Area summation in human vision at and above detection threshold

The initial image-processing stages of visual cortex are well suited to a local (patchwise) analysis of the viewed scene. But the world's structures extend over space as textures and surfaces, suggesting the need for spatial integration. Most models of contrast vision fall shy of this process because (i) the weak area summation at detection threshold is attributed to probability summation (PS) and (ii) there is little or no advantage of area well above threshold. Both of these views are challenged here. First, it is shown that results at threshold are consistent with linear summation of contrast following retinal inhomogeneity, spatial filtering, nonlinear contrast transduction and multiple sources of additive Gaussian noise. We suggest that the suprathreshold loss of the area advantage in previous studies is due to a concomitant increase in suppression from the pedestal. To overcome this confound, a novel stimulus class is designed where: (i) the observer operates on a constant retinal area, (ii) the target area is controlled within this summation field, and (iii) the pedestal is fixed in size. Using this arrangement, substantial summation is found along the entire masking function, including the region of facilitation. Our analysis shows that PS and uncertainty cannot account for the results, and that suprathreshold summation of contrast extends over at least seven target cycles of grating. © 2007 The Royal Society.

MHC class II binding prediction:a little help from a friend

Vaccines are the greatest single instrument of prophylaxis against infectious diseases, with immeasurable benefits to human wellbeing. The accurate and reliable prediction of peptide-MHC binding is fundamental to the robust identification of T-cell epitopes and thus the successful design of peptide- and protein-based vaccines. The prediction of MHC class II peptide binding has hitherto proved recalcitrant and refractory. Here we illustrate the utility of existing computational tools for in silico prediction of peptides binding to class II MHCs. Most of the methods, tested in the present study, detect more than the half of the true binders in the top 5% of all possible nonamers generated from one protein. This number increases in the top 10% and 15% and then does not change significantly. For the top 15% the identified binders approach 86%. In terms of lab work this means 85% less expenditure on materials, labour and time. We show that while existing caveats are well founded, nonetheless use of computational models of class II binding can still offer viable help to the work of the immunologist and vaccinologist.

Source of legitimacy in M-government initiatives in Turkey:concerns human vs. technical resource management

Emerging markets have recently been experiencing a dramatic increased in the number of mobile phone per capita. M-government has, hence, been heralded as an opportunity to leap-frog the technology cycle and provide cheaper and more inclusive and services to all. This chapter explores, within an emerging market context, the legitimacy and resistance facing civil servants’ at the engagement stage with m-government activities and the direct implication for resource management. Thirty in depth interview, in Turkey, are drawn-upon with key ICT civil servant in local organizations. The findings show that three types of resources are perceived as central namely: (i) diffusion of information management, (ii) operating system resource management and (iii) human resource management. The main evidence suggests that legitimacy for each resource management, at local level, is an ongoing struggle where all groups deploy multiples forms of resistance. Overall, greater attention in the resource management strategy for m-government application needs to be devoted to enablers such as civil servants rather than the final consumers or citizens.

Spatial and temporal dependencies of cross-orientation suppression in human vision.

A well-known property of orientation-tuned neurons in the visual cortex is that they are suppressed by the superposition of an orthogonal mask. This phenomenon has been explained in terms of physiological constraints (synaptic depression), engineering solutions for components with poor dynamic range (contrast normalization) and fundamental coding strategies for natural images (redundancy reduction). A common but often tacit assumption is that the suppressive process is equally potent at different spatial and temporal scales of analysis. To determine whether it is so, we measured psychophysical cross-orientation masking (XOM) functions for flickering horizontal Gabor stimuli over wide ranges of spatio-temporal frequency and contrast. We found that orthogonal masks raised contrast detection thresholds substantially at low spatial frequencies and high temporal frequencies (high speeds), and that small and unexpected levels of facilitation were evident elsewhere. The data were well fit by a functional model of contrast gain control, where (i) the weight of suppression increased with the ratio of temporal to spatial frequency and (ii) the weight of facilitatory modulation was the same for all conditions, but outcompeted by suppression at higher contrasts. These results (i) provide new constraints for models of primary visual cortex, (ii) associate XOM and facilitation with the transient magno- and sustained parvostreams, respectively, and (iii) reconcile earlier conflicting psychophysical reports on XOM.

Perception of concurrent sentences with harmonic or frequency-shifted voiced excitation:performance of human listeners and of computational models based on autocorrelation

Keyword identification in one of two simultaneous sentences is improved when the sentences differ in F0, particularly when they are almost continuously voiced. Sentences of this kind were recorded, monotonised using PSOLA, and re-synthesised to give a range of harmonic ?F0s (0, 1, 3, and 10 semitones). They were additionally re-synthesised by LPC with the LPC residual frequency shifted by 25% of F0, to give excitation with inharmonic but regularly spaced components. Perceptual identification of frequency-shifted sentences showed a similar large improvement with nominal ?F0 as seen for harmonic sentences, although overall performance was about 10% poorer. We compared performance with that of two autocorrelation-based computational models comprising four stages: (i) peripheral frequency selectivity and half-wave rectification; (ii) within-channel periodicity extraction; (iii) identification of the two major peaks in the summary autocorrelation function (SACF); (iv) a template-based approach to speech recognition using dynamic time warping. One model sampled the correlogram at the target-F0 period and performed spectral matching; the other deselected channels dominated by the interferer and performed matching on the short-lag portion of the residual SACF. Both models reproduced the monotonic increase observed in human performance with increasing ?F0 for the harmonic stimuli, but not for the frequency-shifted stimuli. A revised version of the spectral-matching model, which groups patterns of periodicity that lie on a curve in the frequency-delay plane, showed a closer match to the perceptual data for frequency-shifted sentences. The results extend the range of phenomena originally attributed to harmonic processing to grouping by common spectral pattern.

Individual differences in human-computer interaction

This thesis initially presents an 'assay' of the literature pertaining to individual differences in human-computer interaction. A series of experiments is then reported, designed to investigate the association between a variety of individual characteristics and various computer task and interface factors. Predictor variables included age, computer expertise, and psychometric tests of spatial visualisation, spatial memory, logical reasoning, associative memory, and verbal ability. These were studied in relation to a variety of computer-based tacks, including: (1) word processing and its component elements; (ii) the location of target words within passages of text; (iii) the navigation of networks and menus; (iv) command generation using menus and command line interfaces; (v) the search and selection of icons and text labels; (vi) information retrieval. A measure of self-report workload was also included in several of these experiments. The main experimental findings included: (i) an interaction between spatial ability and the manipulation of semantic but not spatial interface content; (ii) verbal ability being only predictive of certain task components of word processing; (iii) age differences in word processing and information retrieval speed but not accuracy; (iv) evidence of compensatory strategies being employed by older subjects; (v) evidence of performance strategy differences which disadvantaged high spatial subjects in conditions of low spatial information content; (vi) interactive effects of associative memory, expertise and command strategy; (vii) an association between logical reasoning and word processing but not information retrieval; (viii) an interaction between expertise and cognitive demand; and (ix) a stronger association between cognitive ability and novice performance than expert performance.

Tear analysis and lens-tear interactions:part II. Ocular lipids-nature and fate of meibomian gland phospholipids

Purpose: Published data indicate that the polar lipid content of human meibomian gland secretions (MGS) could be anything between 0.5% and 13% of the total lipid. The tear film phospholipid composition has not been studied in great detail and it has been understood that the relative proportions of lipids in MGS would be maintained in the tear film. The purpose of this work was to determine the concentration of phospholipids in the human tear film. Methods: Liquid chromatography mass spectrometry (LCMS) and thin layer chromatography (TLC) were used to determine the concentration of phospholipid in the tear film. Additionally, an Amplex Red phosphatidylcholine-specific phospholipase C (PLC) assay kit was used for determination of the activity of PLC in the tear film. Results: Phospholipids were not detected in any of the tested human tear samples with the low limit of detection being 1.3 µg/mL for TLC and 4 µg/mL for liquid chromatography mass spectrometry. TLC indicated that diacylglycerol (DAG) may be present in the tear film. PLC was in the tear film with an activity determined at approximately 15 mU/mL, equivalent to the removal of head groups from phosphatidylcholine at a rate of approximately 15 µM/min. Conclusions: This work shows that phospholipid was not detected in any of the tested human tear samples (above the lower limits of detection as described) and suggests the presence of DAG in the tear film. DAG is known to be at low concentrations in MGS. These observations indicate that PLC may play a role in modulating the tear film phospholipid concentration.

Discriminating antigen and non-antigen using proteome dissimilarity II:viral and fungal antigens

Immunogenicity arises via many synergistic mechanisms, yet the overall dissimilarity of pathogenic proteins versus the host proteome has been proposed as a key arbiter. We have previously explored this concept in relation to Bacterial antigens; here we extend our analysis to antigens of viral and fungal origin. Sets of known viral and fungal antigenic and non-antigenic protein sequences were compared to human and mouse proteomes. Both antigenic and non-antigenic sequences lacked human or mouse homologues. Observed distributions were compared using the non-parametric Mann-Whitney test. The statistical null hypothesis was accepted, indicating that antigen and non-antigens did not differ significantly. Likewise, we could not determine a threshold able meaningfully to separate non-antigen from antigen. We conclude that viral and fungal antigens cannot be predicted from pathogen genomes based solely on their dissimilarity to mammalian genomes.

Role of the transgenic human thyrotropin receptor A-subunit in thyroiditis induced by A-subunit immunization and regulatory T cell depletion

Transgenic BALB/c mice that express intrathyroidal human thyroid stimulating hormone receptor (TSHR) A-subunit, unlike wild-type (WT) littermates, develop thyroid lymphocytic infiltration and spreading to other thyroid autoantigens after T regulatory cell (Treg) depletion and immunization with human thyrotropin receptor (hTSHR) adenovirus. To determine if this process involves intramolecular epitope spreading, we studied antibody and T cell recognition of TSHR ectodomain peptides (A–Z). In transgenic and WT mice, regardless of Treg depletion, TSHR antibodies bound predominantly to N-terminal peptide A and much less to a few downstream peptides. After Treg depletion, splenocytes from WT mice responded to peptides C, D and J (all in the A-subunit), but transgenic splenocytes recognized only peptide D. Because CD4+ T cells are critical for thyroid lymphocytic infiltration, amino acid sequences of these peptides were examined for in silico binding to BALB/c major histocompatibility complex class II (IA–d). High affinity subsequences (inhibitory concentration of 50% < 50 nm) are present in peptides C and D (not J) of the hTSHR and mouse TSHR equivalents. These data probably explain why transgenic splenocytes do not recognize peptide J. Mouse TSHR mRNA levels are comparable in transgenic and WT thyroids, but only transgenics have human A-subunit mRNA. Transgenic mice can present mouse TSHR and human A-subunit-derived peptides. However, WT mice can present only mouse TSHR, and two to four amino acid species differences may preclude recognition by CD4+ T cells activated by hTSHR-adenovirus. Overall, thyroid lymphocytic infiltration in the transgenic mice is unrelated to epitopic spreading but involves human A-subunit peptides for recognition by T cells activated using the hTSHR.

Toward the prediction of class I and II mouse major histocompatibility complex-peptide-binding affinity:in silico bioinformatic step-by-step guide using quantitative structure-activity relationships

Quantitative structure-activity relationship (QSAR) analysis is a cornerstone of modern informatics. Predictive computational models of peptide-major histocompatibility complex (MHC)-binding affinity based on QSAR technology have now become important components of modern computational immunovaccinology. Historically, such approaches have been built around semiqualitative, classification methods, but these are now giving way to quantitative regression methods. We review three methods--a 2D-QSAR additive-partial least squares (PLS) and a 3D-QSAR comparative molecular similarity index analysis (CoMSIA) method--which can identify the sequence dependence of peptide-binding specificity for various class I MHC alleles from the reported binding affinities (IC50) of peptide sets. The third method is an iterative self-consistent (ISC) PLS-based additive method, which is a recently developed extension to the additive method for the affinity prediction of class II peptides. The QSAR methods presented here have established themselves as immunoinformatic techniques complementary to existing methodology, useful in the quantitative prediction of binding affinity: current methods for the in silico identification of T-cell epitopes (which form the basis of many vaccines, diagnostics, and reagents) rely on the accurate computational prediction of peptide-MHC affinity. We have reviewed various human and mouse class I and class II allele models. Studied alleles comprise HLA-A*0101, HLA-A*0201, HLA-A*0202, HLA-A*0203, HLA-A*0206, HLA-A*0301, HLA-A*1101, HLA-A*3101, HLA-A*6801, HLA-A*6802, HLA-B*3501, H2-K(k), H2-K(b), H2-D(b) HLA-DRB1*0101, HLA-DRB1*0401, HLA-DRB1*0701, I-A(b), I-A(d), I-A(k), I-A(S), I-E(d), and I-E(k). In this chapter we show a step-by-step guide into predicting the reliability and the resulting models to represent an advance on existing methods. The peptides used in this study are available from the AntiJen database (http://www.jenner.ac.uk/AntiJen). The PLS method is available commercially in the SYBYL molecular modeling software package. The resulting models, which can be used for accurate T-cell epitope prediction, will be made are freely available online at the URL http://www.jenner.ac.uk/MHCPred.

Human intervertebral disc aggrecan inhibits endothelial cell adhesion and cell migration in vitro

STUDY DESIGN: The effect of human intervertebral disc aggrecan on endothelial cell growth was examined using cell culture assays. OBJECTIVE: To determine the response of endothelial cells to human intervertebral disc aggrecan, and whether the amount and type of aggrecan present in the intervertebral disc may be implicated in disc vascularization. SUMMARY OF BACKGROUND DATA: Intervertebral disc degeneration has been associated with a loss of proteoglycan, and the ingrowth of blood vessels and nerves. Neovascularization is a common feature also of disc herniation. Intervertebral disc aggrecan is inhibitory to sensory nerve growth, but the effects of disc aggrecan on endothelial cell growth are not known. METHODS: Aggrecan monomers were isolated separately from the anulus fibrosus and nucleus pulposus of human lumbar intervertebral discs, and characterized to determine the amount and type of sulfated glycosaminoglycan side chains present. The effects of these aggrecan isolates on the cellular adhesion and migration of the human endothelial cell lines, HMEC-1 and EAhy-926, were examined in vitro. RESULTS: Homogenous substrata of disc aggrecan inhibited endothelial cell adhesion and cell spreading in a concentration dependent manner. In substrata choice assays, endothelial cells seeded onto collagen type I migrated over the collagen until they encountered substrata of disc aggrecan, where they either stopped migrating, retreated onto the collagen, or, more commonly, changed direction to align along the collagen-aggrecan border. The inhibitory effect of aggrecan on endothelial cell migration was concentration dependent, and reduced by enzymatic treatment of the aggrecan monomers with a combination of chondroitinase ABC and keratinase/keratinase II. Anulus fibrosus aggrecan was more inhibitory to endothelial cell adhesion than nucleus pulposus aggrecan. However, this difference did not relate to the extent to which the different aggrecan isolates were charged, as determined by colorimetric assay with 1,9-dimethylmethylene blue, or to marked differences in the distribution of chondroitin sulfated and keratan sulfated side chains. CONCLUSIONS: Human intervertebral disc aggrecan is inhibitory to endothelial cell migration, and this inhibitory effect appears to depend, in part, on the presence of glycosaminoglycan side chains on the aggrecan monomer.

Angiotensin II induces soluble fms-Like tyrosine kinase-1 release via calcineurin signaling pathway in pregnancy

Maternal endothelial dysfunction in preeclampsia is associated with increased soluble fms-like tyrosine kinase-1 (sFlt-1), a circulating antagonist of vascular endothelial growth factor and placental growth factor. Angiotensin II (Ang II) is a potent vasoconstrictor that increases concomitant with sFlt-1 during pregnancy. Therefore, we speculated that Ang II may promote the expression of sFlt-1 in pregnancy. Here we report that infusion of Ang II significantly increases circulating levels of sFlt-1 in pregnant mice, thereby demonstrating that Ang II is a regulator of sFlt-1 secretion in vivo. Furthermore, Ang II stimulated sFlt-1 production in a dose- and time-dependent manner from human villous explants and cultured trophoblasts but not from endothelial cells, suggesting that trophoblasts are the primary source of sFlt-1 during pregnancy. As expected, Ang II-induced sFlt-1 secretion resulted in the inhibition of endothelial cell migration and in vitro tube formation. In vitro and in vivo studies with losartan, small interfering RNA specific for calcineurin and FK506 demonstrated that Ang II-mediated sFlt-1 release was via Ang II type 1 receptor activation and calcineurin signaling, respectively. These findings reveal a previously unrecognized regulatory role for Ang II on sFlt-1 expression in murine and human pregnancy and suggest that elevated sFlt-1 levels in preeclampsia may be caused by a dysregulation of the local renin/angiotensin system.

Identifiying human MHC supertypes using bioinformatic methods

Classification of MHC molecules into supertypes in terms of peptide-binding specificities is an important issue, with direct implications for the development of epitope-based vaccines with wide population coverage. In view of extremely high MHC polymorphism (948 class I and 633 class II HLA alleles) the experimental solution of this task is presently impossible. In this study, we describe a bioinformatics strategy for classifying MHC molecules into supertypes using information drawn solely from three-dimensional protein structure. Two chemometric techniques–hierarchical clustering and principal component analysis–were used independently on a set of 783 HLA class I molecules to identify supertypes based on structural similarities and molecular interaction fields calculated for the peptide binding site. Eight supertypes were defined: A2, A3, A24, B7, B27, B44, C1, and C4. The two techniques gave 77% consensus, i.e., 605 HLA class I alleles were classified in the same supertype by both methods. The proposed strategy allowed “supertype fingerprints” to be identified. Thus, the A2 supertype fingerprint is Tyr9/Phe9, Arg97, and His114 or Tyr116; the A3-Tyr9/Phe9/Ser9, Ile97/Met97 and Glu114 or Asp116; the A24-Ser9 and Met97; the B7-Asn63 and Leu81; the B27-Glu63 and Leu81; for B44-Ala81; the C1-Ser77; and the C4-Asn77. action fields calculated for the peptide binding site. Eight supertypes were defined: A2, A3, A24, B7, B27, B44, C1, and C4. The two techniques gave 77% consensus, i.e., 605 HLA class I alleles were classified in the same supertype by both methods. The proposed strategy allowed “supertype fingerprints” to be identified. Thus, the A2 supertype fingerprint is Tyr9/Phe9, Arg97, and His114 or Tyr116; the A3-Tyr9/Phe9/Ser9, Ile97/Met97 and Glu114 or Asp116; the A24-Ser9 and Met97; the B7-Asn63 and Leu81; the B27-Glu63 and Leu81; for B44-Ala81; the C1-Ser77; and the C4-Asn77.

EpiDOCK:a molecular docking-based tool for MHC class II binding prediction

Cellular peptide vaccines contain T-cell epitopes. The main prerequisite for a peptide to act as a T-cell epitope is that it binds to a major histocompatibility complex (MHC) protein. Peptide MHC binder identification is an extremely costly experimental challenge since human MHCs, named human leukocyte antigen, are highly polymorphic and polygenic. Here we present EpiDOCK, the first structure-based server for MHC class II binding prediction. EpiDOCK predicts binding to the 23 most frequent human, MHC class II proteins. It identifies 90% of true binders and 76% of true non-binders, with an overall accuracy of 83%. EpiDOCK is freely accessible at http://epidock.ddg-pharmfac. net. © The Author 2013. Published by Oxford University Press. All rights reserved.

Mitochondrial DNA, segments I and II, its applications in population genetics and forensic sciences

The investigations of human mitochondrial DNA (mtDNA) have considerably contributed to human evolution and migration. The Middle East is considered to be an essential geographic area for human migrations out of Africa since it is located at the crossroads of Africa, and the rest of the world. United Arab Emirates (UAE) population inhabits the eastern part of Arabian Peninsula and was investigated in this study. Published data of 18 populations were included in the statistical analysis. The diversity indices showed (1) high genetic distance among African populations and (2) high genetic distance between African populations and non-African populations. Asian populations clustered together in the NJ tree between the African and European populations. MtDNA haplotypes database of the UAE population was generated. By incorporating UAE mtDNA dataset into the existing worldwide mtDNA database, UAE Forensic Laboratories will be able to analyze future mtDNA evidence in a more significant and consistent manner. ^