## Selection of the week

April 24, 2015

Songs of a Wayfarer by Gustav Mahler, sung by mezzo soprano Sarah Connolly with the BBC Symphony Orchestra.

## Talk at Michigan

April 23, 2015

I gave a talk in the Department of Computational Medicine and Bioinformatics at the University of Michigan yesterday. The video of the talk is here.  The talk is similar to the one I gave at the SMB annual meeting this summer.  My slides can be found here.

## Selection of the week

April 18, 2015

Bela Bartok’s Romanian Folk Dances played by the Sydney Camerata Chamber Orchestra.

## The philosophy of Thomas the Tank Engine

April 16, 2015

My toddler loves to watch the television show Thomas and Friends based on the The Railway Series books by the Rev. Wilbert Audry. The show tells the story of sentient trains on a mythical island off the British coast called Sodor. Each episode is a morality play where one of the trains causes some problem because of a character flaw like arrogance or vanity that eventually comes to the attention of the avuncular head of the railroad, Sr. Topham Hatt (called The Fat Controller in the UK). He mildly chastises the train, who becomes aware of his foolishness (it’s almost always a he) and remedies the situation.

While I think the show has some educational value for small children, it also brings up some interesting ethical and metaphysical questions that could be very relevant for our near future. For one, although the trains are sentient and seem to have full control over their actions, some of them also have human drivers. What are these drivers doing? Are they simply observers or are they complicit in the ill-judged actions of the trains? Should they be held responsible for the mistakes of the train? Who has true control, the driver or the train? Can one over-ride the other? These questions will be on everyone’s minds when the first self-driving cars hit the mass market in a few years.

An even more relevant ethical dilemma regards the place the trains have in society. Are they employees or indentured servants of the railroad company? Are they free to leave the railroad if they want? Do they own possessions? When the trains break down they are taken to the steam works, which is run by a train named Victor. However, humans effect the repairs. Do they take orders from Victor? Presumably, the humans get paid and are free to change jobs so is this a situation where free beings are supervised by slaves?

The highest praise a train can receive from Sir Topham Hatt is that he or she was “very useful.” This is not something one would say to a human employee in a modern corporation. You might say you were very helpful or that your action was very useful but it sounds dehumanizing to say “you are useful.” Thus, Sir Topham Hatt at least, does not seem to consider the trains to be humans. Perhaps, he considers them to be more like domesticated animals. However, these are animals that clearly have aspirations, goals, and feelings of self-worth. It seems to me that they should be afforded the full rights of any other citizen of Sodor. As machines become more and more integrated into our lives, it may well be useful to probe the philosophical quandaries of Thomas and Friends.

## Selection of the week

April 10, 2015

Igor Stravinsky’s ballet Le sacre du printemps (The Rite of Spring), Part 1 with the San Francisco Symphony conducted by Michael Tilson Thomas. This piece ushered in the modern age. It cause minor rioting when first performed in Paris in 1913 but now is considered one of the masterpieces of the 20th century.

## R vs Matlab

April 4, 2015

It has now been almost half a year since I switched from Matlab to open source software and I’ve been amazed at how easy the transition has been. I had planned to replace Matlab with Python, Julia, and R but I have found that R and Julia have been sufficient for my requirements. Maxima is also more than adequate to replace Mathematica. I have become particularly attached to R especially after I started to use R Studio as the interface. I had only used R before as just a statistics tool but it really is a complete programming platform like Matlab. It has very nice graphics capabilities and I find the language very nice to program in. I really like its use of lists where I can pile sets of any type and any size into one object. I also like how R Studio can save your work into Projects, which keeps the whole environment and history in one place. I can then switch between multiple projects and everything comes back. The only thing I miss from Matlab is the command completion history feature, where I could easily find a previous command by just typing the first few letters. Also, I haven’t quite figured out how to output R data into a text file seamlessly yet. I seem to always get extraneous row or column information. I use Julia when I want to write a code that needs to loop fast but for everything else I’ve been reaching for R.

## Selection of the week

April 3, 2015

For Good Friday, here is the famous aria Erbarme dich from Johann Sebastian Bach’s St. Matthew Passion, with mezzosoprano Marianna Pizzolato.

If you have three spare hours, I would listen to the whole thing.  You should do this at least once in your life.

## New paper on gene repression

April 2, 2015

CC Chow, KK Finn, GB Storchan, X Lu, X Sheng, SS Simons Jr., Kinetically-Defined Component Actions in Gene Repression. PLoS Comp Bio. 11:e1004122, (2015)

Abstract

Gene repression by transcription factors, and glucocorticoid receptors (GR) in particular, is a critical, but poorly understood, physiological response. Among the many unresolved questions is the difference between GR regulated induction and repression, and whether transcription cofactor action is the same in both. Because activity classifications based on changes in gene product level are mechanistically uninformative, we present a theory for gene repression in which the mechanisms of factor action are defined kinetically and are consistent for both gene repression and induction. The theory is generally applicable and amenable to predictions if the dose-response curve for gene repression is non-cooperative with a unit Hill coefficient, which is observed for GR-regulated repression of AP1LUC reporter induction by phorbol myristate acetate. The theory predicts the mechanism of GR and cofactors, and where they act with respect to each other, based on how each cofactor alters the plots of various kinetic parameters vs. cofactor. We show that the kinetically-defined mechanism of action of each of four factors (reporter gene, p160 coactivator TIF2, and two pharmaceuticals [NU6027 and phenanthroline]) is the same in GR-regulated repression and induction. What differs is the position of GR action. This insight should simplify clinical efforts to differentially modulate factor actions in gene induction vs. gene repression.

Author Summary

While the initial steps in steroid-regulated gene induction and repression are known to be identical, the same cannot be said of cofactors that modulate steroid-regulated gene activity. We describe the conditions under which a theoretical model for gene repression reveals the kinetically-defined mechanism and relative position of cofactor action. This theory has been validated by experimental results with glucocorticoid receptors. The mode and position of action of four factors is qualitatively identical in gene repression to that previously found in gene induction. What changes is the position of GR action. Therefore, we predict that the same kinetically-defined mechanism usually will be utilized by cofactors in both induction and repression pathways. This insight and simplification should facilitate clinical efforts to maximize desired outcomes in gene induction or repression.

I am so happy that this paper is finally published.  It was a two-year ordeal from the time I had the idea of what to do until it finally came out. This is the second leg of the three-legged stool for a theory of steroid-regulated gene expression. The first was developing the theory for gene induction (e.g. see here) that started over ten years ago when Stoney and I first talked about trying to understand his data and really took off when Karen Ong turned her summer internship into a two-year baccalaureate fellowship. She’s now finishing up the PhD part of her MD-PhD at the Courant Institute at NYU.

In the first leg, we showed that if the dose-response curve for steroid-regulated gene induction (i.e. gene product as a function of ligand concentration), had the form  $a x/ (c+x)$, (which has been variously called noncooperative, Michaelis-Menten function, Hill function with Hill coefficient equal to 1, hyperbolic, first order Hill dose response curve, to give a few), then the dose-response could be written down in closed form.  The theory considers gene induction to be a sequence of complex forming reactions $Y_{i-1} + X_{i} \leftrightarrow Y_i$ for $i = 1, 2, ..., n$, and the dose-response is given by $[Y_n]$ as a function of $[Y_0]$, which in general is a very high order polynomial which is not Michaelis-Menten. However,  when some biophysically plausible conditions on the parameters are met, the polynomial can be represented by the group of lower triangular matrices and can be solved exactly.  We can then use the formulae to make predictions for the mechanisms of various transcription factors.

However, steroids also repress genes and interestingly enough the repression curve is also noncooperative and is given by the linear fractional function $a + bx/(1 + c x)$. The question then was how does this work. I was puzzled for a while on how to solve this but then thought that if we believe that the transcription machinery after initiation is mostly conserved then the induction theory we had previously derived should still be in place. What is different is that in repression instead of steroids initiating the cascade, there was some other agonist and steroid repressed this. In our induction theory, we included the effects of activators and inhibitors from enzyme kinetics, which we called accelerators and decelerators to avoid confusing with previously used terms. Because of the group property of the reactions, basically any function you are interested in has linear-fractional form. I thus postulated that steroids, after binding to a nuclear steroid receptor, acts like a decelerator. I then had to work out all the possible cases for where the decelerator could act and the large number of them made the calculations rather tedious. As a result, I made lots of mistakes initially and the theory just wouldn’t fit the data. I finally had a breakthrough in the fall of 2013 when I was in Taiwan for a workshop and everything started to come together. It then took another six months to work out the details and write the paper, which was then followed by several back and forth’s with the referees, a major rewriting and a final acceptance a few months ago. In the process of working on this paper, I discovered a lot of properties about the induction system that I didn’t realize. I still didn’t believe it was finished until I saw it posted on the PLoS Comp Bio website this week.

I’m currently putting on the finishing touches for revisions on the third leg of the stool now. We have even reunited the band and convinced Karen to take some time away from her thesis to help finish it. This paper is about how partial agonists or antagonists like tamoxifen work, which could have implications for drug development and avoiding side effects. Steroids are not the only ligand that can activate a steroid-regulated gene. The steroid cream that you use for rashes consists of a highly potent steroid agonist. There are also molecules that block or impede the action of steroids by binding to steroid receptors and these are called partial agonists, antagonists or antisteroids. However, steroid receptors are widely expressed and that is why when you take them they can have severe side effects. Hence, it would be nice to be able to control where they act and by how much. This third leg paper is the theory behind how to do this.

## The perils of math pedagogy

March 30, 2015

It seems that the prevailing wisdom in teaching mathematics is to make abstract concepts as concrete as possible. The thinking is that if math can be related to everyday concepts or pictures then it will be more palatable and understandable. I happen to disagree. I think part of what makes math fun is the abstractness of it. You make up some rules and follow them to their logical conclusions. This is also how I see children play. They like to invent make-believe worlds and then play within them according to the rules of the world.

Usually these attempts at concreteness seem harmless enough but I have recently come up with an example where making things concrete is much more confusing than just teaching a rule. The example is in division with remainders. My third grader was asked to “draw” 7 divided by 2 in terms of items and groups. Her instinct was to draw 2 groups with three balls each with one ball remaining, like this

(x x x)

(x x x)

x

She then was supposed to write this as a mixed number, which looking at the diagram she wrote 3 1/3. When she asked me if this is correct I asked her to multiply this by 2 and see if it gets back 7 and when she got 6 2/3, she was extremely confused as to why she didn’t get the right answer. I tried to explain to her that the way she grouped things, the remainder was in terms of the fraction of the number of groups, which is very unintuitive and almost impossible to explain. It would have been even worse if the example was 8 divided by 3.

I then tried to tell her that a better way to think of division is not to ask how many elements would you get if you divided 7 into 2 groups because this amounts to begging the question (phrase used the correct way), since you need to know the answer before you can do the operation. Rather, what you really want to ask is how many groups would you have if you divided 7 items into groups of size 2 (which is a local rule), whereupon the diagram would be

( x x)

(x x)

(x x)

x

Now if you write down the mixed number you get 3 1/2, which is the correct answer. She then argued vehemently with me that this is not what the teacher taught her, which may or may not be true.

I think even most adults would get confused by this example and maybe working through it would give them a new appreciation of division. However, if you wanted children to learn to divide correctly than teaching them the rule is better. To divide 7 by 2 you find the largest integer that multiplied by 2 fits into 7 and what’s left over is divided by 2. Even better, which introduces and motivates fractions, is that you write 7 divided by 2 as 7/2 and this then becomes 3 1/2. If you learn the rule, you will never end up with 3 1/3.

## Selection of the week

March 27, 2015

Leonard Bernstein conducts the “Orchestre National de France” in Hector Berlioz’s (psychedelic) Symphonie Fantastique 5th Movement:Larghetto, Allegro (Songe d’une nuit de Sabbat) in Paris, 1976.

If you have the time, here’s the whole piece played by the Chicago Symphony Orchestra conducted by Stéphane Denève.

## New paper on path integrals

March 24, 2015

Carson C. Chow and Michael A. Buice. Path Integral Methods for Stochastic Differential Equations. The Journal of Mathematical Neuroscience,  5:8 2015.

Abstract: Stochastic differential equations (SDEs) have multiple applications in mathematical neuroscience and are notoriously difficult. Here, we give a self-contained pedagogical review of perturbative field theoretic and path integral methods to calculate moments of the probability density function of SDEs. The methods can be extended to high dimensional systems such as networks of coupled neurons and even deterministic systems with quenched disorder.

This paper is a modified version of our arXiv paper of the same title.  We added an example of the stochastically forced FitzHugh-Nagumo equation and fixed the typos.

## Selection of the week

March 20, 2015

Vivaldi’s Spring from the Four Seasons, with Julia Fischer and the Academy of St. Martin in the Fields.

## Selection of the week

March 13, 2015

The first movement of the Cello (and Piano) Sonata No.1 Op. 38 by Johannes Brahms played by Alisa Weilerstein, cello and  Ilan Rechtman, piano.

Here is the whole thing with Yo Yo Ma and Emanuel Ax

## Jobs at the Allen Institute

March 7, 2015

The Allen Institute for Brain Science is currently recruiting. The positions are listed on this link but in particular see below:

 SCIENTIST I – MODELING, ANALYSIS AND THEORY The Modeling, Analysis and Theory team at the Allen Institute is seeking a candidate with strong mathematical and computational skills who will work closely with both the team as well as experimentalists in order to both maximize the potential of datasets as well as realize that potential via analysis and theory. The successful candidate will be expected to develop analysis for populations of neurons as well as establish theoretical results on cortical computation, object recognition, and related areas in order to aid the Institute in understanding the most complex piece of matter in the universe. Contact: Michael Buice, Scientist II michaelbu@ alleninstitute.org

## Selection of the week

March 7, 2015

Early Romantic composer Felix Mendelssohn’s Song Without Words Op 109 played by English cellist Jacqueline du Pré, whose career was tragically shortened by multiple sclerosis.

## Michael Buice on the dress

March 3, 2015

Read former LBM fellow Michael Buice’s explanation of the dress colour illusion.

Huffington Post: …In the case of the dress, one’s assumptions about lighting have a strong impact on the perceived color. In particular, your perception will be affected by whether your visual system sees the dress as being in bright light or in shadow. Comic book coloristNathan Fairbairn put together the following in order to illustrate these two different potential hypotheses about light and color in the picture.

So what happens if we try to remove contextual information? It so happens that these average colors are close to being inverses of one another. Inverting them gives us:

Inverting the colors in the original photo should approximately “swap” the two colors on the dress, as well as remove contextual information (or perhaps render it nonsensical). The color inverted dress looks like:

I see white-and-gold here, and I saw white-and-gold in the original. My wife is a die hard Black-and-bluer, and she sees the inverted dress as light-blue-and-gold. Notice that the image now has artifacts that look (to me anyway) like damage in an old photograph. This is a sample size of one, so I’m curious to know if this inversion changes the perceptions of any other black-and-bluers out there.

We know that training can alter the “light-from-above” prior, and it seems plausible that people’s differing perceptions of the photo are due to their different experience, and in particular their experience with light, shading, material, and overexposed photographs.

Our brains have to make guesses, but they don’t always make the same guesses, even though we live in the same world. One of the hardest inference problems our brains have to solve is figuring out how everyone else sees the world. Perhaps with some very hard work, I can be a Black-and-bluer, too.

Michael Buice is a scientist at the Allen Institute for Brain Science. His research interests are in identifying and understanding the mechanisms and principles that the nervous system uses to perform the inferences which allow us to perceive the world.

## New paper on steroid-regulated gene expression

February 27, 2015

Research Resource: Modulators of glucocorticoid receptor activity identified by a new high-throughput screening assay

John A. Blackford, Jr., Kyle R. Brimacombe, Edward J. Dougherty , Madhumita Pradhan, Min Shen, Zhuyin Li, Douglas S. Auld, Carson C. Chow, Christopher P. Austin, and S. Stoney Simons, Jr.

Abstract: Glucocorticoid steroids affect almost every tissue-type and thus are widely used to treat a variety of human pathologies. However, the severity of numerous side-effects limits the frequency and duration of glucocorticoid treatments. Of the numerous approaches to control off-target responses to glucocorticoids, small molecules and pharmaceuticals offer several advantages. Here we describe a new, extended high throughput screen in intact cells to identify small molecule modulators of dexamethasone-induced glucocorticoid receptor (GR) transcriptional activity. The novelty of this assay is that it monitors changes in both GR maximal activity (Amax) and EC50, or the position of the dexamethasone dose-response curve. Upon screening 1280 chemicals, ten with the greatest change in the absolute value of Amax or EC50 were selected for further examination. Qualitatively identical behaviors for 60 –90% of the chemicals were observed in a completely different system, suggesting that other systems will be similarly affected by these chemicals. Additional analysis of the ten chemicals in a recently described competition assay determined their kinetically-defined mechanism and site of action. Some chemicals had similar mechanisms of action despite divergent effects on the level of GR-induced product. These combined assays offer a straightforward method of identifying numerous new pharmaceuticals that can alter GR transactivation in ways that could be clinically useful.

## Paper on new version of Plink

February 27, 2015

The paper describing the updated version of the genome analysis software tool Plink has just been published.

Second-generation PLINK: rising to the challenge of larger and richer datasets
Christopher C Chang, Carson C Chow, Laurent CAM Tellier, Shashaank Vattikuti, Shaun M Purcell, and James J Lee

GigaScience 2015, 4:7  doi:10.1186/s13742-015-0047-8

Abstract
Background
PLINK 1 is a widely used open-source C/C++ toolset for genome-wide association studies (GWAS) and research in population genetics. However, the steady accumulation of data from imputation and whole-genome sequencing studies has exposed a strong need for faster and scalable implementations of key functions, such as logistic regression, linkage disequilibrium estimation, and genomic distance evaluation. In addition, GWAS and population-genetic data now frequently contain genotype likelihoods, phase information, and/or multiallelic variants, none of which can be represented by PLINK 1’s primary data format.

Findings
To address these issues, we are developing a second-generation codebase for PLINK. The first major release from this codebase, PLINK 1.9, introduces extensive use of bit-level parallelism, View MathML-time/constant-space Hardy-Weinberg equilibrium and Fisher’s exact tests, and many other algorithmic improvements. In combination, these changes accelerate most operations by 1-4 orders of magnitude, and allow the program to handle datasets too large to fit in RAM. We have also developed an extension to the data format which adds low-overhead support for genotype likelihoods, phase, multiallelic variants, and reference vs. alternate alleles, which is the basis of our planned second release (PLINK 2.0).

Conclusions
The second-generation versions of PLINK will offer dramatic improvements in performance and compatibility. For the first time, users without access to high-end computing resources can perform several essential analyses of the feature-rich and very large genetic datasets coming into use.

Keywords: GWAS; Population genetics; Whole-genome sequencing; High-density SNP genotyping; Computational statistics

This project started out with us trying to do some genomic analysis that involved computing various distance metrics on sequence space. Programming virtuoso Chris Chang stepped in and decided to write some code to speed up the computations. His program, originally called wdist, was so good and fast that we kept asking him to put in more capabilities. Eventually,  he had basically replicated the suite of functions that Plink performed so he contacted Shaun Purcell, the author of Plink, if he could just call his code Plink too and Shaun agreed. We then ran a series of tests on various machines to check the speed-ups compared to the original Plink and gcta. If you do any GWAS analysis at all, I highly recommend you check out Plink 1.9.

## Selection of the week

February 27, 2015

English composer Ralph Vaughn Williams’s Fantasia on Greensleeves played by  Ibis, who are based near here in Arlington Virginia.

## Talk at UMBC

February 20, 2015

I’m giving a talk at University of Maryland, Baltimore County today at noon. The talk will be similar to the one I gave at SMB this past summer.  Slides can be found here.