Syk-dependent Phosphorylation of CLEC-2: A Novel Mechanism of Hem-Immunoreceptor Tyrosine-Based Activation Motif Signaling

The C-type lectin-like receptor CLEC-2 signals via phosphorylation of a single cytoplasmic YXXL sequence known as a hem-immunoreceptor tyrosine-based activation motif (hemITAM). In this study, we show that phosphorylation of CLEC-2 by the snake toxin rhodocytin is abolished in the absence of the tyrosine kinase Syk but is not altered in the absence of the major platelet Src family kinases, Fyn, Lyn, and Src, or the tyrosine phosphatase CD148, which regulates the basal activity of Src family kinases. Further, phosphorylation of CLEC-2 by rhodocytin is not altered in the presence of the Src family kinase inhibitor PP2, even though PLCγ2 phosphorylation and platelet activation are abolished. A similar dependence of phosphorylation of CLEC-2 on Syk is also seen in response to stimulation by an IgG mAb to CLEC-2, although interestingly CLEC-2 phosphorylation is also reduced in the absence of Lyn. These results provide the first definitive evidence that Syk mediates phosphorylation of the CLEC-2 hemITAM receptor with Src family kinases playing a critical role further downstream through the regulation of Syk and other effector proteins, providing a new paradigm in signaling by YXXL-containing receptors

On the Cosmology of Massive Vector Fields with SO(3) Global Symmetry

A relevant reference ([14]) has been added.Comment: 19 pages, plain tex, DF/IST-3/92 and DFFCUL 03-5/199

Parasite fate and involvement of infected cells in the induction of CD4+ and CD8+ T cell responses to Toxoplasma gondii

During infection with the intracellular parasite Toxoplasma gondii, the presentation of parasite-derived antigens to CD4+ and CD8+ T cells is essential for long-term resistance to this pathogen. Fundamental questions remain regarding the roles of phagocytosis and active invasion in the events that lead to the processing and presentation of parasite antigens. To understand the most proximal events in this process, an attenuated non-replicating strain of T. gondii (the cpsII strain) was combined with a cytometry-based approach to distinguish active invasion from phagocytic uptake. In vivo studies revealed that T. gondii disproportionately infected dendritic cells and macrophages, and that infected dendritic cells and macrophages displayed an activated phenotype characterized by enhanced levels of CD86 compared to cells that had phagocytosed the parasite, thus suggesting a role for these cells in priming naïve T cells. Indeed, dendritic cells were required for optimal CD4+ and CD8+ T cell responses, and the phagocytosis of heat-killed or invasion-blocked parasites was not sufficient to induce T cell responses. Rather, the selective transfer of cpsII-infected dendritic cells or macrophages (but not those that had phagocytosed the parasite) to naïve mice potently induced CD4+ and CD8+ T cell responses, and conferred protection against challenge with virulent T. gondii. Collectively, these results point toward a critical role for actively infected host cells in initiating T. gondii-specific CD4+ and CD8+ T cell responses

Exploring molecular variation in Schistosoma japonicum in China

This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. The attached file is the published version of the article

Generative Embedding for Model-Based Classification of fMRI Data

Decoding models, such as those underlying multivariate classification algorithms, have been increasingly used to infer cognitive or clinical brain states from measures of brain activity obtained by functional magnetic resonance imaging (fMRI). The practicality of current classifiers, however, is restricted by two major challenges. First, due to the high data dimensionality and low sample size, algorithms struggle to separate informative from uninformative features, resulting in poor generalization performance. Second, popular discriminative methods such as support vector machines (SVMs) rarely afford mechanistic interpretability. In this paper, we address these issues by proposing a novel generative-embedding approach that incorporates neurobiologically interpretable generative models into discriminative classifiers. Our approach extends previous work on trial-by-trial classification for electrophysiological recordings to subject-by-subject classification for fMRI and offers two key advantages over conventional methods: it may provide more accurate predictions by exploiting discriminative information encoded in ‘hidden’ physiological quantities such as synaptic connection strengths; and it affords mechanistic interpretability of clinical classifications. Here, we introduce generative embedding for fMRI using a combination of dynamic causal models (DCMs) and SVMs. We propose a general procedure of DCM-based generative embedding for subject-wise classification, provide a concrete implementation, and suggest good-practice guidelines for unbiased application of generative embedding in the context of fMRI. We illustrate the utility of our approach by a clinical example in which we classify moderately aphasic patients and healthy controls using a DCM of thalamo-temporal regions during speech processing. Generative embedding achieves a near-perfect balanced classification accuracy of 98% and significantly outperforms conventional activation-based and correlation-based methods. This example demonstrates how disease states can be detected with very high accuracy and, at the same time, be interpreted mechanistically in terms of abnormalities in connectivity. We envisage that future applications of generative embedding may provide crucial advances in dissecting spectrum disorders into physiologically more well-defined subgroups

CLEC-2 signaling via Syk in myeloid cells can regulate inflammatory responses

Myeloid cells express a plethora of C-type lectin receptors (CLRs) that can regulate immune responses. CLEC-2 belongs to the Dectin-1 sub-family of CLRs that possess an extracellular C-type lectin-like domain and a single intracellular hemITAM motif. CLEC-2 is highly expressed on mouse and human platelets where it signals via Syk to promote aggregation. We generated a monoclonal antibody (mAb) against mouse CLEC-2 and found that CLEC-2 is additionally widely expressed on leukocytes and that its expression is upregulated during inflammation. MAb-mediated crosslinking of CLEC-2 leads to hemITAM- dependent signaling via Syk, Ca(2+) and NFAT and, in myeloid cells, modulates the effect of toll-like receptor (TLR) agonists to selectively potentiate production of IL-10. A macrophage/dendritic cell-dependent increase in IL-10 is also observed in mice given anti-CLEC-2 mAb together with LPS. Collectively, these data indicate that CLEC-2 is expressed in myeloid cells and acts as a Syk-coupled CLR able to modulate TLR signaling and inflammatory responses

CLEC-2 is a phagocytic activation receptor expressed on murine peripheral blood neutrophils

CLEC-2 is a member of the “dectin-1 cluster” of C-type lectin-like receptors and was originally thought to be restricted to platelets. In this study, we demonstrate that murine CLEC-2 is also expressed by peripheral blood neutrophils, but only weakly by bone marrow or elicited inflammatory neutrophils. On circulating neutrophils, CLEC-2 can mediate phagocytosis of Ab-coated beads and the production of proinflammatory cytokines, including TNF-α, in response to the CLEC-2 ligand, rhodocytin. CLEC-2 possesses a tyrosine-based cytoplasmic motif similar to that of dectin-1, and we show using chimeric analyses that the activities of this receptor are dependent on this tyrosine. Like dectin-1, CLEC-2 can recruit the signaling kinase Syk in myeloid cells, however, stimulation of this pathway does not induce the respiratory burst. These data therefore demonstrate that CLEC-2 expression is not restricted to platelets and that it functions as an activation receptor on neutrophils

Television and food in the lives of young children

Several mechanisms have been proposed behind the associations between screens and overweight including sedentary behaviour, eating while viewing, and exposure to commercials. Aspects of this association as underlying social factors and the possible confounding factors of social norms in the family that can affect children’s lifestyle have received less attention. TV commercials for food and beverages have been extensively studied and it is important to study the appearance of food in children’s TV programmes in a similar way. The general aim of this thesis is to examine the associations between young children’s screen habits, food habits and anthropometry as well as to analyse food and beverages in children’s television programmes in public service television in Sweden. Data from the European research project Identification and prevention of dietary and lifestyle-induced health effects in children and infants (IDEFICS) has been used in Papers I-III and 25 hours of children’s TV programmes have been analysed for Paper IV. The main findings indicate that children’s TV viewing and total screen time was found to be associated with their increased sweet drink consumption, BMI and waist to height ratio, according to cross-sectional and longitudinal analyses. The association between TV viewing and sweetened beverage consumption was found to be independent of parental norms regarding sweetened beverages. Exposure to commercial TV was associated with consuming sweetened beverages more frequently independently of TV viewing time. One in five foods appearing in the sample of children’s TV programmes was for high-calorie and low-nutrient foods, often appearing with children. The results indicate that it is possible to affect children’s food habits by influencing their TV habits, and that public service television has the potential to improve the way food and eating are depicted in children’s TV programmes

Tratamento endovascular de aneurismas cirsoideos do couro cabeludo Endovascular treatment of scalp cirsoid aneurysms

OBJETIVO: Relatar os resultados da aplicação de técnicas endovasculares no tratamento de aneurismas cirsoideos do couro cabeludo. MATERIAIS E MÉTODOS: Quatro pacientes com diagnóstico de aneurismas cirsoideos foram submetidos ao tratamento por via endovascular. Todos os quatro pacientes incluídos nesta série tinham malformações arteriovenosas e foram tratados apenas com embolização. RESULTADOS: Três pacientes foram submetidos a tratamento endovascular mediante embolização transarterial e um foi tratado por punção direta da porção venosa. Os resultados clínicos e cosméticos foram satisfatórios em todos os pacientes. Não houve recidiva clínica durante o período de acompanhamento. CONCLUSÃO: A via endovascular é uma alternativa segura e eficaz no tratamento dos aneurismas cirsoideos. Embora possa ser efetivamente utilizado como uma alternativa adjuvante ou complementar à cirurgia, especialmente quando é necessário lidar com aferências profundas, a maioria dos casos pode ser totalmente curada apenas com a terapêutica endovascular. A escolha do método de tratamento deve ser baseada em uma variedade de características próprias da lesão, incluindo sua angioarquitetura, tamanho e apresentação clínica.<br>OBJECTIVE: To report results of the application of endovascular techniques in the management of scalp cirsoid aneurysms. MATERIALS AND METHODS: Four patients diagnosed with cirsoid aneurysms were submitted to treatment by endovascular approach. All the four patients included in the present series had arteriovenous malformations and were treated solely by embolization. RESULTS: Three of the patients underwent endovascular treatment by transarterial embolization and one was treated by direct puncture of the venous segment. Both clinical and cosmetic outcomes were satisfactory in all of the patients. Clinical relapse was not observed along the follow-up period. CONCLUSION: The endovascular approach is safe and effective in the management of crisoid aneurysms. Although this technique can be used as an adjuvant or complement to surgery, particularly in cases where deep afferents are involved, complete resolution can be achieved only with endovascular treatment. The choice of treatment method should be based on a range of typical characteristics of the lesion, including angioarchitecture, size and clinical presentation