Data visualization during the early stages of drug discovery

Multidimensional compound optimization is a new paradigm in the drug discovery process, yielding efficiencies during early stages and reducing attrition in the later stages of drug development. The success of this strategy relies heavily on understanding this multidimensional data and extracting useful information from it. This paper demonstrates how principled visualization algorithms can be used to understand and explore a large data set created in the early stages of drug discovery. The experiments presented are performed on a real-world data set comprising biological activity data and some whole-molecular physicochemical properties. Data visualization is a popular way of presenting complex data in a simpler form. We have applied powerful principled visualization methods, such as generative topographic mapping (GTM) and hierarchical GTM (HGTM), to help the domain experts (screening scientists, chemists, biologists, etc.) understand and draw meaningful decisions. We also benchmark these principled methods against relatively better known visualization approaches, principal component analysis (PCA), Sammon's mapping, and self-organizing maps (SOMs), to demonstrate their enhanced power to help the user visualize the large multidimensional data sets one has to deal with during the early stages of the drug discovery process. The results reported clearly show that the GTM and HGTM algorithms allow the user to cluster active compounds for different targets and understand them better than the benchmarks. An interactive software tool supporting these visualization algorithms was provided to the domain experts. The tool facilitates the domain experts by exploration of the projection obtained from the visualization algorithms providing facilities such as parallel coordinate plots, magnification factors, directional curvatures, and integration with industry standard software. © 2006 American Chemical Society.

Interocular masking and summation indicate two stages of divisive contrast gain control

Our understanding of early spatial vision owes much to contrast masking and summation paradigms. In particular, the deep region of facilitation at low mask contrasts is thought to indicate a rapidly accelerating contrast transducer (eg a square-law or greater). In experiment 1, we tapped an early stage of this process by measuring monocular and binocular thresholds for patches of 1 cycle deg-1 sine-wave grating. Threshold ratios were around 1.7, implying a nearly linear transducer with an exponent around 1.3. With this form of transducer, two previous models (Legge, 1984 Vision Research 24 385 - 394; Meese et al, 2004 Perception 33 Supplement, 41) failed to fit the monocular, binocular, and dichoptic masking functions measured in experiment 2. However, a new model with two-stages of divisive gain control fits the data very well. Stage 1 incorporates nearly linear monocular transducers (to account for the high level of binocular summation and slight dichoptic facilitation), and monocular and interocular suppression (to fit the profound 42 Oral presentations: Spatial vision Thursday dichoptic masking). Stage 2 incorporates steeply accelerating transduction (to fit the deep regions of monocular and binocular facilitation), and binocular summation and suppression (to fit the monocular and binocular masking). With all model parameters fixed from the discrimination thresholds, we examined the slopes of the psychometric functions. The monocular and binocular slopes were steep (Weibull ߘ3-4) at very low mask contrasts and shallow (ߘ1.2) at all higher contrasts, as predicted by all three models. The dichoptic slopes were steep (ߘ3-4) at very low contrasts, and very steep (ß>5.5) at high contrasts (confirming Meese et al, loco cit.). A crucial new result was that intermediate dichoptic mask contrasts produced shallow slopes (ߘ2). Only the two-stage model predicted the observed pattern of slope variation, so providing good empirical support for a two-stage process of binocular contrast transduction. [Supported by EPSRC GR/S74515/01]

β-amyloid plaques:Stages in life history or independent origin?

Several types of discrete β-amyloid (Aβ) deposit or senile plaque have been identified in the brains of individuals with Alzheimer's disease and Down's syndrome. The majority of these plaques can be classified into four morphological types: diffuse, primitive, classic and compact. Two hypotheses have been proposed to account for these plaques. Firstly, that the diffuse, primitive, classic and compact plaques develop in sequence and represent stages in the life history of a single plaque type. Secondly, that the different Aβ plaques develop independently and therefore, unique factors are involved in the formation of each type. To attempt to distinguish between these hypotheses, the morphology, ultrastructure, composition, and spatial distribution in the brain of the four types of plaque were compared. Although some primitive plaques may develop from diffuse plaques, the evidence suggests that a unique combination of factors is involved in the pathogenesis of each plaque type and, therefore, supports the hypothesis that the major types of Aβ plaque develop independently.

Diagenesis and aquifer characteristics of the Sherwood Sandstone Group in North Nottinghamshire

The Sherwood Sandstone Group forms an important aquifer in Eastern England, which in North Nottinghamshire comprises the Nottingham Castle and Lenton Sandstone Formations. The aquifer is formed by an alluvial red-bed sequence dominated by medium-coarse grained sandstones which are texturally immature to submature and have only been subjected to shallow burial diagenesis. These sandstones reached the mature stage of the meso diagenetic regime, and four stages are recognized in their diagenetic history depending upon the physical/chemical processes prevailing and the subsequent effect on porosity and permeability. Stage "One" represents changes including dissolution of unstable silicates, clay replacement, red colouration and precipitation of authigenic minerals (quartz, feldspar, illite, l/S, kaolinite, dolomite, ferroan calcite, calcite). The net result of these changes was porosity reduction. Stage "Two" included changes due to mechanical compaction which resulted in minor porosity reduction. Stage "Three" was the main phase of secondary porosity enhancement. Stage "Four" represents changes taking place in the present groundwater where porosity and permeability may have been increased by dissolution and partly reduced by kaolinite precipitation. Porosity measured by water-resaturation and Hg-injection gave average values of 25.63% and 24.85% respectively. The results are comparable and showed marked correlation especially in highly porous/permeable rocks. Porosity measurements from photomicrographs were markedly offset from laboratory results. Horizontal Kw ranged between 1.43 x 10-5 and 1.13 x 10-1 mm/sec, with an average of  1.68 x 10-2 mm/sec. The estimated KHg ranged between 7.29 x 10-6 and 6.99 x 10-2 mm/sec with an average of 1.47 x 10-2 mm/sec. Both results are significantly correlated for highly porous/permeable rocks. The hydraulic properties are highly dependent upon the diagenetic properties (as most of the pores present are of secondary origin) as well as the pore size distribution. The chemistry of these groundwaters indicates that they are under-saturated with respect to dolomite, calcite, K-feldspar, l/S clay, and montmorillonite. The precipitation of kaolinite,and to a lesser extent illite, is favoured in the present groundwater regime.

Cardiac dysfunction and cell damage across clinical stages of severity in growth-restricted fetuses

Objective - The purpose of this study was to assess cardiac function and cell damage in intrauterine growth-restricted (IUGR) fetuses across clinical Doppler stages of deterioration. Study Design - One hundred twenty appropriate-for-gestational-age and 81 IUGR fetuses were classified in stages 1/2/3 according umbilical artery present/absent/reversed end-diastolic blood flow, respectively. Cardiac function was assessed by modified-myocardial performance index, early-to-late diastolic filling ratios, cardiac output, and cord blood B-type natriuretic peptide; myocardial cell damage was assessed by heart fatty acid–binding protein, troponin-I, and high-sensitivity C-reactive protein. Results - Modified-myocardial performance index, blood B-type natriuretic peptide, and early-to-late diastolic filling ratios were increased in a stage-dependent manner in IUGR fetuses, compared with appropriate-for-gestational-age fetuses. Heart fatty acid–binding protein levels were higher in IUGR fetuses at stage 3, compared with control fetuses. Cardiac output, troponin-I, and high-sensitivity C-reactive protein did not increase in IUGR fetuses at any stage. Conclusion - IUGR fetuses showed signs of cardiac dysfunction from early stages. Cardiac dysfunction deteriorates further with the progression of fetal compromise, together with the appearance of biochemical signs of cell damage.

Regional competitiveness, economic growth and stages of development

This paper positions the concept of regional competitiveness within theories concerning regional economic growth and stages of economic development. It examines the sources of regional competitiveness encompassing an analysis based on the particular stage of economic development that the nations within which regions are situated have reached. As a means to achieve this, the paper undertakes an empirical analysis of data stemming from the World Competitiveness Index of Regions, and identifies regional competitiveness as a dual concept that explains relative differences in rates of economic development across regions, as well as an understanding of the future economic growth trajectories of regions at a similar stage of economic development. As with endogenous growth and development theory, the notion of regional competitiveness presented here places knowledge, innovation and entrepreneurship at the forefront of conceptualisations of regional economic differentiation.

Immunological synapse: a mathematical model of the bond formation process:mathematical modelling of the immature synapse

The cell:cell bond between an immune cell and an antigen presenting cell is a necessary event in the activation of the adaptive immune response. At the juncture between the cells, cell surface molecules on the opposing cells form non-covalent bonds and a distinct patterning is observed that is termed the immunological synapse. An important binding molecule in the synapse is the T-cell receptor (TCR), that is responsible for antigen recognition through its binding with a major-histocompatibility complex with bound peptide (pMHC). This bond leads to intracellular signalling events that culminate in the activation of the T-cell, and ultimately leads to the expression of the immune eector function. The temporal analysis of the TCR bonds during the formation of the immunological synapse presents a problem to biologists, due to the spatio-temporal scales (nanometers and picoseconds) that compare with experimental uncertainty limits. In this study, a linear stochastic model, derived from a nonlinear model of the synapse, is used to analyse the temporal dynamics of the bond attachments for the TCR. Mathematical analysis and numerical methods are employed to analyse the qualitative dynamics of the nonequilibrium membrane dynamics, with the specic aim of calculating the average persistence time for the TCR:pMHC bond. A single-threshold method, that has been previously used to successfully calculate the TCR:pMHC contact path sizes in the synapse, is applied to produce results for the average contact times of the TCR:pMHC bonds. This method is extended through the development of a two-threshold method, that produces results suggesting the average time persistence for the TCR:pMHC bond is in the order of 2-4 seconds, values that agree with experimental evidence for TCR signalling. The study reveals two distinct scaling regimes in the time persistent survival probability density prole of these bonds, one dominated by thermal uctuations and the other associated with the TCR signalling. Analysis of the thermal fluctuation regime reveals a minimal contribution to the average time persistence calculation, that has an important biological implication when comparing the probabilistic models to experimental evidence. In cases where only a few statistics can be gathered from experimental conditions, the results are unlikely to match the probabilistic predictions. The results also identify a rescaling relationship between the thermal noise and the bond length, suggesting a recalibration of the experimental conditions, to adhere to this scaling relationship, will enable biologists to identify the start of the signalling regime for previously unobserved receptor:ligand bonds. Also, the regime associated with TCR signalling exhibits a universal decay rate for the persistence probability, that is independent of the bond length.

The isolation and characterization of tescalcin, a novel gene differentially expressed in the mouse testis during the early stages of gonadal differentiation

Gonadal development is an ideal model to study organogenesis because a variety of developmental processes can be studied during the differentiation of the bipotential primordium into testis or ovary. To better understand this process, Representational Difference Analysis of cDNA was used to identify genes that are differentially expressed in mouse gonads at 13.5 days post-coitus. The analysis led to the identification of three testis specific genes and a sequence that was only expressed in the ovary. The male genes identified: renin, Col9a3, and a novel gene termed tescalcin had patterns of expression that suggested a role in testis determination. ^ Studies of the tescalcin gene revealed that it is organized into eight exons and seven introns. The gene was located at 64 cM in mouse chromosome 5, where it spans approximately 35 Kb. Three mRNA variants resulting from alternative splicing of intron 5 were identified in mouse tissues. Gel mobility shift assays demonstrated that Sp1 and Sp3 from Y-1, msc-1, and MIN-6 cells nuclear extracts bind the GC-boxes within the tescalcin proximal promoter. Bisulfite sequencing analysis of tescalcin CpG island revealed that it is differentially methylated in male and female mouse embryonic gonads, and that hypermethylation of this region represses expression of tescalcin in the β-TC3 cell line. ^ The major tescalcin mRNA encodes a protein with 214 amino acids that contains a consensus EF-hand Ca2+-binding domain and an N-myristoylation motif. The amino acid sequence of tescalcin is highly conserved among various species, and it showed the highest homology with calcineurin B homologous proteins 1 and 2, and calcineurin B. Western blot analysis using antibodies generated against the tescalcin protein confirmed its presence in specific mouse tissues and cell lines. Immunohistochemical analysis of mouse embryos confirmed the pattern of expression of tescalcin mRNA in fetal testis. Using pull-down assays, glyceraidehydes-3-phosphate dehydrogenase was identified as an interacting and potential functional partner of tescalcin. ^ The identification and characterization of tescalcin as a novel embryonic testicular marker will contribute to the elucidation of the genetic pathways involved in testis development and likely to the understanding of pathological conditions such as sex reversal and infertility. ^

The impact of bandwidth in structured interviewing and criterion stability in predicting and assessing manager performance across transition and maintenance stages

The current study examined the role of three important components in the use of structured employment interviewing in performance prediction: construct bandwidth, observed communication skill, and the stability/dynamicity of performance criteria over time. A matched sample of 242 hospitality managers was derived from a field data set provided by a large hospitality management organization. Interview data and two years of performance appraisal data were provided. Bandwidth analysis demonstrated only minimal differences in prediction between matched predictor-criterion pairs compared with predictor to overall aggregate ratings (unmatched). The communication skill analysis revealed that this interviewer rated observation significantly predicted a number of the individual performance dimensions as well as overall performance over time. Of the five interview items, the strongest overall predictor of performance was interviewer rated communication skill. The stability/dynamicity analyses demonstrated the performance criteria to be generally stable over the two year period examined, which provides support for the long held notion that performance criteria is stabile over time. However, there were two exceptions. The interview dimension customer service orientation had shifting relationships over time with four of the criteria over the two year period. The performance criteria employee development also demonstrated some instability in its relationships with predictors. Thus, some evidence of dynamicity in performance criteria was revealed. Interestingly, both of the most noteworthy findings in the study involved items that were rated differently than the others in the study. The rated interview item communication skill and the rated performance criteria client satisfaction were ratings that involved a more direct level of observation. Additional analyses also revealed evidence of a general factor of performance. These two themes are more fully covered in the discussion.

Organizational Effectiveness Along Life-Cycle Stages: A Comparison Of Wendy's And McDonald's

"Perceptions of Organizational Effectiveness over Organizational Life Cycles" written by Kim S. Cameron and David S. Whetten, posits a theory regarding organizational effectiveness criteria change as firms develop along the life cycle continuum. Induced from observations obtained from a simulation game, the Cameron and Whetten theory is applied in this article to two real organizations, Wendy's and McDonald's, with the intention of demonstrating that this theory is applicable in "real life" situations.

An evaluation of depression, self-efficacy, satisfaction with life and perceived access to medical care across stages of HIV infection

This survey was designed to identify the incidence and scope of depression, satisfaction with life, self-efficacy and perceived access to medical care for those who are infected with the HIV virus. It also determined whether or not factors such as sexual orientation, ethnicity and socioeconomic status are intervening variables with respect to mental health issues. Subjects were recruited through a purposive sample from South Florida. A total of 871 surveys were used in the analysis. The overall response rate was nearly 90%. The incidence of depression was found to be higher than 75% across all stages of HIV infection. Furthermore, the incidence of depression increased as HIV disease progressed. Satisfaction with life and for the most part, self efficacy were found to decrease slightly as HIV disease progressed. Significant variance in depression, life satisfaction and self efficacy were found across stages of HIV infection. No significant differences between groups that were HIV infected were found for depression, life satisfaction and self efficacy. The severity of depression was found to vary significantly with self efficacy, life satisfaction and access to medical care but not with socioeconomic status. Life satisfaction was found to vary significantly with socioeconomic status, depression and self efficacy but not with access to medical care. Self-efficacy was found to vary significantly with socioeconomic status, depression and life satisfaction but not with access to medical care. Gender and ethnicity were not found to be significant precedent variables in depression for HIV infected individuals. Sexual orientation was found to be a significant precedent variable for depression, life satisfaction and self efficacy.

Seawater carbonate chemistry and biological processes during experiments with early life stages of the blue mussel Mytilus edulis, 2010

Several experiments have shown a decrease of growth and calcification of organisms at decreased pH levels. There is a growing interest to focus on early life stages that are believed to be more sensitive to environmental disturbances such as hypercapnia. Here, we present experimental data, acquired in a commercial hatchery, demonstrating that the growth of planktonic mussel (Mytilus edulis) larvae is significantly affected by a decrease of pH to a level expected for the end of the century. Even though there was no significant effect of a 0.25-0.34 pH unit decrease on hatching and mortality rates during the first 2 days of development nor during the following 13-day period prior to settlement, final shells were respectively 4.5±1.3 and 6.0±2.3% smaller at pHNBS~7.8 (pCO2~1100-1200 µatm) than at a control pHNBS of ~8.1 (pCO2~460-640 µatm). Moreover, a decrease of 12.0±5.4% of shell thickness was observed after 15d of development. More severe impacts were found with a decrease of ~0.5 pHNBS unit during the first 2 days of development which could be attributed to a decrease of calcification due to a slight undersaturation of seawater with respect to aragonite. Indeed, important effects on both hatching and D-veliger shell growth were found. Hatching rates were 24±4% lower while D-veliger shells were 12.7±0.9% smaller at pHNBS~7.6 (pCO2~1900 µatm) than at a control pHNBS of ~8.1 (pCO2~540 µatm). Although these results show that blue mussel larvae are still able to develop a shell in seawater undersaturated with respect to aragonite, the observed decreases of hatching rates and shell growth could lead to a significant decrease of the settlement success. As the environmental conditions considered in this study do not necessarily reflect the natural conditions experienced by this species at the time of spawning, future studies will need to consider the whole larval cycle (from fertilization to settlement) under environmentally relevant conditions in order to investigate the potential ecological and economical losses of a decrease of this species fitness in the field.

Exploring the stages of change and perceived barriers to treatment models within the context of parental adherence to an early intervention program

Parent-mediated early intervention programs depend on the willingness and ability of parents to complete prescribed activities with their children. In other contexts, internal factors, such as stages of change, and external factors, such as barriers to treatment, have been shown to correlate with adherence to service. This researcher modified the Stages of Change Questionnaire as well as the Barriers to Treatment Participation Scale (BTPS) to use with this population. Despite initial interest, twenty-three parent participants were referred to the researcher over the course of three years, with only five parents taking part in the study. A population base ten times that of the current sample would be required recruit enough participants (fifty-one) to provide sufficient power. This feasibility study discusses the results of the five parent participants. Findings suggest that the modified Stages of Change Questionnaire may not be sensitive enough for use with the current sample, while the modified BTPS may yield useful information for service providers.