Microsoft Matlab Accelerator?

What is this? Just stumbled on it - any experiences?

Fast subroutines for Matlab programs

This library provides highly optimized versions of primitive functions such as repmat, set intersection, and gammaln. It provides efficient random number generators and evaluation of common probability densities. It provides routines for counting floating-point operations (FLOPS), useful for benchmarking algorithms. There are also some useful utilities such as filename globbing and parsing of variable-length argument lists.

http://research.microsoft.com/en-us/downloads/db1653f0-1308-4b45-b358-d8e1011385a0/default.aspx

Amino-acid imbalance explains extension of lifespan by dietary restriction in Drosophila

Richard C. Grandison, Matthew D. W. Piper and Linda Partridge

Dietary restriction extends healthy lifespan in diverse organisms and reduces fecundity1,2. It is widely assumed to induce adaptive reallocation of nutrients from reproduction to somatic maintenance, aiding survival of food shortages in nature3–6. If this were the case, long life under dietary restriction and high fecundity under full feeding would be mutually exclusive, through competition for the same limiting nutrients. Here we report a test of this idea in which we identified the nutrients producing the responses of lifespan and fecundity to dietary restriction in Drosophila. Adding essential amino acids to the dietary restriction condition increased fecundity and decreased lifespan, similar to the effects of full feeding, with other nutrients having little or no effect. However, methionine alone was necessary and sufficient to increase fecundity as much as did full feeding, but without reducing lifespan. Reallocation of nutrients therefore does not explain the responses to dietary restriction. Lifespan was decreased by the addition of amino acids, with an interaction between methionine and other essential amino acids having a key role. Hence, an imbalance in dietary amino acids away from the ratio optimal for reproduction shortens lifespan during full feeding and limits fecundity during dietary restriction. Reduced activity of the insulin/insulin-like growth factor signalling pathway extends lifespan in diverse organisms7, and we find that it also protects against the shortening of lifespan with full feeding. In other organisms, including mammals, it may be possible to obtain the benefits to lifespan of dietary restriction without incurring a reduction in fecundity, through a suitable balance of nutrients in the diet.

http://www.nature.com/nature/journal/vaop/ncurrent/pdf/nature08619.pdf

Detection of sequential polyubiquitylation on a millisecond timescale

Nathan W. Pierce, Gary Kleiger, Shu-ou Shan and Raymond J. Deshaies

Abstract | The pathway by which ubiquitin chains are generated on substrate through a cascade of enzymes consisting of an E1, E2 and E3 remains unclear. Multiple distinct models involving chain assembly on E2 or substrate have been proposed. However, the speed and complexity of the reaction have precluded direct experimental tests to distinguish between potential pathways. Here we introduce new theoretical and experimental methodologies to address both limitations. A quantitative framework based on product distribution predicts that the really interesting new gene (RING) E3 enzymes SCFCdc4 and SCFb-TrCP work with the E2 Cdc34 to build polyubiquitin chains on substrates by sequential transfers of single ubiquitins. Measurements with millisecond time resolution directly demonstrate that substrate polyubiquitylation proceeds sequentially. Our results present an unprecedented glimpse into themechanism of RING ubiquitin ligases and illuminate the quantitative parameters that underlie the rate and pattern of ubiquitin chain assembly.

http://www.nature.com/nature/journal/v462/n7273/pdf/nature08595.pdf

Direct cell reprogramming is a stochastic process amenable to acceleration

Jacob Hanna, Krishanu Saha, Bernardo Pando, Jeroen van Zon, Christopher J. Lengner, Menno P. Creyghton, Alexander van Oudenaarden & Rudolf Jaenisch

Abstract | Direct reprogramming of somatic cells into induced pluripotent stem (iPS) cells can be achieved by overexpression of Oct4, Sox2, Klf4 and c-Myc transcription factors, but only a minority of donor somatic cells can be reprogrammed to pluripotency. Here we demonstrate that reprogramming by these transcription factors is a continuous stochastic process where almost all

mouse donor cells eventually give rise to iPS cells on continued growth and transcription factor expression.Additional inhibition of the p53/p21 pathway or overexpression of Lin28 increased the cell division rate and resulted in an accelerated kinetics of iPS cell formation that was directly proportional to the increase in cell proliferation. In contrast, Nanog overexpression accelerated reprogramming in a predominantly cell-division-rate-independent manner. Quantitative analyses define distinct cell-division-rate-dependent and -independent modes for accelerating the stochastic course of reprogramming, and suggest that the number of cell divisions is a key parameter driving epigenetic reprogramming to pluripotency.

http://www.nature.com/nature/journal/v462/n7273/pdf/nature08592.pdf

Forcing cells to change lineages

Thomas Graf, Tariq Enver

Abstract | The ability to produce stem cells by induced pluripotency (iPS reprogramming) has rekindled an interest in earlier studies showing that transcription factors can directly convert specialized cells from one lineage to another. Lineage reprogramming has become a powerful tool to study cell fate choice during differentiation, akin to inducing mutations for the discovery of gene functions. The lessons learnt provide a rubric for how cells may be manipulated for therapeutic purposes.

http://www.nature.com/nature/journal/v462/n7273/pdf/nature08533.pdf

Reconstruction of the yeast Snf1 kinase regulatory network reveals its role as a global energy regulator

Renata Usaite, Michael C Jewett, Ana Paula Oliveira, John R Yates III, Lisbeth Olsson and Jens Nielsen

Highly conserved among eukaryotic cells, the AMP-activated kinase (AMPK) is a central regulator of carbon metabolism. To map the complete network of interactions around AMPK in yeast (Snf1) and to evaluate the role of its regulatory subunit Snf4, we measured global mRNA, protein and metabolite levels in wild type, Dsnf1, Dsnf4, and Dsnf1Dsnf4 knockout strains. Using four newly developed computational tools, including novel DOGMA sub-network analysis, we showed the benefits of three-level ome-data integration to uncover the global Snf1 kinase role in yeast. We for the first time identified Snf1’s global regulation on gene and protein expression levels, and showed that yeast Snf1 has a far more extensive function in controlling energy metabolism than reported earlier. Additionally, we identified complementary roles of Snf1 and Snf4. Similar to the function of AMPK in humans, our findings showed that Snf1 is a low-energy checkpoint and that yeast can be used more extensively as a model system for studying the molecular mechanisms underlying the global regulation of AMPK in mammals, failure of which leads to metabolic diseases.

http://www.nature.com/msb/journal/v5/n1/pdf/msb200967.pdf

Dissection of a complex transcriptional response using genome-wide transcriptional modelling

Martino Barenco, Daniel Brewer, Efterpi Papouli, Daniela Tomescu, Robin Callard, Jaroslav Stark

and Michael Hubank

Abstract | Modern genomics technologies generate huge data sets creating a demand for systems level, experimentally verified, analysis techniques. We examined the transcriptional response to DNA damage in a human T cell line (MOLT4) using microarrays. By measuring both mRNA accumulation and degradation over a short time course, we were able to construct a mechanistic model of the transcriptional response. The model predicted three dominant transcriptional activity profiles—an early response controlled by NFjB and c-Jun, a delayed response controlled by p53, and a late response related to cell cycle re-entry. The method also identified, with defined confidence limits, the transcriptional targets associated with each activity. Experimental inhibition of NFjB, c-Jun and p53 confirmed that target predictions were accurate. Model predictions directly explained 70% of the 200 most significantly upregulated genes in the DNA-damage response. Genome-wide transcriptional modelling (GWTM) requires no prior knowledge of either transcription factors or their targets. GWTM is an economical and effective method for identifying the main transcriptional activators in a complex response and confidently predicting their targets.

http://www.nature.com/msb/journal/v5/n1/pdf/msb200984.pdf

Information processing and signal integration in bacterial quorum sensing

Pankaj Mehta, Sidhartha Goyal, Tao Long, Bonnie L. Bassler and Ned S. Wingreen

Abstract | Bacteria communicate using secreted chemical signaling molecules called autoinducers in a process known as quorum sensing. The quorum-sensing network of the marine bacterium Vibrio harveyi uses three autoinducers, each known to encode distinct ecological information. Yet how cells integrate and interpret the information contained within these three autoinducer signals remains a mystery. Here, we develop a new framework for analyzing signal integration on the basis of information theory and use it to analyze quorum sensing in V. harveyi. We quantify how much the cells can learn about individual autoinducers and explain the experimentally observed input–output relation of the V. harveyi quorum-sensing circuit. Our results suggest that the need to limit interference between input signals places strong constraints on the architecture of bacterial signalintegration networks, and that bacteria probably have evolved active strategies for minimizing this interference. Here, we analyze two such strategies: manipulation of autoinducer production and feedback on receptor number ratios.

http://www.nature.com/msb/journal/v5/n1/pdf/msb200979.pdf

Synthetic biology: understanding biological design from synthetic circuits

Shankar Mukherji and Alexander van Oudenaarden

Abstract | An important aim of synthetic biology is to uncover the design principles of natural biological systems through the rational design of gene and protein circuits. Here, we highlight how the process of engineering biological systems — from synthetic promoters to the control of cell–cell interactions — has contributed to our understanding of how endogenous systems are put together and function. Synthetic biological devices allow us to grasp intuitively the ranges of behaviour generated by simple biological circuits, such as linear cascades and interlocking feedback loops, as well as to exert control over natural processes, such as gene expression and population dynamics.

http://www.nature.com/nrg/journal/v10/n12/pdf/nrg2697.pdf

Daughter-Specific Transcription Factors Regulate Cell Size Control in Budding Yeast

Stefano Di Talia, Hongyin Wang, Jan M. Skotheim,Adam P. Rosebrock, Bruce Futcher, Frederick R. Cross

Abstract | In budding yeast, asymmetric cell division yields a larger mother and a smaller daughter cell, which transcribe different genes due to the daughter-specific transcription factors Ace2 and Ash1. Cell size control at the Start checkpoint has long been considered to be a main regulator of the length of the G1 phase of the cell cycle, resulting in longer G1 in the smaller daughter cells. Our recent data confirmed this concept using quantitative time-lapse microscopy. However, it has been proposed that daughter-specific, Ace2-dependent repression of expression of the G1 cyclin CLN3 had a dominant role in delaying daughters in G1. We wanted to reconcile these two divergent perspectives on the origin of long daughter G1 times. We quantified size control using single-cell time-lapse imaging of fluorescently labeled budding yeast, in the presence or absence of the daughter-specific transcriptional regulators Ace2 and Ash1. Ace2 and Ash1 are not required for efficient size control, but they shift the domain of efficient size control to larger cell size, thus increasing cell size requirement for Start in daughters. Microarray and chromatin immunoprecipitation experiments show that Ace2 and Ash1 are direct transcriptional regulators of the G1 cyclin gene CLN3. Quantification of cell size control in cells expressing titrated levels of Cln3 from ectopic promoters, and from cells with mutated Ace2 and Ash1 sites in the CLN3promoter, showed that regulation of CLN3 expression by Ace2 and Ash1 can account for the differential regulation of Start in response to cell size in mothers and daughters. We show how daughter-specific transcriptional programs can interact with intrinsic cell size control to differentially regulate Start in mother and daughter cells. This work demonstrates mechanistically how asymmetric localization of cell fate determinants results in cell-type-specific regulation of the cell cycle.

http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1000221

How to make primers for direct integration into markers of BY4741

Tutorial | I have been captivated by the idea of directly integrating a PCR product into the yeast genome. The integration usually is done at one of the auxotrophic marker loci in the lab strain. These regions contain the remains of the original gene or a crippled version of the gene. Since integration there requires homology, and the genes have been deleted using different strategies, I did set to make a set of primer fragments or overhangs that I could use to directly target to the deleted regions of, in my case, BY4741. You can find a notebook containing the annotated genomic sequences for a few markers, a Word file with the fragment themselves and the relevant literature here.

Experimental evolution of bet hedging

Hubertus J. E. Beaumont, Jenna Gallie, Christian Kost, Gayle C. Ferguson & Paul B. Rainey

Abstract | Bet hedging -stochastic switching between phenotypic states— is a canonical example of an evolutionary adaptation that facilitates persistence in the face of fluctuating environmental conditions. Although bet hedging is found in organisms ranging frombacteria to humans, direct evidence for an adaptive origin of this behaviour is lacking. Here we report the de novo evolution of bet hedging in experimental bacterial populations. Bacteria were subjected to an environment that continually favoured new phenotypic states. Initially, our regime drove the successive evolution of novel phenotypes by mutation and selection; however, in two (of 12) replicates this trend was broken by the evolution of bet-hedging genotypes that persisted because of rapid stochastic phenotype switching. Genome re-sequencing of one of these switching types revealed ninemutations that distinguished it fromthe ancestor. The final mutation was both necessary and sufficient for rapid phenotype switching; nonetheless, the evolution of bet hedging was contingent upon earliermutations that altered the relative fitness effect of the finalmutation. These findings capture the adaptive evolution of bet hedging in the simplest of organisms, and suggest that riskspreading strategies may have been among the earliest evolutionary solutions to life in fluctuating environments.

http://www.nature.com/nature/journal/v462/n7269/pdf/nature08504.pdf

The transcription unit architecture of the Escherichia coli genome

Byung-Kwan Cho, Karsten Zengler, Yu Qiu1, Young Seoub Park, Eric M Knight, Christian L Barrett, Yuan Gao & Bernhard Ø Palsson

Abstract | Bacterial genomes are organized by structural and functional elements, including promoters, transcription start and termination sites, open reading frames, regulatory noncoding regions, untranslated regions and transcription units. Here, we iteratively integrate high-throughput, genome-wide measurements of RNA polymerase binding locations and mRNA transcript abundance, 5′ sequences and translation into proteins to determine the organizational structure of the Escherichia coli K-12 MG1655 genome. Integration of the organizational elements provides an experimentally annotated transcription unit architecture, including alternative transcription start sites, 5′ untranslated region, boundaries and open reading frames of each transcription unit. A total of 4,661 transcription units were identified, representing an increase of >530% over current knowledge. This comprehensive transcription unit architecture allows for the elucidation of condition-specific uses of alternative sigma factors at the genome scale. Furthermore, the transcription unit architecture provides a foundation on which to construct genome-scale transcriptional and translational regulatory networks.

http://www.nature.com/nbt/journal/v27/n11/pdf/nbt.1582.pdf

Quantitative effect of scaffold abundance on signal propagation

Stephen A Chapman and Anand R Asthagiri

Abstract | Protein scaffolds bring together multiple components of a signalling pathway, thereby promoting signal propagation along a common physical ‘backbone’. Scaffolds play a prominent role in natural signalling pathways and provide a promising platform for synthetic circuits. To better understand how scaffolding quantitatively affects signal transmission, we conducted an in vivo sensitivity analysis of the yeast mating pathway to a broad range of perturbations in the abundance of the scaffold Ste5. Our measurements show that signal throughput exhibits a biphasic dependence on scaffold concentration and that altering the amount of scaffold binding partners reshapes this biphasic dependence. Unexpectedly, the wild-type level of Ste5 is B10-fold below the optimum needed to maximize signal throughput. This sub-optimal configuration may be a tradeoff as increasing Ste5 expression promotes baseline activation of the mating pathway. Furthermore, operating at a sub-optimal level of Ste5 may provide regulatory flexibility as tuning Ste5 expression up or down directly modulates the downstream phenotypic response. Our quantitative analysis reveals performance tradeoffs in scaffold-based modules and defines engineering challenges for implementing molecular scaffolds in synthetic pathways.

http://www.nature.com/msb/journal/v5/n1/pdf/msb200973.pdf

Harnessing gene expression to identify the genetic basis of drug resistance

Bo-Juen Chen, Helen C Causton, Denesy Mancenido, Noel L Goddard, Ethan O Perlstein and Dana Pe’er

Abstract | The advent of cost-effective genotyping and sequencing methods have recently made it possible to ask questions that address the genetic basis of phenotypic diversity and how natural variants

interact with the environment.We developed Camelot (CAusal Modelling with Expression Linkage for cOmplex Traits), a statistical method that integrates genotype, gene expression and phenotype data to automatically build models that both predict complex quantitative phenotypes and identify genes that actively influence these traits. Camelot integrates genotype and gene expression data, both generated under a reference condition, to predict the response to entirely different conditions. We systematically applied our algorithm to data generated from a collection of yeast segregants, using genotype and gene expression data generated under drug-free conditions to predict the response to 94 drugs and experimentally confirmed 14 novel gene–drug interactions. Our approach is robust, applicable to other phenotypes and species, and has potential for applications in personalized medicine, for example, in predicting how an individual will respond to a previously unseen drug.

http://www.nature.com/msb/journal/v5/n1/pdf/msb200969.pdf

Reconstruction of the yeast Snf1 kinase regulatory network reveals its role as a global energy regulator

Renata Usaite, Michael C Jewett, Ana Paula Oliveira, John R Yates III, Lisbeth Olsson and Jens Nielsen

Abstract | Highly conserved among eukaryotic cells, the AMP-activated kinase (AMPK) is a central regulator of carbon metabolism. To map the complete network of interactions around AMPK in yeast (Snf1) and to evaluate the role of its regulatory subunit Snf4, we measured global mRNA, protein and metabolite levels in wild type, Dsnf1, Dsnf4, and Dsnf1Dsnf4 knockout strains. Using four newly developed computational tools, including novel DOGMA sub-network analysis, we showed the benefits of three-level ome-data integration to uncover the global Snf1 kinase role in yeast. We for the first time identified Snf1’s global regulation on gene and protein expression levels, and showed that yeast Snf1 has a far more extensive function in controlling energy metabolism than reported earlier. Additionally, we identified complementary roles of Snf1 and Snf4. Similar to the function of AMPK in humans, our findings showed that Snf1 is a low-energy checkpoint and that yeast can be used more extensively as a model system for studying the molecular mechanisms underlying the global regulation of AMPK in mammals, failure of which leads to metabolic diseases.

http://www.nature.com/msb/journal/v5/n1/pdf/msb200967.pdf

Natural genetic variation in transcriptome reflects network structure inferred with major effect mutations: insulin/TOR and associated phenotypes

Sergey V Nuzhdin, Jennifer A Brisson, Andrew Pickering,

Marta L Wayne, Lawrence G Harshman and Lauren M McIntyre

Abstract | Background: A molecular process based genotype-to-phenotype map will ultimately enable us to predict how genetic variation among individuals results in phenotypic alterations. Building such a map is, however, far from straightforward. It requires understanding how molecular variation reshapes developmental and metabolic networks, and how the functional state of these networks modifies phenotypes in genotype specific way. We focus on the latter problem by describing genetic variation in transcript levels of genes in the InR/TOR pathway among 72 Drosophila melanogaster genotypes.

Abstract | Results: We observe tight co-variance in transcript levels of genes not known to influence each other through direct transcriptional control. We summarize transcriptome variation with factor analyses, and observe strong co-variance of gene expression within the dFOXO-branch and within the TOR-branch of the pathway. Finally, we investigate whether major axes of transcriptome variation shape phenotypes expected to be influenced through the InR/TOR pathway. We find limited evidence that transcript levels of individual upstream genes in the InR/TOR pathway predict fly phenotypes in expected ways. However, there is no evidence that these effects are mediated through the major axes of downstream transcriptome variation.

Abstract | Conclusion: In summary, our results question the assertion of the 'sparse' nature of genetic networks, while validating and extending candidate gene approaches in the analyses of complex traits.

http://www.biomedcentral.com/content/pdf/1471-2164-10-124.pdf

A bibliography on learning causal networks of gene interactions

by Florian Markowetz

Abstract | This is a collection of references on learning regulatory and signaling networks. It contains articles from biology and bioinformatics, as well as theoretical background in mathematics and computer science. I annotated each article with an URL where it can be found and downloaded.

http://www.molgen.mpg.de/~markowet/docs/network-bib.pdf

Direct cell reprogramming is a stochastic process amenable to acceleration

Jacob Hanna*, Krishanu Saha*, Bernardo Pando, Jeroen van Zon, Christopher J. Lengner, Menno P. Creyghton, Alexander van Oudenaarden & Rudolf Jaenisch

Abstract | Direct reprogramming of somatic cells into induced pluripotent stem (iPS) cells can be achieved by overexpression of Oct4, Sox2, Klf4 and c-Myc transcription factors, but only a minority of donor somatic cells can be reprogrammed to pluripotency. Here we demonstrate that reprogramming by these transcription factors is a continuous stochastic process where almost all mouse donor cells eventually give rise to iPS cells on continued growth and transcription factor expression. Additional inhibition of the p53/p21 pathway or overexpression of Lin28 increased the cell division rate and resulted in an accelerated kinetics of iPS cell formation that was directly proportional to the increase in cell proliferation. In contrast, Nanog overexpression accelerated reprogramming in a predominantly cell-division-rate-independent manner. Quantitative analyses define distinct cell-division-rate-dependent and -independent modes for accelerating the stochastic course of reprogramming, and suggest that the number of cell divisions is a key parameter driving epigenetic reprogramming to pluripotency.

http://www.nature.com/nature/journal/vaop/ncurrent/pdf/nature08592.pdf

What are the consequences of the disappearing human microbiota?

Martin J. Blaser and Stanley Falkow

Abstract | Humans and our ancestors have evolved since the most ancient times with a commensal microbiota. The conservation of indicator species in a niche-specific manner across all of the studied human population groups suggests that the microbiota confer conserved benefits on humans. Nevertheless, certain of these organisms have pathogenic properties and, through medical practices and lifestyle changes, their prevalence in human populations is changing, often to an extreme degree. In this Essay, we propose that the disappearance of these ancestral indigenous organisms, which are intimately involved in human physiology, is not entirely beneficial and has consequences that might include post-modern conditions such as obesity and asthma.

http://www.nature.com/nrmicro/journal/v7/n12/pdf/nrmicro2245.pdf

Bacterial responses to photo-oxidative stress

Eva C. Ziegelhoffer and Timothy J. Donohue

Abstract | Singlet oxygen is one of several reactive oxygen species that can destroy biomolecules, microorganisms and other cells. Traditionally, the response to singlet oxygen has been termed photo-oxidative stress, as light-dependent processes in photosynthetic cells are major biological sources of singlet oxygen. Recent work identifying a core set of singlet oxygen stress response genes across various bacterial species highlights the importance of this response for survival by both photosynthetic and non-photosynthetic cells. Here, we review how bacterial cells mount a transcriptional response to photo-oxidative stress in the context of what is known about bacterial stress responses to other reactive oxygen species.

http://www.nature.com/nrmicro/journal/v7/n12/pdf/nrmicro2237.pdf

The spectrum of latent tuberculosis: rethinking the biology and intervention strategies

Clifton E. Barry 3rd, Helena I. Boshoff, Véronique Dartois, Thomas Dick, Sabine Ehrt, JoAnne Flynn, Dirk Schnappinger, Robert J. Wilkinson and Douglas Young

Abstract | Immunological tests provide evidence of latent tuberculosis in one third of the global population, which corresponds to more than two billion individuals. Latent tuberculosis is defined by the absence of clinical symptoms but carries a risk of subsequent progression to clinical disease, particularly in the context of co-infection with HIV. In this Review we discuss the biology of latent tuberculosis as part of a broad range of responses that occur following infection with Mycobacterium tuberculosis, which result in the formation of physiologically distinct granulomatous lesions that provide microenvironments with differential ability to support or suppress the persistence of viable bacteria. We then show how this model can be used to develop a rational programme to discover effective drugs for the eradication of M. tuberculosis infection.

http://www.nature.com/nrmicro/journal/v7/n12/pdf/nrmicro2236.pdf