Similarity Queries for Temporal Toxicogenomic Expression Profiles

We present an approach for answering similarity queries about gene expression time series that is motivated by the task of characterizing the potential toxicity of various chemicals. Our approach involves two key aspects. First, our method employs a novel alignment algorithm based on time warping. Our time warping algorithm has several advantages over previous approaches. It allows the user to impose fairly strong biases on the form that the alignments can take, and it permits a type of local alignment in which the entirety of only one series has to be aligned. Second, our method employs a relaxed spline interpolation to predict expression responses for unmeasured time points, such that the spline does not necessarily exactly fit every observed point. We evaluate our approach using expression time series from the Edge toxicology database. Our experiments show the value of using spline representations for sparse time series. More significantly, they show that our time warping method provides more accurate alignments and classifications than previous standard alignment methods for time series

EDGE3: A web-based solution for management and analysis of Agilent two color microarray experiments

<p>Abstract</p> <p>Background</p> <p>The ability to generate transcriptional data on the scale of entire genomes has been a boon both in the improvement of biological understanding and in the amount of data generated. The latter, the amount of data generated, has implications when it comes to effective storage, analysis and sharing of these data. A number of software tools have been developed to store, analyze, and share microarray data. However, a majority of these tools do not offer all of these features nor do they specifically target the commonly used two color Agilent DNA microarray platform. Thus, the motivating factor for the development of EDGE³was to incorporate the storage, analysis and sharing of microarray data in a manner that would provide a means for research groups to collaborate on Agilent-based microarray experiments without a large investment in software-related expenditures or extensive training of end-users.</p> <p>Results</p> <p>EDGE³has been developed with two major functions in mind. The first function is to provide a workflow process for the generation of microarray data by a research laboratory or a microarray facility. The second is to store, analyze, and share microarray data in a manner that doesn't require complicated software. To satisfy the first function, EDGE³has been developed as a means to establish a well defined experimental workflow and information system for microarray generation. To satisfy the second function, the software application utilized as the user interface of EDGE³is a web browser. Within the web browser, a user is able to access the entire functionality, including, but not limited to, the ability to perform a number of bioinformatics based analyses, collaborate between research groups through a user-based security model, and access to the raw data files and quality control files generated by the software used to extract the signals from an array image.</p> <p>Conclusion</p> <p>Here, we present EDGE³, an open-source, web-based application that allows for the storage, analysis, and controlled sharing of transcription-based microarray data generated on the Agilent DNA platform. In addition, EDGE³provides a means for managing RNA samples and arrays during the hybridization process. EDGE³is freely available for download at <url>http://edge.oncology.wisc.edu/</url>.</p

The tip cross-sectional areas of poisoned bone arrowheads from southern Africa

Abstract: Current hunter-gatherers from the Kalahari in southern Africa are well-known for their use of poisoned arrowheads, and it is assumed that this tradition spanned most of the Holocene in the region. Recent archaeological work, however, indicates that the techno-behaviour may have originated sometime during the Pleistocene. Tracing the use of poisoned arrowheads through time is not an easy task. Here I explore the use of the tip cross-sectional area (TSCA) metric to analyse relatively large samples of bone points that are ethno-historically associated with Kalahari San poisoned arrow hunting. I add the southern African poisoned bone arrowhead TSCA range to the previous ranges established for North American atlatl dart tips, North American arrowheads and large thrusting spears. Based on the results obtained from 445 artefacts spanning historical, Later and Middle Stone Age phases, I show that poisoned bone arrowheads may have been in use in southern Africa throughout the last 60 000 years, and that a methodical effort to trace stone-tipped poison arrowheads may be warranted

Clustered alignments of gene-expression time series data

Motivation: Characterizing and comparing temporal gene-expression responses is an important computational task for answering a variety of questions in biological studies. Algorithms for aligning time series represent a valuable approach for such analyses. However, previous approaches to aligning gene-expression time series have assumed that all genes should share the same alignment. Our work is motivated by the need for methods that identify sets of genes that differ in similar ways between two time series, even when their expression profiles are quite different

Thalamic inputs to dorsomedial striatum are involved in inhibitory control: evidence from the five-choice serial reaction time task in rats

Rationale Corticostriatal circuits are widely implicated in the top-down control of attention including inhibitory control and behavioural flexibility. However, recent neurophysiological evidence also suggests a role for thalamic inputs to striatum in behaviours related to salient, reward-paired cues. Objectives Here, we used designer receptors exclusively activated by designer drugs (DREADDs) to investigate the role of parafascicular (Pf) thalamic inputs to the dorsomedial striatum (DMS) using the five-choice serial reaction time task (5CSRTT) in rats. Methods The 5CSRTT requires sustained attention in order to detect spatially and temporally distributed visual cues and provides measures of inhibitory control related to impulsivity (premature responses) and compulsivity (perseverative responses). Rats underwent bilateral Pf injections of the DREADD vector, AAV2-CaMKIIa-HA-hM4D(Gi)-IRES-mCitrine. The DREADD agonist, clozapine N-oxide (CNO; 1 μl bilateral; 3 μM) or vehicle, was injected into DMS 1 h before behavioural testing. Task parameters were manipulated to increase attention load or reduce stimulus predictability respectively. Results We found that inhibition of the Pf-DMS projection significantly increased perseverative responses when stimulus predictability was reduced but had no effect on premature responses or response accuracy, even under increased attentional load. Control experiments showed no effects on locomotor activity in an open field. Conclusions These results complement previous lesion work in which the DMS and orbitofrontal cortex were similarly implicated in perseverative responses and suggest a specific role for thalamostriatal inputs in inhibitory control

Stromal cells differentially regulate neutrophil and lymphocyte recruitment through the endothelium

Stromal fibroblasts modify the initial recruitment of leucocytes by endothelial cells (EC), but their effects on subsequent transendothelial migration remain unclear. Here, EC and dermal or synovial fibroblasts were cultured on opposite surfaces of 3-lm pore filters and incorporated in static or flow-based migration assays. Fibroblasts had little effect on tumour necrosis factor-a-induced transendothelial migration of neutrophils,but tended to increase the efficiency of migration away from the endothelium.Surprisingly, similar close contact between EC and fibroblasts strongly reduced lymphocyte migration in static assays, and nearly abolished stable lymphocyte adhesion from flow. Fibroblasts did not alter endothelial surface expression of adhesion molecules or messenger RNA for chemokines. Inhibition of attachment did not occur when EC-fibroblast contact was restricted by using 04-lm pore filters, but under these conditions pre-treatment with heparinase partially inhibited adhesion. In the 3-lm pore co-cultures, inhibition of metalloproteinase activity partially recovered lymphocyte adhesion, but addition of CXCL12 (SDF-1a) to the endothelial surface did not. Hence, the ability of EC to present activating chemokines for lymphocytes may have been enzymatically inhibited by direct contact with fibroblasts. To avoid contact, we cultured EC and fibroblasts on separate 3-lm pore filters one above the other. Here,fibroblasts promoted the transendothelial migration of lymphocytes. Fibroblasts generate CXCL12, but blockade of CXCL12 receptor had no effect on lymphocyte migration. While stromal cells can provide signal(s)promoting leucocyte migration away from the sub-endothelial space,direct cell contact (which might occur in damaged tissue) may cause disruption of chemokine signalling, specifically inhibiting lymphocyte rather than neutrophil recruitment

Limits to Poisson's ratio in isotropic materials

A long-standing question is why Poisson's ratio v nearly always exceeds 0.2 for isotropic materials, whereas classical elasticity predicts v to be between -1 to 1/2. We show that the roots of quadratic relations from classical elasticity divide v into three possible ranges: -1 < v <= 0, 0 <= v <= 1/5, and 1/5 <= v < 1/2. Since elastic properties are unique there can be only one valid set of roots, which must be 1/5 <= v < 1/2 for consistency with the behavior of real materials. Materials with Poisson's ratio outside of this range are rare, and tend to be either very hard (e.g., diamond, beryllium) or porous (e.g., auxetic foams); such substances have more complex behavior than can be described by classical elasticity. Thus, classical elasticity is inapplicable whenever v < 1/5, and the use of the equations from classical elasticity for such materials is inappropriate.Comment: Physical Review B, in pres

Identification of new states in 26Si using the29Si(3He,6He)26Si reaction and consequences for the 25Al(p,y)26Si reaction rate in explosive hydrogen burning environments

We have studied the [Formula Presented] reaction and have identified new states in [Formula Presented] at [Formula Presented] and [Formula Presented] Based on these measurements and other recent evidence, we suggest spin-parity assignments of [Formula Presented] for the 5.678 MeV state and [Formula Presented] for the 5.945 MeV state, which would account for all the “missing” unnatural parity states in [Formula Presented] in the excitation energy region important to hydrogen burning in novae. New reaction rates are presented for the [Formula Presented] reaction based on this possible assignment of states

Workflows for Quantitative Data Analysis in The Social Sciences

The background is given to how statistical analysis is used by quantitative social scientists. Developing statistical analyses requires substantial effort, yet there are important limitations in current practice. This has motivated the authors to create a more systematic and effective methodology with supporting tools. The approach to modelling quantitative data analysis in the social sciences is presented. Analysis scripts are treated abstractly as mathematical functions and concretely as web services. This allows individual scripts to be combined into high-level workflows. A comprehensive set of tools allows workflows to be defined, automatically validated and verified, and automatically implemented. The workflows expose opportunities for parallel execution, can define support for proper fault handling, and can be realised by non-technical users. Services, workflows and datasets can also be readily shared. The approach is illustrated with a realistic case study that analyses occupational position in relation to health

Continuous succinic acid production by Actinobacillus succinogenes on xylose‑enriched hydrolysate

BACKGROUND : Bio-manufacturing of high-value chemicals in parallel to renewable biofuels has the potential to dramatically improve the overall economic landscape of integrated lignocellulosic biorefineries. However, this will require the generation of carbohydrate streams from lignocellulose in a form suitable for efficient microbial conversion and downstream processing appropriate to the desired end use, making overall process development, along with selection of appropriate target molecules, crucial to the integrated biorefinery. Succinic acid (SA), a high-value target molecule, can be biologically produced from sugars and has the potential to serve as a platform chemical for various chemical and polymer applications. However, the feasibility of microbial SA production at industrially relevant productivities and yields from lignocellulosic biorefinery streams has not yet been reported. RESULTS : Actinobacillus succinogenes 130Z was immobilised in a custom continuous fermentation setup to produce SA on the xylose-enriched fraction of a non-detoxified, xylose-rich corn stover hydrolysate stream produced from deacetylation and dilute acid pretreatment. Effective biofilm attachment, which serves as a natural cell retention strategy to increase cell densities, productivities and resistance to toxicity, was accomplished by means of a novel agitator fitting. A maximum SA titre, yield and productivity of 39.6 g L−1, 0.78 g g−1 and 1.77 g L−1 h−1 were achieved, respectively. Steady states were obtained at dilution rates of 0.02, 0.03, 0.04, and 0.05 h−1 and the stirred biofilm reactor was stable over prolonged periods of operation with a combined fermentation time of 1550 h. Furthermore, it was found that a gradual increase in the dilution rate was required to facilitate adaptation of the culture to the hydrolysate, suggesting a strong evolutionary response to the toxic compounds in the hydrolysate. Moreover, the two primary suspected fermentation inhibitors, furfural and HMF, were metabolised during fermentation with the concentration of each remaining at zero across all steady states. CONCLUSIONS : The results demonstrate that immobilised A. succinogenes has the potential for effective conversion of an industrially relevant, biomass-derived feed stream to succinic acid. Furthermore, due to the attractive yields, productivities and titres achieved in this study, the process has the potential to serve as a means for value-added chemical manufacturing in the integrated biorefinery.The National Research Foundation (NRF) and the US Department of Energy Bioenergy Technologies Office.http://biotechnologyforbiofuels.biomedcentral.comam201