Cracking the BAFF code.

The tumour necrosis factor (TNF) family members B cell activating factor (BAFF) and APRIL (a proliferation-inducing ligand) are crucial survival factors for peripheral B cells. An excess of BAFF leads to the development of autoimmune disorders in animal models, and high levels of BAFF have been detected in the serum of patients with various autoimmune conditions. In this Review, we consider the possibility that in mice autoimmunity induced by BAFF is linked to T cell-independent B cell activation rather than to a severe breakdown of B cell tolerance. We also outline the mechanisms of BAFF signalling, the impact of ligand oligomerization on receptor activation and the progress of BAFF-depleting agents in the clinical setting

Uncertainty-based comparison of the effect of the area shape function on material characterisation in nanoindentation testing

Instrumented Indentation Test (IIT) is largely exploited in industry and academia to achieve multi-scale mechanical characterisation, i.e. ranging from nano- and micro-structure to bulk, of several properties, e.g. Young's modulus, stress-strain curve, creep, and relaxation. IIT is particularly suited to cope with the challenges of the current industrial framework to achieve multi-objective characterisation and requirements of zero-defect manufacturing and zero waste. In fact, IIT requires limited sample preparation and is a non-destructive technique with high throughput. IIT consists of applying a loading-unloading force cycle on the specimen. The capability of continuously measuring the indenter displacement in the material, i.e. being a depth-sensing technique, is the essential feature of IIT. This allows the mechanical characterisation by knowing the shape of the indenter and hence the relationship between the indentation depth and the projected area of the surface in contact between the indenter and the specimen. The relationship is described by the area shape function, whose parameters require calibration according to ISO 14577-2:2015. For a given indenter geometry, several alternative models are available in the literature. These describe both the geometry and the possible presence of errors, e.g. blunt tip and wear effect. However, a comparison of the choice of the different alternatives, when they are equally nominally applicable, is lacking in the literature, although it prescribes some applicability ranges. This work exploits a simulative approach based on bootstrap sampling to estimate the uncertainty of the calibration of area shape function parameters in the nano-range, where the effect is critical. The uncertainty is then propagated to compare performances of different area shape function models on the mechanical characterisation, i.e. indentation hardness and Young's modulus estimate, within a rigorous metrological framework. Results are shown for standard reference materials, i.e. SiO2 and W, to ensure proper composition homogeneity and neglect edge effects, i.e. pile-up and sink-in

Prevalence and diagnostic distribution of medically unexplained painful somatic symptoms across 571 major depressed outpatients.

OBJECTIVE: To assess the prevalence and distribution of medically unexplained painful somatic symptoms (PSSs) versus nonpainful somatic symptoms (NPSSs) in patients diagnosed with major depressive episode (MDE). METHOD: A total of 571 outpatients diagnosed with MDE according to DSM-IV-TR criteria were consecutively enrolled into a cross-sectional, multicentric, observational study over a period of 7 months. Subjects were evaluated by means of the ad hoc validated 30-item Somatic Symptoms Checklist (SSCL-30) and Zung’s questionnaires for depression and anxiety. The 32-item Hypomania Checklist (HCL-32) was also administered in order to explore any eventual association of PSSs or NPSSs with sub-threshold (DSM-IV-TR [Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision] not recognized) bipolar disorder (BD). RESULTS: In our sample, just 183 patients (32%) did not report painful somatic symptoms (NPSSs). Of these, 90 patients (15.76%) had no somatic symptoms at all. The remaining 388 (68%) had at least one PSS being subdivided as follows: 248 (43%) had one or two PSSs, while 140 (25%) experienced two or more. Patients with at least one PSS also reported a greater number of nonpainful somatic symptoms than NPSS. Bipolar patients (associated with higher HCL-32 scores) were less represented across PSS cases than NPSS subjects. Conversely, females were more prone to having a higher number of total somatic symptoms (and bipolar features). CONCLUSION: PSSs are common in patients with MDE, especially among those patients reporting fewer somatic symptoms in general as opposed to those patients who exhibit more somatic symptoms (both PSSs and NPSSs) with lower relative number of PSSs. A major therapeutic implication is that antidepressant monotherapy could be used with more confidence in unexplained PSS patients than in NPSS patients because of the latter group’s lower frequency of (sub)-threshold bipolar features

Los docentes bonaerenses : las políticas educativas vistas desde el aula

Este Cuaderno compila tres estudios promovidos desde la Secretaría de Investigación de la UNIPE sobre los docentes bonaerenses. Las síntesis indagan sobre la condición laboral, sus trayectorias formativas, demandas de capacitación y percepciones sobre aspectos pedagógicos centrales. Permiten asimismo aproximarse a las visiones que tienen sobre las políticas orientadas a la inclusión y a la reducción de las brechas digitales. La masificación, la extensión de la obligatoriedad, la introducción en las escuelas de nuevas tecnologías constituyen políticas educativas con implicancias directas en las clases y el trabajo docente. Estas investigaciones permiten visibilizar la diversidad de modos en que dichas políticas llegan a las aulas

Interference with heparin binding and oligomerization creates a novel anti-inflammatory strategy targeting the chemokine system

Abstract A hallmark of autoimmunity and other chronic diseases is the overexpression of chemokines resulting in a detrimental local accumulation of proinflammatory immune cells. Chemokines play a pivotal role in cellular recruitment through interactions with both cell surface receptors and glycosaminoglycans (GAGs). Anti-inflammatory strategies aimed at neutralizing the chemokine system have to-date targeted inhibition of the receptor-ligand interaction with receptor antagonists. In this study, we describe a novel strategy to modulate the inflammatory process in vivo through mutation of the essential heparin-binding site of a proinflammatory chemokine, which abrogates the ability of the protein to form higher-order oligomers, but retains receptor activation. Using well-established protocols to induce inflammatory cell recruitment into the peritoneal cavity, bronchoalveolar air spaces, and CNS in mice, this non-GAG binding variant of RANTES/CCL5 designated [44AANA47]-RANTES demonstrated potent inhibitory capacity. Through a combination of techniques in vitro and in vivo, [44AANA47]-RANTES appears to act as a dominant-negative inhibitor for endogenous RANTES, thereby impairing cellular recruitment, not through a mechanism of desensitization. [44AANA47]-RANTES is unable to form higher-order oligomers (necessary for the biological activity of RANTES in vivo) and importantly forms nonfunctional heterodimers with the parent chemokine, RANTES. Therefore, although retaining receptor-binding capacity, altering the GAG-associated interactive site of a proinflammatory chemokine renders it a dominant-negative inhibitor, suggesting a powerful novel approach to generate disease-modifying anti-inflammatory reagents.</jats:p

Unlikely friends? Oprah Winfrey and restorative justice

In recent years, restorative justice has surfaced as a new criminal justice practice in diverse parts of the world. Often, it appears that these practices have emerged in complete isolation from one another. This prompts us to question what it is that has allowed restorative justice to become an acceptable way of dealing with criminal justice issues, or in Foucault's terms, the ‘conditions of emergence’ of restorative justice. This article explores one of numerous potential ‘conditions of emergence’ of restorative justice — the discourses of the ‘therapeutic’, ‘recovery’, ‘self-help’ and ‘New Age’ movements. It aims to investigate the ways in which the taken-for-granted nature of these discourses have, in part, permitted restorative practices to become an approved way of ‘doing justice’