum, making a living from his vineyard, his ship
and other business.


221 - 238 -
The Ethics and Economics of Ptolemaic Religious Associations
MONSON, A.
Abstract :
This paper considers the economic status of the members
in Ptolemaic religious associations and offers a model to explain why
they participated. Drawing on Charles Tilly’s comparative study of
trust networks, I suggest that religious associations institutionalized
informal ethical norms into formal rules that lowered the costs of
transacting and facilitated cooperation among villagers. The rules
related to legal disputes illustrate how associations exercised this
power and even tried to prevent the Ptolemaic state from intruding in
their network.

Source: Petters online Journals

Happy Birthday Jane!

 


My daughter was born on this day in Geneva Switzerland some significant number of years ago. It was one of the best days of my life.

Happy Birthday Jane.

I think I'll Skip This One!

 
There's so much going on at the Experimental Biology meeting you just can't hope to see everything. You have to be ruthless in making decisions about what to attend and what to skip. Sometimes there are important talks going on at the same time and you just can't decide.

In addition to the formal talks there are lots of the things on the notice boards that look exciting. On the other hand, there are lots of things that don't.

Today I have to set aside time for the poster sessions because that's where I get a lot of ideas for my textbook (and for blogging). I also want to visit the displays in Publishers' Row and in the scientific equipment/supplies areas. I won't have time for church or fellowship meetings.

Washington Convention Center

 
The Washington Convention Center is a wonderful facility. It covers four city blocks in downtown Washington just north of Massachusetts Ave. between 7th and 9th. It's about a fifteen minute walk due north of the Capitol where the Congress is housed. The neighborhoods on the South, North, East, and West sides of the building are good examples of the diversity of a typical American city.

The inside of the building is huge and the facilities are as good as, or better than any I've seen in other cities.

I love Washington. Whenever I'm here I think it's the best city in the United States. If only they could fix the parking problem ....

Noncoding DNA and Junk DNA

Scientific American has published another short note on junk DNA [Jumping 'Junk' DNA May Fuel Mammalian Evolution]. RPM noticed that there was no reference to the actual study being quoted in the article so it wasn't possible to verify the accuracy of the reporting [Junk DNA in Scientific American]. I couldn't find it either when I looked last week but it has now appeared on the PNAS website [Thousands of human mobile element fragments undergo strong purifying selection near developmental genes]. RPM also complained about the over-use of the term "junk DNA" in the Scientific American Article. That's what I want to discuss.

The author of the Scientific American article, JR Minkle, has responded on the Scientific American website [The DNA Formerly Known as Junk]. Minkle is a science writer who has covered a lot of stories in many different fields. As far as I know Minkle has not written very much about biology before summarizing the work in the PNAS paper. There was a time when all the science in that journal was written by scientists who were experts in the field [The Demise of Scientific American]. Anyway, that's not the main point here. JR Minkle has listened to the critics and made a decision to avoid the term "junk DNA" from now on.

That's a bad decision. RPM never asked anyone to avoid the word "junk." He merely called for appropriate use. Ryan Gregory has serious doubts about the usefulness of the term as he explains in his excellent article A word about "junk DNA".. If you want to keep up with the discussion about junk DNA you need to read that article—but you don't need to agree with everything in it. :-)

Gregory has also commented on the Scientific American article by proposing a new term, Junctional DNA, to describe DNA that probably has a function but that function isn't known. According to him, this avoids the confusion between using "junk" DNA to describe DNA that we really know to be junk (pseudogenes) and DNA for which no function has been discovered so we assume it has none.

I think we don't need to go there. It's sufficient to remind people that lots of DNA outside of genes has a function and these functions have been known for decades. Thus, it is highly inappropriate to assume that all non-genic DNA is junk and no scientist should ever do this. Note that I'm avoiding the term "noncoding" DNA here. This is because to me the term "coding DNA" only refers to the coding region of a gene that encodes a protein. Thus, in my mind, there are many genes for RNAs that are not properly called coding regions so they would fall into the noncoding DNA category. Also, introns in eukaryotic genomes would be "noncoding DNA" as far as I'm concerned. I think that Ryan Gregory and others use the term "noncoding DNA" to refer to all DNA that's not part of a gene instead of all DNA that's not part of the coding region of a protein encoding gene. I'm not certain of this.

The importance of the term "junk DNA" is to highlight the fact that it has not evolved by natural selection. This is a point I made in one of my first blog postings way back in November [Bill Dembski Needs Help, Again] and again a few days later [The IDiots Don't Understand Junk DNA] [Two Kooks in a Pod].

This isn't original. Everyone knows that junk DNA poses a major threat to both Intelligent Design Creationism and adaptationism [Junk DNA Disproves Intelligent Design Creationism] [Evolution by Accident]. Read Gregory's article for the short concise version of this dispute. What it means is that junk DNA threatens the worldviews of both Dembski and Dawkins!

Science writers often get trapped into thinking like an adaptationist when it comes to junk DNA. Remember that according to the adaptationist worldview the existence of huge amounts of truly nonfunctional DNA in a genome must be a problem. It can't be explained if natural selection is a powerful driving force behind most of evolution. You can't propose that all minor changes in behavioral genes, for example, have been selected and then turn around and admit that 95% of the human genome is junk!

Adaptationists celebrate every discovery that some little bit of DNA has found a function. That's because in their heart of hearts they think that almost all of the junk DNA will eventually be found to have a function. This is one of the reasons why papers like the PNAS paper mentioned above get so much attention.

I want to keep the term "junk DNA" to refer to all functionless DNA. That includes DNA for which we have direct and indirect evidence of no function (pseudogenes, most of intron DNA, corrupted transposons etc.) and it also includes the rest of the DNA for which no function has currently been discovered and we think it's junk because it's not conserved (among other reasons). Junk DNA is not noncoding DNA and anyone who claims otherwise just doesn't know what they're talking about.

The term "junk DNA" forces people to think about the underlying causes of evolution. It makes them stop to appreciate the fact that modern organisms could have evolved with useless DNA in their genomes and the only way this could have happened is if there's a lot more to evolution than just natural selection and adaptation. It's a good term. It's an accurate term. It's a useful term. And it makes people think.

Saturday, April 28, 2007

Undergraduate Research

 
My society has a long history of sponsoring undergraduate research and inviting undergraduates to present their work in a poster session at this meeting. I look forward to seeing these posters and meeting some of the undergraduates who did the work.

This is a contest. There's a prize for the best poster, I think it's several thousand dollars. Judges interview all the students who are dutifully standing by their posters. It's a lot of fun.

I took a photo of the poster session from a small balcony overlooking the giant exhibit area. This was the only session for today—all the rest start tommorrow. The reason for having the undergraduate posters first is so the prize can be awarded at a special presentation tomorrow at noon. As you can see in the photo, the poster session was well attended. By the time I got downstairs there were two or three people in front of every poster.

This was an impressive group of students. I had serious science discussions with about a dozen presenters. I don't think I could identify the winner because some of the topics were way outside my areas of knowledge but here are two posters that I liked very much.

Amit Gautam is an undergraduate at Johns Hopkins. He works with bacterial release factors. These are proteins that terminate protein synthesis and stimulate the release of the completed polypeptide chain from the translation complex (ribocsome). His particular release factor comes in two different conformations. You can see them just over his left shoulder. The compact version is what was seen when purified protein was crystallized. The elongated form was the conformation observed when the release factor was bound to the ribosome.

The extended form is almost certainly the active form since it spans the distance between the termination codon and the site where the completed polypeptide is bound to tRNA in the P site. The protein has to do this to function, that's why the compact form was a surprise when it was first discovered.

Amit reasoned that the release factor had to shift from the compact form in solution to the extended form when it attached to ribosomes. He also reasoned that if he could block that shift the release factor would not work.

Amit introduced two cysteine residues into the release factor at positions that were in close contact in the compact form but far apart in the extended form. He predicted that a disulfide bond would form when the release factor was folded into the compact form and this covalent bond would lock it into the compact form preventing, it from adopting the extended form when it bound to ribosomes. As predicted, the modified release factor formed a disulfide bridge and was unable to catalyze release.

Under reducing conditions the disulfide bridge is disrupted and the release factor regains full activity. This is a nice example of a prediction and an experiment that tests the prediction. It's a nice piece of work.

Beccy Joscwitz used the split ubiquitin yeast two hybrid system to look for proteins that interacted with a membrane protein in yeast [see Technology reveals 'lock and key' proteins behind diseases]. She's a very impressive student and seems to be right on top of the work. She knew most of the problems and she also knew when to ask questions. I think the judges were very impressed.

Beccy, like Amit, wants to be scientist. Any graduate school would be lucky to have them.

What Do Scientists Eat?

 
There are six societies at this meeting: American Association of Anatomists; The American Physiological Society, American Society for Biochemistry and Molecular Biology,American Society for Investigative Pathology; American Society for Nutrition; and American Society fpr Pharmacology and Experimental Therapeutics. The slogan for the conference is "Today's Research: Tomorrow's Health."

So, you might be wondering what this group would eat for lunch? I was, especially since I was practically starving by the time noon hour rolled around.

There's an excellent food court in the lower level of the Washington Convention Center. I love food courts. This one had seven stations.
  1. Center Plate (sandwiches,salads, yogurt)
  2. Cluck Universal Chicken (fried chicken)
  3. Foggy Bottom (burgers, fries, hot dogs)
  4. Hannam's Caribbean Cuisine (spicy Caribbean dishes)
  5. Philadelphia (cheese steaks)
  6. Tam's Asian Cuisine (chinese food)
  7. Wolfgang Puck (pizza, salads)
What would 12,000 scientists working in health-related fields choose for lunch. The winner was obvious. There were three times as many people lined up at one of the stations. The most popular food was ....

Tam's Asian cuisine. There was nobody at the Center Plate—the station with the "healthiest" choices. Everyone was buying General Tso's Chicken .... mmmmmmm, good. Lots of calories. Lots of fat.

I don't know what they'll be buying tomorrow. Stay tuned.

Experimental Biology 2007: Registration

 
The Experimental Biology meetings are huge. There are thousand of people attending and one of the major road blocks at such meetings is getting registered and collecting all the material you need. It's a good idea to arrive early to avoid the rush and that's just what I did this morning.

Here's one corner of the registration area where there's a short lineup for late registration. Fortunately, I registered online several months ago so all I had to do was stand in line to pick up my badge. There were 12 lines and none of them had more than two people. This will change as the day wares on.

The next stop was to get a loot bag. Yes, that's right, you get loot bags at these parties just like when you were ten years old and you went to Erin's birthday party. My loot bag was a shoulder bag with advertising, three heavy books, and a bundle of other (mostly useless) stuff. Here's me with my registration badge around my neck holding two kilos worth of abstracts and programs.

The program is 560 pages. I haven't read it yet. The abstract books contain short, one-paragraph, summaries of all the talks and posters. There are 1444 pages of abstracts and each one has four or five abstracts. The print is very small. I haven't read them all yet.

These days all scientific meetings have a cyber cafe with wireless internet access and that's where I am right now. Back in the olden days when these meetings used to be in Atlantic City, there were other distractions but today there are dozens of people in here tapping away on their laptops. I can't waste any more time. I've got to start reading the program to see where I'm supposed to me. It's 9AM and things are starting to happen. There are about 20 things going on at any one time. I don't know how I'm going to begin.

In fairness, this isn't as overwhelming as it seems. I'm here mostly to attend the meetings sponsored by the American Society of Biochemistry and Molecular Biology (ASBMB). I just need to concentrate on what they're doing. I can pretty much ignore the sessions run by the other societies 'cause it's very unlikely that they will have something that interests me. Whew! That's a relief. That cuts the number of abstracts down to only 2500.

The exhibits are always a big attraction. I like the publishers row. That's where you find all the latest books on biochemistry, molecular biology, and genetics. It's fun talking to the reps from the publishers. I expect that the John Wiley & Sons booth will be getting a lot of attention. I'm sure there will be lots of people at the Pearson/Prentice Hall booth lining up to buy my book!

Friday, April 27, 2007

Thursday, April 26, 2007

Progress on the Archimedes Palimpsest


From BBC
Works by mathematician Archimedes and the politician Hyperides had already been found buried within the book, known as the Archimedes Palimpsest.
But now advanced imaging technology has revealed a third text - a commentary on the philosopher Aristotle.
Project director William Noel called it a "sensational find".

The prayer book was written in the 13th Century by a scribe called John Myronas.
read the rest

Similar story from National Greographic
News stories on a Paper read at the
AMERICAN PHILOSOPHICAL SOCIETY
ANNUAL GENERAL MEETING

April 25 – 27, 2007

Benjamin Franklin Hall

427 Chestnut Street
Philadelphia

WILLIAM NOEL
Curator of Manuscripts and Rare Books
Walters Art Museum , Baltimore , MD
and
ROGER L. EASTON, JR.
Chester F. Carlson Center for Imaging Science
Rochester Institute of Technology
Infinite Possibilities: Eight Years of Study of the Archimedes Palimpsest

Archimedes Palimpsest homepage

video of a "Google Talk" by Will Noel Roger L. Easton, Jr. Michael B. Toth

ABSTRACT The Archimedes Palimpsest is a 10th Century medieval manuscript that is the subject of an ongoing technical, scientific and conservation effort at the Walters Art Museum in Baltimore, Maryland. Since 1999, the multidisciplinary team has been disbinding, conserving, imaging, analyzing, transcribing and studying the 174 parchment folios – yielding approximately 400Gb of data to date. The Palimpsest, which the team affectionately calls “Archie,” includes at least seven treatises by Archimedes: The only copies of two of his Treatises, /The Method/ and /Stomachion/; the only copy in Greek of /On Floating Bodies;/ and copies of the /Equilibrium of Planes/, /Spiral Lines/, /The Measurement of the Circle/, and /Sphere and Cylinder/. It also contains 10 pages of text by the 4th century B.C. Attic Greek orator Hyperides; six folios from a Neo-Platonic philosophical text that has yet to be identified, but may be commentaries on Aristotle; four folios from a liturgical book; and twelve pages from two different books, the text of which has yet to be deciphered. «

SOURCE: BBC NEWS

Should Creationist Students Be Allowed into College?

 
Read all about it in the Stanford News [Kennedy lectures on challenges facing K-12 science education].
High school students who are taught creationism instead of evolutionary theory lack the critical thinking skills that are necessary for college, according to Stanford President Emeritus Donald Kennedy.
That sounds like something sensible although I'm not sure the correlation is a cause and effect relationship. Perhaps the lack of critical thinking skills and the teaching of creationism have a deeper cause?

I don't think that a student should be banned from college just because they're a creationist but I do think they need to demonstrate that they're ready for college. The ideal situation would be to have standardized entrance exams. The SAT's don't count.
Kennedy is currently serving as an expert witness for the University of California Regents, who are being sued by a group of Christian schools, students and parents for refusing to allow high school courses taught with creationist textbooks to fulfill the laboratory science requirement for UC admission. After reading several creationist biology texts, Kennedy said he found "few instances in which students are being introduced to science as a process—that is, the way in which scientists work or carry out experiments, or the way in which they analyze and interpret the results of their investigations."

Kennedy said that the textbooks use "ridicule and inappropriately drawn metaphors" concerning evolution to discourage students from formulating independent opinions. "Even with respect to the hypothesis that dominates them—namely, that biological complexity and organic diversity are the result of special creation—critical thinking is absent," he added.
I don't see why a college or university should be obliged to accept a creationist biology course as a legitimate science course.

[HatTip: RichardDawkins.net]

Project Steve

 
Project Steve just added it's 800th person named Steve. If you don't know what Project Steve is then hop on over to the NCSE website and find out [Project Steve: n > 800].

John Wiley & Sons Apologizes to Shelley Batts

 
Read about it at Retrospectacle [VICTORY! A Happy Resolution].

D HAGEDORN, WÖRTERLISTEN aus den Registern von Publikationen griechischer und lateinischer dokumentarischer Papyri und Ostraka

WÖRTERLISTEN
aus den Registern
von Publikationen griechischer und lateinischer
dokumentarischer Papyri und Ostraka
die 10. korrigierte und erweiterte Fassung der WoerterListen (einschliesslich des Kontraerindex) zur Benutzung oder zum Download zur Verfuegung. Neu sind seit der letzten Fassung u.a. die Register folgender Publikationen integriert worden:

P.Ammon II
P.Berl. Cohen
P.Sijp.
SPP III2 1-118
SPP III2 119-238
SPP III2 449-582

Source: Papy=L

Wednesday, April 25, 2007

J.N. Birdsall, Collected papers in Greek and Georgian textual criticism


Contents: Textual criticism and New Testament studies -- A hundred years and more since Westcott and Hort: where have we got to in the textual criticism of the New Testament? -- The Western text in the Second Century -- The New Testament text known to Photius: a reconsideration -- The Bodmer Papyrus of the Gospel of John -- The text of Jude in Þ72 -- A further decipherment of Papyrus G2323 of the Papyrussammlung of the Oesterr. Nationalbibliothek-- The text and scholia of the Codex von der Goltz and its allies, and their bearing upon the text of the works of Origen, especially the Commentary on Romans -- Rational eclecticism and the oldest manuscripts: a comparative study of the Bodmer and the Chester Beatty Papyri of the Gospel of Luke -- Two lectionaries in Birmingham -- The geographical and cultural origin of Codex Bezae Cantabrigiensis; a survey of the Status Quaestionis, mainly from the palaeographical standpoint -- A fresh examination of the fragments of the Gospel of St. Luke in MS 0171 and an attempted reconstruction with special reference to the recto -- John x.29 -- Presbytēs in Philemon 9: a study in conjectural emendation -- The Marcosians' text of Jesus' cry of jubilation (Matt. 11.26/ Lk. 10.21) -- The Georgian version of the Book of Revelation -- Diatessaric readings in 'The Martyrdom of St. Abo of Tiflis'? -- Gospel allusions in the Georgian martyrdom of St. Šušanik -- Georgian studies and the New Testament -- The Euthalian material and its Georgian versions -- The Old Syriac Gospels and the Georgian version: the question of relationship -- 'The Martyrdom of St. Eustathius of Mzketha' and the Diatessaron: an investigation -- The sources of the Pepysian Gospel harmony and its links with the Diatessaron Appendix: A complete bibliography of the papers of J.N. Birdsall.

Source Worldcat

REVIEW of David Sider, The library of the Villa dei Papiri

Wm. A. Johnson
Journal of Roman archaeology. 19, (2006): 493

Also reviewed in BMCR by Jan P. Stronk.

cover and contents
Gettty bookstore

Source: Worldcat

REVIEW of Cartonnage Papyri in Context. New Ptolemaic Documents from Abu Sir al-Malaq

A Jordens; E
Gnomon. 78, no. 1, (2006): 36

See Joe Manning's review in BMCR

REVIEW of Kölner Papyri (P. Köln) 9. Band

P Schubert
Gnomon. 78, no. 6, (2006): 554

Inhalt

REVIEW of Bookrolls and Scribes in Oxyrhynchus

Efrosyni Stigka
The Classical world. 100, no. 1, (2006): 67

Source: worldcat

U-Toronto Press

See Susan Stephens' Review in BMCR

REVIEW of P.Oxy. LXIX

SILVIA BARBANTANI
The Classical Review, 57, no. 1 (2007): 64-67

Catalogue Published: Zwischen Magie und Wissenschaft

Froschauer, Harald / Römer, Cornelia
Zwischen Magie und Wissenschaft
Ärzte und Heilkunst in den Papyri aus Ägypten
Nilus 13
140 S., zahlr. S/W-Abbildungen im Text, 7 Farbtafeln (2007)
ISBN: 978-3-901232-81-7
Preis: 29,00 EUR
Inhalt
See the description of the exhibition, Wednesday, March 28, 2007 entry
Source: Worldcat

Riboflavin (Vitamin B2), FMN and FAD

 
Monday's Molecule was Flavin Adenine Dinucleotide or FAD [Monday's Molecule #23]. The flavin moiety is the three ring structure at the top of the figure. It's attached to a sugar called ribitol drawn in an open chain conformation. The ribitol, in turn, is attached to a single phosphate group at the other end.

The structure shown in black is called flavin mononucleotide or FMN. The blue structure is an AMP group so the complete FAD molecule (black + blue) called a dinucleotide. FMN and FAD are important coenzymes that carry electrons from one reaction to another. We've already encountered FAD last week when we described the pyruvate dehdrogenase reaction. In that reaction the FAD molecule picked up two electrons from the lipoamide swinging arm and passed them on to NAD+.

FMN and FAD are required for important reactions in all species. They are made from riboflavin (right). Riboflavin can be synthesized in bacteria, protists, fungi, plants and some animals but mammals have lost the ability to make it. Instead, we have to obtain riboflavin from our food and that's why it's a vitamin in humans (vitamin B2). (It's not a "vitamin" in other species since they can make it themselves.)

Riboflavin deficiency is quite rare because we can usually get enough from the bacteria that inhabit our intestines. The most common cases of riboflavin deficiency are seen in chronic alcoholics who often show deficiencies in many other vitamins as well.

FMN and FAD are tightly bound to the enzymes that require them as cofactors. These enzymes often have a characteristic yellow color because of the flavin. One of the most famous enzymes in biochemistry is a flavoprotein called "Old Yellow Enzyme," which turned out to be an NADPH oxidase.

FMN and FAD are cofactors that can carry one or two electrons as shown below. This makes them similar to ubiquinone. There are many reactions that exchange electrons between FMN/FAD and ubiquinone in short electron transport chains. The passage of electrons from one cofactor/coenzyme to another is governed by well-defined chemical rules developed by chemists and biochemists at the beginning of the last century.


Who Owns the Data?

 
Shelley Batts was threatened with legal action for posting a figure and a table from a scientific paper [When Fair Use Isn't Fair]. This is an important issue that's only going to get worse on science blogs. My own feeling is that it's fair use to post stuff from papers in the scientific literature as long as it is properly attributed.

One of the advantages of the online journals is that they specifically allow this. Here's the official word from the PLoS website.

Everything we publish is freely available online throughout the world, for you to read, download, copy, distribute, and use (with attribution) any way you wish. No permission required.
If large corporations like John Wiley & Sons are going to threaten to sick lawyers on bloggers like Shelley then we'll just have to ignore everything that's published in their journals. That's what I'm going to do from now on.

[Hat Tip: Gene Expression]

Tangled Bank #78

 
Tangled Bank #78 has been posted at About: Archaeology. There's a brief list of articles on the framing debate in case anyone hasn't had enough. Don't be turned off. There's lot of good stuff as well. In addition, there's a link to one of my articles but y'all have read that already.

Unintelligent Design

 
A reader send this. Thanks, Mike.


 

Tuesday, April 24, 2007

Review of City of the Sharp Nosed Fishes in the NEW STATESMAN


Unearthing history

William Dalrymple

City of the Sharp-Nosed Fish: Greek lives in Roman Egypt
Peter Parsons
Weidenfeld & Nicolson, 320pp, £25
ISBN 0297645889

Archaeology is a notoriously slow and painstaking science: months of careful brushing and trowelling often yield little more than a few pieces of bone, the odd rusty coin and a pile of discarded pottery. Few excavations get off to the sort of start achieved by two Oxford archaeologists, B P Grenfell and A S Hunt, when they sailed down the Nile in 1896 in search of papyrus.

Papyrus was a material up to then largely ignored by Victorian scholars, who had tended to concentrate their attentions on classical inscriptions on stone. Intending to change this, and track down a few lost fragments of classical Greek and early Christian literature, the two scholars decided to investigate the mounds in the Egyptian village of El-Bahnasa, having heard rumours that illicit antiquity dealers had been finding papyri there.

The modern village squatted on the site formerly occupied by Oxyrhynchus, which means "City of the Sharp-Nosed Fish". Of this great Greek metropolis remarkably little was left: a lithograph published in 1798 by Denon, one of the artists of the Napoleonic Survey of Egypt, showed little more than a few mounds, a single Roman column, the dome of a mosque and some palm trees. It was certainly nothing like the usual destinations of European archaeological expeditions such as the tombs of the Pharaohs, which, not long before, the Italian adventurer Belzoni had been entering with the aid of a battering ram; less still did the nondescript mounds resemble the Great Pyramids, one of whose hidden chambers had recently been penetrated by a rival British team who, with the characteristic delicacy of the Victorians abroad, achieved their results by the liberal use of dynamite. read the rest

Source: Google news sv papyri

Monday, April 23, 2007

Regulating Pyruvate Dehydrogenase

 
There are three basic ways to regulate the activity of an enzyme. The cell can control the synthesis of the enzyme by regulating the expression of the gene; the enzyme activity can be modified by binding small effector molecules that alter the structure of the enzyme (allosteric regulation); or the activity can be changed by covalent modification.

The activity of the pyruvate dehydrogenase complex (PDC) is controlled by the most common form of covalent modification, phosphorylation. There's an enzyme called pyruvate dehydrogenase kinase (PDH kinase, PDHK) that attaches phosphate groups to the E1 subunit of PDC. The phosphorylated form of PDC is inactive. Another enzyme called PDH phosphatase (PDP) removes the phosphate groups making the enzyme active again.

THEME:
Pyruvate
Dehydrogenase

PDH kinase binds to the E2 subunits, specifically the lipoamide swinging arm [The Structure of the Pyruvate Dehydrogenase Complex]. There are four different PDH kinases and two different PDH phosphatases expressed in different tissues. Thus, the kinases and phosphatases are regulated, in part, at the level of gene expression. It turns out that they are also allosteric enzymes.

Knoechel et al. (2006) have looked at the structure of PHD kinase 2 (PDHK2) and located the sites of binding of several molecules that control activity of the kinase. One of the most important allosteric inhibitors is pyruvate. When pyruvate binds to PDH kinase 2 it blocks the kinase (phosphorylation) activity by changing the shape of the protein. Since phosphorylation of PDC doesn't occur, the pyruvate dehydrogenase complex remains active. Previously phosphorylated PDC becomes active because the phosphate is removed by PDH phosphatase.


The regulation makes sense. As pyruvate accumulates inside the cell you want to activate the pyruvate dehydrogenase complex in order to convert the pyruvate to acetyl CoA. As pyruvate levels fall the PDH kinase will no longer be inhibited and PDC will be inactivated by phosphorylation.

It wasn't possible to crystallize PDH kinase in the presence of pyruvate but it was possible to solve the structure of the enzyme with a similar molecule bound at the active site. The molecule is dichloroacetate (DCA) a molecule that inhibits PDH kinase by binding to the pyruvate site. Unlike pyruvate, DCA inhibition is pretty much irreversible.

Cancer cells often have inactivated pyruvate dehydrogenase complex for reasons that aren't clear (but see references in the link below). Treatment of cancer cells with DCA reactivates the pyruvate dehydrogenase complex and this leads eventually to the death of the cancer cells— at least in some cases. Unfortunately, dichloroacetate (DCA) is toxic so using it to treat cancer is a case of the cure being almost as bad as the disease.

This has not prevented growth of an underground economy in DCA by people who are desperate to cure their cancers. The situation is a mess. Read blogs by Abel Pharmboy at Terra Sigillata and Orac at Respectful Insolence for lots more information. There's a nice summary of their posts at Perversion of Good Science.

Pharmaceutical companies are very interested in finding a non-toxic inhibitor of PDH kinase 2. In fact, the paper by Knoechel et al. is mostly work done at Pfizer Ltd, in the UK. Their goal is to characterize as many inhibitors as possible.
Knoechel, T.R., Tucker, A.D., Robinson, C.M., Phillips, C., Taylor, W., Bungay, P.J., Kasten, S.A., Roche, T.E., and Brown, D.G. (2006) Regulatory roles of the N-terminal domain based on crystal structures of human pyruvate dehydrogenase kinase 2 containing physiological and synthetic ligands. Biochemistry 45:402-15. [doi: 10.1021/bi051402s]

Sequence Similarity and Intelligent Design Creationism

 
Logan Gage posted a message on Evolution News& Views where he discusses the interpretation of sequences similarity [What Exactly Does Genetic Similarity Demonstrate?].
As Francis Collins, head of the project which mapped the human genome, has written of DNA sequence similarities, “This evidence alone does not, of course, prove a common ancestor” because an intelligent cause can reuse successful design principles. We know this because we are intelligent agents ourselves, and we do this all the time. We take instructions we have written for one thing and use them for another. The similarity is not the result of a blind mechanism but rather the result of our intelligent activity.
This is an old argument. It ignores the fact that sequence similarities match the phylogenies determined independently from comparative morphology and the fossil record. This is the "twin nested hierachies" evidence for evolution and it's powerful evidence indeed. Furthermore, it ignores the fact that the differences in sequences correspond closely to what we expect from evolution by random genetic drift.

In order to sustain the argument that an intelligent designer is responsible for this data you pretty much have to argue that the designer (whoever that might be) went out of his way to deceive us into thinking it's due to evolution. But that's not why I'm commenting on this article.
Some design proponents think the evidence for common ancestry is good (e.g., Michael Behe), while others—citing the fossil record, especially The Cambrian Explosion—do not. But neither group thinks that sequence similarity alone proves either common ancestry or the Darwinian mechanism, as so many science writers of our day seem eager to assume.
I congratulate Logan Gage for acknowledging that there are disagreements within the Intelligent Design Creationist camp. That's not something we see very often. However, I think he may be distorting Behe's position a little bit. Perhaps he means to place all the emphasis on "similarity alone" but that seems to be a quibble. Here's what Behe says in Darwin's Black Box on pages 175-177. Judge for yourself whether Behe thinks sequence analysis provides strong support for common descent.
When methods were developed in the 1950s to determine the sequences of proteins, it became possible to compare the sequence of one protein with another. A question that was immediately asked was whether analogous proteins in different species, like human hemoglobin and horse hemoglobin, had the same amino acid sequence. [The question was asked because it was a prediction of evolution-LAM]. The answer was intriguing: horse and human hemoglobins were very similar but not identical. Their amino acids were the same in 129 out of 146 positions in one of the protein chains of hemoglobin, but different in the remaining positions. When the sequences of the hemoglobins of monkey, chicken, frog, and others became available, their sequences could be compared with human hemoglobin and with each other. Monkey hemoglobin had 5 differences with that of humans; chickens had 26 differences; and frogs had 46 differences. These similarities were highly suggestive. Many researchers concluded that similar sequences strongly supported descent from a common ancestor.

For the most part it was shown that analogous proteins from species that were already thought to be closely related (like man and chimp, or duck and chicken) were pretty similar in sequence, and proteins from species thought to be distantly related (such as skunk and skunk cabbage) were not that similar. In fact, for some proteins one could correlate the amount of sequence similarity with the estimated time since various species were thought to have last shared a common ancestor and the correlation was quite good. Emile Zuckerkandl and Linus Pauling then proposed the molecular clock theory, which says that the correlation is caused by proteins accumulating mutations over time. The molecular clock has been vigorously debated since it was proposed, and many issues surrounding it are still contended. Overall, however, it remains a viable possibility....

The three general topics of papers published in JME [the Journal of Molecular Evolution]—the origin of life, mathematical models of evolution, and sequence analysis—have included many intricate, difficult, and erudite studies. Does such valuable and interesting work contradict this book's message? Not at all. To say that Darwinian evolution cannot explain everything in nature is not to say that evolution, random mutation, and natural selection do not occur, they have been observed (at least in cases of microevolution) many different times. Like the sequence analysts, I believe the evidence strongly supports common descent. But the root question remains unanswered: What has caused complex systems to form? No one has ever explained in detailed, scientific fashion how mutation and natural selection could build the complex, intricate structures discussed in this book.
The reason for bringing this up is to show that Behe accepts common descent and sequence similarity is strong evidence of common descent. It would be nice if the Intelligent Design Creationists acknowledged this and discussed the sum total of the evidence and not just the sound bite version of sequence similarity.

[I'd like to make it clear that I do not support everything Behe says. It's become clear to me recently that I need to add disclaimers such as this whenever I make a complicated point.]

Experimental Biology in Washington D.C.

 


I'm going to the Experimental Biology meeting in Washington this weekend. Is anyone else going to be there? Email me so we can get together.

Goodbye Mixing Memory

 
Chris over at Mixing Memory posted an article on the comparision between the Women's Suffrage Movement and other attempts to change public opinion [You're No Suffragist]. He completley misunderstood the point of what I was saying so I posted a comment to help direct him toward the truth. I also took a poke at him for deliberately mispelling my name in the first paragraph of his posting.

My comment didn't survive on his blog. Now you see the following comment from him.
First, my apologies to anyone who's responded to Larry's comment. I deleted it, because I don't want him dirtying up my blog.

Next, Matt, I have nothing but contempt or the nouveau atheists (I use that phrase to convey their tackiness, in case that wasn't apparent). I have been saying as much for about 6 months now, and will continue to do so. I won't apologize for it, either. They deserve nothing but contempt. And it should be noted that contempt for a relatively small, privileged group does not entail contempt for anyone else (I do have contempt for other groups, of course, but most people on the planet I'm OK with) or a broad sense of superiority. Do I feel superior to them? Anyone who's read a few books would. Do I feel superior to everyone else? Certainly not.

Mike, atheists should respond by pointing out how insane that kind of talk is. They should note that saying a group is not really American, or doesn't matter, sounds more and more like, say, Nazi antisemitic rhetoric when it's used by people in power (and that includes people in the media, who are, obviously, in positions of power). Of course, one doesn't have to call all religious people stupid, and advocate for the eradication of religion (which, I should add, also sounds a lot like Nazi rhetoric) to do so. I have nothing against being mean by itself. I have something against being mean, stupid, and totalitarian (little "t").

Richard, my point is that, by and large, they aren't even being "rude" in the same way. Instead, what they're trying to do is force their narrow world view on the entire rest of the world (go read Moran and others' talk of ridding the world of superstition, by which they mean all religious beliefs, on their blogs), through aggression and violence. Granted, it's rhetorical aggression and violence, but it's still aggression and violence. And perhaps worst of all, it is rhetoric with no obligation to facts or truth. Perhaps a better name for the nouveau atheists would be "evangelical" or "proselytizer" atheists.
I've decided not to read Mixing Memory any more. I'm thinking that Chris has gone off the rails and I don't want to be the one that tips him over the edge.

Monday's Molecule #23

 
Name this molecule. It's related to last week's theme on pyruvate and pyruvate dehydrogenase.

As usual, there's a connection between Monday's molecule and this Wednesday's Nobel Laureate. This one's got something to do with the type of reactions that involve today's molecule. The prize (free lunch) goes to the person who correctly identifies both the molecule and the Nobel Laureate. (Previous free lunch winners are ineligible for one month from the time they first won.)

Comments will be blocked for 24 hours. Comments are now open.

Google Earth View of the Sandwalk

 

 
John Spraggs sent me this Google Earth view of the Sandwalk behind Down House (upper right). The Sandwalk path follows the line of trees at the bottom of the garden to the small woods at the lower left.

Thanks, John.

Sunday, April 22, 2007

Suffragettes

 
I started a little controversy over on Greg Laden's blog when I responded to the umteenth claim that militant approaches to a debate never achieve anything [Larry Moran]. I said,
Everyone keeps repeating this mantra as though it were the gospel truth. The historical evidence says otherwise. There are dozens of examples of things that used to be “militant” approaches that have become accepted standards today.

Here’s just one example. Do you realize that women used to march in the streets with placards demanding that they be allowed to vote? At the time the suffragettes were criticized for hurting the cause. Their radical stance was driving off the men who might have been sympathetic to women’s right to vote if only those women had stayed in their proper place.

Now I’m not saying that all militant approaches are going to win in the end. Far form it. Most of them are destined for the dustheap of history. What I am saying is that trying to shut down the “militants” on the grounds that they are counter-productive is not logical. It’s a way of “framing” the discussion to make it sound like your opposition to the militants has a scientific basis.
PZ liked the suffragette idea and expanded on it [We Aim to Misbehave] and [Rude Ladies].

Now Amanda Marcotte has picked it up at Pandagon [They didn’t realize that you got it the third time you asked with a pretty please]. Read her blog to find out just how "gentile" those women were one hundred years ago.
I see the Feminists For Life and their horrible project of trying to rewrite history so that suffrage-era feminists come across as pleasantly enamored of servitude is going well. It’s hard to generalize at all about suffragists, since, you know, the struggle went on for decades and incorporated thousands of women. One thing you can say with certainty is they were rude and offensive by definition, since for a woman to be proper, she had to accept second class citizenship uncomplainingly. But seriously, atheists aren’t even waving placards, much less holding hunger strikes, firebombing, or whipping some jujitsu on some cops.

More to the point, suffragists didn’t actually get very far until they did in fact start openly insulting men. Mere equality between men and women wasn’t considered reason enough to extend the franchise to women, but when the purity movement latched onto suffrage and started pushing the message that women were better than men, then things changed. Men were considered drunken, violent assholes who needed women’s civilizing hand to get them in shape. It was a sorry thing that it had to get to that point in order for women to get the vote, and hopefully the lesson has been learned for future reference.* Now, as PZ notes, the way different levels of oppression certainly demanded different reactions, so there’s no reason to fault the suffragists for any radical action they had to take in order to obtain justice. But it’s silly to think of them as sweet little old ladies who’d never hurt a fly. They put up with a lot of shit, from having vegetables pelted at them in public to having police arrest them in ways that maximized the violence and humiliation.
Please don't lose sight of the main point about the comparison between the women's suffrage movement and atheists like Dawkins, PZ, and me. We're not trying to justify our position by comparing it to that of the suffragettes (suffragists). All we're trying to do is destroy this silly myth that all social change came about by speaking softly and being nice to everyone. There are lots of examples where "militant" behavior triggered social change. It doesn't always justify "militant' behavior but if you're going to fight Dawkins then at least use sensible arguments.

Saturday, April 21, 2007

Gene Genie #5

 
The Neurophilosopher has just posted Gene Genie #5. There are posts from Hsein-Hsein Lei at Genetics & Health; Leslie, who writes a blog called Paternal Age and De Novo Single Gene Disorders etc.; Bertalan at Scienceroll; Grrl Scientist, who blogs at Living the Scientific Life; Tim at Sciencesque; and me.

I think we knocked off another dozen genes or so. Only about 23,500 to go.

Egyptologists keep ancient world fresh


Egyptologists keep ancient world fresh
Photo
The Toledo Museum of Art's papyrus funerary book of Tamesia is nearly 12 feet long and 10 inches high and is written in Middle Egyptian; this represents only a portion of it.

Zoom | Photo Reprints

By JENNI LAIDMAN
BLADE SCIENCE WRITER

Being dead was a bit of an ordeal for ancient Egyptians.

Take Tamesia.

After she died around the time BC turned to AD, she had to charm knife-wielding gate keepers of the afterlife, convince 42 gods of her sinlessness, and finally see her heart weighed against the truth, knowing that any slip meant this seat of consciousness would be kibble for a waiting monster with a crocodile head, hippo hind parts, and the chest and forelegs of a leopard.

From the triumphant look of the Egyptian woman depicted on the burial papyrus, arms upraised as though signaling a touchdown, Tamesia waltzed into the afterlife intact.

But if it weren't for Terry Wilfong, of the University of Michigan, another part of Tamesia's burial papyrus would not come true. more

Source: Google news

Framing Framing

 
If, like me, you're confused about the message that Mooney and Nisbet are conveying then I urge you to listen to this podcast [Matthew Nisbet]. Here's the introduction on the Point of Inquiry website.
In this discussion with D.J. Grothe, Nisbet explores the issue of “framing science” in the public mind, how scientists may be failing at effectively communicating the importance of the implications of science for society, and steps the science community may take to more expertly sell their science to a disinterested public. He also argues about Richard Dawkins and his effect on the public appreciation of science, and the impact of linking atheism with science for issues such as stem-cell research, teaching evolution in the public schools, and global warming.
Nisbet links to the podcast on his website [Podcast: More on Framing (and Dawkins)] where he says,
In this week's show, host DJ Grothe and I engage in a lively forty-five minute discussion. You can listen here.

I offer more details on:

--> the nature of framing and media influence.
--> does framing mean false spin?
--> the likely negative impact of Dawkins.
--> communication strategy specific to the teaching of evolution in schools.
--> what the Discovery Institute understood about framing (also see this post.)
--> the role of framing in the debates over climate change and stem cell research.
--> the use of "science navigators" in communication campaigns.
-->an effective means for engaging the broader American public on atheism.
I take that to mean that Nisbet thinks he did a good job of explaining these things during the interview.

I urge everyone who has an interest in this debate to take the time (45 minutes) to listen to the interview. At the end of it you should have a very good idea of the issues. Nisbet tries to frame the framing debate to make it look like it's all about "proper" media communication. He sets himself up—along with Chris Mooney—as the social scientist who really understands how society works. Scientists are the social bumpkins who need a lot of coaching from the "experts."

It doesn't work for me. To me it reveals that Nisbet is simply expressing his own personal opinion about many issues. For example, he makes it very clear that, in his opinion, Dawkins is harming the cause of science education. The interview is full of spin framing about how unimportant it is that Dawkins has a book on the bestseller list. Some of the contortions that Nisbet puts us through are actually quite funny. The interviewer (Grothe) really has him twisting in the wind at several points.

After listing to the interview I think I now know enough about Nisbet to ignore him from now on. He doesn't have anything useful to say as far as I'm concerned so this is the end of my involvement in this debate. The fans of framing will no doubt be ecstatic about the interview.

I'm reminded of the two cultures debates in the 1960's. If you don't know what I'm talking about then please follow the link to the Wikipedia article.

Computers in Papyrology and Paleography

This was posted on the DIGITAL CLASSICIST list yesterday:


Dear all -

I have been asked by the British Machine Vision Association to
consider running a day on "Computers in Papyrology and
Paleography" - specifically the use of computer imaging and image
processing. The definitions for the day can be interpreted very
broadly.

Such a day would probably run in Leeds, probably in late 07/early
08.

This message is to ask
1. Might you be interested?
2. If so, might you be prepared to contribute a paper?
3. Might you be able to nominate a keynote speaker
[perhaps yourself :-)]?

I would be grateful if you could forward this message to anyone
you feel might like to receive it.

Professor Roger Boyle Mail: roger@comp.leeds.ac.uk
* Head, School of Computing Phone: 0113 3435487
* University of Leeds Mobile: 0771 5049478
* Leeds, LS2 9JT Fax: 0113 3435468
* UK http://www.comp.leeds.ac.uk/roger

Friday, April 20, 2007

Human Genes for the Pyruvate Dehydrogenase Complex

 
The pyruvate dehydrogenase complex (PDC) catalyzes a very important metabolic reaction: the conversion of pyruvate to acetyl-CoA [Pyruvate Dehydrogenase Reaction]. The complex consists of three components: E1 a dimer of E1α and E1β polypeptides; E2, and E3 [The Structure of the Pyruvate Dehydrogenase Complex].

Each of them are encoded by separate genes so there are four human genes required. We'll see shortly that there are two additional genes for a total of six. The E3 subunit is shared with two other enzymes: 2-oxoglutarate dehydrogenase (a citric acid cycle enzyme) and 2-oxo acid dehydrogenase (a enzyme required for amino acid degradation) [Pyruvate Dehydrogenase Evolution].

The gene for E1α: is called PDHA1 and it's located on the X chromosome at p22.2-p22.1 [Entrez Gene = 5160]. There are more than three dozen alleles that give rise to symptoms ranging from mild lactic acidosis to developmental defects. The accumulation of lactate is due to the fact that it can't be converted to pyruvate because the defect in pyruvate dehydrogenase causes buildup of pyruvate in the cell [Pyruvate]. Males often die at an early age. (Note that males are homozygous for mutant alleles because the gene is on the X chromosome) [OMIM 300502]. Females are also affected because only one X chromosome is active and if it happens to be the one carrying the mutations the entire cell is affected [Calico Cats].

A testis specific copy of the E1α: gene is called PDHA2 and it's located on chromosome 4 (q22-q23) [Entrez Gene = 5161].

The gene for E1β: is called PDHB on chromosome 3 near p21.1-p14.2 [Entrez Gene = 5162]. There are only two known alleles that cause a problem. Both are homozygous lethals but only after birth. The infants have severe problems and fail to develop normally [OMIM 179060]. Death usually occurs within a year of birth. It's likely that other mutations are embryonic lethals so we never see them as genetic diseases [Most Metabolic Diseases Affect Unimportant Genes].

The gene for the E2 subunit is called DLAT (dihydrolipoamide s-acetyltransferase). It is located on the chromosome 11 at q23.1 [Entrez Gene = 1737 ]. Two alleles are known to cause problems but the patients respond well to dietary treatment [OMIM 608770]. It's very likely that more severe genetic defects are embryonic lethals.

The gene for the E3 subunit is called DLD [Entrez Gene = 1738]. It is located on chromosome 7 at q31-q32. There are many alleles of this gene and some of them cause genetic diseases. The phenotype results from a defect in amino acid metabolism and not from a defect in pyruvate dehydrogenase. Recall that the E3 subunit of PDC is shared with 2-oxo acid dehydrogenase, an enzyme required for the breakdown of branched chain amino acids. Deficiencies in the enzyme activity lead to accumulation of breakdown products that are secreted in the urine. This gives rise to a characteristic odor resembling maple syrup [OMIM 238331]. The particular genetic disease associated with the DLD genes is called maple syrup urine disease type III

There is one other minor component of the pyruvate dehydrogenase complex in humans. Protein X binds to E3. It is encoded by the PDHX gene on chromosome 11 (p13). There are no known alleles in the OMIM database.

Pyruvate Dehydrogenase Evolution

 
Before discussing the origin of the pyruvate dehydrogenase complex (PDC) we need a little background information. There are three different reactions catalyzed by enzyme complexes resembling the pyruvate dehydrogenase complex. For example, one of the reactions of the citric acid cycle is the conversion of 2-oxoglutarate (α-ketoglutarate) to succinyl-CoA. As you can see from the reaction below it is very similar to the pyruvate dehydrogenase reaction. The main difference is that the substrate, 2-oxoglutarate, has five carbons while pyruvate only has three. The part of the molecule that reacts is the top part with a carboxyl (-COO-) that is lost as CO2 and a keto (-C=O) that ends up being attached to coenzyme A via a sulfhydryl linkage.


It should come as no surprise that this reaction is catalyzed by an enzyme called 2-oxoglutarate dehydrogenase (OGDH, also known by its old name: α-ketoglutarate dehydrogenase) (EC 1.1.4.2) that's almost identical to pyruvate dehydrogenase. In fact, both PDC and OGDH evolved from a common ancestral enzyme. We know that the citric acid cycle enzyme is a late comer because many species of bacteria don't have it. Indeed, they don't even have a citric acid cycle.

So we need to look elsewhere if we are going to find the source of PDC. The most primitive enzymatic reaction is almost certainly one that's required in amino acid metabolism.1 In this case it's a reaction involved in the degradation of the branched chain amino acids; leucine, valine, and isoleucine. Look at the pathway below.

The first step in the degradation is the removal of the amino group (-NH3+) and its replacement with an oxygen to form a keto (-C=O) group. This creates three similar 2-oxo acids (α-keto acids) all of which resemble 2-oxoglutarate and pyruvate. All three of the 2-oxo (α-keto) acids are acted upon by the same enzyme called branched chain 2-oxoacid dehygrogenase (OADH, BCOADH, α-ketoacid dehydrogenase) (EC 1.2.4.4) to create an acyl-CoA product. This is the same reaction as that catalyze by the pyruvate dehydrogenase complex except that the R group in pyruvate is -CH3 while in the case of the branched chain dehydrogenase it's a three, four, or five carbon branched structure.

BCOADH is found in all species. It is the most "primitive" enzyme. Like PDC it has a complex structure with three different subunits. E1 catalyzes the decarboxylation reaction. E2 catalyzes the formation of acyl-CoA—it has the lipoamide swinging arm. E3 catalyzes the oxidation of the lipoamide and the reduction of NAD+.

It looks like the "primitive" BCOADH could also catalyze the oxidative decarboxylation of pyruvate. In fact some of the modern enzymes still have residual activity towards the other substrates. Over time, the genes for some of the subunits duplicated and the two enzymes (PDC and BCOADH) diverged as they became more specialized for their modern substrates.

We can see the result if we look at the phylogenetic tree for the E2 subunit (below). This figure is from a paper by Scharrenberger & Martin (2002). They use a slightly different nomenclature (PDH=pyruvate dehydrogenase complex). This is an unrooted tree so you can't really tell which enzyme came first but, as I explained above, there is good reason to believe that the E2 from PDC and the E2 from OGDH evolved from the E2 gene for BCOADH via successive duplications.


Recall that the E2 subunits form the core of the complex (left). They contain the lipoamide swinging arm that carries substrate to three different active sites. The E3 subunits of the three enzymes are identical. There is only one E3 gene and it supplies the dihydrolipoamide dehydrogenase activity for BCOADH, PDC, and OADH.

The situation with the E1 subunit is more complicated. This is the part of the enzyme that recognizes the different types of substrate (e.g. pyruvate, 2-oxo acids, 2-oxoglutarate) so it makes sense that the three enzymes have different E1 subunits. All the eukaryotic versions of the PDC E1 subunit are related to the E1 subunit from BOADH. So are most of the bacterial versions. Other bacterial versions of the PDC E1 subunit are not related to those of the other enzymes (Schreiner et al. 2005).

The conclusion from the molecular data is that the pyruvate dehydrogenase complex evolved from the branched chain 2-oxo acid complex about 2 billion years ago. Subsequently, in some bacterial lineages a different E1 subunit replaced the one that's homologous to the BCOADH subunit. The α-proteobacteria and cyanobacteria lineages that gave rise to mitochondria and chloroplast respectively, retained the PDC E1 subunit that is related to BCOADH enzymes. This explains the eukaryotic versions of PDC.

1. This is a common theme in the evolution of metabolic enzymes. The evidence suggests strongly that amino acid metabolism is more ancient than most carbohydrate metabolism.

Schreiner, M.E., Fiur, D., Holatko, J., Patek, M. and Eikmanns, B.J. (2005) E1 enzyme of the pyruvate dehydrogenase complex in Corynebacterium glutamicum: molecular analysis of the gene and phylogenetic aspects. J Bacteriol. 187:6005-18.

Schnarrenberger, C. and Martin, W.. (2002) Evolution of the enzymes of the citric acid cycle and the glyoxylate cycle of higher plants. A case study of endosymbiotic gene transfer. Eur J Biochem. 269:868-83.

Some Bacteria Don't Need Pyruvate Dehydrogenase

Recall that the pyruvate dehydrogenase complex catalyzes the conversion of pyruvate to acetyl-CoA. This is an important reaction in all living cells because acetyl-CoA is required for fatty acid synthesis. The reaction is important in animals because acetyl-CoA enters the citric acid cycle where it is broken down to carbon dioxide and the energy is captured by the mitochondrial electron transport system in the form of ATP. This step isn't so important in most bacteria because they don't have a citric acid cycle. Most species can also save the two carbon atoms of the acetyl group in acetyl-CoA and use them to build carbohydrates such as glucose. Animals can't do this.

You would think that the pyruvate dehydrogenase complex (PDC) must be ubiquitous since it catalyzes such an important reaction. Not so. PDC is the only enzyme in eukaryotes but some bacteria have another enzyme that can make acetyl-CoA. As you might expect, the bacteria that gave rise to mitochondria do have a PDC that's related to the eukaryotic enzyme. This is because the genes were transferred from those bacteria to their eukaryotic hosts when the endosymbiotic event occurred about two billion years ago.

Lots of different kinds of bacteria have a similar PDC but some have a completely different enzyme called pyruvate:ferredoxin oxidoreducatase (PFOR) (E.C. 1.2.7.1) (Chabrière et al. 2001). This enzyme catalyzes a very similar reaction where pyruvate undergoes an oxidative decarboxylation yielding CO2 and acetyl-CoA. The difference is that instead of having a complicated electron transport chain where electrons are passed to lipoamide, FAD+, and finally NAD+ [Pyruvate Dehydrogenase Reaction], the PFOR reaction is much simpler. Here electrons are transferred to ferredoxin, a small iron-containing protein.

The structure of pyruvate:ferredoxin oxidoreductase has been worked out from a combination of X-ray diffraction data and electron microscopy, just as we saw with the pyruvate dehydrogenase complex [The Structure of the Pyruvate Dehydrogenase Complex]. The structure of one such enzyme, from the bacterium Desulfovibrio vulgaris, is shown in the figure above. This complex consists of eight copies of the enzyme (Garczarek et al. 2007). In other species a simple two-copy complex suffices.

Ferredoxin is a cofactor in many biochemical reactions. As a general rule, enzymes that use ferredoxin are more ancient than enzymes that involve NAD+ as a cofactor. Ferredoxin metabolism doesn't need oxygen and the available evidence suggests that oxygen wasn't present in the ancient atmosphere. Modern bacteria that use pyruvate:ferredoxin oxidoreductase (PFOR) instead of the pyruvate dehydrogenase complex (PDC) are capable of anaerobic growth (without oxygen).

The structure of many ferredoxins have been solved. The one shown on the left is from Pseudomonas aeruginosa. It's a typical example (Giastas et al. 2006). The protein is quite small and most ferredoxins contain two iron-suflur (Fe-S) complexes. These are box-like structures formed from iron molecules (red) and sulfur molecules (yellow). They are bound to the protein through the sulfhydyl groups of the amino acid cysteine. Electrons are carried by the iron ions.
Fe3+ + e- → Fe2+
There's another important reason why PFOR is important in some bacteria. Look at the PDC reaction shown above. The arrow points in one direction indicating that this reaction is essentially irreversible. It can't be used to fix carbon dioxide by combining it with the acetyl group to make pyruvate. That's not true of the much simpler PFOR reaction. In fact, the reverse reaction is the main CO2 fixing reaction in many photosynthetic bacteria and in methanogens (bacteria that use methane as a carbon source).

But we're getting distracted. The point is that the pyruvate dehydrogenase complex probably arose late in evolution after photosynthetic bacteria had transformed the atmosphere into one that contained significant levels of oxygen. Where did such a complicated protein complex come from?

Chabriere, E., Vernede, X., Guigliarelli, B., Charon, M.H., Hatchikian, E.C. and Fontecilla-Camps, J.C. (2001) Crystal structure of the free radical intermediate of pyruvate:ferredoxin oxidoreductase. Science 294:2559-63.

Garczarek, F., Dong, M., Typke, D., Witkowska, H.E., Hazen, T.C., Nogales, E., Biggin, M.D., and Glaeser, R.M..(2007) Octomeric pyruvate-ferredoxin oxidoreductase from Desulfovibrio vulgaris. J Struct Biol. 2007 Feb 17; [Epub ahead of print] .

Giastas, P., Pinotsis, N., Efthymiou, G., Wilmanns, M., Kyritsis, P., Moulis, J.M., and Mavridis, I.M..(2006) The structure of the 2[4Fe-4S] ferredoxin from Pseudomonas aeruginosa at 1.32-Å resolution: comparison with other high-resolution structures of ferredoxins and contributing structural features to reduction potential values. J. Biol. Inorg. Chem. 11:445-58.