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.

Diverse functional motifs within the three intracellular loops of the CGRP1 receptor

The CGRP1 receptor exists as a heterodimeric complex between a single-pass transmembrane accessory protein (RAMP1) and a family B G-protein-coupled receptor (GPCR) called the calcitonin receptor-like receptor (CLR). This study investigated the structural motifs found in the intracellular loops (ICLs) of this receptor. Molecular modeling was used to predict active and inactive conformations of each ICL. Conserved residues were altered to alanine by site-directed mutagenesis. cAMP accumulation, cell-surface expression, agonist affinity, and CGRP-stimulated receptor internalization were characterized. Within ICL1, L147 and particularly R151 were important for coupling to Gs. R151 may interact directly with the G-protein, accessing it following conformational changes involving ICL2 and ICL3. At the proximal end of ICL3, I290 and L294, probably lying on the same face of an α helix, formed a G-protein coupling motif. The largest effects on coupling were observed with I290A; additionally, it reduced CGRP affinity and impaired internalization. 1290 may interact with TM6 to stabilize the conformation of ICL3, but it could also interact directly with Gs. R314, at the distal end of ICL3, impaired G-protein coupling and to a lesser extent reduced CGRP affinity; it may stabilize the TM6-ICL3 junction by interacting with the polar headgroups of membrane phospholipids. Y215 and L214 in ICL2 are required for cell-surface expression; they form a microdomain with H216 which has the same function. This study reveals similarities between the activation of CLR and other GPCRs in the role of TM6 and ICL3 but shows that other conserved motifs differ in their function. © 2006 American Chemical Society.

Role of plasma in femtosecond laser pulse propagation

This paper describes physics of nonlinear ultra-short laser pulse propagation affected by plasma created by the pulse itself. Major applications are also discussed. Nonlinear propagation of the femtosecond laser pulses in gaseous and solid transparent dielectric media is a fundamental physical phenomenon in a wide range of important applications such as laser lidars, laser micro-machining (ablation) and microfabrication etc. These applications require very high intensity of the laser field, typically 1013–1015 TW/cm2. Such high intensity leads to significant ionisation and creation of electron-ion or electron-hole plasma. The presence of plasma results into significant multiphoton and plasma absorption and plasma defocusing. Consequently, the propagation effects appear extremely complex and result from competitive counteraction of the above listed effects and Kerr effect, diffraction and dispersion. The theoretical models used for consistent description of laser-plasma interaction during femtosecond laser pulse propagation are derived and discussed. It turns out that the strongly nonlinear effects such self-focusing followed by the pulse splitting are essential. These phenomena feature extremely complex dynamics of both the electromagnetic field and plasma density with different spatio-temporal structures evolving at the same time. Some numerical approaches capable to handle all these complications are also discussed. ©2006 American Institute of Physics

Is subclinical thyroid dysfunction in the elderly associated with depression or cognitive dysfunction?

Background: Widespread use of automated sensitive assays for thyroid hormones and thyroid-stimulating hormone (TSH) has increased identification of mild thyroid dysfunction, especially in elderly patients. The clinical significance of this dysfunction, however, remains uncertain, and associations with cognitive impairment, depression, and anxiety are unconfirmed. Objective: To determine the association between mild thyroid dysfunction and cognition, depression, and anxiety in elderly persons. Design: Cross-sectional study. Associations were explored through mixed-model analyses. Setting: Primary care practices in central England. Patients: 5865 patients 65 years of age or older with no known thyroid disease who were recruited from primary care registers. Measurements: Serum TSH and free thyroxine (T4) were measured. Depression and anxiety were assessed by using the Hospital Anxiety and Depression Scale (HADS), and cognitive functioning was established by using the Middlesex Elderly Assessment of Mental State and the Folstein Mini-Mental State Examination. Comorbid conditions, medication use, and sociodemographic profiles were recorded. Results: 295 patients met the criteria for subclinical thyroid dysfunction (127 were hyperthyroid, and 168 were hypothyroid). After confounding variables were controlled for, statistically significant associations were seen between anxiety (HADS score) and TSH level (P = 0.013) and between cognition and both TSH and free T4 levels. The magnitude of these associations lacked clinical relevance: A 50-mIU/L increase in the TSH level was associated with a 1-point reduction in the HADS anxiety score, and a 1-point increase in the Mini-Mental State Examination score was associated with an increase of 50 mIU/L in the TSH level or 25 pmol/L in the free T4 level. Limitations: Because of the low participation rate, low prevalence of subclinical thyroid dysfunction, and other unidentified recruitment biases, participants may not be representative of the elderly population. Conclusions: After the confounding effects of comorbid conditions and use of medication were controlled for, subclinical thyroid dysfunction was not associated with depression, anxiety, or cognition. © 2006 American College of Physicians.

Role of plasma in femtosecond laser pulse propagation

This paper describes physics of nonlinear ultra-short laser pulse propagation affected by plasma created by the pulse itself. Major applications are also discussed. Nonlinear propagation of the femtosecond laser pulses in gaseous and solid transparent dielectric media is a fundamental physical phenomenon in a wide range of important applications such as laser lidars, laser micro-machining (ablation) and microfabrication etc. These applications require very high intensity of the laser field, typically 1013–1015 TW/cm2. Such high intensity leads to significant ionisation and creation of electron-ion or electron-hole plasma. The presence of plasma results into significant multiphoton and plasma absorption and plasma defocusing. Consequently, the propagation effects appear extremely complex and result from competitive counteraction of the above listed effects and Kerr effect, diffraction and dispersion. The theoretical models used for consistent description of laser-plasma interaction during femtosecond laser pulse propagation are derived and discussed. It turns out that the strongly nonlinear effects such self-focusing followed by the pulse splitting are essential. These phenomena feature extremely complex dynamics of both the electromagnetic field and plasma density with different spatio-temporal structures evolving at the same time. Some numerical approaches capable to handle all these complications are also discussed. ©2006 American Institute of Physics

Changes in ocular physiology, tear film characteristics, and symptomatology with 18 months silicone hydrogel contact lens wear

Purpose. The purpose of this study was to evaluate the longitudinal changes in ocular physiology, tear film characteristics, and symptomatology experienced by neophyte silicone hydrogel (SiH) contact lens wearers in a daily-wear compared with a continuous-wear modality and with the different commercially available lenses over an 18-month period. Methods. Forty-five neophyte subjects were enrolled in the study and randomly assigned to wear one of two SiH materials: lotrafilcon A or balafilcon A lenses on either a daily- (LDW; BDW) or continuous-wear (LCW; BCW) basis. Additionally, a group of noncontact lens-wearing subjects (control group) was also recruited and followed over the same study period. Objective and subjective grading of ocular physiology were carried out together with tear meniscus height (TMH) and noninvasive tear breakup time (NITBUT). Subjects also subjectively rated symptoms and judgments with lens wear. After initial screening, subsequent measurements were taken after 1, 3, 6, 12, and 18 months. Results. Subjective and objective grading of ocular physiology revealed a small increase in bulbar, limbal, and palpebral hyperemia as well as corneal staining over time with both lens materials and regimes of wear (p < 0.05). No significant changes in NITBUT or TMH were found (p > 0.05). Subjective symptoms and judgment were not material- or modality-specific. Conclusions. Daily and continuous wear of SiH contact lenses induced small but statistically significant changes in ocular physiology and symptomatology. Clinical measures of tear film characteristics were unaffected by lens wear. Both materials and regimes of wear showed similar clinical performance. Long-term SiH contact lens wear is shown to be a successful option for patients. Copyright © 2006 American Academy of Optometry.

Dynamic measurement of accommodation and pupil size using the portable Grand Seiko FR-5000 autorefractor

PURPOSE. The purpose of this study was to evaluate the potential of the portable Grand Seiko FR-5000 autorefractor to allow objective, continuous, open-field measurement of accommodation and pupil size for the investigation of the visual response to real-world environments and changes in the optical components of the eye. METHODS. The FR-5000 projects a pair of infrared horizontal and vertical lines on either side of fixation, analyzing the separation of the bars in the reflected image. The measurement bars were turned on permanently and the video output of the FR-5000 fed into a PC for real-time analysis. The calibration between infrared bar separation and the refractive error was assessed over a range of 10.0 D with a model eye. Tolerance to longitudinal instrument head shift was investigated over a ±15 mm range and to eye alignment away from the visual axis over eccentricities up to 25.0°. The minimum pupil size for measurement was determined with a model eye. RESULTS. The separation of the measurement bars changed linearly (r = 0.99), allowing continuous online analysis of the refractive state at 60 Hz temporal and approximately 0.01 D system resolution with pupils >2 mm. The pupil edge could be analyzed on the diagonal axes at the same rate with a system resolution of approximately 0.05 mm. The measurement of accommodation and pupil size were affected by eccentricity of viewing and instrument focusing inaccuracies. CONCLUSIONS. The small size of the instrument together with its resolution and temporal properties and ability to measure through a 2 mm pupil make it useful for the measurement of dynamic accommodation and pupil responses in confined environments, although good eye alignment is important. Copyright © 2006 American Academy of Optometry.

Anisotropic surface energetics and wettability of macroscopic form I paracetamol crystals

Advancing (θA) and receding (θR) contact angles were measured with several probe liquids on the external facets (201), (001), (011), and (110) of macroscopic form I paracetamol crystals as well as the cleaved (internal) facet (010). For the external crystal facets, dispersive surface energies γd calculated from the contact angles were found to be similar (34 ± 1 mJ/m2), while the polar components varied significantly. Cleaving the crystals exposed a more apolar (010) surface with very different surface properties, including γd = 45 ± 1 mJ/m2. The relative surface polarity (γp/γ) of the facets in decreasing order was (001) > (011) > (201) > (110) > (010), which agreed with the fraction of exposed polar hydroxyl groups as determined from C and O 1s X-ray photoelectron spectroscopy (XPS) spectra, and could be correlated with the number of non-hydrogen-bonded hydroxyl groups per unit area present for each crystal facet, based on the known crystal structures. In conclusion, all facets of form I paracetamol crystals examined exhibited anisotropic wetting behavior and surface energetics that correlated to the presence of surface hydroxyl groups.  © 2006 American Chemical Society.

Plasma assisted femtosecond laser inscription in dielectrics

Principles of the femtosecond fabrication of the optoelectronic components in glass are explained and illustrated by examples of the in-bulk writing. The results of the experimental investigation of the dependence of the induced index change on the pulse energy and the numerical modelling of the corresponding laser-glass interaction are presented. The distribution of the plasma density is simulated that may bridge the gap between the models of the pulse propagation and the induced permanent refractive index change. © 2006 American Institute of Physics.

GIP(Lys16PAL) and GIP(LyS37PAL):novel long-acting acylated analogues of glucose-dependent insulinotropic polypeptide with improved antidiabetic potentia

Glucose-dependent insulinotropic polypeptide (GIP) is a physiological insulin releasing peptide. We have developed two novel fatty acid derivatized GIP analogues, which bind to serum albumin and demonstrate enhanced duration of action in vivo. GIP(Lys16PAL) and GIP(Lys37PAL) were resistant to dipeptidyl peptidase IV (DPP IV) degradation. In vitro studies demonstrated that GIP analogues retained their ability to activate the GIP receptor through production of cAMP and to stimulate insulin secretion. Intraperitoneal administration of GIP analogues to obese diabetic (ob/ob) mice significantly decreased the glycemic excursion and elicited increased and prolonged insulin responses compared to native GIP. A protracted glucose-lowering effect was observed 24 h following GIP(Lys37PAL) administration. Once a day injection for 14 days decreased nonfasting glucose, improved glucose tolerance, and enhanced the insulin response to glucose. These data demonstrate that fatty acid derivatized GIP peptides represent a novel class of long-acting stable GIP analogues for therapy of type 2 diabetes. © 2006 American Chemical Society.

Online learning in discrete hidden Markov models

We present and analyze three different online algorithms for learning in discrete Hidden Markov Models (HMMs) and compare their performance with the Baldi-Chauvin Algorithm. Using the Kullback-Leibler divergence as a measure of the generalization error we draw learning curves in simplified situations and compare the results. The performance for learning drifting concepts of one of the presented algorithms is analyzed and compared with the Baldi-Chauvin algorithm in the same situations. A brief discussion about learning and symmetry breaking based on our results is also presented. © 2006 American Institute of Physics.

The evolution of learning systems:to Bayes or not to be

Bayesian algorithms pose a limit to the performance learning algorithms can achieve. Natural selection should guide the evolution of information processing systems towards those limits. What can we learn from this evolution and what properties do the intermediate stages have? While this question is too general to permit any answer, progress can be made by restricting the class of information processing systems under study. We present analytical and numerical results for the evolution of on-line algorithms for learning from examples for neural network classifiers, which might include or not a hidden layer. The analytical results are obtained by solving a variational problem to determine the learning algorithm that leads to maximum generalization ability. Simulations using evolutionary programming, for programs that implement learning algorithms, confirm and expand the results. The principal result is not just that the evolution is towards a Bayesian limit. Indeed it is essentially reached. In addition we find that evolution is driven by the discovery of useful structures or combinations of variables and operators. In different runs the temporal order of the discovery of such combinations is unique. The main result is that combinations that signal the surprise brought by an example arise always before combinations that serve to gauge the performance of the learning algorithm. This latter structures can be used to implement annealing schedules. The temporal ordering can be understood analytically as well by doing the functional optimization in restricted functional spaces. We also show that there is data suggesting that the appearance of these traits also follows the same temporal ordering in biological systems. © 2006 American Institute of Physics.

A cross-national comparison of cultural value orientations of Indian, Polish, Russian and American employees

This study examines the cultural value orientations (VOs) of employees (managerial and non-managerial) working in three categories of organizations (professional, technical and local services) in India, Poland, Russia and the USA. The analysis is conducted at both the national and organizational levels. The paper hypothesizes cultural differences at the country level and cultural similarities among employees working for professional and technical oriented organizations and divergence in the VOs of employees working for local services organizations. It also hypothesizes differences in the VOs of managerial and non-managerial employees in the four countries. The investigation has been conducted with the help of a questionnaire survey of 1,852 respondents. The outcomes of the analysis show that there are both cross-country cultural differences and similarities among the VOs of employees of the four nations. Further, significant cultural convergence emerges in the VOs of employees working for both professional and technical organizations, however, no significant cultural similarities or differences are observed for employees of service-based organizations in the four countries. There are some similarities emerging between managerial employees in the research countries. The research contributes to the fields of cross-cultural management, international management and international human resource management.

A multivariate spatial analysis of vowel formants in American English

This paper presents the results of a multivariate spatial analysis of 38 vowel formant variables in the language of 402 informants from 236 cities from across the contiguous United States, based on the acoustic data from the Atlas of North American English (Labov, Ash & Boberg, 2006). The results of the analysis both confirm and challenge the results of the Atlas. Most notably, while the analysis identifies similar patterns as the Atlas in the West and the Southeast, the analysis finds that the Midwest and the Northeast are distinct dialect regions that are considerably stronger than the traditional Midland and Northern dialect region indentified in the Atlas. The analysis also finds evidence that a western vowel shift is actively shaping the language of the Western United States.

The process of coping in King-Kopetzky Syndrome

Our object was to describe the process of coping in King-Kopetzky syndrome and hypothesise how the process is mediated. We used a qualitative study using open-ended interviews. The data were gathered purposefully from 19 cases in the first phase of the study. Accounts were then compared deductively with six accounts from a previous interview-based study. Maximum contrast was sought in cases and in experience of clinical interventions. Participants were recruited from Hearing Therapy services in Bath and North East Somerset Primary Care Trust and The Welsh Hearing Institute. Interviews were conducted in participants’ homes or clinic setting. Coping was determined by the concept that the individual developed about their hearing difficulties. The process of conceptualizing involves reconciling the symptoms experienced with the information obtained from clinicians. The process is mediated by the context in which hearing difficulties occur and the interventions that are received. Forming a coherent concept of hearing difficulties facilitates coping. Clinicians can assist this process by giving patients with King-Kopetzky Syndrome an explanation of the condition.