Innate-like control of human iNKT cell autoreactivity via the hypervariable CDR3beta loop

Invariant Natural Killer T cells (iNKT) are a versatile lymphocyte subset with important roles in both host defense and immunological tolerance. They express a highly conserved TCR which mediates recognition of the non-polymorphic, lipid-binding molecule CD1d. The structure of human iNKT TCRs is unique in that only one of the six complementarity determining region (CDR) loops, CDR3beta, is hypervariable. The role of this loop for iNKT biology has been controversial, and it is unresolved whether it contributes to iNKT TCR:CD1d binding or antigen selectivity. On the one hand, the CDR3beta loop is dispensable for iNKT TCR binding to CD1d molecules presenting the xenobiotic alpha-galactosylceramide ligand KRN7000, which elicits a strong functional response from mouse and human iNKT cells. However, a role for CDR3beta in the recognition of CD1d molecules presenting less potent ligands, such as self-lipids, is suggested by the clonal distribution of iNKT autoreactivity. We demonstrate that the human iNKT repertoire comprises subsets of greatly differing TCR affinity to CD1d, and that these differences relate to their autoreactive functions. These functionally different iNKT subsets segregate in their ability to bind CD1d-tetramers loaded with the partial agonist alpha-linked glycolipid antigen OCH and structurally different endogenous beta-glycosylceramides. Using surface plasmon resonance with recombinant iNKT TCRs and different ligand-CD1d complexes, we demonstrate that the CDR3beta sequence strongly impacts on the iNKT TCR affinity to CD1d, independent of the loaded CD1d ligand. Collectively our data reveal a crucial role for CDR3beta for the function of human iNKT cells by tuning the overall affinity of the iNKT TCR to CD1d. This mechanism is relatively independent of the bound CD1d ligand and thus forms the basis of an inherent, CDR3beta dependent functional hierarchy of human iNKT cells.

Improved effectiveness of partner notification for patients with sexually transmitted infections: systematic review

OBJECTIVE: To examine the effectiveness of methods to improve partner notification by patient referral (index patient has responsibility for informing sex partners of their exposure to a sexually transmitted infection). DESIGN: Systematic review of randomised trials of any intervention to supplement simple patient referral. DATA SOURCES: Seven electronic databases searched (January 1990 to December 2005) without language restriction, and reference lists of retrieved articles. REVIEW METHODS: Selection of trials, data extraction, and quality assessment were done by two independent reviewers. The primary outcome was a reduction of incidence or prevalence of sexually transmitted infections in index patients. If this was not reported data were extracted according to a hierarchy of secondary outcomes: number of partners treated; number of partners tested or testing positive; and number of partners notified, located, or elicited. Random effects meta-analysis was carried out when appropriate. RESULTS: 14 trials were included with 12 389 women and men diagnosed as having gonorrhoea, chlamydia, non-gonococcal urethritis, trichomoniasis, or a sexually transmitted infection syndrome. All studies had methodological weaknesses that could have biased their results. Three strategies were used. Six trials examined patient delivered partner therapy. Meta-analysis of five of these showed a reduced risk of persistent or recurrent infection in patients with chlamydia or gonorrhoea (summary risk ratio 0.73, 95% confidence interval 0.57 to 0.93). Supplementing patient referral with information for partners was as effective as patient delivered partner therapy. Neither strategy was effective in women with trichomoniasis. Two trials found that providing index patients with chlamydia with sampling kits for their partners increased the number of partners who got treated. CONCLUSIONS: Involving index patients in shared responsibility for the management of sexual partners improves outcomes. Health professionals should consider the following strategies for the management of individual patients: patient delivered partner therapy, home sampling for partners, and providing additional information for partners.

Modulating the granularity of category formation by global cortical states

The unsupervised categorization of sensory stimuli is typically attributed to feedforward processing in a hierarchy of cortical areas. This purely sensory-driven view of cortical processing, however, ignores any internal modulation, e.g., by top-down attentional signals or neuromodulator release. To isolate the role of internal signaling on category formation, we consider an unbroken continuum of stimuli without intrinsic category boundaries. We show that a competitive network, shaped by recurrent inhibition and endowed with Hebbian and homeostatic synaptic plasticity, can enforce stimulus categorization. The degree of competition is internally controlled by the neuronal gain and the strength of inhibition. Strong competition leads to the formation of many attracting network states, each being evoked by a distinct subset of stimuli and representing a category. Weak competition allows more neurons to be co-active, resulting in fewer but larger categories. We conclude that the granularity of cortical category formation, i.e., the number and size of emerging categories, is not simply determined by the richness of the stimulus environment, but rather by some global internal signal modulating the network dynamics. The model also explains the salient non-additivity of visual object representation observed in the monkey inferotemporal (IT) cortex. Furthermore, it offers an explanation of a previously observed, demand-dependent modulation of IT activity on a stimulus categorization task and of categorization-related cognitive deficits in schizophrenic patients.

Identification of platelet function defects by multi-parameter assessment of thrombus formation.

Assays measuring platelet aggregation (thrombus formation) at arterial shear rate mostly use collagen as only platelet-adhesive surface. Here we report a multi-surface and multi-parameter flow assay to characterize thrombus formation in whole blood from healthy subjects and patients with platelet function deficiencies. A systematic comparison is made of 52 adhesive surfaces with components activating the main platelet-adhesive receptors, and of eight output parameters reflecting distinct stages of thrombus formation. Three types of thrombus formation can be identified with a predicted hierarchy of the following receptors: glycoprotein (GP)VI, C-type lectin-like receptor-2 (CLEC-2)>GPIb>α6β1, αIIbβ3>α2β1>CD36, α5β1, αvβ3. Application with patient blood reveals distinct abnormalities in thrombus formation in patients with severe combined immune deficiency, Glanzmann's thrombasthenia, Hermansky-Pudlak syndrome, May-Hegglin anomaly or grey platelet syndrome. We suggest this test may be useful for the diagnosis of patients with suspected bleeding disorders or a pro-thrombotic tendency.

Quarks and a Unified Theory of Nature Fundamental Forces

Quarks were introduced 50 years ago opening the road towards our understanding of the elementary constituents of matter and their fundamental interactions. Since then, a spectacular progress has been made with important discoveries that led to the establishment of the Standard Theory that describes accurately the basic constituents of the observable matter, namely quarks and leptons, interacting with the exchange of three fundamental forces, the weak, electromagnetic and strong force. Particle physics is now entering a new era driven by the quest of understanding of the composition of our Universe such as the unobservable (dark) matter, the hierarchy of masses and forces, the unification of all fundamental interactions with gravity in a consistent quantum framework, and several other important questions. A candidate theory providing answers to many of these questions is string theory that replaces the notion of point particles by extended objects, such as closed and open strings. In this short note, I will give a brief overview of string unification, describe in particular how quarks and leptons can emerge and discuss what are possible predictions for particle physics and cosmology that could test these ideas.

Quarks and a unified theory of Nature fundamental forces

Quarks were introduced 50 years ago opening the road towards our understanding of the elementary constituents of matter and their fundamental interactions. Since then, a spectacular progress has been made with important discoveries that led to the establishment of the Standard Theory that describes accurately the basic constituents of the observable matter, namely quarks and leptons, interacting with the exchange of three fundamental forces, the weak, electromagnetic and strong force. Particle physics is now entering a new era driven by the quest of understanding of the composition of our Universe such as the unobservable (dark) matter, the hierarchy of masses and forces, the unification of all fundamental interactions with gravity in a consistent quantum framework, and several other important questions. A candidate theory providing answers to many of these questions is string theory that replaces the notion of point particles by extended objects, such as closed and open strings. In this short note, I will give a brief overview of string unification, describe in particular how quarks and leptons can emerge and discuss what are possible predictions for particle physics and cosmology that could test these ideas.

The effect of male coloration on female mate choice in closely related Lake Victoria cichlids (Haplochromis nyererei complex)

We studied the effect of male coloration on interspeciÆc female mate choice in two closely related species of haplochromine cichlids from Lake Victoria. The species differ primarily in male coloration. Males of one species are red, those of the other are blue. We re- corded the behavioral responses of females to males of both species in paired male trials under white light and under monochromatic light, under which the interspecific differences in coloration were masked. Females of both species exhibited species-assortative mate choice when colour differences were visible, but chose non-assortatively when colour differences were masked by light conditions. Neither male behaviour nor overall female response frequencies differed between light treatments. That female preferences could be altered by manipulating the perceived colour pattern implies that the colour itself is used in interspecific mate choice, rather than other characters. Hence, male coloration in haplochromine cichlids does underlie sexual selection by direct mate choice, involving the capacity for individual assessment of potential mates by the female. Females of both species responded more frequently to blue males under monochromatic light. Blue males were larger and displayed more than red males. This implies a hierarchy of choice criteria. Females may use male display rates, size, or both when colour is unavailable. Where available, colour has gained dominance over other criteria. This may explain rapid speciation by sexual selection on male coloration, as proposed in a recent mathematical model.

Geometry-Aware Multiscale Image Registration via OBBTree-Based Polyaffine Log-Demons

Non-linear image registration is an important tool in many areas of image analysis. For instance, in morphometric studies of a population of brains, free-form deformations between images are analyzed to describe the structural anatomical variability. Such a simple deformation model is justified by the absence of an easy expressible prior about the shape changes. Applying the same algorithms used in brain imaging to orthopedic images might not be optimal due to the difference in the underlying prior on the inter-subject deformations. In particular, using an un-informed deformation prior often leads to local minima far from the expected solution. To improve robustness and promote anatomically meaningful deformations, we propose a locally affine and geometry-aware registration algorithm that automatically adapts to the data. We build upon the log-domain demons algorithm and introduce a new type of OBBTree-based regularization in the registration with a natural multiscale structure. The regularization model is composed of a hierarchy of locally affine transformations via their logarithms. Experiments on mandibles show improved accuracy and robustness when used to initialize the demons, and even similar performance by direct comparison to the demons, with a significantly lower degree of freedom. This closes the gap between polyaffine and non-rigid registration and opens new ways to statistically analyze the registration results.

Imaging emotional brain functions: conceptual and methodological issues

This article reviews the psychophysiological and brain imaging literature on emotional brain function from a methodological point of view. The difficulties in defining, operationalising and measuring emotional activation and, in particular, aversive learning will be considered. Emotion is a response of the organism during an episode of major significance and involves physiological activation, motivational, perceptual, evaluative and learning processes, motor expression, action tendencies and monitoring/subjective feelings. Despite the advances in assessing the physiological correlates of emotional perception and learning processes, a critical appraisal shows that functional neuroimaging approaches encounter methodological difficulties regarding measurement precision (e.g., response scaling and reproducibility) and validity (e.g., response specificity, generalisation to other paradigms, subjects or settings). Since emotional processes are not only the result of localised but also of widely distributed activation, a more representative model of assessment is needed that systematically relates the hierarchy of high- and low-level emotion constructs with the corresponding patterns of activity and functional connectivity of the brain.

Angiopoietin-1 induces sprouting angiogenesis in vitro

Sprouting of new capillaries from pre-existing blood vessels is a hallmark of angiogenesis during embryonic development and solid tumor growth [1]. In addition to the vascular endothelial growth factor (VEGF) and its receptors, the Tie receptors and their newly identified ligands, the angiopoietins, have been implicated in the control of blood vessel formation [2,3]. Although 'knockouts' of the gene encoding the Tie2 receptor, or its activating ligand angiopoietin-1 (Ang1), result in embryonic lethality in mice due to an absence of remodeling and sprouting of blood vessels [4,5], biological activity in vitro has not yet been described for this receptor-ligand system. In an assay in which a monolayer of endothelial cells were cultured on microcarrier beads and embedded in three-dimensional fibrin gels, recombinant Ang1 (0.5-10 nM) induced the formation of capillary sprouts in a dose-dependent manner that was completely inhibited by soluble Tie2 receptor extracellular domains. In contrast with VEGF, which also induced sprouting of capillaries, Ang1 was only very weakly mitogenic for endothelial cells. Suboptimal concentrations of VEGF and Ang1 acted synergistically to induce sprout formation. Thus, the biological activity of Ang1 in vitro is consistent with the specific phenotype of mice deficient in Tie2 or Ang1. The data suggest that, like in other developmental systems, blood vessel formation requires a hierarchy of master-control genes in which VEGF and angiopoietins, along with their receptors, are amongst the most important regulators.

Applied Graph Theory in Computer Vision and Pattern Recognition

This book will serve as a foundation for a variety of useful applications of graph theory to computer vision, pattern recognition, and related areas. It covers a representative set of novel graph-theoretic methods for complex computer vision and pattern recognition tasks. The first part of the book presents the application of graph theory to low-level processing of digital images such as a new method for partitioning a given image into a hierarchy of homogeneous areas using graph pyramids, or a study of the relationship between graph theory and digital topology. Part II presents graph-theoretic learning algorithms for high-level computer vision and pattern recognition applications, including a survey of graph based methodologies for pattern recognition and computer vision, a presentation of a series of computationally efficient algorithms for testing graph isomorphism and related graph matching tasks in pattern recognition and a new graph distance measure to be used for solving graph matching problems. Finally, Part III provides detailed descriptions of several applications of graph-based methods to real-world pattern recognition tasks. It includes a critical review of the main graph-based and structural methods for fingerprint classification, a new method to visualize time series of graphs, and potential applications in computer network monitoring and abnormal event detection.

Intraspecific Aggregation Alters Competitive Interactions in Experimental Plant Communities

We tested the prediction from spatial competition models that intraspecific aggregation may promote coexistence and thus maintain biodiversity with experimental communities of four annual species. Monocultures, three-species mixtures, and the four-species mixture were sown at two densities and with either random or intraspecifically aggregated distributions. There was a hierarchy of competitive abilities among the four species. The weaker competitors showed higher aboveground biomass in the aggregated distribution compared to the random distribution, especially at high density. In one species, intraspecific aggregation resulted in an 86% increase in the number of flowering individuals and a 171% increase in the reproductive biomass at high density. The competitively superior species had a lower biomass in the aggregated distribution than in the random distribution at high density. The data support the hypothesis that the spatial distribution of plants profoundly affects competition in such a way that weaker competitors increase their fitness while stronger competitors are suppressed when grown in the neighborhood of conspecifics. This implies that the spatial arrangement of plants in a community can be an important determinant of species coexistence and biodiversity.

Exact Unification and Admissibility

A new hierarchy of "exact" unification types is introduced, motivated by the study of admissible rules for equational classes and non-classical logics. In this setting, unifiers of identities in an equational class are preordered, not by instantiation, but rather by inclusion over the corresponding sets of unified identities. Minimal complete sets of unifiers under this new preordering always have a smaller or equal cardinality than those provided by the standard instantiation preordering, and in significant cases a dramatic reduction may be observed. In particular, the classes of distributive lattices, idempotent semigroups, and MV-algebras, which all have nullary unification type, have unitary or finitary exact type. These results are obtained via an algebraic interpretation of exact unification, inspired by Ghilardi's algebraic approach to equational unification.