Bookmarked Information flow and optimization in transcriptional regulation by Gašper Tkačik, Curtis G. Callan Jr., and William Bialek (PNAS August 26, 2008 105 (34) 12265-12270)
In the simplest view of transcriptional regulation, the expression of a gene is turned on or off by changes in the concentration of a transcription factor (TF). We use recent data on noise levels in gene expression to show that it should be possible to transmit much more than just one regulatory bit. Realizing this optimal information capacity would require that the dynamic range of TF concentrations used by the cell, the input/output relation of the regulatory module, and the noise in gene expression satisfy certain matching relations, which we derive. These results provide parameter-free, quantitative predictions connecting independently measurable quantities. Although we have considered only the simplified problem of a single gene responding to a single TF, we find that these predictions are in surprisingly good agreement with recent experiments on the Bicoid/Hunchback system in the early Drosophila embryo and that this system achieves ∼90% of its theoretical maximum information transmission.
https://doi.org/10.1073/pnas.0806077105
Bookmarked An information-theoretic framework for resolving community structure in complex networks by Martin Rosvall and Carl T. Bergstrom (PNAS May 1, 2007 104 (18) 7327-7331; )
To understand the structure of a large-scale biological, social, or technological network, it can be helpful to decompose the network into smaller subunits or modules. In this article, we develop an information-theoretic foundation for the concept of modularity in networks. We identify the modules of which the network is composed by finding an optimal compression of its topology, capitalizing on regularities in its structure. We explain the advantages of this approach and illustrate them by partitioning a number of real-world and model networks.
https://doi.org/10.1073/pnas.0611034104
Bookmarked Book review of Information theory in biology by N. Rashevsky (The bulletin of mathematical biophysics, June 1954, Volume 16, Issue 2, pp 183–185)

Information theory in biology by Henry Quastler, Editor. 1953. 273 pp. Urbana: University of Illinois Press

There are two kinds of scientific books worth reading. One is the monograph or treatise type, in which a more or less large field of science is presented in a systematic way, and in the form of a product as finished as possible at the given time. This kind of book may be considered a source of knowledge then available. The other type of book may present a collection of chapters or individual articles which do not claim to be a complete and systematic treatment of the subject; however the reader not only finds interesting ideas there, but the reading as such suggests new ideas. Such books are useful. For, although a rough and unfinished idea per se does not even remotely have the value of a well-elaborated scientific study, yet no elaborate study, no important theory, can be developed without first having a few rough ideas.

The book under consideration definitely belongs to the second category: it is a collection of essays. As the editor states in the Introduction (p. 2) : "The papers in this volume are of a very different degree of maturity. They range from authoritative reviews of well-known facts to hesitant and tentative formulations of embryonic ideas." He further states (p. 3): "We are aware of the fact that this volume is largely exploratory."

If the above is to be considered as a shortcoming, then the reviewer does not need to dwell on it, because the editor, and undoubtedly the authors, are fully aware of it, and duly warn the reader. If we evaluate the book from the point of view of how many ideas it suggests to the reader, then, at least so far as this reviewer is concerned, it must be considered a great success.

Bookmarked ARACNE: An Algorithm for the Reconstruction of Gene Regulatory Networks in a Mammalian Cellular Context by Adam A. Margolin, Ilya Nemenman, Katia Basso, Ulf Klein, Chris Wiggins, Gustavo Stolovitzky, Riccardo Dalla Favera, Andrea Califano (BMC Bioinformatics, Vol. 7, No. Suppl 1. (20 March 2006), S7, )

Background: Elucidating gene regulatory networks is crucial for understanding normal cell physiology and complex pathologic phenotypes. Existing computational methods for the genome-wide ``reverse engineering'' of such networks have been successful only for lower eukaryotes with simple genomes. Here we present ARACNE, a novel algorithm, using microarray expression profiles, specifically designed to scale up to the complexity of regulatory networks in mammalian cells, yet general enough to address a wider range of network deconvolution problems. This method uses an information theoretic approach to eliminate the majority of indirect interactions inferred by co-expression methods. Results: We prove that ARACNE reconstructs the network exactly (asymptotically) if the effect of loops in the network topology is negligible, and we show that the algorithm works well in practice, even in the presence of numerous loops and complex topologies. We assess ARACNE's ability to reconstruct transcriptional regulatory networks using both a realistic synthetic dataset and a microarray dataset from human B cells. On synthetic datasets ARACNE achieves very low error rates and outperforms established methods, such as Relevance Networks and Bayesian Networks. Application to the deconvolution of genetic networks in human B cells demonstrates ARACNE's ability to infer validated transcriptional targets of the c MYC proto-oncogene. We also study the effects of mis estimation of mutual information on network reconstruction, and show that algorithms based on mutual information ranking are more resilient to estimation errors.

doi:10.1186/1471-2105-7-s1-s7

Bookmarked An information-based sequence distance and its application to whole mitochondrial genome phylogeny. by M. Li, J. H. Badger, X. Chen, S. Kwong, P. Kearney, H. Zhang (Bioinformatics. 2001 Feb;17(2):149-54.)

MOTIVATION: Traditional sequence distances require an alignment and therefore are not directly applicable to the problem of whole genome phylogeny where events such as rearrangements make full length alignments impossible. We present a sequence distance that works on unaligned sequences using the information theoretical concept of Kolmogorov complexity and a program to estimate this distance.

RESULTS: We establish the mathematical foundations of our distance and illustrate its use by constructing a phylogeny of the Eutherian orders using complete unaligned mitochondrial genomes. This phylogeny is consistent with the commonly accepted one for the Eutherians. A second, larger mammalian dataset is also analyzed, yielding a phylogeny generally consistent with the commonly accepted one for the mammals.

AVAILABILITY: The program to estimate our sequence distance, is available at http://www.cs.cityu.edu.hk/~cssamk/gencomp/GenCompress1.htm. The distance matrices used to generate our phylogenies are available at http://www.math.uwaterloo.ca/~mli/distance.html.

PMID: 11238070

Bookmarked Measuring the similarity of protein structures by means of the universal similarity metric. by N. Krasnogor, D. A. PeltaN. Krasnogor, D. A. Pelta (Bioinformatics. 2004 May 1;20(7):1015-21. Epub 2004 Jan 29.)

MOTIVATION: As an increasing number of protein structures become available, the need for algorithms that can quantify the similarity between protein structures increases as well. Thus, the comparison of proteins' structures, and their clustering accordingly to a given similarity measure, is at the core of today's biomedical research. In this paper, we show how an algorithmic information theory inspired Universal Similarity Metric (USM) can be used to calculate similarities between protein pairs. The method, besides being theoretically supported, is surprisingly simple to implement and computationally efficient.

RESULTS: Structural similarity between proteins in four different datasets was measured using the USM. The sample employed represented alpha, beta, alpha-beta, tim-barrel, globins and serpine protein types. The use of the proposed metric allows for a correct measurement of similarity and classification of the proteins in the four datasets.

AVAILABILITY: All the scripts and programs used for the preparation of this paper are available at http://www.cs.nott.ac.uk/~nxk/USM/protocol.html. In that web-page the reader will find a brief description on how to use the various scripts and programs.

PMID: 14751983 DOI: 10.1093/bioinformatics/bth031

Bookmarked Information theory in living systems, methods, applications, and challenges. by R. A. Gatenby, B. R. FriedenR. A. Gatenby, B. R. Frieden (Bull Math Biol. 2007 Feb;69(2):635-57. Epub 2006 Nov 3.)

Living systems are distinguished in nature by their ability to maintain stable, ordered states far from equilibrium. This is despite constant buffeting by thermodynamic forces that, if unopposed, will inevitably increase disorder. Cells maintain a steep transmembrane entropy gradient by continuous application of information that permits cellular components to carry out highly specific tasks that import energy and export entropy. Thus, the study of information storage, flow and utilization is critical for understanding first principles that govern the dynamics of life. Initial biological applications of information theory (IT) used Shannon's methods to measure the information content in strings of monomers such as genes, RNA, and proteins. Recent work has used bioinformatic and dynamical systems to provide remarkable insights into the topology and dynamics of intracellular information networks. Novel applications of Fisher-, Shannon-, and Kullback-Leibler informations are promoting increased understanding of the mechanisms by which genetic information is converted to work and order. Insights into evolution may be gained by analysis of the the fitness contributions from specific segments of genetic information as well as the optimization process in which the fitness are constrained by the substrate cost for its storage and utilization. Recent IT applications have recognized the possible role of nontraditional information storage structures including lipids and ion gradients as well as information transmission by molecular flux across cell membranes. Many fascinating challenges remain, including defining the intercellular information dynamics of multicellular organisms and the role of disordered information storage and flow in disease.

PMID: 17083004 DOI: 10.1007/s11538-006-9141-5

Global classical solutions of the Boltzmann equation with long-range interactions

Bookmarked Global classical solutions of the Boltzmann equation with long-range interactions (pnas.org)

Finally, after 140 years, Robert Strain and Philip Gressman at the University of Pennsylvania have found a mathematical proof of Boltzmann’s equation, which predicts the motion of gas molecules.

Abstract

This is a brief announcement of our recent proof of global existence and rapid decay to equilibrium of classical solutions to the Boltzmann equation without any angular cutoff, that is, for long-range interactions. We consider perturbations of the Maxwellian equilibrium states and include the physical cross-sections arising from an inverse-power intermolecular potential r-(p-1) with p > 2, and more generally. We present here a mathematical framework for unique global in time solutions for all of these potentials. We consider it remarkable that this equation, derived by Boltzmann (1) in 1872 and Maxwell (2) in 1867, grants a basic example where a range of geometric fractional derivatives occur in a physical model of the natural world. Our methods provide a new understanding of the effects due to grazing collisions.

via pnas.org

 

In Law Schools, Grades Go Up, Just Like That

Bookmarked In Law Schools, Grades Go Up, Just Like That (New York Times)
In the last two years, at least 10 law schools have made their grading systems more lenient to give their students a better chance in a soft job market.

Is GPA tampering and grade inflation going too far with changes like this?

Stem cell treatment goes from lab to operating room | CNN.com

Bookmarked Stem cell treatment goes from lab to operating room (cnn.com)
Imagine having your back cut open, part of your spine removed, a stabilizing device that resembles a mini oil rig mounted on your back, the outer membrane of your spinal cord sliced open and experimental stem cells injected into it -- all for the advancement of science because it's not expected to benefit you.

Another article announcing the first stem cells being transplanted into a human patient in the United States. I worked with the researchers and surgeon in this experiment and built the microinjectors that were used in the lead up experiments as well as for this first patient.

Atlanta, Georgia — Imagine having your back cut open, part of your spine removed, a stabilizing device that resembles a mini oil rig mounted on your back, the outer membrane of your spinal cord sliced open and experimental stem cells injected into it — all for the advancement of science because it’s not expected to benefit you.

John Cornick, 51, did just that earlier this month as part of a groundbreaking clinical trial.

Almost a year ago, Cornick was told he had ALS — better known as Lou Gehrig’s disease. The diagnosis left him “fairly devastated,” he says.

He knew the prospects were grim because there is no cure.

But John wasn’t giving up so quickly, nor was his wife, Gina.

“I knew he was a fighter from the beginning and he really wanted to do something,” Gina Cornick says. She found information about a clinical trial on online and immediately signed him up, even though she had no idea where it was being held.

ALS destroys the nerve cells in the brain and spine which control muscle movement. When the brain can no longer tell muscles to move, they eventually die, depriving the patient of the ability to move arms and legs and eventually breathe.

The goal of this phase 1 trial is to determine whether fetal stem cells can safely be injected into the spinal cord. Ultimately, researchers hope to show that these cells may slow or halt the progression of the fatal disease.

But for now, the only goal is establishing safety.

Clinical trial

The Cornicks live in North Carolina, just a few hours from Atlanta, Georgia’s Emory University, the site of the trial. It is the first FDA-approved clinical trial to inject fetal stem cells directly into the spinal cord of an adult.

Dr. Jonathan Glass, director of Emory’s ALS center, is overseeing the trial. Cornick and two previous patients in the trial are heroes, says Glass, because at this point, the trial will likely produce only information, not results.

“In reality what do these patients have? Time, families and their life and we’re putting all of these at risk,” says Glass.

Dr. Lucie Bruijn, science director of the ALS Association, says the progress being made in this clinical trial is exciting. “We’ve been able to move it forward … from animal testing now into actual patients.” The treatment had not been tried in humans before.

Glass hopes this trial will lead to a new form of treatment for people with ALS. “We’re testing multiple things: We’re testing the safety of the surgery; we’re testing the cells; we’re testing immunosuppressants[because scientists do not know whether the body will reject the cells].” They are also testing how well Cornick handles this major surgical procedure, says Glass.

“After we’re finished with the first 12 or 18 patients we will know whether this is surgery that patients can tolerate.”

As he was prepped for surgery, Cornick was hopeful but realistic. “Well, of course you’d like to get up and walk … but I know that’s not going to happen.”

Stem cells

The stem cells used in the surgery are shipped overnight from Maryland, where Neuralstem, the company funding the trial, is based. The stem cells’ source is donated tissue from the spinal cord of an 8-week old aborted fetus, which was donated to the company. The company has developed a method that enables growth of millions of stem cells from this single source of human nerve stem cells.

Before the surgery can begin, a technician at Emory has to verify that a majority of stem cells made it to Atlanta alive. At least 70 percent have to be viable. In this case three samples under the microscope showed 85 percent of the cells arrived alive.

Lead researcher Dr. Eva Feldman, a neurologist at the University of Michigan, designed the trial just four years ago. After a lot of animal testing, her team determined that using fetal nerve stems rather than human embryonic or adult stem cells (such as bone marrow stem cells) was most effective, she says.

Stem cells have the ability to turn into different cells in the body. However, human embryonic stem cells, which come from 4- or 5-day-old embryos, also been found to sometimes turn into cancer cells. Fetal stem cells, such as those used in this trial, are a few weeks older and have already taken on a specific identity — in this case nerve cells.

Feldman says the fetal stem cells used in this trial did not become any of the unwanted cell types. “That’s very, very important,” she says.

Surgery

Animal testing also proved very useful when it came to figuring out how to actually inject the stem cells. Emory University’s neurosurgeon Dr. Nicholas Boulis invented the device that holds the needle that injects the stem cells. The goal is to inject the cells without injuring the spine and causing even more paralysis. He practiced on 100 pigs before attempting the procedure on a human.

Boulis says it’s critical that the injection be done in a very slow and controlled way.

“If you inject quickly, you’re going to create pressure at the head of the needle and that can cause damage,” Boulis says. That pressure can also inflate an area in the spinal cord which could cause the stem cells to seep back out of the cord when the needle is pulled out, he says. “So by pumping [cells] in slowly you have more security that you are not going to have reflux and you’re not going to have damage.”

Dr. Jeffrey Rothstein, who heads the ALS research center at Johns Hopkins University and is not connected to this trial, said work on this method is a big achievement. “This is purely about how to surgically deliver cellular therapy to spinal cord,” he says. “It’s never been done before.”

After the spinal cord was exposed, the injections began. Cornick got five — each one contains about 100,000 stem cells.

The four-and-a-half hour surgery went smoothly, Boulis, says. “There were no surprises.”

Post-surgery

A day after surgery, Cornick was lying flat in a hospital bed, chatting and laughing with some friends from North Carolina.

One week after surgery, he says he felt amazingly well and was still hopeful the cells would do some good for him.

Two weeks later Cornick’s stitches were removed and he was able to drive home. But he will be making frequent visits back to Atlanta as Glass and his team continue to monitor him.

Neuralstem’s Chief Scientific Officer Karl Johe says after the trial’s safety board reviews all existing data, including Cornick’s results, a fourth patient can be treated with the stem cells.

“Patients Four, Five and Six will receive twice as many [stem cell] injections,” Johe says. They will get five more injections on the other side of the spinal cord compared with Cornicks’s surgery.

Cornick expects the researchers will follow his progress for a long time. He says he understands the need for people to be willing to participate in experimental research like this.

“For me it just seemed like the right thing to do. I almost felt I had an obligation to do this,” he says. “To help other people and myself.”

Source: Stem cell treatment goes from lab to operating room – CNN.com

First U.S. stem cells transplanted into spinal cord | CNN.com

Bookmarked First U.S. stem cells transplanted into spinal cord (cnn.com)
For the first time in the United States, stem cells have been directly injected into the spinal cord of a patient, researchers announced Thursday.

A recent article announcing the first stem cells being transplanted into a human patient in the United States. I worked with the researchers and surgeon in this experiment and built the microinjectors that were used in the lead up experiments as well as for this first patient.

ATLANTA, Georgia (CNN) — For the first time in the United States, stem cells have been directly injected into the spinal cord of a patient, researchers announced Thursday.

Doctors injected stem cells from 8-week-old fetal tissue into the spine of a man in his early 60s who has advanced ALS, or amyotrophic lateral sclerosis. It was part of a clinical trial designed to determine whether it is safe to inject stem cells into the spinal cord and whether the cells themselves are safe.

ALS is a fatal neurodegenerative disease that causes the deterioration of specific nerve cells in the brain and spinal cord called motor neurons, which control muscle movement. About 30,000 Americans have ALS at any given time, according to the ALS Association.

There is no cure for ALS, which is better known as Lou Gehrig’sdisease, named after the New York Yankees’ first baseman and Hall of Famer who retired from baseball in the 1930s after being diagnosed with the disease.

As the illness progresses, patients lose their ability to walk, talk and breathe. Patients usually die within two to five years of diagnosis, according the ALS Association.

Neuralstem Inc., a Rockville, Maryland-based biotech company, received approval from the U.S. Food and Drug Administration to conduct the clinical trial in September. The company is fully funding the research and provides the stem cells that are being injected into the patients.

Neuralstem announced the start of the clinical trial in a news release Thursday.

Longtime ALS researcher and University of Michigan neurologist Dr. Eva Feldman is overseeing the first human clinical trial of a stem cell treatment in ALS patients.

“We are entering a new era of cell therapeutics for ALS, and in my opinion, it is an new era of hope for patients with ALS,” Feldman said.

At least 12 patients are expected to participate in this early research. They are to receive the stem cell transplants at Emory University in Atlanta, Georgia.

“This is the first study to see if the invasive injection into the spinal cord is safe for the patient,” said Lucie Bruijn, science director of the ALS Association.

This first patient in the clinical trial received several injections of stem cells into the lumbar region of the spinal cord, the area that controls leg function, because most ALS patients first lose muscle function in their legs, according to Karl Johe, Neuralstem’s chairman and chief scientific officer.

Bruijn says there have been a few other occasions outside the United States in which fetal stem cells have been injected into a patient, “but not necessarily using a very [rigorous] trial design.” She adds that there were also a couple of small studies in Italy that injected other types of stem cells into a few patients but that this is the first FDA-approved trial in the United States.

“Our biggest hope for stem cells is to significantly slow the progression the disease,” Bruijn said.

The ALS Association is not providing funding for this clinical trial, but it has supported the work of Dr. Nick Boulis, the Emory neurosurgeon who developed the surgical technique used to inject the stem cells.

Johe invented the technology that allows the company to manufacture billions of copies of stem cells that are taken from a single source of spinal cord cells: cells that were extracted from fetal tissue, which was donated to the company.

“The cells are human neural stem cells,” Johe said, acknowledging that the introduction of stem cells is a very invasive procedure.

“What we are attempting is a novel approach by directly injecting them into the middle of the spinal cord, which to our knowledge has never been done before,” Johe said.

Researchers plan to follow this and future patients participating in this trial for a long time to determine the safety of the procedure.

These particular stem cells — which came from the spinal cord of an 8-week-old fetus — are neural stem cells, which have the ability to turn into different types of nerve cells. These are not the same stem cells as the controversial human embryonic stem cells, which destroy the embryo when the stem cells are removed.

Johe says that once the safety of this type of transplant is determined, he and his colleagues hope to see whether this is a possible treatment for ALS.

“This is not a cure. We are not replacing those motor neurons [nerve cells which tell muscles to contract]. These stem cells don’t generate motor neurons. Instead they protect the still-functioning motor neurons,” Johe explained.

Bruijn says that injecting stem cells into the spinal cord — in the region where the motor neurons are located that affect ALS — is a breakthrough. But she cautions that this is only the first step in the first part of this clinical trial. It’s too early to draw any conclusions about the effectiveness of this treatment, especially since the trial has only just begun.

She notes that everyone involved with the study and other ALS patients have to wait and see what the results of the clinical trial will be.

The FDA granted the first approval for injecting human embryonic stem cells into humans to Menlo Park, California-based Geron Corporation in January 2009. Their trials were expected to start last summer but have yet to begin.

Source: First U.S. stem cells transplanted into spinal cord – CNN.com

Bookmarked The structure of degradable quantum channels by Toby S. Cubitt, Mary Beth Ruskai, Graeme Smith (Journal of Mathematical Physics 49, 102104 (2008))
Degradable quantum channels are among the only channels whose quantum and private classical capacities are known. As such, determining the structure of these channels is a pressing open question in quantum information theory. We give a comprehensive review of what is currently known about the structure of degradable quantum channels, including a number of new results as well as alternate proofs of some known results. In the case of qubits, we provide a complete characterization of all degradable channels with two dimensional output, give a new proof that a qubit channel with two Kraus operators is either degradable or anti-degradable, and present a complete description of anti-degradable unital qubit channels with a new proof. For higher output dimensions we explore the relationship between the output and environment dimensions (dB and dE, respectively) of degradable channels. For several broad classes of channels we show that they can be modeled with an environment that is “small” in the sense of ΦC. Such channels include all those with qubit or qutrit output, those that map some pure state to an output with full rank, and all those which can be represented using simultaneously diagonal Kraus operators, even in a non-orthogonal basis. Perhaps surprisingly, we also present examples of degradable channels with “large” environments, in the sense that the minimal dimension dE>dB. Indeed, one can have dE>14d2B. These examples can also be used to give a negative answer to the question of whether additivity of the coherent information is helpful for establishing additivity for the Holevo capacity of a pair of channels. In the case of channels with diagonal Kraus operators, we describe the subclasses that are complements of entanglement breaking channels. We also obtain a number of results for channels in the convex hull of conjugations with generalized Pauli matrices. However, a number of open questions remain about these channels and the more general case of random unitary channels.

Alternate version on arXiv: https://arxiv.org/abs/0802.1360 

Bookmarked Automated on-chip rapid microscopy, phenotyping and sorting of C. elegans. by Kwanghun Chung, Matthew M. Crane, Hang Lu (Nature Methods [22 Jun 2008, 5(7):637-643])
Microscopy, phenotyping and visual screens are frequently applied to model organisms in combination with genetics. Although widely used, these techniques for multicellular organisms have mostly remained manual and low-throughput. Here we report the complete automation of sample handling, high-resolution microscopy, phenotyping and sorting of Caenorhabditis elegans. The engineered microfluidic system, coupled with customized software, has enabled high-throughput, high-resolution microscopy and sorting with no human intervention and may be combined with any microscopy setup. The microchip is capable of robust local temperature control, self-regulated sample-loading and automatic sample-positioning, while the integrated software performs imaging and classification of worms based on morphological and intensity features. We demonstrate the ability to perform sensitive and quantitative screens based on cellular and subcellular phenotypes with over 95% accuracy per round and a rate of several hundred worms per hour. Screening time can be reduced by orders of magnitude; moreover, screening is completely automated.

[.pdf]

Related: https://www.news.gatech.edu/2008/06/23/automated-microfluidic-device-reduces-time-screen-small-organisms