The Multiscale Systems Immunology project: software for cell-based immunological simulation.

BACKGROUND: Computer simulations are of increasing importance in modeling biological phenomena. Their purpose is to predict behavior and guide future experiments. The aim of this project is to model the early immune response to vaccination by an agent based immune response simulation that incorporates realistic biophysics and intracellular dynamics, and which is sufficiently flexible to accurately model the multi-scale nature and complexity of the immune system, while maintaining the high performance critical to scientific computing. RESULTS: The Multiscale Systems Immunology (MSI) simulation framework is an object-oriented, modular simulation framework written in C++ and Python. The software implements a modular design that allows for flexible configuration of components and initialization of parameters, thus allowing simulations to be run that model processes occurring over different temporal and spatial scales. CONCLUSION: MSI addresses the need for a flexible and high-performing agent based model of the immune system.

CONSERVATIVE AND PROGFESSIVE ASPECTS OF THE SONATA FROM LATE BEETHOVEN TO PROKOFIEV

The term 'sonata' arose in the early seventeenth-century Baroque period and was originally used to distinguish instrumental (sonata) music from vocal music. Later. the sonata style, as a reliable yet flexible compositional framework, was extensively shaped and utilized throughout the Classical period. Subsequently, in the Romantic period, freer creative, individualistic. and expressive musical elements began to be preferred by composers in their use of harmonj., tone color, form, and rhythm. However, even during the revolutionary Romantic period in music. the compositions which did not have a pre-defined format (character pieces, etc) were often comfortably framed and limited within the recognizable boundaries provided by the Classical sonata style. The sonata format, when used as a tool in musical composition, provides logical boundaries that may serve to organize any unexpected emotional expressions on the part of the composer. Yet the sonata framework is also flexible enough to allow freedom of expression. In the Romantic period and beyond, composers had relied, some more than others, upon the sonata's adaptable blend of stability and flexibility. In my opinion, it is more persuasive to express oneself musically within the framework of an established musical style. Thus, I have chosen my dissertation topic as the performance of six pieces incorporating elements of the reliable and flexible sonata style. The sonata of each composer that I have selected clearly demonstrates a tension between logic and emotion expressed within the sonata framework. However, the compositions can be divided interestingly into two groups, such as 'conservative' and 'progressive' group. The 'conservative' group consists of composers who seemed to strive for greater freedom of self-expression within the constraints of the traditional sonata form. On the other hand, the 'progressive' group consists of composers who seemed more to rely upon the sonata form to rein in and add stability to their highly individual and emotional musical ideas. It is my hope that this project will provide a stimulating viewpoint from which to consider the evolution and utilization of the sonata style especially as it is applied to the composition and performance of these six diverse and interesting pieces.

Differential Apaf-1 levels allow cytochrome c to induce apoptosis in brain tumors but not in normal neural tissues.

Brain tumors are typically resistant to conventional chemotherapeutics, most of which initiate apoptosis upstream of mitochondrial cytochrome c release. In this study, we demonstrate that directly activating apoptosis downstream of the mitochondria, with cytosolic cytochrome c, kills brain tumor cells but not normal brain tissue. Specifically, cytosolic cytochrome c is sufficient to induce apoptosis in glioblastoma and medulloblastoma cell lines. In contrast, primary neurons from the cerebellum and cortex are remarkably resistant to cytosolic cytochrome c. Importantly, tumor tissue from mouse models of both high-grade astrocytoma and medulloblastoma display hypersensitivity to cytochrome c when compared with surrounding brain tissue. This differential sensitivity to cytochrome c is attributed to high Apaf-1 levels in the tumor tissue compared with low Apaf-1 levels in the adjacent brain tissue. These differences in Apaf-1 abundance correlate with differences in the levels of E2F1, a previously identified activator of Apaf-1 transcription. ChIP assays reveal that E2F1 binds the Apaf-1 promoter specifically in tumor tissue, suggesting that E2F1 contributes to the expression of Apaf-1 in brain tumors. Together, these results demonstrate an unexpected sensitivity of brain tumors to postmitochondrial induction of apoptosis. Moreover, they raise the possibility that this phenomenon could be exploited therapeutically to selectively kill brain cancer cells while sparing the surrounding brain parenchyma.

An active learning approach for rapid characterization of endothelial cells in human tumors.

Currently, no available pathological or molecular measures of tumor angiogenesis predict response to antiangiogenic therapies used in clinical practice. Recognizing that tumor endothelial cells (EC) and EC activation and survival signaling are the direct targets of these therapies, we sought to develop an automated platform for quantifying activity of critical signaling pathways and other biological events in EC of patient tumors by histopathology. Computer image analysis of EC in highly heterogeneous human tumors by a statistical classifier trained using examples selected by human experts performed poorly due to subjectivity and selection bias. We hypothesized that the analysis can be optimized by a more active process to aid experts in identifying informative training examples. To test this hypothesis, we incorporated a novel active learning (AL) algorithm into FARSIGHT image analysis software that aids the expert by seeking out informative examples for the operator to label. The resulting FARSIGHT-AL system identified EC with specificity and sensitivity consistently greater than 0.9 and outperformed traditional supervised classification algorithms. The system modeled individual operator preferences and generated reproducible results. Using the results of EC classification, we also quantified proliferation (Ki67) and activity in important signal transduction pathways (MAP kinase, STAT3) in immunostained human clear cell renal cell carcinoma and other tumors. FARSIGHT-AL enables characterization of EC in conventionally preserved human tumors in a more automated process suitable for testing and validating in clinical trials. The results of our study support a unique opportunity for quantifying angiogenesis in a manner that can now be tested for its ability to identify novel predictive and response biomarkers.

The Innate Immune System in Acute and Chronic Wounds.

Significance: This review article provides an overview of the critical roles of the innate immune system to wound healing. It explores aspects of dysregulation of individual innate immune elements known to compromise wound repair and promote nonhealing wounds. Understanding the key mechanisms whereby wound healing fails will provide seed concepts for the development of new therapeutic approaches. Recent Advances: Our understanding of the complex interactions of the innate immune system in wound healing has significantly improved, particularly in our understanding of the role of antimicrobials and peptides and the nature of the switch from inflammatory to reparative processes. This takes place against an emerging understanding of the relationship between human cells and commensal bacteria in the skin. Critical Issues: It is well established and accepted that early local inflammatory mediators in the wound bed function as an immunological vehicle to facilitate immune cell infiltration and microbial clearance upon injury to the skin barrier. Both impaired and excessive innate immune responses can promote nonhealing wounds. It appears that the switch from the inflammatory to the proliferative phase is tightly regulated and mediated, at least in part, by a change in macrophages. Defining the factors that initiate the switch in such macrophage phenotypes and functions is the subject of multiple investigations. Future Directions: The review highlights processes that may be useful targets for further investigation, particularly the switch from M1 to M2 macrophages that appears to be critical as dysregulation of this switch occurs during defective wound healing.

Rapid immunological diagnosis of active tuberculosis, and differentiation from asymptomatic infection

info:eu-repo/semantics/nonPublished

Genetic deficiency of the fourth component of complement :clinical, immunological and genetical studies in a further family. IXth International Complement Workshop

info:eu-repo/semantics/published

Immunological Signatures Identifying Different Stages of Latent Mycobacterium tuberculosis Infection and Discriminating Latent from Active Tuberculosis in Humans

Objectives: One third of the world population is considered latently infected with Mycobacterium tuberculosis(LTBI) and sterilizing this reservoir of bacteria that may reactivate is required for tuberculosis (TB) elimination. Thegroup of individuals with LTBI is heterogeneous with some of them being more at risk to develop TB disease thanothers. Improved diagnosis of subjects with LTBI is needed, allowing to differentiate subjects with LTBI from thosewith active TB, and to select among LTBI subjects those who are more at risk to develop active TB. We havecharacterized at the cellular level both the quantitative and qualitative T cell responses to different mycobacterialantigens in selected populations of infected subjects in order to identify new biomarkers that could help to identify M.tuberculosis-infected subjects and to stratify them in risk groups for reactivation of the infection.Methods: Lymphoblast frequencies and cytokine production (IFN-γ, TNF-α, IL-2) among CD4+ and CD8+ T cellswere analyzed by flow cytometry after in vitro stimulation with the latency antigen heparin-binding haemagglutinin(HBHA) or early-secreted antigen Target-6 (ESAT-6) of peripheral blood mononuclear cells from clinically wellcharacterized M. tuberculosis-infected humans (28 LTBI, 22 TB disease,12 controls). The LTBI group definedaccording to the Center for Disease Control guidelines was subdivided into QuantiFERON-TB Gold in-Tube (QFT)positive and negative subgroups.Results: Similar to TB patients, QFT+ LTBI subjects had higher proportions of HBHA-induced TNF-αsingle+ CD4+lymphocytes than QFT- LTBI subjects (p<0.05). Compared to LTBI subjects, TB patients had higher frequencies ofESAT-6-induced CD8+ lymphoblasts (p<0.001), higher proportions of ESAT-6-induced IFN-γ+TNF-α+ CD4+ Tlymphocytes (p<0.05), and lower proportions of HBHA-induced IFN-γ+TNF-α+IL-2+ (p<0.05) CD4+ T lymphocytes.Conclusions: These data provide new biomarkers to discriminate active TB from LTBI, and more interestingly,help to identify LTBI subjects with increased likelihood to develop TB disease.

Preliminary results on clinical and immunological effects of thymopentin in AIDS

SCOPUS: ar.j

Classical and quantum aspects of the extended antifield formalism

Agrégation de l'enseignement supérieur, Orientation sciences

An investigation of the aspects of occupant behavior required for evacuation modeling

This article examines occupant behavior exhibited during evacuation conditions. This is based on a review of a wide range of published literature concerned with evacuation. Factors influencing evacuation performance can be categorized into four broad areas, namely, configurational, environmental, procedural, and, most importantly, behavioral. The contributory factors associated with each of the four influencing categories are examined in detail and it is suggested that these factors should be represented within evacuation models.

Aspects of midwifery care 2: 'enhanced role' and social aspects

This is the second in a series of six papers presenting key findings from a national study that was undertaken to investigate the role and responsibilities of midwives and to identify and address continuing educational need. The background to the study and the titles of other papers in the series were outlined in the first paper. This paper focuses on two key aspects of the midwife’s role: ‘enhanced role’ activities and social and emotional care. The implications of the findings for practice and education are discussed.

Aspects of midwifery care 3: organisation of midwifery care

This is the third in a series of six papers presenting key findings from a national study that was undertaken to investigate the role and responsibilities of midwives and to identify continuing educational need. The background to the study and the titles of the other papers in the series have been outlined in the first paper. Issues related to the way midwifery care is organized nationally are discussed in this paper. Midwives and supervisors indicated a strong commitment to providing woman-centred care in a caring and sensitive manner, often in the face of enormous structural and organizational change. This paper addresses key issues that arose for midwives and supervisors when planning and providing an optimum quality service.