CiteULike: balicea's library [2265 articles]

Population genetic and phylogenetic evidence for positive selection on regulatory mutations at the factor VII locus in humans.

MW Hahn — 2007-10-16T21:35:49-00:00

Genetics, Vol. 167, No. 2. (June 2004), pp. 867-877.

The abundance of cis-regulatory polymorphisms in humans suggests that many may have been important in human evolution, but evidence for their role is relatively rare. Four common polymorphisms in the 5' promoter region of factor VII (F7), a coagulation factor, have been shown to affect its transcription and protein abundance both in vitro and in vivo. Three of these polymorphisms have low-frequency alleles that decrease expression of F7 and may provide protection against myocardial infarction (heart attacks). The fourth polymorphism has a minor allele that increases the level of transcription. To look for evidence of natural selection on the cis-regulatory variants flanking F7, we genotyped three of the polymorphisms in six Old World populations for which we also have data from a group of putatively neutral SNPs. Our population genetic analysis shows evidence for selection within humans; surprisingly, the strongest evidence is due to a large increase in frequency of the high-expression variant in Singaporean Chinese. Further characterization of a Japanese population shows that at least part of the increase in frequency of the high-expression allele is found in other East Asian populations. In addition, to examine interspecific patterns of selection we sequenced the homologous 5' noncoding region in chimpanzees, bonobos, a gorilla, an orangutan, and a baboon. Analysis of these data reveals an excess of fixed differences within transcription factor binding sites along the human lineage. Our results thus further support the hypothesis that regulatory mutations have been important in human evolution.

Gene Regulation: Boundaries within Limits

Sandhya Payankaulam — 2008-08-04T16:23:15-00:00

Current Biology, Vol. 18, No. 15. (5 August 2008), pp. R653-R655.

Summary Quantitative measurements of the Hunchback transcription factor in Drosophila embryos show that its target genes can respond with a high degree of precision to the exact level of the protein, simulating a continuous, analog readout, while other target genes show a combinatorial effect, resembling a Boolean logic element.

Transcriptional Control in the Segmentation Gene Network of Drosophila

Mark Schroeder — 2007-01-01T19:51:52-00:00

PLoS Biology, Vol. 2, No. 9. (1 September 2004), e271.

The segmentation gene network of Drosophila consists of maternal and zygotic factors that generate, by transcriptional (cross-) regulation, expression patterns of increasing complexity along the anterior-posterior axis of the embryo. Using known binding site information for maternal and zygotic gap transcription factors, the computer algorithm Ahab recovers known segmentation control elements (modules) with excellent success and predicts many novel modules within the network and genome-wide. We show that novel module predictions are highly enriched in the network and typically clustered proximal to the promoter, not only upstream, but also in intronic space and downstream. When placed upstream of a reporter gene, they consistently drive patterned blastoderm expression, in most cases faithfully producing one or more pattern elements of the endogenous gene. Moreover, we demonstrate for the entire set of known and newly validated modules that Ahab's prediction of binding sites correlates well with the expression patterns produced by the modules, revealing basic rules governing their composition. Specifically, we show that maternal factors consistently act as activators and that gap factors act as repressors, except for the bimodal factor Hunchback. Our data suggest a simple context-dependent rule for its switch from repressive to activating function. Overall, the composition of modules appears well fitted to the spatiotemporal distribution of their positive and negative input factors. Finally, by comparing Ahab predictions with different categories of transcription factor input, we confirm the global regulatory structure of the segmentation gene network, but find odd skipped behaving like a primary pair-rule gene. The study expands our knowledge of the segmentation gene network by increasing the number of experimentally tested modules by 50%. For the first time, the entire set of validated modules is analyzed for binding site composition under a uniform set of criteria, permitting the definition of basic composition rules. The study demonstrates that computational methods are a powerful complement to experimental approaches in the analysis of transcription networks.

Networks, Dynamics, and the Small-World Phenomenon

Duncan Watts — 2005-09-02T20:32:17-00:00

The American Journal of Sociology, Vol. 105, No. 2. (1999), pp. 493-527.

The small-world phenomenon formalized in this article as the coincidence of high local clustering and short global separation, is shown to be a general feature of sparse, decentralized networks that are neither completely ordered nor completely random. Networks of this kind have received little attention, yet they appear to be widespread in the social and natural sciences, as is indicated here by three distinct examples. Furthermore, small admixtures of randomness to an otherwise ordered network can have a dramatic impact on its dynamical, as well as structural, properties-a feature illustrated by a simple model of disease transmission.

Correction of muscle artefacts in the EEG power spectrum.

T Gasser — 2008-08-05T17:59:35-00:00

Clinical Neurophysiology, Vol. 116 (2005), pp. 2044-2050.

To provide a method for correcting muscle artefacts in fast band power at EEG derivations. We define an indicator of surface EMG as power in the band 51.0-69.0Hz ('muscle power'). This indicator is used to approximately eliminate the contribution of muscle activity on fast band power via a regression model. Results: (I) Patients show a larger proportion of muscle activity in fast band power. (2) There is a clear topographic pattern, frontal-temporal derivations being most susceptible to EMG artefacts. (3) The contribution of surface EMG can be drastically reduced by the proposed correction method. (4) Without correction, results for fast bands can be biased when e.g. comparing control and patient groups and the proposed correction method by and large eliminates this bias. Conclusions: It is advisable to correct the quantitative EEG reflecting fast activity for the extent of EMG artefacts. Significance: To render the quantitative EEG more valid as an indicator of cerebral activity.

Discerning static and causal interactions in genome-wide reverse engineering problems.

M Zampieri — 2008-05-15T02:58:28-00:00

Bioinformatics (Oxford, England) (8 May 2008)

MOTIVATION: In the past years devising methods for discovering gene regulatory mechanisms at a genome-wide level has become a fundamental topic in the field of systems biology. The aim is to infer gene-gene interactions in an increasingly sophisticated and reliable way through the continuous improvement of reverse engineering algorithms exploiting microarray data. RESULTS: This work is inspired by the several studies suggesting that co-expression is mostly related to "static" stable binding relationships, like belonging to the same protein complex, rather than other types of interactions more of a "causal" and transient nature (e.g. transcription factor-binding site interactions). The aim of this work is to verify if direct or conditional network inference algorithms (e.g. Pearson correlation for the former, partial Pearson correlation for the latter) are indeed useful in discerning static from causal dependencies in artificial and real gene networks (derived from E.coli and S.cerevisiae). CONTACT: altafini@sissa.it.

Alternative splicing and protein structure evolution.

F Birzele — 2008-02-26T20:44:21-00:00

Nucleic Acids Res, Vol. 36, No. 2. (February 2008), pp. 550-558.

Alternative splicing is thought to be one of the major sources for functional diversity in higher eukaryotes. Interestingly, when mapping splicing events onto protein structures, about half of the events affect structured and even highly conserved regions i.e. are non-trivial on the structure level. This has led to the controversial hypothesis that such splice variants result in nonsense-mediated mRNA decay or non-functional, unstructured proteins, which do not contribute to the functional diversity of an organism. Here we show in a comprehensive study on alternative splicing that proteins appear to be much more tolerant to structural deletions, insertions and replacements than previously thought. We find literature evidence that such non-trivial splicing isoforms exhibit different functional properties compared to their native counterparts and allow for interesting regulatory patterns on the protein network level. We provide examples that splicing events may represent transitions between different folds in the protein sequence-structure space and explain these links by a common genetic mechanism. Taken together, those findings hint to a more prominent role of splicing in protein structure evolution and to a different view of phenotypic plasticity of protein structures.

AMPK and PPARδ Agonists Are Exercise Mimetics.

Vihang — 2008-08-02T05:23:09-00:00

Cell (2008)

The benefits of endurance exercise on general health make it desirable to identify orally active agents that would mimic or potentiate the effects of exercise to treat metabolic diseases. Although certain natural compounds, such as reseveratrol, have endurance-enhancing activities, their exact metabolic targets remain elusive. We therefore tested the effect of pathway-specific drugs on endurance capacities of mice in a treadmill running test. We found that PPARβ/δ agonist and exercise training synergistically increase oxidative myofibers and running endurance in adult mice. Because training activates AMPK and PGC1α, we then tested whether the orally active AMPK agonist AICAR might be sufficient to overcome the exercise requirement. Unexpectedly, even in sedentary mice, 4 weeks of AICAR treatment alone induced metabolic genes and enhanced running endurance by 44%. These results demonstrate that AMPK-PPARδ pathway can be targeted by orally active drugs to enhance training adaptation or even to increase endurance without exercise.

AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha.

S Jäger — 2008-06-05T02:24:20-00:00

Proceedings of the National Academy of Sciences of the United States of America, Vol. 104, No. 29. (17 July 2007), pp. 12017-12022.

Activation of AMP-activated kinase (AMPK) in skeletal muscle increases glucose uptake, fatty acid oxidation, and mitochondrial biogenesis by increasing gene expression in these pathways. However, the transcriptional components that are directly targeted by AMPK are still elusive. The peroxisome-proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) has emerged as a master regulator of mitochondrial biogenesis; furthermore, it has been shown that PGC-1alpha gene expression is induced by exercise and by chemical activation of AMPK in skeletal muscle. Using primary muscle cells and mice deficient in PGC-1alpha, we found that the effects of AMPK on gene expression of glucose transporter 4, mitochondrial genes, and PGC-1alpha itself are almost entirely dependent on the function of PGC-1alpha protein. Furthermore, AMPK phosphorylates PGC-1alpha directly both in vitro and in cells. These direct phosphorylations of the PGC-1alpha protein at threonine-177 and serine-538 are required for the PGC-1alpha-dependent induction of the PGC-1alpha promoter. These data indicate that AMPK phosphorylation of PGC-1alpha initiates many of the important gene regulatory functions of AMPK in skeletal muscle.

AMPK and transcriptional regulation.

SL McGee — 2007-11-14T16:26:53-00:00

Front Biosci, Vol. 13 (2008), pp. 3022-3033.

The AMP-activated protein kinase (AMPK) is an energy sensing enzyme that once activated, promotes energy production and limits energy utilisation to ensure cellular survival. In addition to targeting numerous metabolic enzymes for this purpose, it is becoming apparent that AMPK can also regulate a number of transcriptional processes. These processes ensure cell survival through the inhibition of cell cycle and growth mechanisms, and also prepare the cell for future perturbations in energy balance by increasing the capacity of the cell to produce ATP. While these adaptations might be inextricably linked through regulation of the proliferation-differentiation process, recent studies have identified a number of transcriptional regulators as AMPK substrates that give insights into the regulation of transcription by AMPK in a number of metabolically active tissues.

Computational methods for transcriptional regulation.

ED Siggia — 2006-08-25T21:25:29-00:00

Curr Opin Genet Dev, Vol. 15, No. 2. (April 2005), pp. 214-221.

How is the information from a thousand gene-expression arrays, the location of more than two hundred regulatory factors, and nine sequenced genomes to be integrated into a global view of the regulatory network in budding yeast? Computational methods that fit incomplete noisy data provide the outlines of regulatory pathways, but the errors are not quantified. In the fly, embryonic patterning has proved amenable to computational prediction, but only when the DNA-binding preferences of the relevant factors are taken into account. In both these model organisms, simply restricting attention to regulatory sequences that align with related species (i.e. "conserved") discards much information regarding what is functional.

Do viruses form lineages across different domains of life?

DH Bamford — 2008-07-29T16:56:36-00:00

Research in microbiology, Vol. 154, No. 4. (May 2003), pp. 231-236.

The scarce characterisation of the viral world has hampered our efforts to appreciate the magnitude and diversity of the viral domain. It appears that almost every species can be infected by a number of viruses. As our knowledge of viruses increases, it appears that this myriad of viruses may be organised into a reasonably low number of viral lineages including members infecting hosts belonging to different domains of life. Viruses belonging to a lineage share a common innate "self" that refers to structural and assembly principles of the virion. This hypothesis has a few consequences. All viruses are old, maybe preceding cellular life, and virus origins are polyphyletic, as opposed to the idea of a monophyletic origin of cellular life.

Comparative genomics: Difference of expression

Rasmus Nielsen — 2006-03-08T21:23:33-00:00

Nature, Vol. 440, No. 7081. (March 2006), pp. 161-161.

Spectral biclustering of microarray data: coclustering genes and conditions.

Y Kluger — 2005-01-18T23:58:47-00:00

Genome Res, Vol. 13, No. 4. (April 2003), pp. 703-716.

Global analyses of RNA expression levels are useful for classifying genes and overall phenotypes. Often these classification problems are linked, and one wants to find "marker genes" that are differentially expressed in particular sets of "conditions." We have developed a method that simultaneously clusters genes and conditions, finding distinctive "checkerboard" patterns in matrices of gene expression data, if they exist. In a cancer context, these checkerboards correspond to genes that are markedly up- or downregulated in patients with particular types of tumors. Our method, spectral biclustering, is based on the observation that checkerboard structures in matrices of expression data can be found in eigenvectors corresponding to characteristic expression patterns across genes or conditions. In addition, these eigenvectors can be readily identified by commonly used linear algebra approaches, in particular the singular value decomposition (SVD), coupled with closely integrated normalization steps. We present a number of variants of the approach, depending on whether the normalization over genes and conditions is done independently or in a coupled fashion. We then apply spectral biclustering to a selection of publicly available cancer expression data sets, and examine the degree to which the approach is able to identify checkerboard structures. Furthermore, we compare the performance of our biclustering methods against a number of reasonable benchmarks (e.g., direct application of SVD or normalized cuts to raw data).

The use and analysis of microarray data.

A Butte — 2005-02-17T17:31:05-00:00

Nat Rev Drug Discov, Vol. 1, No. 12. (December 2002), pp. 951-960.

Functional genomics is the study of gene function through the parallel expression measurements of genomes, most commonly using the technologies of microarrays and serial analysis of gene expression. Microarray usage in drug discovery is expanding, and its applications include basic research and target discovery, biomarker determination, pharmacology, toxicogenomics, target selectivity, development of prognostic tests and disease-subclass determination. This article reviews the different ways to analyse large sets of microarray data, including the questions that can be asked and the challenges in interpreting the measurements.

Tissue-driven hypothesis of genomic evolution and sequence-expression correlations.

Xun Gu — 2007-02-23T21:55:17-00:00

Proc Natl Acad Sci U S A (14 February 2007)

To maintain normal physiological functions, different tissues may have different developmental constraints on expressed genes. Consequently, the evolutionary tolerance for genomic evolution varies among tissues. Here, we formulate this argument as a "tissue-driven hypothesis" based on the stabilizing selection model. Moreover, several predicted genomic correlations are tested by the human-mouse microarray data. Our results are as follows. First, between the human and mouse, we have elaborated the among-tissue covariation between tissue expression distance (Eti) and tissue sequence distance (Dti). This highly significant Eti - Dti correlation emerges when the expression divergence and protein sequence divergence are under the same tissue constraints. Second, the tissue-driven hypothesis further explains the observed significant correlation between the tissue expression distance (between the human and mouse) and the duplicate tissue distance (Tdup) between human (or mouse) paralogous genes. In other words, between-duplicate and interspecies expression divergences covary among tissues. Third, for genes with the same expression broadness, we found that genes expressed in more stringent tissues (e.g., neurorelated) generally tend to evolve more slowly than those in more relaxed tissues (e.g., hormone-related). We conclude that tissue factors should be considered as an important component in shaping the pattern of genomic evolution and correlations.

Evolution of genes and genomes on the Drosophila phylogeny

2007-11-07T19:25:43-00:00

Nature, Vol. 450, No. 7167. (November 2007), pp. 203-218.

Living with death: the evolution of the mitochondrial pathway of apoptosis in animals

A Oberst — 2008-05-03T19:52:13-00:00

Cell Death and Differentiation, Vol. aop, No. current.

Exercise and gene expression: physiological regulation of the human genome through physical activity

Frank Booth — 2008-07-28T01:16:52-00:00

J Physiol, Vol. 543, No. 2. (1 September 2002), pp. 399-411.

10.1113/jphysiol.2002.019265

Aged human muscle demonstrates an altered gene expression profile consistent with an impaired response to exercise.

AC Jozsi — 2008-01-25T13:15:24-00:00

Mech Ageing Dev, Vol. 120, No. 1-3. (1 December 2000), pp. 45-56.

The gene expression profile of skeletal muscle from healthy older (62-75 years old) compared with younger (20-34 years old) men demonstrated elevated expression of genes typical of a stress or damage response, and decreased expression of a gene encoding a DNA repair/cell cycle checkpoint protein. Although the expression of these genes was relatively unaffected by a single bout of resistance exercise in older men, acute exercise altered gene expression in younger men such that post-exercise gene expression in younger men was similar to baseline gene expression in older men. The lack of response of muscle from older subjects to resistance exercise was also apparent in the expression of the inflammatory response gene IL-1beta, which did not differ between the age groups at baseline, but increased within 24 h of the exercise bout only in younger subjects. Other genes with potentially important roles in the adaptation of muscle to exercise, specifically in the processes of angiogenesis and cell proliferation, showed a similar response to exercise in older compared with younger subjects. Only one gene encoding the multifunctional, early growth response transcription factor EGR-1, showed an opposite pattern of expression in response to exercise, acutely decreasing in younger and increasing in older subjects. These results may provide a molecular basis for the inherent variability in the response of muscle from older as compared with younger individuals to resistance training.

Apoptosis and exercise.

S Phaneuf — 2008-07-03T21:19:05-00:00

Medicine and science in sports and exercise, Vol. 33, No. 3. (March 2001), pp. 393-396.

This brief review will discuss an exciting new area in exercise science, namely the role of apoptosis or programmed cell death in exercise. Apoptotic cell death differs morphologically and biochemically from necrotic cell death, although both appear to occur after exercise. Accelerated apoptosis has been documented to occur in a variety of disease states, such as AIDS and Alzheimer's disease, as well as in the aging heart. In striking contrast, failure to activate this genetically regulated cell death may result in cancer and certain viral infections. We will discuss factors that may activate apoptosis during and after exercise and the importance of cell turnover after exercise. We will also discuss differences in apoptosis between lymphocyte and skeletal muscle cells. We speculate that exercise-induced apoptosis is a normal regulatory process that serves to remove certain damaged cells without a pronounced inflammatory response, thus ensuring optimal body function.

Reversing age-associated immunosenescence via exercise.

ML Kohut — 2008-06-23T22:19:30-00:00

Exercise immunology review, Vol. 10 (2004), pp. 6-41.

Decreases in immune responsiveness with age are thought to contribute to the increased incidence and severity of infectious disease among the elderly. Several interventions, including exercise, have been proposed to restore immune function in older populations. The findings from some, but not all studies, support the possibility that exercise may attenuate immunosenescence. In recent years, the role of exercise in modulating immune response has been examined using models that may have clinical relevance, such as the response to vaccines and novel antigens. Taken together, the accumulated data suggest that exercise may be an efficacious therapy for restoring immune function in the elderly. In general, long term exercise interventions appear to show the most promise. Exercise related improvements have been reported with respect to antibody titre, T cell function, macrophage response, alterations of the T(H)1/T(H)2 cytokine balance, the level of pro-inflammatory cytokines, and changes in naïve/memory cell ratio. However, current data is minimal, and many questions remain including: the mechanisms that are involved, the potential clinical impact, the appropriate type or dose of exercise, and whether the benefits extend to all populations including frail, older adults. This review summarizes the major findings of these studies and proposes directions for future exploration.

Stage-specific expression of alpha1,2-fucosyltransferase and alpha1, 3-fucosyltransferase (FT) during mouse embryogenesis.

N Liu — 2008-07-28T00:41:31-00:00

European journal of biochemistry / FEBS, Vol. 265, No. 1. (1 October 1999), pp. 258-263.

Lex [Galbeta1-4(Fucalpha1-3)GlcNAc] and Ley [Fucalpha1-2Galbeta1-4(Fucalpha1-3)GlcNAc] are both stage-specific embryonic antigens. Lex is first detected on the blastomeres of the 8-cell stage embryo, which correlates with the onset of blastomere compaction. Ley is highly expressed on the surface of the blastocyst, which has been shown to be involved in blastocyst attachment in the mouse. In the present study, mouse alpha1,2-FT (also known as FUT1) and alpha1,3-FT (also known as Fuc-TIV), which were responsible for Lex and Ley formation, were examined in preimplantation stage embryos by reverse transcription-PCR and in situ hybridization. alpha1,3-FT mRNA was detected in all embryos of preimplantation stage, while alpha1,2-FT mRNA emerged in the later stage embryos from 8-cell to 16-cell to the blastocyst. These results indicated the expression of Ley was regulated by alpha1,2-FT. In situ hybridization showed that these two enzyme mRNAs were detected only in morula and blastocyst stage embryos. The alpha1,2-FT and alpha1, 3-FT mRNAs were located in both the inner cell mass and the trophoblast cells. 2-Cell and 4-cell embryos were isolated from the oviduct and cultured in vitro to the 8-cell, morula and blastocyst stage. The expression of alpha1,2-FT and alpha1,3-FT were observed in these embryos developed in vitro; immunohistochemical analysis also showed that Ley expression was positive. These results suggested the stage-specific expression of Ley on the embryos was synthesized by endogenous alpha1,2-FT and alpha1,3-FT rather than transfer from other sources. In addition, the expression of alpha1, 2-FT was differentially regulated and the uterine factor was not prerequisite of the expression of Ley.

Colonization of Venus

Geoffrey Landis — 2008-07-27T23:22:18-00:00

SPACE TECHNOLOGY AND APPLICATIONS INT.FORUM-STAIF 2003: Conf.on Thermophysics in Microgravity; Commercial/Civil Next Generation Space Transportation; Human Space Exploration; Symps.on Space Nuclear Power and Propulsion (20th); Space Colonization (1st), Vol. 654, No. 1. (2003), pp. 1193-1198.

Establishment and stabilization of earthlike conditions on Venus

SL Gillett — 2008-07-27T23:22:46-00:00

Journal of the British Interplanetary Society, Vol. 44 (April 1991), pp. 151-156.

Removing its massive atmosphere is the single greatest obstacle in terraforming Venus. Reacting it with externally derived material is difficult because of the great mass required and because many reducing agents readily accessible elsewhere in the solar system (e.g., C-H compounds) cannot be used because they yield gaseous species that exacerbate the greenhouse effect. Ca and/or Mg metal, refined from Mercury, are possible reductants. Manufacturing such an extraordinary amount of free, reactive metal for atmosphere reduction will require an extremely high order of self-replicating, differentiating robots and thus is not a near-term project. Stabilizing earthlike conditions will be difficult; little water and hypersaline seas, to reduce the vapor pressure of water, are possible stratagems.

Terraforming Venus Quickly

P Birch — 2008-07-27T23:22:48-00:00

Journal of the British Interplanetary Society, Vol. 44 (1991), pp. 157-167.

Not Available

Colonization of Venus

GA Landis — 2008-07-27T23:22:51-00:00

Vol. 654 (January 2003), pp. 1193-1198.

Although the surface of Venus is an extremely hostile environment, at about 50 kilometers above the surface the atmosphere of Venus is the most earthlike environment (other than Earth itself) in the solar system. It is proposed here that in the near term, human exploration of Venus could take place from aerostat vehicles in the atmosphere, and that in the long term, permanent settlements could be made in the form of cities designed to float at about fifty kilometer altitude in the atmosphere of Venus.

Cell and environment interactions in tumor microregions: the multicell spheroid model.

RM Sutherland — 2008-07-28T00:12:25-00:00

Science (New York, N.Y.), Vol. 240, No. 4849. (8 April 1988), pp. 177-184.

Abnormal vascularization of malignant tumors is associated with the development of microregions of heterogeneous cells and environments. Experimental models such as multicell spheroids and a variety of new techniques are being used to determine the characteristics of these microregions and to study the interactions of the cells and microenvironments. The special cellular microecology of tumors influences responsiveness to therapeutic agents and has implications for future directions in cancer research.

Less is more, except when less is less: Studying joint effects.

C R Weinberg — 2008-07-25T14:43:13-00:00

Genomics (18 July 2008)

Most diseases are complex in that they are caused by the joint action of multiple factors, both genetic and environmental. Over the past few decades, the mathematical convenience of logistic regression has served to enshrine the multiplicative model, to the point where many epidemiologists believe that departure from additivity on a log scale implies that two factors interact in causing disease. Other terminology in epidemiology, where students are told that inequality of relative risks across levels of a second factor should be seen as "effect modification," reinforces an uncritical acceptance of multiplicative joint effect as the biologically meaningful no-interaction null. Our first task, when studying joint effects, is to understand the limitations of our definitions for "interaction," and recognize that what statisticians mean and what biologists might want to mean by interaction may not coincide. Joint effects are notoriously hard to identify and characterize, even when asking a simple and unsatisfying question, like whether two effects are log-additive. The rule of thumb for such efforts is that a factor-of-four sample size is needed, compared with that needed to demonstrate main effects of either genes or exposures. So strategies have been devised that focus on the most informative individuals, either through risk-based sampling for a cohort, or case-control sampling, extreme phenotype sampling, pooling, two-stage sampling, exposed-only, or case-only designs. These designs gain efficiency, but at a cost of flexibility in models for joint effects. A relatively new approach avoids population controls by genotyping case-parent triads. Because it requires parents, the method works best for diseases with onset early in life. With this design, the role of autosomal genetic variants is assessed by in effect treating the nontransmitted parental alleles as controls for affected offspring. Despite advantages for looking at genetic effects, the triad design faces limitations when examining joint effects of genetic and environmental factors. Because population-based controls are not included, main effects for exposures cannot be estimated, and consequently one only has access to inference related to a multiplicative null. We have proposed a hybrid approach that offers the best features of both case-parent and case-control designs. Through genotyping of parents of population-based controls and assuming Mendelian transmission, power is markedly enhanced. One can also estimate main effects for exposures and now flexibly assess models for joint effects.

Computing Knock-Out Strategies in Metabolic Networks

Utz-Uwe Haus — 2008-03-28T19:15:54-00:00

Journal of Computational Biology, Vol. 15, No. 3. (2008), pp. 259-268.

Given a metabolic network in terms of its metabolites and reactions, our goal is to efficiently compute the minimal knock-out sets of reactions required to block a given behavior. We describe an algorithm that improves the computation of these knock-out sets when the elementary modes (minimal functional subsystems) of the network are given. We also describe an algorithm that computes both the knock-out sets and the elementary modes containing the blocked reactions directly from the description of the network and whose worst-case computational complexity is better than the algorithms currently in use for these problems. Computational results are included.

A gene network approach to modeling early neurogenesis in Drosophila.

G Marnellos — 2008-07-24T08:54:41-00:00

Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing (1998), pp. 30-41.

We have produced a model of genetic regulation to simulate how neuroblasts and sensory organ precursor (SOP) cells differentiate from proneural clusters of equivalent cells. Parameters of the model (mainly gene interaction strengths) are optimized in order to fit schematic patterns of expression, drawn from the literature, of genes that are involved in this process of cell fate specification. The model provides suggestions about the role of lateral signalling in neurogenesis and yields specific and testable predictions about the timing and position of appearance of neuroblasts and SOPs within proneural clusters, and about the dynamics of gene expression in individual cells. Experimental testing of these predictions and fits to more accurate quantitative data will help determine which set of model parameters can best describe early neurogenesis.

Compositional Evolution: The Impact of Sex, Symbiosis, and Modularity on the Gradualist Framework of Evolution (Vienna Series in Theoretical Biology)

Richard Watson — 2008-07-25T14:58:33-00:00

(17 February 2006)

No biological concept has had greater impact on the way we view ourselves and the world around us than the theory of evolution by natural selection. Darwin's masterful contribution was to provide an algorithmic model (a formal step-by-step procedure) of how adaptation may take place in biological systems. However, the simple process of linear incremental improvement that he described is only one algorithmic possibility, and certain biological phenomena provide the possibility of implementing alternative processes. In _Compositional Evolution_, Richard Watson uses the tools of computer science and computational biology to show that certain mechanisms of genetic variation (such as sex, gene transfer, and symbiosis) allowing the combination of preadapted genetic material enable an evolutionary process, compositional evolution, that is algorithmically distinct from the Darwinian gradualist framework. After reviewing the gradualist framework of evolution and outlining the analogous principles at work in evolutionary computation, Watson describes the compositional mechanisms of evolutionary biology and provides computational models that illustrate his argument. He uses models such as the genetic algorithm as well as novel models to explore different evolutionary scenarios, comparing evolution based on spontaneous point mutation, sexual recombination, and symbiotic encapsulation. He shows that the models of sex and symbiosis are algorithmically distinct from simpler stochastic optimization methods based on gradual processes. Finally, Watson discusses the impact of compositional evolution on our understanding of natural evolution and, similarly, the utility of evolutionary computation methods for problem solving and design.

A network-based method for target selection in metabolic networks

R Guimera — 2007-10-09T15:44:46-00:00

Bioinformatics, Vol. 23, No. 13. (1 July 2007), pp. 1616-1622.

Motivation: The lack of new antimicrobials, combined with increasing microbial resistance to old ones, poses a serious threat to public health. With hundreds of genomes sequenced, systems biology promises to help in solving this problem by uncovering new drug targets. Results: Here, we propose an approach that is based on the mapping of the interactions between biochemical agents, such as proteins and metabolites, onto complex networks. We report that nodes and links in complex biochemical networks can be grouped into a small number of classes, based on their role in connecting different functional modules. Specifically, for metabolic networks, in which nodes represent metabolites and links represent enzymes, we demonstrate that some enzyme classes are more likely to be essential, some are more likely to be species-specific and some are likely to be both essential and specific. Our network-based enzyme classification scheme is thus a promising tool for the identification of drug targets. Contact: rguimera@northwestern.edu Supplementary information: Supplementary data are available at Bioinformatics online. 10.1093/bioinformatics/btm150

Gene by environment interactions.

RC Culverhouse — 2008-07-22T00:54:52-00:00

Genetic epidemiology, Vol. 31 Suppl 1 (2007)

This paper summarizes the contributions of group 8 to the Genetic Analysis Workshop 15. Group 8 focused on ways to address the possibility that genetic and environmental effects on phenotype may not be independent, but instead may interact in ways that could play important roles in determining phenotype. Among the eight contributors to this group, all three data sets (expression data, rheumatoid arthritis data, and simulated data) were analyzed. Contributions to this section fell into the two broad categories of refining the data (e.g. stratifying or weighting based on a covariate value) and explicitly modeling the interactions. The contributions also illustrate that there are at least two possible goals for such studies. One goal is simply to identify factors contributing to phenotype in the presence of interactions that might mask the signal to univariate methods. A related but distinct goal is to characterize an interaction (e.g. to determine if the interaction is significant).

Pyrosequencing sheds light on DNA sequencing.

M Ronaghi — 2008-01-28T06:32:23-00:00

Genome Res, Vol. 11, No. 1. (January 2001), pp. 3-11.

DNA sequencing is one of the most important platforms for the study of biological systems today. Sequence determination is most commonly performed using dideoxy chain termination technology. Recently, pyrosequencing has emerged as a new sequencing methodology. This technique is a widely applicable, alternative technology for the detailed characterization of nucleic acids. Pyrosequencing has the potential advantages of accuracy, flexibility, parallel processing, and can be easily automated. Furthermore, the technique dispenses with the need for labeled primers, labeled nucleotides, and gel-electrophoresis. This article considers key features regarding different aspects of pyrosequencing technology, including the general principles, enzyme properties, sequencing modes, instrumentation, and potential applications.

Glucocorticoids enhance taste aversion memory via actions in the insular cortex and basolateral amygdala

Maria Miranda — 2008-07-21T13:38:16-00:00

Learn. Mem., Vol. 15, No. 7. (7 July 2008), pp. 468-476.

It is well established that glucocorticoid hormones strengthen the consolidation of hippocampus-dependent spatial and contextual memory. The present experiments investigated glucocorticoid effects on the long-term formation of conditioned taste aversion (CTA), an associative learning task that does not depend critically on hippocampal function. Corticosterone (1.0 or 3.0 mg/kg) administered subcutaneously to male Sprague-Dawley rats immediately after the pairing of saccharin consumption with the visceral malaise-inducing agent lithium chloride (LiCl) dose-dependently increased aversion to the saccharin taste on a 96-h retention test trial. In a second experiment, rats received corticosterone either immediately after saccharin consumption or after the LiCl injection, when both stimuli were separated by a 3-h time interval, to investigate whether corticosterone enhances memory of the gustatory or visceral stimulus presentation. Consistent with the finding that the LiCl injection, but not saccharin consumption, increases endogenous corticosterone levels, corticosterone selectively enhanced CTA memory when administered after the LiCl injection. Suppression of this training-induced release of corticosterone with the synthesis-inhibitor metyrapone (35 mg/kg) impaired CTA memory, and was dose-dependently reversed by post-training supplementation of corticosterone. Moreover, direct post-training infusions of corticosterone into the insular cortex or basolateral complex of the amygdala, two brain regions that are critically involved in the acquisition and consolidation of CTA, also enhanced CTA retention, whereas post-training infusions into the dorsal hippocampus were ineffective. These findings provide evidence that glucocorticoid effects on memory consolidation are not limited to hippocampus-dependent spatial/contextual information, but that these hormones also modulate memory consolidation of discrete-cue associative learning via actions in other brain regions. 10.1101/lm.964708

Beyond transcription factors: The role of chromatin modifying enzymes in regulating transcription required for memory

Ruth Barrett — 2008-07-21T13:36:50-00:00

Learn. Mem., Vol. 15, No. 7. (26 June 2008), pp. 460-467.

One of the alluring aspects of examining chromatin modifications in the role of modulating transcription required for long-term memory processes is that these modifications may provide transient and potentially stable epigenetic marks in the service of activating and/or maintaining transcriptional processes. These, in turn, may ultimately participate in the molecular mechanisms required for neuronal changes subserving long-lasting changes in behavior. As an epigenetic mechanism of transcriptional control, chromatin modification has been shown to participate in maintaining cellular memory (e.g., cell fate) and may underlie the strengthening and maintenance of synaptic connections required for long-term changes in behavior. Epigenetics has become central to several fields of neurobiology, where researchers have found that regulation of chromatin modification has a significant role in epilepsy, drug addiction, depression, neurodegenerative diseases, and memory. In this review, we will discuss the role of chromatin modifying enzymes in memory processes, as well as how recent studies in yeast genetics and cancer biology may impact the way we think about how chromatin modification and chromatin remodeling regulate neuronal function. 10.1101/lm.917508

Uncertainty, Neuromodulation, and Attention

Angela Yu — 2006-01-23T11:38:22-00:00

Neuron, Vol. 46, No. 4. (19 May 2005), pp. 681-692.

SummaryUncertainty in various forms plagues our interactions with the environment. In a Bayesian statistical framework, optimal inference and prediction, based on unreliable observations in changing contexts, require the representation and manipulation of different forms of uncertainty. We propose that the neuromodulators acetylcholine and norepinephrine play a major role in the brain's implementation of these uncertainty computations. Acetylcholine signals expected uncertainty, coming from known unreliability of predictive cues within a context. Norepinephrine signals unexpected uncertainty, as when unsignaled context switches produce strongly unexpected observations. These uncertainty signals interact to enable optimal inference and learning in noisy and changeable environments. This formulation is consistent with a wealth of physiological, pharmacological, and behavioral data implicating acetylcholine and norepinephrine in specific aspects of a range of cognitive processes. Moreover, the model suggests a class of attentional cueing tasks that involve both neuromodulators and shows how their interactions may be part-antagonistic, part-synergistic.

Natural image statistics for digital image forensics

Siwei Lyu — 2008-07-18T19:32:30-00:00

(2005)

Chair-Hany Farid

Sharing and reusing gene expression profiling data in neuroscience.

X Wan — 2008-04-23T18:04:10-00:00

Neuroinformatics, Vol. 5, No. 3. (2007), pp. 161-175.

As public availability of gene expression profiling data increases, it is natural to ask how these data can be used by neuroscientists. Here we review the public availability of high-throughput expression data in neuroscience and how it has been reused, and tools that have been developed to facilitate reuse. There is increasing interest in making expression data reuse a routine part of the neuroscience tool-kit, but there are a number of challenges. Data must become more readily available in public databases; efforts to encourage investigators to make data available are important, as is education on the benefits of public data release. Once released, data must be better-annotated. Techniques and tools for data reuse are also in need of improvement. Integration of expression profiling data with neuroscience-specific resources such as anatomical atlases will further increase the value of expression data.

The use of logic relationships to model colon cancer gene expression networks with mRNA microarray data.

X Ruan — 2008-07-17T13:35:49-00:00

Journal of biomedical informatics, Vol. 41, No. 4. (August 2008), pp. 530-543.

The ultimate goal of genomics research is to describe the network of molecules and interactions that govern all biological functions and disease processes in cells. Nonlinear interactions among genes in terms of their logic relationships play a key role for deciphering the networks of molecules that underlie cellular function. We present a method based on a graph coloring scheme and information theory to identify the gene expression network with lower and higher order logic interactions of genes. The analysis of oncogenes and suppressor genes from a colon cancer mRNA microarray dataset identifies a gene expression network with directionality and weights that reflects intracellular communication pathways. The success of the proposed method in mining hidden, complicated gene interactions and reliably interpreting experimental results suggests that the proposed method is a useful tool for understanding cancer systems. Extension of this method holds the potential to be fruitful for understanding other complex, nonsymmetric systems.

Identification of gene interactions associated with disease from gene expression data using synergy networks

John Watkinson — 2008-01-31T10:05:47-00:00

BMC Systems Biology, Vol. 2, No. 1. (2008)

BACKGROUND:Analysis of microarray data has been used for the inference of gene-gene interactions. If, however, the aim is the discovery of disease-related biological mechanisms, then the criterion for defining such interactions must be specifically linked to disease.RESULTS:Here we present a computational methodology that jointly analyzes two sets of microarray data, one in the presence and one in the absence of a disease, identifying gene pairs whose correlation with disease is due to cooperative, rather than independent, contributions of genes, using the recently developed information theoretic measure of synergy. High levels of synergy in gene pairs indicates possible membership of the two genes in a shared pathway and leads to a graphical representation of inferred gene-gene interactions associated with disease, in the form of a "synergy network." We apply this technique on a set of publicly available prostate cancer expression data and successfully validate our results, confirming that they cannot be due to pure chance and providing a biological explanation for gene pairs with exceptionally high synergy.CONCLUSIONS:Thus, synergy networks provide a computational methodology helpful for deriving "disease interactomes" from biological data. When coupled with additional biological knowledge, they can also be helpful for deciphering biological mechanisms responsible for disease.

PALEONTOLOGY: New Tricks with Old Bones

Rachel Mackelprang — 2008-07-17T13:52:50-00:00

Science, Vol. 321, No. 5886. (11 July 2008), pp. 211-212.

10.1126/science.1161890

Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls

2007-06-07T05:46:18-00:00

Nature, Vol. 447, No. 7145. (7 June 2007), pp. 661-678.

Sodium channel genes and the evolution of diversity in communication signals of electric fishes: Convergent molecular evolution.

Zakon — 2008-07-15T04:50:56-00:00

PNAS USA, Vol. 103, No. 10. (2006), pp. 3675-3680.

We investigated whether the evolution of electric organs and electric signal diversity in two independently evolved lineages of electric fishes was accompanied by convergent changes on the molecular level. We found that a sodium channel gene (Nav1.4a) that is expressed in muscle in nonelectric fishes has lost its expression in muscle and is expressed instead in the evolutionarily novel electric organ in both lineages of electric fishes. This gene appears to be evolving under positive selection in both lineages, facilitated by its restricted expression in the electric organ. This view is reinforced by the lack of evidence for selection on this gene in one electric species in which expression of this gene is retained in muscle. Amino acid replacements occur convergently in domains that influence channel inactivation, a key trait for shaping electric communication signals. Some amino acid replacements occur at or adjacent to sites at which disease-causing mutations have been mapped in human sodium channel genes, emphasizing that these replacements occur in functionally important domains. Selection appears to have acted on the final step in channel inactivation, but complementarily on the inactivation “ball” in one lineage, and its receptor site in the other lineage. Thus, changes in the expression and sequence of the same gene are associated with the independent evolution of signal complexity.

Superfast Vocal Muscles Control Song Production in Songbirds

Coen Elemans — 2008-07-15T04:37:13-00:00

PLoS ONE, Vol. 3, No. 7. (July 2008), e2581.

Birdsong is a widely used model for vocal learning and human speech, which exhibits high temporal and acoustic diversity. Rapid acoustic modulations are thought to arise from the vocal organ, the syrinx, by passive interactions between the two independent sound generators or intrinsic nonlinear dynamics of sound generating structures. Additionally, direct neuromuscular control could produce such rapid and precisely timed acoustic features if syringeal muscles exhibit rare superfast muscle contractile kinetics. However, no direct evidence exists that avian vocal muscles can produce modulations at such high rates. Here, we show that 1) syringeal muscles are active in phase with sound modulations during song over 200 Hz, 2) direct stimulation of the muscles in situ produces sound modulations at the frequency observed during singing, and that 3) syringeal muscles produce mechanical work at the required frequencies and up to 250 Hz in vitro. The twitch kinematics of these so-called superfast muscles are the fastest measured in any vertebrate muscle. Superfast vocal muscles enable birds to directly control the generation of many observed rapid acoustic changes and to actuate the millisecond precision of neural activity into precise temporal vocal control. Furthermore, birds now join the list of vertebrate classes in which superfast muscle kinetics evolved independently for acoustic communication.

Lateral Transfer of a Lectin-Like Antifreeze Protein Gene in Fishes

Laurie Graham — 2008-07-15T04:30:43-00:00

PLoS ONE, Vol. 3, No. 7. (July 2008), e2616.

Fishes living in icy seawater are usually protected from freezing by endogenous antifreeze proteins (AFPs) that bind to ice crystals and stop them from growing. The scattered distribution of five highly diverse AFP types across phylogenetically disparate fish species is puzzling. The appearance of radically different AFPs in closely related species has been attributed to the rapid, independent evolution of these proteins in response to natural selection caused by sea level glaciations within the last 20 million years. In at least one instance the same type of simple repetitive AFP has independently originated in two distant species by convergent evolution. But, the isolated occurrence of three very similar type II AFPs in three distantly related species (herring, smelt and sea raven) cannot be explained by this mechanism. These globular, lectin-like AFPs have a unique disulfide-bonding pattern, and share up to 85% identity in their amino acid sequences, with regions of even higher identity in their genes. A thorough search of current databases failed to find a homolog in any other species with greater than 40% amino acid sequence identity. Consistent with this result, genomic Southern blots showed the lectin-like AFP gene was absent from all other fish species tested. The remarkable conservation of both intron and exon sequences, the lack of correlation between evolutionary distance and mutation rate, and the pattern of silent vs non-silent codon changes make it unlikely that the gene for this AFP pre-existed but was lost from most branches of the teleost radiation. We propose instead that lateral gene transfer has resulted in the occurrence of the type II AFPs in herring, smelt and sea raven and allowed these species to survive in an otherwise lethal niche.

Can Machines Think? Interaction and Perspective Taking with Robots Investigated via fMRI

Sören Krach — 2008-07-15T04:24:28-00:00

PLoS ONE, Vol. 3, No. 7. (July 2008), e2597.

Background: When our PC goes on strike again we tend to curse it as if it were a human being. Why and under which circumstances do we attribute human-like properties to machines? Although humans increasingly interact directly with machines it remains unclear whether humans implicitly attribute intentions to them and, if so, whether such interactions resemble human-human interactions on a neural level. In social cognitive neuroscience the ability to attribute intentions and desires to others is being referred to as having a Theory of Mind (ToM). With the present study we investigated whether an increase of human-likeness of interaction partners modulates the participants' ToM associated cortical activity. Methodology/Principal Findings: By means of functional magnetic resonance imaging (subjects n = 20) we investigated cortical activity modulation during highly interactive human-robot game. Increasing degrees of human-likeness for the game partner were introduced by means of a computer partner, a functional robot, an anthropomorphic robot and a human partner. The classical iterated prisoner's dilemma game was applied as experimental task which allowed for an implicit detection of ToM associated cortical activity. During the experiment participants always played against a random sequence unknowingly to them. Irrespective of the surmised interaction partners' responses participants indicated having experienced more fun and competition in the interaction with increasing human-like features of their partners. Parametric modulation of the functional imaging data revealed a highly significant linear increase of cortical activity in the medial frontal cortex as well as in the right temporo-parietal junction in correspondence with the increase of human-likeness of the interaction partner (computer<functional robot<anthropomorphic robot<human). Conclusions/Significance: Both regions correlating with the degree of human-likeness, the medial frontal cortex and the right temporo-parietal junction, have been associated with Theory-of-Mind. The results demonstrate that the tendency to build a model of another's mind linearly increases with its perceived human-likeness. Moreover, the present data provides first evidence of a contribution of higher human cognitive functions such as ToM in direct interactions with artificial robots. Our results shed light on the long-lasting psychological and philosophical debate regarding human-machine interaction and the question of what makes humans being perceived as human.

Minimally invasive high-speed imaging of sarcomere contractile dynamics in mice and humans.

ME Llewellyn — 2008-07-15T04:16:20-00:00

Nature, Vol. doi:10.1038/nature07104

Sarcomeres are the basic contractile units of striated muscle. Our knowledge about sarcomere dynamics has primarily come from in vitro studies of muscle fibres1 and analysis of optical diffraction patterns obtained from living muscles2, 3. Both approaches involve highly invasive procedures and neither allows examination of individual sarcomeres in live subjects. Here we report direct visualization of individual sarcomeres and their dynamical length variations using minimally invasive optical microendoscopy4 to observe second-harmonic frequencies of light generated in the muscle fibres5, 6 of live mice and humans. Using microendoscopes as small as 350 m in diameter, we imaged individual sarcomeres in both passive and activated muscle. Our measurements permit in vivo characterization of sarcomere length changes that occur with alterations in body posture and visualization of local variations in sarcomere length not apparent in aggregate length determinations. High-speed data acquisition enabled observation of sarcomere contractile dynamics with millisecond-scale resolution. These experiments point the way to in vivo imaging studies demonstrating how sarcomere performance varies with physical conditioning and physiological state, as well as imaging diagnostics revealing how neuromuscular diseases affect contractile dynamics.

Neuronal Competition and Selection During Memory Formation

Jin-Hee Han — 2007-04-20T14:15:29-00:00

Science, Vol. 316, No. 5823. (20 April 2007), pp. 457-460.

Competition between neurons is necessary for refining neural circuits during development and may be important for selecting the neurons that participate in encoding memories in the adult brain. To examine neuronal competition during memory formation, we conducted experiments with mice in which we manipulated the function of CREB (adenosine 3',5'-monophosphate response element-binding protein) in subsets of neurons. Changes in CREB function influenced the probability that individual lateral amygdala neurons were recruited into a fear memory trace. Our results suggest a competitive model underlying memory formation, in which eligible neurons are selected to participate in amemorytrace as a function of their relative CREB activity at the time of learning. 10.1126/science.1139438