Short Threads of Reading Queue

Here are some academic papers, articles, and blog posts I have put into my reading queue over the past few weeks that I have found interesting and/or comment-worthy. I have organized them into threads (e.g. streams of consciousness) here:

Short thread on cell biology and genomics:

[1] Xie, J. et.al   Autocrine signaling based selection of combinatorial antibodies that transdifferentiate human stem cells. PNAS, doi:10.1073/pnas.1306263110 (2013).

[2] Williams, R.B.H. et.al   The influence of genetic variation on gene expression. Genome Research, 17, 1707-1716 (2007).

In [1], the researchers use a combination of receptor antibodies to reprogram a cell's fate. Yet more evidence that cellular reprogramming is not only possible, but involves more than just a few transcription factors or a spontaneous transformation. The science in [2] is a pre-RNA-seq study on the effects of standing genome variation on steady-state gene expression. A good early review, although there is now more current/specific work available.

Short thread on economics, markets, and technology:

[1] Yglesias, M.   Who gets rich when robots take our jobs. Moneybox blog, May 13 (2013).

Mr. Spacely from "The Jetsons". He's rich and George Jetson is not.

[2] Falk, A. and Szech, N.   Morals and Markets. Science, 707, 340 (2013).

After reading [1], I come away with the impression that the only thing that can be economically gained from automation is a bolstering of the arbitrary claim (e.g. Russian roulette) to genius (e.g. even patent trolling qualifies). Apparently, it is more relevant (and fleeting) than ever. This is part of a trend that has lead to productivity gains of the last 40 years becoming locked up in corporations and/or an executive elite. Again, automation has helped this trend along, although automation does not always result in this outcome.

In [2], a curious finding is reported. If you are part of a market, you are more likely to let a mouse die for a lower amount of money. A novel addition to the experimental moral philosophy field. Not quite sure if this is an exercise in mutually-assured moral behavior (e.g. bystander effect), or a call to make judgments about economic value in isolation. Is there more than meets the eye to this simple set of experiments? As an aside, how does this relate to the psychology of auctions?

Short thread on subjectivity in the brain:

[1] Wittmann, M. et.al   The neural substrates of subjective time dilation. Frontiers in Human Neuroscience, doi:10.3389/neuro.09.002.2010 (2010).

[2] Schurger, A. et.al   Reproducibility distinguishes conscious from nonconscious neural representations. Science, 327, 97 (2010).

Apparently, 2010 was a good year for investigating subjectivity in the brain. How do we measure engagement with a piece of art or the practice of culture? In [1], changes in activity patterns among the "cognitive control" and "default activity" brain networks mediate subjective responses to visual motion. In [2], neural activity related to conscious, neural correlates of subjectivity must be both of a certain duration and intensity as well as being reproducible. While subjective experiences can be transient and unique, their neural correlates are not.

Happy 50th birthday, Chaos theory!

[1] Arbesman, S.   The Fiftieth Anniversary of Chaos. Social Dimension blog, May 17 (2013).

[2] Lorenz, E.N.   Deterministic Nonperiodic Flow. Journal of Atmospheric Science, 20, 130-141 (1963).

[3] Motter, A.E. and Campbell, D.K.   Chaos at Fifty. Physics Today, May, 27 (2013).

This feature got a pretty decent response on my micro-blog, Tumbld Thoughts: happy 50th birthday to the study of chaos [1]. A worldview first proposed (in formal fashion) by Edward Lorenz in a landmark paper on weather prediction called “Deterministic Nonperiodic Flow” [2]. Later, the field would grow to encompass analytical strategies such as nonperiodic attractors, bifurcation maps, and fractals.

As a new way to describe physical phenomena and complex systems with a high degree of nonlinearity and subtle unpredictabilities (e.g. the butterfly effect), chaos shattered the notion of a clockwork universe [3]. As a paradigm shifting concept, chaos theory has the potential to enrich all areas of science [4].

Image on left is from [1], and image at the right is from [3]. For the latest work in the field, check out the journal “Chaos: an interdisciplinary journal of nonlinear science”.

For examples from brain science, see the following two articles and book:

* Robson, D.   Disorderly genius: How chaos drives the brain. New Scientist, June 29 (2009). YouTube video.

* Kitzbichler, M.G., Smith, M.L., Christensen, S.R., Bullmore, E.   Broadband Criticality of Human Brain Network Synchronization. PLoS Computational Biology, 5(3), e1000314 (2009).

* Freeman, W.J.   Neurodynamics: an exploration in mesoscopic brain dynamics. Springer, Berlin (2006).

Intriguing evolution stuff:

Zimmer, C.   Enlisting a virtual pack, to study canine minds. New York Times, April 22 (2013).

The Dognition website.

This is a story about Dr. Hare, the Anthropologist (the study of humans) interested in canine cognition. Can we throw any more species in there? Oh yes -- apparently dogs are more intelligent than their wolf wild-type cousins (determined by something called the "pointing test"). So to make this assessment more scientific, Dr. Hare came up with a test for dog intelligence. He also founded a company called Dognition, which is collecting data from dogs worldwide. But there's no such thing as a Dog IQ just yet. It will be interesting to see how intelligence corresponds with breed and degree of artificial selection for specific traits.

Evolutionary "gut check":

Burger, O. et.al   Human mortality improvement in evolutionary context. PNAS, doi:10.1073/ pnas.1215627109 (2013).

This is a paper that I could not quite figure out. My gut says that something is not quite right/being accounted for here. Are they using ethnographically-observed hunter gatherer populations to derive an evolutionary baseline? If so, can they truly demonstrate that these populations actually represent such a baseline? Also, it seems to me that increases in life expectancy may involve the elimination of early mortality (due to warfare, violence, and disease) rather than a biological or cultural adaptation (particularly one on the order of those that distinguish between sister taxa, as the one that distinguishes human hunter-gatherers and chimps).

...and, finally, actual robots!

ICRA 2013 Conference website. Held in Karlsruhe, Germany, and sponsored by IEEE.

Erico Guizzo reports for IEEE Spectrum from ICRA (Robotics Conference), and brings us (among many other interesting things) a feature on Entropica:

LEFT: Screenshots of Entropica configurations (social network interactions and a pole balancing task). RIGHT: real-world (e.g. Primate) behaviors (termite dipping/tool use and stock market trading).

Wissner-Gross, A.D. and Freer, C.E.   Causal Entropic Forces. Physical Review Letters, 110, 168702 (2013).

Hewitt, J.   The emergence of complex behaviors through causal entropic forces. Phys.org, April 22 (2013).

Using a robotic model, it can be demonstrated that general intelligence (in the form of causal generalization) may be amplified or otherwise result from entropy maximization. This is related to work done on ant trails, showing that they conform to Fermat's principle of least time.

Perhaps it's not too late.....or too soon

Just found out (via IEEE Spectrum) about an interesting contest sponsored by Intel and the HYVE [1]. It's called the Intel Future Contest. The point is to come up with an idea for a an idealized application for a smart sensor suite. What do you do with it? Use it in the home? Use it to monitor your health? Or use it in your favorite hobby [2]? See the description below:

"Imagine five years into the future. You have on you (or with you) this new sensing technology. It can see, hear, remember and understand everything around you all the time".

They also provide a number of criteria to keep in mind during the design process. These are included in the table below:

The deadline is December 18. To submit, they require a series of sketches or something similar. Judges will (hopefully) be fair and impartial [3]. Categories include: healthcare, communication, work, knowledge production, entertainment, infrastructure and environmental modeling, creative expression, and an "other" category. If you have an idea (that you are not submitting or have already submitted), perhaps you could also submit it in the comments section below [4]. 

NOTES:

[1] a self-proclaimed "open-source innovation company".

[2] skydiving reference and pic (below) courtesy Ars Technica and Google I/O 2012 keynote address.

[3] one of the judges is Mark Roth, who I recognize as the conductor of experiments on SO2-induced hibernation in mice (metabolic flexability).

[4] to see the pool of submissions (which features some impressive ideas), go to this site. My submission, "Sensor-enabled Relativistic Virtual Worlds", can be viewed here (or Figshare version here).

Retinas, retinas, and technology

Recently, Apple and LG premiered a new technology called the retina display, which features an ultra-high pixel density [1]. For people with 20/20 vision, the pixel density of the display is actually higher than the sampling density of the viewer's retina. It is a principle similar to fast-flicker fusion, or the perception of coherent motion from a sequence of still frames presented at high-frequency. But what about people with degenerating retinas [2]? Fortunately, there are emerging technologies that can improve their viewing experiences as well (see Figure 1). These innovations are not yet ready for market, but are based on recent advances in BioMEMS and cell therapy.

Figure 1. LEFT: An image of the retina display from a next-generation iPhone. COURTESY: [1]. RIGHT: picture of the highly-complex architecture of the retina, in relation to the rest of the eye. COURTESY: [3].

According to two recent papers [4,5], there are two routes to repairing macular degeneration: stimulating existing cells in a way that re-activates them, or introducing precursor cells that can integrate into the retinal architecture. Using photovoltaic implants (Figure 2) made primarily from silicon [6], Mathieson et.al [4] 
were able to recover vision in the rat eye. There approach relies on the observation that loss of vision in degenerative diseases is primarily due to loss of cells in the outer layer (cells they characterize as "image capturing" photoreceptors), while cells in the inner layer (cells they characterize as "image processing" units) remain well- preserved. Loss of function due to degeneration is thus a blockage of this feed-forward component (e.g. from outer layer to inner layer). Using this model, the inner layer of cells can be stimulated 
in a way that mimics the effects of ambient light being processed by the outer layer cells.

This was done using the system shown in Figure 2. A camera was used to capture images in the environment. This was then converted into pulsed NIR (near-infrared) illumination, projected onto the retina using a pair of goggles (see Figure 2). Each pixel on the micropatterned array converted this signal into stimulation currents, which were delivered locally to inner layer neurons. For a rat retina, an entire micropatterned array is 0.8 x 1.2mm in size. A single pixel on this array is about 70um in size, and can elicit a neuronal response (in this case, neural ganglion cell action potentials fired as spike trains). The number of these activity bursts could be modulated by manpulating properties of the NIR stimulus such as irradiance and pulse width. Overall, among six healthy and five degenerate rats, the prosthetic seemed to recover visual function measured as bursts of retinal ganglion cell spikes. However, there are several technical challenges for implementing such a system in the eye for the long-term. One of these is maintaining a normal physiological temperature during pulsed light stimulation. A more fundamental limit involves the curvature of the eye cup (see Figure 1, right) limiting the maximum size of a single array, as graphene is not a highly compliant material. 

Figure 2: RIGHT: Histology of bionic retina demonstrating the size and placement of the implanted device. Notice the implant geometry with respect to the cell populations of interest. COURTESY: Image at left is from Figure 1 in [4], image at right is from Figure 6 in [4].

Pearson et.al [5] decided to take the cell therapy route to solving the same problem. Cell therapy has had many technical challenges in the course of its development [7], but in the past few years a number of promising studies have been published [8]. The cell therapy approach operates from the premise that a general loss of photoreceptors leads to the degradation of sight. There are no assumptions made about how the architecture functions, there simply needs to be an existing architecture in place in which transplanted cells may take root. In the attempt to regenerate this retinal architecture, 200,000 rod precursor cells were transplanted into knockout mice [9]. Of this number, up to 16% of cells are able to successfully (e.g,. functionally) integrate into target area. Some of these cells include a transgene which allows identifying high expression for the gene Nrl [10] using a GFP reporter. When the entire cell population is sorted for the Nrl+ criterion, the efficiency of cellular intergration is improved 20- to 30-fold. 

But what does it mean to functionally integrate? From a purely descriptive standpoint, integration is the ability of cells to migrate to specific target tissues and fully differentiate into mature cells. To fully assess their functionality, a number of assays are performed. Immunohistochemistry and ultrastructural analysis used to find hallmarks of fully-functioning neural cells. Notably, the transplanted rod precursors form triad synapses with existing bipolar and horizontal cells. Transplanted cells are also light repsonsive and exhibit dim-flash kinetics [11], which suggests normal function (see Figure 3). Finally, a number of behavioral tests for visually-guided behaviors such as spatial navigation and visual tracking [12], suggests that integrated cells drive these behaviors in a manner similar to what is seen in healthy, wild-type mice.

Figure 3. TOP: Measurement of dim-flash kinetics in mice using voltage-sensitive dye imaging techniques. BOTTOM: Results of the dye imaging for several different experimental conditions. For the combined panels (far right), the black patches represent mature rods, while red patches represent regenerated rods, and blue patches represent rods derived from Nrl/GFP+ (transplanted) cells. 
COURTESY: Figure 2 from [5].

While the level of development for retinal-related bionic technologies [13] is not as advanced as for visual display technologies, the promise is much greater. It is hard to say which approach is better or worse. Rather, these approaches might be used in combination, and one approach might be superior to another in select cases. Regardless, this is a relatively new and fast-growing area with much potential for new developments and great innovations. Stay tuned.

References:
[1] For more information on the retina display technology, please see the following links: http://en.wikipedia.org/wiki/Retina_display,    
http://www.apple.com/ipodtouch/features/retina-display.html


[2] Degenerating retinal function can either result from a retinopathy (due to diabetes, inflammation, or hypertension) or normal aging. For more information, please see: http://en.wikipedia.org/wiki/Retinopathy

[3] For more information on function and structure of the retina and vertebrate eye, please see: http://webvision.med.utah.edu/book/part-i-foundations/simple-anatomy-of-the-retina/

[4] Mathieson, K. et.al   Photovoltaic retinal prosthesis with high pixel density. Nature Photonics, 6, 391-397 (2012).

[5] Pearson et.al   Restoration of vision after transplantation of photoreceptors. Nature, 485, 99-103 (2012).

[6] Silicon is not the only material being used for implantation. A range of polymers can be used, provided they have the proper characteristics. For example, graphene is fast becoming a primary candidate material for regenerative medicine applications. Graphene is both biocompatible and conductive. Graphene can also be fabricated at nanoscale dimensions using layered deposition techniques. While modern graphene transistor arrays are primarily used as a sensing technology, technical limitations may be overcome that will enable greater computational ability (which will improve their usefulness as retinal prosthetics).

For more information, please see: Hess et.al   Biocompatible graphene transistor array reads cellular signals.
Advanced Materials, 23, 5045-5049 (2011) AND Schmidt, C.   The Bionic Material. Nature, 483, S37 (2012).

[7] Daley, G.Q.   The Promise and Perils of Stem Cell Therapeutics. Cell Stem Cell, 10(6), 740-749 (2012).

[8] Kim, S.U. and de Vellis, J.   Stem Cell-based Cell Therapy in Neurological Diseases: a review. Journal of Neuroscience Research, 87, 2183-2200 (2009).

[9] The knockout phenotype is Gnat double negative (-/-). This phenotype is naturally degenerate for the formation of a normal retinal phenotype. For more information on the function of Gnat (a family of acetyltransferases), please see: Vetting, M.W. Structure and functions of the GNAT superfamily of acetyltransferases. Archives of Biochemistry and Biophysics, 433, 212-226 (2005).

[10] Nrl is the gene that codes for the neural retina-specific leucine zipper protein. For more information, please see: http://ghr.nlm.nih.gov/gene/NRL.

[11] Dim-flash kinetics should be observed in rods that contain active photopigment, and is assayed in the context of light adaptation. For an example (in Salamanders), please see: Sakurai, K. et.al   Variation in rhodopsin kinase expression alters the dim flash response shut off and the light adaptation in rod photoreceptors. Investigations in Ophthalmology and Visual Science, 52(9), 6793-6800 (2011).

[12] tests include a version of the Morris water maze. For more information, please see Methods of [5].

[13] For more information on the development of prosthetic technologies (articles in Nature-related journals), please see: http://go.nature.com/hxbyrm.

Turing Machine Doodle

Today's Google doodle is a short Turing machine demo, in honor of Alan Turing's posthumous 100th birthday*. Nice*.

BONUS: here is a link to a short (5 minute) film called "Codebreaker" on Alan Turing's lifetime achievements.

* although the ultimate tribute would have been to build a Turing machine using sprites.

* culmination of the Turing Centenary year.

UPDATE (9/8/2012): I found a tribute to Turing from a computational neuroscience perspective in the latest issue of Trends in Cognitive Science, (Volume 16, Issue 9, 447–448). Featuring: Christof Koch, James McClelland, and Terry Sejnowski among others.

 

Google Doodle - Robert Noyce

Another interesting Google doodle, this time it is in honor of Robert Noyce (the honor being a posthumous birthday), the co-inventor of the integrated circuit.

Advances in Neuroengineering

A recent event put on by the IEEE EMBS focused on recent advances in Neuroengineering, or the interfacing of the nervous systems. Neuroengineering is an emerging approach to treating disabilities, understanding the brain, and building closed-loop control systems for brain-machine computer applications. Here are the sessions (on IEEE.tv):

Advances in neuroengineering

Understanding and treating conditions of the brain

One interesting topic brought up at these session was "microsleeps". Using advanced monitoring techniques, the presence of signatures akin to attentional lapses have been discovered. Microsleeps are sleep states that last on very short time scales. The presence of microsleeps could only be detected using electrophysiological techniques. This might be useful in predicting the onset of apnea episodes, or instances when a driver or heavy machine operator is about to deficus from their
task.

There are also therapeutic applications of these methods. The most intriguing would be to couple the real-time monitoring of muscle and brain activity with cutting edge gene and cell therapy treatments. The videos are worth the watch.