CiteULike: Author Robertson

Pair programming and agile software development: experiences in a college setting

Linda Sherrell — 2008-07-24T17:36:35-00:00

J. Comput. Small Coll., Vol. 22, No. 2. (December 2006), pp. 145-153.

Stem cell transcriptome profiling via massive-scale mRNA sequencing.

Nicole Cloonan — 2008-06-25T20:30:50-00:00

Nature methods (30 May 2008)

We developed a massive-scale RNA sequencing protocol, short quantitative random RNA libraries or SQRL, to survey the complexity, dynamics and sequence content of transcriptomes in a near-complete fashion. This method generates directional, random-primed, linear cDNA libraries that are optimized for next-generation short-tag sequencing. We surveyed the poly(A)(+) transcriptomes of undifferentiated mouse embryonic stem cells (ESCs) and embryoid bodies (EBs) at an unprecedented depth (10 Gb), using the Applied Biosystems SOLiD technology. These libraries capture the genomic landscape of expression, state-specific expression, single-nucleotide polymorphisms (SNPs), the transcriptional activity of repeat elements, and both known and new alternative splicing events. We investigated the impact of transcriptional complexity on current models of key signaling pathways controlling ESC pluripotency and differentiation, highlighting how SQRL can be used to characterize transcriptome content and dynamics in a quantitative and reproducible manner, and suggesting that our understanding of transcriptional complexity is far from complete.

Chromatin remodeling, histone modifications, and DNA methylation - how does it all fit together?

Theresa Geiman — 2008-07-24T15:06:28-00:00

Journal of Cellular Biochemistry, Vol. 87, No. 2. (2002), pp. 117-125.

DNA methylation is important in the control of gene transcription and chromatin structure. The complexities of this process are just beginning to be elucidated in relationship to other epigenetic mechanisms. Exciting new research in the areas of histone methylation and chromatin remodeling make it clear just how important the connections between these various mechanisms and DNA methylation are for the control of chromosome structure and gene expression. Emerging evidence suggests that chromatin remodeling enzymes and histone methylation are essential for proper DNA methylation patterns. Other histone modifications, such as acetylation and phosphorylation, in turn, affect histone methylation and histone methylation also appears to be highly reliant on chromatin remodeling enzymes. This review will summarize what is likely only the beginning of a flood of new information that will ultimately link all epigenetic modifications of the mammalian genome. A model will also be put forth to account for how chromatin modifications lead to genomic DNA methylation patterns. J. Cell. Biochem. 87: 117-125, 2002. Published 2002 Wiley-Liss, Inc.

Cell fate decisions within the mouse organizer are governed by graded Nodal signals.

SD Vincent — 2008-07-24T14:38:42-00:00

Genes & development, Vol. 17, No. 13. (1 July 2003), pp. 1646-1662.

It is well known that cell fate decisions in the mouse organizer region during gastrulation ultimately govern gut formation and patterning, left-right axis determination, and development of the central nervous system. Previous studies suggest that signaling pathways activated by Nodal, bone morphogenetic protein (BMP), and Wnt ligands coordinately regulate patterning of the streak and the formation of midline organizing tissues, but the specific contributions of these molecules within discrete cell lineages are poorly defined. Here we removed Smad2 activity in the epiblast, using a conditional inactivation strategy. Abrogation of Smad2 does not compromise primitive streak (PS) formation or gastrulation movements, but rather results in a failure to correctly specify the anterior definitive endoderm (ADE) and prechordal plate (PCP) progenitors. To selectively lower Nodal activity in the posterior epiblast, we generated a novel allele lacking the proximal epiblast enhancer (PEE) governing Nodal expression in the PS. As for conditional inactivation of Smad2, germ-line deletion of the PEE selectively disrupts development of the anterior streak. In striking contrast, the node and its midline derivatives, the notochord and floor plate, develop normally in both categories of mutant embryos. Finally, we show that removal of one copy of Smad3 in the context of a Smad2-deficient epiblast results in a failure to specify all axial midline tissues. These findings conclusively demonstrate that graded Nodal/Smad2 signals govern allocation of the axial mesendoderm precursors that selectively give rise to the ADE and PCP mesoderm.

The embryonic stem cell transcription factors Oct-4 and FoxD3 interact to regulate endodermal-specific promoter expression.

Y Guo — 2008-07-24T14:24:42-00:00

Proceedings of the National Academy of Sciences of the United States of America, Vol. 99, No. 6. (19 March 2002), pp. 3663-3667.

The POU homeodomain protein Oct-4 and the Forkhead Box protein FoxD3 (previously Genesis) are transcriptional regulators expressed in embryonic stem cells. Down-regulation of Oct-4 during gastrulation is essential for proper endoderm development. After gastrulation, FoxD3 is generally down-regulated during early endoderm formation, although it specifically remains expressed in the embryonic neural crest. In these studies, we have found that Oct-4 and FoxD3 can bind to identical regulatory DNA sequences. In addition, Oct-4 physically interacted with the FoxD3 DNA-binding domain. Cotransfection of Oct-4 and FoxD3 expression vectors activated the osteopontin enhancer, which is expressed in totipotent embryonic stem cells. FoxA1 and FoxA2 (previously HNF-3alpha and HNF-3beta) are Forkhead Box transcription factors that participate in liver and lung formation from foregut endoderm. Although FoxD3 activated the FoxA1 and FoxA2 promoters, Oct-4 inhibited FoxD3 activation of the FoxA1 and FoxA2 endodermal promoters. These data indicate that Oct-4 functions as a corepressor of FoxD3 to provide embryonic lineage-specific transcriptional regulatory activity to maintain appropriate developmental timing.

The Foxh1-dependent autoregulatory enhancer controls the level of Nodal signals in the mouse embryo.

DP Norris — 2008-07-24T14:02:07-00:00

Development (Cambridge, England), Vol. 129, No. 14. (July 2002), pp. 3455-3468.

The TGFbeta-related growth factor Nodal governs anteroposterior (AP) and left-right (LR) axis formation in the vertebrate embryo. A conserved intronic enhancer (ASE), containing binding sites for the fork head transcription factor Foxh1, modulates dynamic patterns of Nodal expression during early mouse development. This enhancer is responsible for early activation of Nodal expression in the epiblast and visceral endoderm, and at later stages governs asymmetric expression during LR axis formation. We demonstrate ASE activity is strictly Foxh1 dependent. Loss of this autoregulatory enhancer eliminates transcription in the visceral endoderm and decreases Nodal expression in the epiblast, but causes surprisingly discrete developmental abnormalities. Thus lowering the level of Nodal signaling in the epiblast disrupts both orientation of the AP axis and specification of the definitive endoderm. Targeted removal of the ASE also dramatically reduces left-sided Nodal expression, but the early events controlling LR axis specification are correctly initiated. However loss of the ASE disrupts Lefty2 (Leftb) expression and causes delayed Pitx2 expression leading to late onset, relatively minor LR patterning defects. The feedback loop is thus essential for maintenance of Nodal signals that selectively regulate target gene expression in a temporally and spatially controlled fashion in the mouse embryo.

Formation of the definitive endoderm in mouse is a Smad2-dependent process.

KD Tremblay — 2008-07-24T12:50:14-00:00

Development (Cambridge, England), Vol. 127, No. 14. (July 2000), pp. 3079-3090.

TGFbeta growth factors specify cell fate and establish the body plan during early vertebrate development. Diverse cellular responses are elicited via interactions with specific cell surface receptor kinases that in turn activate Smad effector proteins. Smad2-dependent signals arising in the extraembryonic tissues of early mouse embryos serve to restrict the site of primitive streak formation and establish anteroposterior identity in the epiblast. Here we have generated chimeric embryos using lacZ-marked Smad2-deficient ES cells. Smad2 mutant cells extensively colonize ectodermal and mesodermal populations without disturbing normal development, but are not recruited into the definitive endoderm lineage during gastrulation. These experiments provide the first evidence that TGFbeta signaling pathways are required for specification of the definitive endoderm lineage in mammals and identify Smad2 as a key mediator that directs epiblast derivatives towards an endodermal as opposed to a mesodermal fate. In largely Smad2-deficient chimeras, asymmetric nodal gene expression is maintained and expression of pitx2, a nodal target, is also unaffected. These results strongly suggest that other Smad(s) act downstream of Nodal signals in mesodermal populations. We found Smad2 and Smad3 transcripts both broadly expressed in derivatives of the epiblast. However, Smad2 and not Smad3 mRNA is expressed in the visceral endoderm, potentially explaining why the primary defect in Smad2 mutant embryos originates in this cell population.

Nodal signalling in the epiblast patterns the early mouse embryo.

J Brennan — 2008-07-24T12:46:26-00:00

Nature, Vol. 411, No. 6840. (21 June 2001), pp. 965-969.

Shortly after implantation the mouse embryo comprises three tissue layers. The founder tissue of the embryo proper, the epiblast, forms a radially symmetric cup of epithelial cells that grows in close apposition to the extra-embryonic ectoderm and the visceral endoderm. This simple cylindrical structure exhibits a distinct molecular pattern along its proximal-distal axis. The anterior-posterior axis of the embryo is positioned later by coordinated cell movements that rotate the pre-existing proximal-distal axis. The transforming growth factor-beta family member Nodal is known to be required for formation of the anterior-posterior axis. Here we show that signals from the epiblast are responsible for the initiation of proximal-distal polarity. Nodal acts to promote posterior cell fates in the epiblast and to maintain molecular pattern in the adjacent extra-embryonic ectoderm. Both of these functions are independent of Smad2. Moreover, Nodal signals from the epiblast also pattern the visceral endoderm by activating the Smad2-dependent pathway required for specification of anterior identity in overlying epiblast cells. Our experiments show that proximal-distal and subsequent anterior-posterior polarity of the pregastrulation embryo result from reciprocal cell-cell interactions between the epiblast and the two extra-embryonic tissues.

Buccal DNA collection: comparison of buccal swabs with FTA cards.

E Milne — 2008-07-23T15:54:34-00:00

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, Vol. 15, No. 4. (April 2006), pp. 816-819.

Collection and analysis of DNA, most commonly from blood or buccal cells, is becoming more common in epidemiologic studies. Buccal samples, which are painless to take and relatively easily collected, are often the preferred source. There are several buccal cell collection methods: swabs, brushes, mouthwash, and treated cards, such as FTA or IsoCode cards. Few studies have systematically compared methods of buccal cell collection with respect to DNA yield and amplification success under similar conditions. We compared buccal DNA collection and amplification using buccal swabs and FTA cards in 122 control subjects from our Australian case-control study of childhood acute lymphoblastic leukaemia. Buccal DNA was quantified using a real-time PCR for beta-actin and genotyped at the loci of three polymorphisms (MTHFR 677C>T, ACE I/D, and XPD 1012G>A). PCR was successful with DNA from buccal swabs for 62% to 89% of subjects and from FTA cards for 83% to 100% of subjects, depending on the locus. The matched pair odds ratios (95% confidence interval) comparing success of FTA cards with buccal swabs are as follows: MTHFR 677C>T using PCR-RFLP, 12.5 (11.6-13.5) and using real-time PCR, 130.0 (113.1-152.8); ACE I/D using PCR-amplified fragment length polymorphism, 3.36 (3.2-3.5); XPD 1012G>A using real-time PCR, 150.0 (132.7-172.3). FTA cards are a robust DNA collection method and generally produce DNA suitable for PCR more reliably than buccal swabs. There are, however, technical challenges in handling discs punched from FTA cards that intending users should be aware of.

FaThumb: a facet-based interface for mobile search

Amy Karlson — 2007-01-14T17:44:28-00:00

(2006), pp. 711-720.

Sizing the Bacillus anthracis PA63 Channel with Nonelectrolyte Poly(Ethylene Glycols)

Brian Nablo — 2008-07-23T00:09:03-00:00

Biophys. J., Vol. 95, No. 3. (1 August 2008), pp. 1157-1164.

Nonelectrolyte polymers of poly(ethylene glycol) (PEG) were used to estimate the diameter of the ion channel formed by the Bacillus anthracis protective antigen 63 (PA63). Based on the ability of different molecular weight PEGs to partition into the pore and reduce channel conductance, the pore appears to be narrower than the one formed by Staphylococcus aureus alpha-hemolysin. Numerical integration of the PEG sample mass spectra and the channel conductance data were used to refine the estimate of the pore's PEG molecular mass cutoff ([~]1400 g/mol). The results suggest that the limiting diameter of the PA63 pore is <2 nm, which is consistent with an all-atom model of the PA63 channel and previous experiments using large ions. 10.1529/biophysj.107.121715

CandidTree: visualizing structural uncertainty in similar hierarchies

Lee — 2007-12-08T15:35:31-00:00

Information Visualization, Vol. 6, No. 3. (25 October 2007), pp. 233-246.

FindPeaks 3.1: a tool for identifying areas of enrichment from massively parallel short-read sequencing technology

Anthony Fejes — 2008-07-21T09:08:32-00:00

Bioinformatics, Vol. 24, No. 15. (1 August 2008), pp. 1729-1730.

Summary: Next-generation sequencing can provide insight into protein-DNA association events on a genome-wide scale, and is being applied in an increasing number of applications in genomics and meta-genomics research. However, few software applications are available for interpreting these experiments. We present here an efficient application for use with chromatin-immunoprecipitation (ChIP-Seq) experimental data that includes novel functionality for identifying areas of gene enrichment and transcription factor binding site locations, as well as for estimating DNA fragment size distributions in enriched areas. The FindPeaks application can generate UCSC compatible custom WIG' track files from aligned-read files for short-read sequencing technology. The software application can be executed on any platform capable of running a Java Runtime Environment. Memory requirements are proportional to the number of sequencing reads analyzed; typically 4 GB permits processing of up to 40 million reads. Availability: The FindPeaks 3.1 package and manual, containing algorithm descriptions, usage instructions and examples, are available at http://www.bcgsc.ca/platform/bioinfo/software/findpeaks Source files for FindPeaks 3.1 are available for academic use. Contact: afejes@bcgsc.ca 10.1093/bioinformatics/btn305

Ecosystem services and agriculture: Cultivating agricultural ecosystems for diverse benefits

Scott Swinton — 2008-07-21T21:51:45-00:00

Ecological Economics, Vol. 64, No. 2. (15 December 2007), pp. 245-252.

Crop and rangelands are over 25% of the Earth's land area, and they are expanding. Agricultural ecosystems rely on a suite of supporting ecosystem services to provide food, fiber and fuel as well as a range of accompanying but non-marketed ecosystem services (ES). Ecosystem services from agriculture include regulation of water and climate systems, aesthetic and cultural services, as well as enhanced supporting services (such as soil fertility). Many of these ES are appreciated by people, but they lack markets, so they lack the incentives for provision that come with prices. For public policy decisions to take them into account, non-market valuation techniques are needed, such as travel cost, contingent valuation, hedonic valuation, and cost-based or factor-income approaches. This article offers an overview of ES from agriculture and non-market valuation methods as it introduces the articles in this special section on "Ecosystem Services and Agriculture." Understanding how ecological functions generate ES is fundamental to management, but so too is understanding how humans perceive and value those services. Research is required both to design cost-effective incentives to provide ES and to measure which kinds of ES could provide the greatest overall welfare benefits to society. Agricultural ecosystems offer newly recognized potential to deliver more diverse ecosystem services and mitigate the level of past ecosystem disservices. This special section of Ecological Economics conveys both how these are becoming possible and the challenges to science and public policy design of turning that potential into reality.

Emerging research methods for understanding mobile technology use

Penny Hagen — 2006-08-14T15:40:13-00:00

(2005), pp. 1-10.

Comparison of language used and patterns of communication in interprofessional and multidisciplinary teams

D Sheehan — 2008-07-18T00:47:13-00:00

Journal of Interprofessional Care, Vol. 21, No. 1. (2007), pp. 17-30.

Can the language used and the patterns of communication differentiate a multidisciplinary team from an interprofessional team? This research question arose from an unexpected outcome of a study that investigated clinical reasoning of health professional team members in the elder care wards of two different hospitals. The issue at stake was the apparent disparity in the way in which the two teams communicated. To further explore this, the original transcribed interview data was analysed from a symbolic interactionist perspective in order that the language and communication patterns between the two teams could be identified and compared. Differences appeared to parallel the distinctions between multidisciplinary and interprofessional teams as reported in the literature. Our observations were that an interprofessional team was characterized by its use of inclusive language, continual sharing of information between team members and a collaborative working approach. In the multidisciplinary team, the members worked in parallel, drawing information from one another but did not have a common understanding of issues that could influence intervention. The implications of these communication differences for team members, team leaders and future research are then discussed.

Biology in the 1980s, plus or minus a decade.

M Robertson — 2008-07-17T14:21:36-00:00

Nature, Vol. 285, No. 5764. (5 June 1980), pp. 358-359.

GroupBar: The TaskBar Evolved

G Smith — 2008-07-17T12:30:44-00:00

(2003)

Our studies have shown that as displays become larger, users leave more windows open for easy multitasking. A larger number of windows, however, may increase the time that users spend arranging and switching between tasks. We introduce GroupBar, a task management system for dealing with the profusion of windows on the PC desktop. Designed to offer the same basic form and function as the existing Microsoft Windows^TM TaskBar, GroupBar additionally allows users to group windows into higher-level...

Scalable Fabric: flexible task management

George Robertson — 2008-04-21T22:14:55-00:00

(2004), pp. 85-89.

Integrating PCR theory and bioinformatics into a research-oriented primer design exercise.

AL Robertson — 2008-07-17T08:17:00-00:00

CBE life sciences education, Vol. 7, No. 1. (2008), pp. 89-95.

Polymerase chain reaction (PCR) is a conceptually difficult technique that embodies many fundamental biological processes. Traditionally, students have struggled to analyze PCR results due to an incomplete understanding of the biological concepts (theory) of DNA replication and strand complementarity. Here we describe the design of a novel research-oriented exercise that prepares students to design DNA primers for PCR. Our exercise design includes broad and specific learning goals and assessments of student performance and perceptions. We developed this interactive Primer Design Exercise using the principles of scientific teaching to enhance student understanding of the theory behind PCR and provide practice in designing PCR primers to amplify DNA. In the end, the students were more poised to troubleshoot problems that arose in real experiments using PCR. In addition, students had the opportunity to utilize several bioinformatics tools to gain an increased understanding of primer quality, directionality, and specificity. In the course of this study many misconceptions about DNA replication during PCR and the need for primer specificity were identified and addressed. Students were receptive to the new materials and the majority achieved the learning goals.

Aligning goals, assessments, and activities: an approach to teaching PCR and gel electrophoresis.

AR Phillips — 2008-07-17T08:17:13-00:00

CBE life sciences education, Vol. 7, No. 1. (2008), pp. 96-106.

Polymerase chain reaction (PCR) and gel electrophoresis have become common techniques used in undergraduate molecular and cell biology labs. Although students enjoy learning these techniques, they often cannot fully comprehend and analyze the outcomes of their experiments because of a disconnect between concepts taught in lecture and experiments done in lab. Here we report the development and implementation of novel exercises that integrate the biological concepts of DNA structure and replication with the techniques of PCR and gel electrophoresis. Learning goals were defined based on concepts taught throughout the cell biology lab course and learning objectives specific to the PCR and gel electrophoresis lab. Exercises developed to promote critical thinking and target the underlying concepts of PCR, primer design, gel analysis, and troubleshooting were incorporated into an existing lab unit based on the detection of genetically modified organisms. Evaluative assessments for each exercise were aligned with the learning goals and used to measure student learning achievements. Our analysis found that the exercises were effective in enhancing student understanding of these concepts as shown by student performance across all learning goals. The new materials were particularly helpful in acquiring relevant knowledge, fostering critical-thinking skills, and uncovering prevalent misconceptions.

Spatio-temporal prediction and inference by V1 neurons

Guo — 2007-08-20T19:52:19-00:00

European Journal of Neuroscience, Vol. 26, No. 4. (August 2007), pp. 1045-1054.

The diagnosis and treatment of baroreflex failure.

D Robertson — 2008-07-15T05:26:29-00:00

The New England journal of medicine, Vol. 329, No. 20. (11 November 1993), pp. 1449-1455.

BACKGROUND. Baroreflexes originate in the great vessels of the neck and thorax and prevent arterial pressure from rising or falling excessively. METHODS. This study was undertaken to clarify the cause, clinical spectrum, and therapy of this disorder. We studied 11 patients with baroreflex failure presenting as severe, labile hypertension and hypotension, often with headache, diaphoresis, and emotional instability, and characterized by the failure of exogenous vasoactive substances to alter heart rate. Each underwent hemodynamic monitoring and biochemical, physiologic, and pharmacologic testing. RESULTS. The patients' maximal systolic blood pressures ranged from 164 to 280 mm Hg, and their minimal systolic pressures ranged from 58 to 96 mm Hg. Plasma norepinephrine and epinephrine concentrations were sometimes many times normal during blood-pressure surges. All the patients had excessive pressor and tachycardia responses to the mental-arithmetic and cold pressor tests and marked hypersensitivity to clonidine. The underlying causes of baroreflex failure included the familial paraganglioma syndrome, neck surgery or radiation therapy for pharyngeal carcinoma, bilateral lesions of the nucleus tractus solitarii, and surgical section of the glossopharyngeal nerves; in two patients the cause was unknown. Therapy with clonidine reduced the frequency of attacks by 81 percent and attenuated the elevated blood pressure and heart rate in the attacks that occurred. CONCLUSIONS. The syndrome of baroreflex failure should be considered in patients with otherwise unexplained labile hypertension. Clonidine attenuates the pressor and tachycardic surges in baroreflex failure.

Does the Jarman–Bell principle at intra-specific level explain sexual segregation in polygynous ungulates? Sex differences in forage digestibility in Soay sheep

F Pérez-Barbería — 2008-07-14T10:46:24-00:00

Oecologia, Vol. 157, No. 1. (2008), pp. 21-30.

Abstract The Jarman–Bell principle states that large-bodied mammalian herbivores can subsist on lower quality diets because of their lower metabolism requirement/gut capacity ratio. Two major hypotheses for sexual segregation (the behaviour in which animals of the same species aggregate by sex) base their foundations on extending this principle to the intraspecific level, despite the lack of experimental evidence to support this. The first proposes that the larger males can process fibre (low-quality diet) more efficiently than the smaller females, leading to sexual segregation by habitat partitioning due to selection of different food quality and/or quantity (sexual dimorphism–body size hypothesis). The second suggests that the longer time and extra rumination required to digest low-quality food will cause asynchrony of behaviour between males and females, which then leads to sexual segregation (activity budget hypothesis). To provide experimental evidence for the Jarman–Bell principle at the intraspecific level we carried out a set of digestibility trials in Soay sheep (Ovis aries) using grass hay as the diet to test whether sexual dimorphism in body mass can produce significant sexual differences in the efficiency of food digestion. Males were slightly more efficient in digesting forage than females that were at least 30% smaller than the males. Overall, there was a decrease in faecal output of 1 g/kg body mass in favour of males. These differences were not due to differences in food selection, passage rates or faecal particle size and it was not clear why males were more efficient in digesting forage. Although these results do not directly support arguments for either the sexual dimorphism–body size or activity budget hypotheses, they do indicate that the physiological argument upon which the Jarman–Bell principle is founded also operates at the intraspecific level and may be an important factor influencing sexual segregation.

The design space of input devices

Stuart Card — 2007-01-16T03:43:37-00:00

(1990), pp. 117-124.

A bewildering variety of devices for communication from humans to computers now exists on the market. In order to make sense of this variety, and to aid in the design of new input devices, we propose a framework for describing and analyzing input devices. Following Mackinlay's semantic analysis of the design space for graphical presentations, our goal is to provide tools for the generation and test of input device designs. The descriptive tools we have created allow us to describe the semantics of a device and measure its expressiveness. Using these tools, we have built a taxonomy of input devices that goes beyond earlier taxonomies of Buxton & Baecker and Foley, Wallace, & Chan. In this paper, we build on these descriptive tools, and proceed to the use of human performance theories and data for evaluation of the effectiveness of points in this design space. We focus on two figures of merit, footprint and bandwidth, to illustrate this evaluation. The result is the systematic integration of methods for both generating and testing the design space of input devices.

Formation of z ~ 6 quasars from hierarchical galaxy mergers

Yuexing Li — 2008-07-10T15:29:13-00:00

(26 Jun 2007)

The discovery of luminous quasars at redshift z ~ 6 indicates the presence of supermassive black holes (SMBHs) of mass ~10^9 Msun when the Universe was less than one billion years old. This finding presents several challenges for theoretical models. Here, we present the first multi-scale simulations that, together with a self-regulated model for the SMBH growth, produce a luminous quasar at z ~ 6.5 in the LCDM paradigm. We follow the hierarchical assembly history of the most massive halo in a ~ 3 Gpc^3 volume, and find that this halo of ~ 8x 10^12 Msun forming at z ~ 6.5 after several major mergers is able to reproduce a number of observed properties of SDSS J1148+5251, the most distant quasar detected at z =6.42 (Fan et al. 2003). Moreover, the SMBHs grow through gas accretion below the Eddington limit in a self-regulated manner owing to feedback. We find that the progenitors experience significant star formation (up to 10^4 Msun/yr) preceding the major quasar phase such that the stellar mass of the quasar host reaches 10^12 Msun at z ~ 6.5, consistent with observations of significant metal enrichment in SDSS J1148+5251. Our results provide a viable formation mechanism for z ~ 6 quasars in the standard LCDM cosmology, and demonstrate a common, merger-driven origin for the rarest quasars and the fundamental SMBH-host correlation in a hierarchical Universe.(Abridged)

The Relation Between Quasar and Merging Galaxy Luminosity Functions and the Merger-Induced Star Formation Rate of the Universe

Philip Hopkins — 2006-02-16T10:05:34-00:00

(15 Feb 2006)

Using a model for self-regulated growth of black holes (BHs) in mergers involving gas-rich galaxies, we study the relationship between quasars and the population of merging galaxies and predict the merger-induced star formation rate density of the Universe. Mergers drive nuclear gas inflows, fueling starbursts and 'buried quasars' until accretion feedback expels the gas, rendering a briefly visible optical quasar. Star formation is shut down and accretion declines, leaving a passively evolving remnant with properties typical of red, elliptical galaxies. Based on evolution of these events in our simulations, we demonstrate that the observed statistics of merger rates, luminosity functions (LFs) and mass functions, SFR distributions, specific SFRs, quasar and quasar host galaxy LFs, and elliptical/red galaxy LFs are self-consistent and follow from one another as predicted by the merger hypothesis. We use our simulations to de-convolve both quasar and merging galaxy LFs to determine the birthrate of black holes of a given final mass and merger rates as a function of stellar mass. We use this to predict the merging galaxy LF in several observed wavebands, color-magnitude relations, mass functions, absolute and specific SFR distributions and SFR density, and quasar host galaxy LFs, as a function of redshift from z=0-6. We invert this and predict e.g. quasar LFs from observed merger LFs or SFR distributions. Our results agree well with observations, but idealized models of quasar lightcurves are ruled out by comparison of merger and quasar observations at >99.9% confidence. Using only observations of quasars, we estimate the contribution of mergers to the SFR density of the Universe even to high redshifts z~4.

A generalized frame synchronizer

P Robertson — 2008-07-08T14:53:29-00:00

Global Telecommunications Conference, 1992. Conference Record., GLOBECOM '92. Communication for Global Users., IEEE (1992), pp. 365-369 vol.1.

A modification of the class of frame synchronizers which maximize a likelihood function is proposed. If the stage following the frame sync unit is able to distinguish incorrect from correct syncs, then supplying several alternative frame starting positions effectively improves the synchronization performance. The performance of such a scheme is evaluated analytically and using simulations. As an example system, a frame sync unit followed by a decoder is assumed. The improvement achieved can amount to several decibels, and is excellent at high signal-to-noise ratios. The average overhead, required in the subsequent processing stages is evaluated and shown to be small at signal-to-noise ratios of interest. No changes need to be made to the frame structure, and only slight modifications of the receiver, are necessary

Improving frame synchronization when using convolutional codes

P Robertson — 2008-07-08T14:27:43-00:00

Global Telecommunications Conference, 1993, including a Communications Theory Mini-Conference. Technical Program Conference Record, IEEE in Houston. GLOBECOM '93., IEEE (1993), pp. 1606-1611 vol.3.

Presents a method of improving the performance of a frame synchronizer when the data frames are convolutionally encoded and terminated. Termination of the data helps to ensure correct decoding and reduces the effective rate of the code, especially for short data sequences. The synchronizer makes use of the symbols transmitted for termination in order to increase the probability of correct frame synchronization. The author derives an optimum decision rule and several suboptimal algorithms that considerably reduce computation and complexity. Improvement of several dB in frame sync performance was found by simulations. The technique can be applied to “one shot” (e.g. packet) or continuous transmission applications. Furthermore, no changes need to be made to the frame structure, only modifications of the receiver

The Impact of Prevention on Reducing the Burden of Cardiovascular Disease

Richard Kahn — 2008-07-08T01:39:42-00:00

Circulation (7 July 2008), CIRCULATIONAHA.108.190186.

Objective--Cardiovascular disease (CVD) is prevalent and expensive. While many interventions are recommended to prevent CVD, the potential effects of a comprehensive set of prevention activities on CVD morbidity, mortality, and costs have never been evaluated. We therefore determined the effects of 11 nationally recommended prevention activities on CVD-related morbidity, mortality, and costs in the United States.Research Design and Methods--We used person-specific data from a representative sample of the US population (National Health and Nutrition Education Survey IV) to determine the number and characteristics of adults aged 20-80 years in the United States today who are candidates for different prevention activities related to CVD. We used the Archimedes model to create a simulated population that matched the real US population, person by person. We then used the model to simulate a series of clinical trials that examined the effects over the next 30 years of applying each prevention activity one by one, or altogether, to those who are candidates for the various activities and compared the health outcomes, quality of life, and direct medical costs to current levels of prevention and care. We did this under two sets of assumptions about performance and compliance: 100% success for each activity and lower levels of success considered aggressive but still feasible.Results--Approximately 78% of adults aged 20-80 years alive today in the United States are candidates for at least one prevention activity. If everyone received the activities for which they are eligible, myocardial infarctions and strokes would be reduced by 63% and 31%, respectively. If more feasible levels of performance are assumed, myocardial infarctions and strokes would be reduced 36% and 20%, respectively. Implementation of all prevention activities would add approx221 million life-years and 244 million quality-adjusted life-years to the US adult population over the coming 30 years, or an average of 1.3 years of life expectancy for all adults. Of the specific prevention activities, the greatest benefits to the US population come from providing aspirin to high-risk individuals, controlling pre-diabetes, weight reduction in obese individuals, lowering blood pressure in people with diabetes, and lowering LDL cholesterol in people with existing coronary artery disease (CAD). As currently delivered and at current prices, most prevention activities are expensive when considering direct medical costs; smoking cessation is the only prevention strategy that is cost-saving over 30 years.Conclusions--Aggressive application of nationally recommended prevention activities could prevent a high proportion of the CAD events and strokes that are otherwise expected to occur in adults in the United States today. However, as they are currently delivered, most of the prevention activities will substantially increase costs. If preventive strategies are to achieve their full potential, ways must be found to reduce the costs and deliver prevention activities more efficiently. 10.1161/CIRCULATIONAHA.108.190186

The structural basis of ribozyme-catalyzed RNA assembly.

MP Robertson — 2007-11-15T11:58:31-00:00

Science, Vol. 315, No. 5818. (16 March 2007), pp. 1549-1553.

Life originated, according to the RNA World hypothesis, from self-replicating ribozymes that catalyzed ligation of RNA fragments. We have solved the 2.6 angstrom crystal structure of a ligase ribozyme that catalyzes regiospecific formation of a 5' to 3' phosphodiester bond between the 5'-triphosphate and the 3'-hydroxyl termini of two RNA fragments. Invariant residues form tertiary contacts that stabilize a flexible stem of the ribozyme at the ligation site, where an essential magnesium ion coordinates three phosphates. The structure of the active site permits us to suggest how transition-state stabilization and a general base may catalyze the ligation reaction required for prebiotic RNA assembly.

Worldwide variations in the prevalence of symptoms of atopic eczema in the International Study of Asthma and Allergies in Childhood.

H Williams — 2008-07-04T01:42:27-00:00

The Journal of allergy and clinical immunology, Vol. 103, No. 1 Pt 1. (January 1999), pp. 125-138.

BACKGROUND: Little is known about the prevalence of atopic eczema outside Northern Europe. OBJECTIVES: We sought to describe the magnitude and variation in the prevalence of atopic eczema symptoms throughout the world. METHODS: A cross-sectional questionnaire survey was conducted on random samples of schoolchildren aged 6 to 7 years and 13 to 14 years from centers in 56 countries throughout the world. Those children with a positive response to being questioned about the presence of an itchy relapsing skin rash in the last 12 months that had affected their skin creases were considered to have atopic eczema. Children whose atopic eczema symptoms resulted in sleep disturbance for 1 or more nights per week were considered to have severe atopic eczema. RESULTS: Complete data was available for 256,410 children aged 6 to 7 years in 90 centers and 458,623 children aged 13 to 14 years in 153 centers. The prevalence range for symptoms of atopic eczema was from less than 2% in Iran to over 16% in Japan and Sweden in the 6 to 7 year age range and less than 1% in Albania to over 17% in Nigeria for the 13 to 14 year age range. Higher prevalences of atopic eczema symptoms were reported in Australasia and Northern Europe, and lower prevalences were reported in Eastern and Central Europe and Asia. Similar patterns were seen for symptoms of severe atopic eczema. CONCLUSIONS: Atopic eczema is a common health problem for children and adolescents throughout the world. Symptoms of atopic eczema exhibit wide variations in prevalence both within and between countries inhabited by similar ethnic groups, suggesting that environmental factors may be critical in determining disease expression. Studies that include objective skin examinations are required to confirm these findings.

Inflammation and atherosclerosis.

GK Hansson — 2008-07-03T20:10:21-00:00

Annual review of pathology, Vol. 1 (2006), pp. 297-329.

Atherosclerosis, the cause of myocardial infarction, stroke, and ischemic gangrene, is an inflammatory disease. The atherosclerotic process is initiated when cholesterol-containing low-density lipoproteins accumulate in the intima and activate the endothelium. Leukocyte adhesion molecules and chemokines promote recruitment of monocytes and T cells. Monocytes differentiate into macrophages and upregulate pattern recognition receptors, including scavenger receptors and toll-like receptors. Scavenger receptors mediate lipoprotein internalization, which leads to foam-cell formation. Toll-like receptors transmit activating signals that lead to the release of cytokines, proteases, and vasoactive molecules. T cells in lesions recognize local antigens and mount T helper-1 responses with secretion of pro-inflammatory cytokines that contribute to local inflammation and growth of the plaque. Intensified inflammatory activation may lead to local proteolysis, plaque rupture, and thrombus formation, which causes ischemia and infarction. Inflammatory markers are already used to monitor the disease process and anti-inflammatory therapy may be useful to control disease activity.

Data mountain: using spatial memory for document management

George Robertson — 2006-05-11T08:29:49-00:00

(1998), pp. 153-162.

The O-linked glycosylation of secretory/shed MUC1 from advanced breast cancer patient serum

Sarah Storr — 2008-07-02T13:43:13-00:00

Glycobiology (10 March 2008), cwn022.

MUC1 is a high molecular weight glycoprotein that is over-expressed in breast cancer. Aberrant O-linked glycosylation of MUC1 in cancer has been implicated in disease progression. We investigated the O-linked glycosylation of MUC1 purified from the serum of an advanced breast cancer patient. O-glycans were released by hydrazinolysis and analyzed by liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) and by high performance liquid chromatography (HPLC) coupled with sequential exoglycosidase digestions. Core 1 type glycans (83%) dominated the profile which also confirmed high levels of sialylation: 80% of the glycans were mono-, di- or tri-sialylated. Core 2 type structures contributed approximately 17% of the assigned glycans and the oncofoetal Thomsen-Friedenreich (TF) antigen (Gal1-3GalNAc) accounted for 14% of the total glycans. Interestingly, two core 1 type glycans were identified that had sialic acid 2--8 linked to sialylated core 1 type structures (9% of the total glycan pool). This is the first O-glycan analysis of MUC1 from the serum of a breast cancer patient; the results suggest that amongst the cell lines commonly used to express recombinant MUC1 the T47D cell line processes glycans that are most similar to patient derived material. 10.1093/glycob/cwn022

A multi-model approach to the detection of web-based attacks

Christopher Kruegel — 2008-07-01T01:26:34-00:00

Comput. Netw., Vol. 48, No. 5. (August 2005), pp. 717-738.

Very fast empirical prediction and rationalization of protein pKa values.

H Li — 2007-10-16T14:56:51-00:00

Proteins, Vol. 61, No. 4. (1 December 2005), pp. 704-721.

A very fast empirical method is presented for structure-based protein pKa prediction and rationalization. The desolvation effects and intra-protein interactions, which cause variations in pKa values of protein ionizable groups, are empirically related to the positions and chemical nature of the groups proximate to the pKa sites. A computer program is written to automatically predict pKa values based on these empirical relationships within a couple of seconds. Unusual pKa values at buried active sites, which are among the most interesting protein pKa values, are predicted very well with the empirical method. A test on 233 carboxyl, 12 cysteine, 45 histidine, and 24 lysine pKa values in various proteins shows a root-mean-square deviation (RMSD) of 0.89 from experimental values. Removal of the 29 pKa values that are upper or lower limits results in an RMSD = 0.79 for the remaining 285 pKa values.

Automating mimicry attacks using static binary analysis

Christopher Kruegel — 2008-06-30T11:09:08-00:00

(2005), pp. 11-11.

Separate contributions of enhanced and suppressed sensitivity to the auditory attentional filter

Michael Tan — 2008-06-28T11:42:10-00:00

Hearing Research, Vol. 241, No. 1-2. (July 2008), pp. 18-25.

Three experiments used a probe-signal method to determine the extent to which exposure-related changes in sensitivity result from an immediate effect of stimulation and from a cumulative effect of repeated stimulation. In the first experiment, a fixed-frequency cue was followed by a same-frequency target (on 75% of trials) or a different-frequency probe (on 25% of trials). In the second experiment, a cue frequency selected randomly from a set of five was followed by a same-frequency target, or one of four different-frequency probes. Targets and probes were randomly selected independently of the cue frequency and all were equiprobable (20%). Target detection showed an average 3.4 dB advantage over probe detection. In the third experiment, tones with a randomly selected frequency were detected better when cued by a tone of the same-frequency than when presented without a prior cue. The cued tones showed an average 2.6 dB advantage over the uncued tones. Together, these results suggest that two mechanisms contribute to changes in sensitivity following auditory stimulation: first, an immediate enhancement of target detection produced by an auditory cue and second, a suppression of non-target frequencies caused by the expectation of a target.

Four new derivatives of the broad-host-range cloning vector pBBR1MCS, carrying different antibiotic-resistance cassettes

Michael Kovach — 2007-04-11T03:26:50-00:00

Gene, Vol. 166, No. 1. (1 December 1995), pp. 175-176.

Four new antibiotic-resistant derivatives of the broad-host-range (bhr) cloning vector pBBR1MCS have been constructed. These new plasmids have several advantages over many of the currently available bhr vectors in that: (i) they are relatively small (< 5.3 kb), (ii) they possess an extended multiple cloning site (MCS), (iii) they allow direct selection of recombinant plasmid molecules in Escherichia coli via disruption of the LacZ[alpha] peptide, (iv) they are mobilizable when the RK2 transfer functions are provided in trans and (v) they are compatible with IncP, IncQ and IncW group plasmids, as well as with ColE1- and P15a-based replicons.

Enterprise Architecture As Strategy: Creating a Foundation for Business Execution

Jeanne Ross — 2007-05-15T10:15:29-00:00

(08 August 2006)

Enterprise architecture defines a firm’s needs for standardized tasks, job roles, systems, infrastructure, and data in core business processes. Thus, it helps a company to articulate how it will compete in a digital economy and it guides managers’ daily decisions to realize their vision of success. This book clearly explains enterprise architecture’s vital role in enabling—or constraining—the execution of business strategy. The book provides clear frameworks, thoughtful case examples, and a proven-effective structured process for designing and implementing effective enterprise architectures.

Okapi at TREC-6 - Automatic ad hoc, VLC, routing, filtering and QSDR

S Walker — 2008-06-26T20:00:23-00:00

this paper; comparisons between passage and non-passage runs can be seen in a few of the tables.

In Vivo and in Vitro Stability of the Broad-Host-Range Cloning Vector pBBR1MCS in Six Brucella Species

Philip Elzer — 2008-06-26T01:50:08-00:00

Plasmid, Vol. 33, No. 1. (January 1995), pp. 51-57.

Previous studies have shown that the broad-host-range plasmid pBBR1MCS can be used for genetic complementation in Brucella abortus. To extend these observations, the in vivo and in vitro stability of pBBR1MCS was evaluated in the six currently recognized species of the genus Brucella. pBBR1MCS was readily introduced into all of the strains tested by electroporation and was stably maintained in broth cultures without antibiotic selection during five serial passages over a 10-day period. Furthermore, isolates of all six Brucella strains containing pBBR1MCS obtained from the spleens of BALB/c mice 1 week postinfection maintained the plasmid. Although pBBR1MCS maintains the mobilization locus present in the parental plasmid pBBR1CM, attempts to detect transfer of pBBR1MCS between Brucella strains by conjugation were unsuccessful. These results demonstrate the in vitro and in vivo stability of pBBR1MCS in Brucella spp. and reinforce the usefulness of this cloning vector for the genetic analysis of these organisms.

Four new derivatives of the broad-host-range cloning vector pBBR1MCS, carrying different antibiotic-resistance cassettes.

ME Kovach — 2006-03-15T16:52:25-00:00

Gene, Vol. 166, No. 1. (1 December 1995), pp. 175-176.

Four new antibiotic-resistant derivatives of the broad-host-range (bhr) cloning vector pBBR1MCS have been constructed. These new plasmids have several advantages over many of the currently available bhr vectors in that: (i) they are relatively small (< 5.3 kb), (ii) they possess an extended multiple cloning site (MCS), (iii) they allow direct selection of recombinant plasmid molecules in Escherichia coli via disruption of the LacZ alpha peptide, (iv) they are mobilizable when the RK2 transfer functions are provided in trans and (v) they are compatible with IncP, IncQ and IncW group plasmids, as well as with ColE1- and P15a-based replicons.

The Arabidopsis Circadian Clock Incorporates a cADPR-Based Feedback Loop

Antony Dodd — 2008-06-24T14:19:13-00:00

Science, Vol. 318, No. 5857. (14 December 2007), pp. 1789-1792.

Transcriptional feedback loops are a feature of circadian clocks in both animals and plants. We show that the plant circadian clock also incorporates the cytosolic signaling molecule cyclic adenosine diphosphate ribose (cADPR). cADPR modulates the circadian oscillator's transcriptional feedback loops and drives circadian oscillations of Ca2+ release. The effects of antagonists of cADPR signaling, manipulation of cADPR synthesis, and mathematical simulation of the interaction of cADPR with the circadian clock indicate that cADPR forms a feedback loop within the plant circadian clock. 10.1126/science.1146757

The determinants of carboxyl pKa values in turkey ovomucoid third domain.

H Li — 2008-06-23T12:24:35-00:00

Proteins, Vol. 55, No. 3. (15 May 2004), pp. 689-704.

A computational methodology for protein pK(a) predictions, based on ab initio quantum mechanical treatment of part of the protein and linear Poisson-Boltzmann equation treatment of the bulk solvent, is presented. The method is used to predict and interpret the pK(a) values of the five carboxyl residues (Asp7, Glu10, Glu19, Asp27, and Glu43) in the serine protease inhibitor turkey ovomucoid third domain. All the predicted pK(a) values are within 0.5 pH units of experiment, with a root-mean-square deviation of 0.31 pH units. We show that the decreased pK(a) values observed for some of the residues are primarily due to hydrogen bonds to the carboxyl oxygens. Hydrogen bonds involving amide protons are shown to be particularly important, and the effect of hydrogen bonding is shown to be nonadditive. Hydrophobic effects are also shown to be important in raising the pK(a). Interactions with charged residues are shown to have relatively little effect on the carboxyl pK(a) values in this protein, in general agreement with experiment.

DiscoverySpace: an interactive data analysis application

Neil Robertson — 2007-01-09T21:10:31-00:00

Genome Biology, Vol. 8 (08 January 2007), R6.

Combining nanoliposomal ceramide with sorafenib synergistically inhibits melanoma and breast cancer cell survival to decrease tumor development.

MA Tran — 2008-06-22T16:10:35-00:00

Clinical cancer research : an official journal of the American Association for Cancer Research, Vol. 14, No. 11. (1 June 2008), pp. 3571-3581.

PURPOSE: Deregulation of phosphatidylinositol 3-kinase/Akt and Ras/Raf/mitogen-activated protein kinase/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase pathways occurs in melanoma and breast cancer, deregulating normal cellular apoptosis and proliferation. Therapeutic cocktails simultaneously targeting these pathways could promote synergistically acting tumor inhibition. However, agents with manageable toxicity and mechanistic basis for synergy need identification. The purpose of this study is to evaluate the preclinical therapeutic efficacy and associated toxicity of combining sorafenib with nanoliposomal ceramide. EXPERIMENTAL DESIGN: Effects of sorafenib and nanoliposomal ceramide as single and combinatorial agents were examined on cultured cells using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt assays and CalcuSyn software used to assess synergistic or additive inhibition. Western blotting measured cooperative effects on signaling pathways. Rates of proliferation, apoptosis, and angiogenesis were measured in size- and time-matched tumors to identify mechanistic basis for inhibition. Toxicity was evaluated measuring animal weight, blood toxicity parameters, and changes in liver histology. RESULTS: Sorafenib and nanoliposomal ceramide synergistically inhibited cultured cells by cooperatively targeting mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling. A 1- to 2-fold increase in cellular apoptosis and 3- to 4-fold decrease in cellular proliferation were observed following combination treatment compared with single agents, which caused synergistically acting inhibition. In vivo, an approximately 30% increase in tumor inhibition compared with sorafenib treatment alone and an approximately 58% reduction in tumor size compared with nanoliposomal ceramide monotherapy occurred by doubling apoptosis rates with negligible systemic toxicity. CONCLUSIONS: This study shows that nanoliposomal ceramide enhances effectiveness of sorafenib causing synergistic inhibition. Thus, a foundation is established for clinical trials evaluating the efficacy of combining sorafenib with nanoliposomal ceramide for treatment of cancers.

Identification and isolation of three proteasome subunits and their encoding genes from Trypanosoma brucei

Lan Huang — 2008-06-21T05:28:17-00:00

Molecular and Biochemical Parasitology, Vol. 102, No. 2. (20 August 1999), pp. 211-223.

We have determined peptide sequences of three Trypanosoma brucei proteasome subunit proteins by mass spectrometry of tryptic digests of the proteins purified by two-dimensional (2-D) polyacrylamide gel electrophoresis. Three genes identified by the sequence of their cDNA encode the peptides identified in these three proteins. The three proteins predicted from the gene sequences have significant similarity to other known proteasome subunits and represent an [alpha]6 type subunit (TbPSA6), and two [beta]-type subunits belonging to the [beta]1-type (TbPSB1) and [beta]2 type (TbPSB2). The sequences of both [beta]-subunits predict formation of catalytically active subunits through proteolytic processing. The prediction is supported by the presence in each of the two [beta]-subunits of a tryptic peptide that has the correctly processed N-terminus that creates the threonine nucleophile of the mature protein. This peptide cannot be generated by trypsin because of the required cleavage of a glycine-threonine bond. It is thus likely that there are at least two catalytically active [beta]-subunits, TbPSB1 and TbPSB2, present in the mature 20S proteasome from T. brucei.

The sea urchin kinome: a first look.

CA Bradham — 2008-06-18T19:29:58-00:00

Developmental biology, Vol. 300, No. 1. (1 December 2006), pp. 180-193.

This paper reports a preliminary in silico analysis of the sea urchin kinome. The predicted protein kinases in the sea urchin genome were identified, annotated and classified, according to both function and kinase domain taxonomy. The results show that the sea urchin kinome, consisting of 353 protein kinases, is closer to the Drosophila kinome (239) than the human kinome (518) with respect to total kinase number. However, the diversity of sea urchin kinases is surprisingly similar to humans, since the urchin kinome is missing only 4 of 186 human subfamilies, while Drosophila lacks 24. Thus, the sea urchin kinome combines the simplicity of a non-duplicated genome with the diversity of function and signaling previously considered to be vertebrate-specific. More than half of the sea urchin kinases are involved with signal transduction, and approximately 88% of the signaling kinases are expressed in the developing embryo. These results support the strength of this nonchordate deuterostome as a pivotal developmental and evolutionary model organism.