The phenotype of circulating follicular-helper T cells in patients with rheumatoid arthritis defines CD200 as a potential therapeutic target

Rheumatoid arthritis (RA) is a systemic autoimmune disease primarily affecting synovial joints in which the development of autoantibodies represents a failure of normal tolerance mechanisms, suggesting a role for follicular helper T cells (TFH) in the genesis of autoimmunity. To determine whether quantitative or qualitative abnormalities in the circulating TFH cell population exist, we analysed by flow cytometry the number and profile of these cells in 35 patients with RA and 15 matched controls. Results were correlated with patient characteristics, including the presence of autoantibodies, disease activity, and treatment with biologic agents. Circulating TFH cells from patients with RA show significantly increased expression of the immunoglobulin superfamily receptor CD200, with highest levels seen in seropositive patients (P=0.0045) and patients treated with anti-TNFα agents (P=0.0008). This occurs in the absence of any change in TFH numbers or overt bias towards Th1, Th2, or Th17 phenotypes. CD200 levels did not correlate with DAS28 scores (P=0.887). Although the number of circulating TFH cells is not altered in the blood of patients with RA, the TFH cells have a distinct phenotype. These differences associate TFH cells with the pathogenesis of RA and support the relevance of the CD200/CD200R signalling pathway as a potential therapeutic target

Controversies on cosmetic outcomes in black women after breast conservation therapy: hyperperception or hyperpigmentation?

Multiple studies have reported inferior cosmetic outcomes after breast conservation surgery and adjuvant radiation therapy in black women. However, cosmetic analysis scales contemporarily utilized in the field of radiation oncology rely largely on subjective visual and tactile perception. These methods are undeniably fraught with intraobserver and interobserver variability. Herein, we uncover how and why these methods may unwittingly and disparately misjudge cosmetic outcomes in black women, and the clinical ramifications thereof. In addition, we highlight more objective cosmetic outcomes assessment programs that promise to yield more reproducible and unbiased results

A whole blood monokine-based reporter assay provides a sensitive and robust measurement of the antigen-specific T cell response

<p>Abstract</p> <p>Background</p> <p>The ability to measure T-cell responses to antigens is proving critical in the field of vaccine development and for understanding immunity to pathogens, allergens and self-antigens. Although a variety of technologies exist for this purpose IFNγ-ELISpot assays are widely used because of their sensitivity and simplicity. However, ELISpot assays cannot be performed on whole blood, and require relatively large volumes of blood to yield sufficient numbers of peripheral blood mononuclear cells. To address these deficiencies, we describe an assay that measures antigen-specific T cell responses through changes in monokine gene transcription. The biological amplification of the IFNγ signal generated by this assay provides sensitivity comparable to ELISpot, but with the advantage that responses can be quantified using small volumes of whole blood.</p> <p>Methods</p> <p>Whole blood or peripheral blood mononuclear cells (PBMCs) from healthy controls and immunosuppressed recipients of solid organ transplants were incubated with peptide pools covering viral and control antigens or mitogen for 20 hours. Total RNA was extracted and reverse transcribed before amplification in a TaqMan qPCR reaction using primers and probes specific for MIG (CXCL9), IP-10 (CXCL10) and HPRT. The induction of MIG and IP-10 in response to stimuli was analysed and the results were compared with those obtained by ELISpot.</p> <p>Results</p> <p>Antigen-specific T cell responses can be measured through the induction of MIG or IP-10 gene expression in PBMCs or whole blood with results comparable to those achieved in ELISpot assays. The biological amplification generated by IFNγ-R signaling allows responses to be detected in as little as 25 μL of whole blood and enables the assay to retain sensitivity despite storage of samples for up to 48 hours prior to processing.</p> <p>Conclusions</p> <p>A monokine-based reporter assay provides a sensitive measure of antigen-specific T cell activation. Assays can be performed on small volumes of whole blood and remain accurate despite delays in processing. This assay may be a useful tool for studying T cell responses, particularly when samples are limited in quantity or when storage or transportation is required before processing.</p

Corporate Citizenship in the New Century: Accountability, Transparency, and Global Stakeholder Engagement

This report from the Conference Board Working Group and Research Forum on Global Corporate Citizenship raises several issues for research and study; it aims at defining corporate citizenship leadership, and discusses how to manage citizenship in a global company. It examines corporate philanthropic programmes and activities through case studies and reporting citizenship practices

Module detection in complex networks using integer optimisation

<p>Abstract</p> <p>Background</p> <p>The detection of <it>modules or community structure </it>is widely used to reveal the underlying properties of complex networks in biology, as well as physical and social sciences. Since the adoption of modularity as a measure of network topological properties, several methodologies for the discovery of community structure based on modularity maximisation have been developed. However, satisfactory partitions of large graphs with modest computational resources are particularly challenging due to the NP-hard nature of the related optimisation problem. Furthermore, it has been suggested that optimising the modularity metric can reach a resolution limit whereby the algorithm fails to detect smaller communities than a specific size in large networks.</p> <p>Results</p> <p>We present a novel solution approach to identify community structure in large complex networks and address resolution limitations in module detection. The proposed algorithm employs modularity to express network community structure and it is based on mixed integer optimisation models. The solution procedure is extended through an iterative procedure to diminish effects that tend to agglomerate smaller modules (resolution limitations).</p> <p>Conclusions</p> <p>A comprehensive comparative analysis of methodologies for module detection based on modularity maximisation shows that our approach outperforms previously reported methods. Furthermore, in contrast to previous reports, we propose a strategy to handle resolution limitations in modularity maximisation. Overall, we illustrate ways to improve existing methodologies for community structure identification so as to increase its efficiency and applicability.</p

Optimization of Adjuvant Radiation in Breast Conservation Therapy: Can We Minimize without Compromise?

Adjuvant breast radiation therapy after breast conservation surgery is recommended as it yields significant reduction in the risk of local recurrence, and confers a potential overall survival benefit. Although the standard breast radiation regimen has historically been delivered over 5–7 weeks; more novel, shorter courses of breast radiation are currently being employed, offering the advantage of more convenience and less time-commitment. Herein, we review the recent literature substantiating these abbreviated radiation treatment approaches and the methods of delivery thereof. In addition, we discuss imaged guided techniques currently being utilized to further refine the delivery of adjuvant breast radiation therapy

Modulating Integrin αIIbβ3 Activity through Mutagenesis of Allosterically Regulated Intersubunit Contacts

This document is the Accepted Manuscript version of a Published Work that appeared in final form in Biochemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.biochem.9b00430.Integrin αIIbβ3, a transmembrane heterodimer, mediates platelet aggregation when it switches from an inactive to an active ligand-binding conformation following platelet stimulation. Central to regulating αIIbβ3 activity is the interaction between the αIIb and β3 extracellular stalks, which form a tight heterodimer in the inactive state and dissociate in the active state. Here, we demonstrate that alanine replacements of sensitive positions in the heterodimer stalk interface destabilize the inactive conformation sufficiently to cause constitutive αIIbβ3 activation. To determine the structural basis for this effect, we performed a structural bioinformatics analysis and found that perturbing intersubunit contacts with favorable interaction geometry through substitutions to alanine quantitatively accounted for the degree of constitutive αIIbβ3 activation. This mutational study directly assesses the relationship between favorable interaction geometry at mutation-sensitive positions and the functional activity of those mutants, giving rise to a simple model that highlights the importance of interaction geometry in contributing to the stability between protein–protein interactions.NIH P01 HL40387NIH R35 GM122603National Science Foundation 1709506National Science Foundation 165011

Simple or complex? a case study of physical and mental health comorbidity

People with epilepsy are significantly more likely to have a mental health disorder than those without a chronic illness. The reasons for this are multiple but may include the mental health difficulties being perceived as complex due to the presence of a chronic illness. In part due to the apparent complexity of the co-occurring physical and mental illness, many are not offered evidence-based treatment (EBT) for the mental health disorder. There is little guidance to inform clinicians about the interventions to use to treat mental health disorders in people with epilepsy. The present paper reports a case of treatment for depression using a standard EBT in a young person with epilepsy. The patient also had clinically significant symptoms of anxiety and an eating disorder and would be considered ‘complex’ according to standard criteria. The intervention, however, was relatively simple and was delivered as guided self-help via 10 weekly telephone calls of approximately 30 minutes duration, and two follow-up calls at one month and three months post-intervention. Self-report and parent-report questionnaire measures were completed before and after the intervention, and at both follow-up time points. A blind-rated online diagnostic interview measure was also completed before and after the intervention. The young person and her family also completed a qualitative interview of their experiences of the intervention. This simple intervention was effective in working towards the client's goals, although pre–post measurement on standard measures was variable. This interesting case raises questions about whether patients with mental and physical comorbidities are complex, or just perceived as complex

Concert recording 2019-11-03a

[Track 1]. Lasciatemi morire / C. Monteverdi -- [Track 2]. The little horses / A. Copland -- [Track 3]. Caro mio ben / T. Giordani -- [Track 4]. Sure on this shining night / S. Barber -- [Track 5]. Sophia Chiocco\u27s Piece one -- [Track 6]. Sophia Chiocco\u27s Piece two -- [Track 7]. Porgi amor from Le nozze di Figaro / W. A. Mozart -- [Track 8]. Le temps des Lilas / E. Chausson -- [Track 9]. Se Florindo e Fedele / A. Scarlatti -- [Track 10]. Loveliest of trees / J. Duke -- [Track 11]. Automne / G. Faure -- [Track 12]. Lass from the Low Countree / J.J. Niles -- [Track 13]. Donde lieta usci from La Boheme / G. Puccini -- [Track 14]. Sure on this shining night / Barber -- [Track 15]. Chanson d\u27Automne / R. Hahn -- [Track 16]. Der wanderer / F. Schubert -- [Track 17]. La vita fugge / I. Pizzetti -- [Track 18]. Die allmacht ; [Track 19]. Der tod und das madchen / F. Schubert -- [Track 20]. Take, o take those lips away / A. Beach -- [Track 21]. Silent noon / R. Vaughan Williams -- [Track 22]. After all white horses are in bed / G. Walker -- [Track 23]. Se vuol Ballare from Le nozze di Figaro / Mozart -- [Track 24]. O nyet, molyu, ne ukhodi, op. 4, no. 1 / S. Rachmaninoff -- [Track 25]. Serenade Japonaise / J. Vieu -- [Track 26]. Lift me into heaven slowly from Cowboy songs / L. Larsen -- [Track 27]. Theoulf\u27s Piece one -- [Track 28]. Theodore Rulf\u27s Piece two -- [Track 29]. In diesen heil\u27 gen Hallen