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Causes and consequences of human migration : an evolutionary perspective
Up-to-date and comprehensive, this book is an integration of the biological, cultural and historical dimensions of population movement.
Book
IL-17 cytokines preferentially act on naïve CD4+ T cells with the IL-17AF heterodimer inducing the greatest functional changes
CD4 + T-helper 17 (Th17) T cells are a key population in protective immunity during infection and in self-tolerance/autoimmunity. Through the secretion of IL-17, Th17 cells act in promotion of inflammation and are thus a major potential therapeutic target in autoimmune disorders. Recent reports have brought to light that the IL-17 family cytokines, IL-17A, IL-17F and IL-17AF, can directly act on CD4 + T-cells, both in murine and human systems, inducing functional changes in these cells. Here we show that this action is preferentially targeted toward naïve, but not memory, CD4 + T-cells. Naïve cells showed transcriptome changes as early as 48 hours post-IL-17 exposure, whereas memory cells remained unaffected as late as 7 days. These functional differences occurred despite similar IL-17 receptor expression on these subsets and were maintained in co-culture/transwell systems, with each subset maintaining its functional response to IL-17. Importantly, there were differences in downstream transcriptional signaling by the three IL-17 cytokines, with the IL-17AF heterodimer conferring both the greatest transcriptional change and most altered functional consequences. Detailed transcriptome analysis provides important insights into the genes and pathways that are modulated as a result of IL-17-mediated signaling and may serve as targets of future therapies.
Journal Article
Ligand-engineered bandgap stability in mixed-halide perovskite LEDs
Lead halide perovskites are promising semiconductors for light-emitting applications because they exhibit bright, bandgap-tunable luminescence with high colour purity
1
,
2
. Photoluminescence quantum yields close to unity have been achieved for perovskite nanocrystals across a broad range of emission colours, and light-emitting diodes with external quantum efficiencies exceeding 20 per cent—approaching those of commercial organic light-emitting diodes—have been demonstrated in both the infrared and the green emission channels
1
,
3
,
4
. However, owing to the formation of lower-bandgap iodide-rich domains, efficient and colour-stable red electroluminescence from mixed-halide perovskites has not yet been realized
5
,
6
. Here we report the treatment of mixed-halide perovskite nanocrystals with multidentate ligands to suppress halide segregation under electroluminescent operation. We demonstrate colour-stable, red emission centred at 620 nanometres, with an electroluminescence external quantum efficiency of 20.3 per cent. We show that a key function of the ligand treatment is to ‘clean’ the nanocrystal surface through the removal of lead atoms. Density functional theory calculations reveal that the binding between the ligands and the nanocrystal surface suppresses the formation of iodine Frenkel defects, which in turn inhibits halide segregation. Our work exemplifies how the functionality of metal halide perovskites is extremely sensitive to the nature of the (nano)crystalline surface and presents a route through which to control the formation and migration of surface defects. This is critical to achieve bandgap stability for light emission and could also have a broader impact on other optoelectronic applications—such as photovoltaics—for which bandgap stability is required.
The binding of multidentate ligands to the surface of lead halide perovskite nanocrystals suppresses the formation of surface defects that result in halide segregation, yielding materials with efficient and colour-stable red emission.
Journal Article
Process evaluation of a randomised controlled trial of PBS-based staff training for challenging behaviour in adults with intellectual disability
Positive Behaviour Support (PBS) for challenging behaviour is a complex intervention. Process evaluation is pivotal in fully understanding the mechanisms and contextual factors that impact on participant outcomes.
To conduct a process evaluation of a national clinical trial investigating the impact of PBS-based staff training on the level of challenging behaviour in adults with intellectual disability.
The Medical Research Council guidance for process evaluation of complex interventions was followed. Semi-structured interviews with 62 stakeholders from the intervention arm (service users, family and paid carers, service managers, staff who delivered the intervention and PBS trainers), quantitative data from the study database and an external evaluation of the quality of the PBS plans were used.
Twenty-one health staff volunteered to be trained in delivering PBS. Available log data from 17 therapists revealed that they worked with 63 participants a median of 11.50 hours (IQR 8-32). Only 33 out of 108 reports had included all elements of the intervention. Another 47 reports had some elements of the intervention. All PBS plans were rated weak, indicating insufficient quality to impact challenging behaviour. Stakeholders reported an appreciation of PBS and its potential to impact quality of care and engagement with the participant. However, they also identified important challenges including managing PBS-related caseloads, paid carer turnover and service commitment to the delivery of PBS.
PBS-based staff training was well received, but therapists found it difficult to undertake all the elements of the intervention in routine care. Implementing a workforce training strategy is important to better define the active components of PBS, and resource implications if the intervention is no better than usual care.
Journal Article
Goodhart’s law: when waiting times became a target, they stopped being a good measure
[...]even in 2005, when we knew that mental health policies were not being implemented, 2 a major health trust \"was asked to make savings to make up for budget overspends by other trusts.\" None declared. 1 Campbell P Boyle A Higginson I. Should we scrap the target of a maximum four hour wait in emergency departments? BMJ 2017; 359: j4857. doi:10.1136/bmj.j4857 29070598 2 Cole A. Mental health plans are not being fully implemented in England.
Journal Article
CONTRACT AS PROPERTY: TRIANGLES AND TRAGIC CHOICES
According to the “Inadequacy Thesis”, the law's refusal to extend the tort of conversion to interferences with contractual rights is evidence of systemic ossification and proof of its failure to protect the most valuable asset class in the modern economy. Whilst it is true that, like chattels, the benefit of contractual rights can be usurped by third parties, transforming such rights into objects of property is the wrong solution to the problem. This article departs from previous analyses by stressing that the analogue of acts of interference with contractual rights is not the conversion of a chattel but a “triangle dispute”. The problem raised by triangle disputes is not how to reach the primary wrongdoer, but how to allocate the loss between the innocent parties. Invoking the concept of “property” cannot solve this problem. Its efficient solution is to be found in better contracts, not more property.
Journal Article
IL-17 cytokines preferentially act on naïve CD4.sup.+ T cells with the IL-17AF heterodimer inducing the greatest functional changes
CD4.sup.+ T-helper 17 (Th17) T cells are a key population in protective immunity during infection and in self-tolerance/autoimmunity. Through the secretion of IL-17, Th17 cells act in promotion of inflammation and are thus a major potential therapeutic target in autoimmune disorders. Recent reports have brought to light that the IL-17 family cytokines, IL-17A, IL-17F and IL-17AF, can directly act on CD4.sup.+ T-cells, both in murine and human systems, inducing functional changes in these cells. Here we show that this action is preferentially targeted toward naïve, but not memory, CD4.sup.+ T-cells. Naïve cells showed transcriptome changes as early as 48 hours post-IL-17 exposure, whereas memory cells remained unaffected as late as 7 days. These functional differences occurred despite similar IL-17 receptor expression on these subsets and were maintained in co-culture/transwell systems, with each subset maintaining its functional response to IL-17. Importantly, there were differences in downstream transcriptional signaling by the three IL-17 cytokines, with the IL-17AF heterodimer conferring both the greatest transcriptional change and most altered functional consequences. Detailed transcriptome analysis provides important insights into the genes and pathways that are modulated as a result of IL-17-mediated signaling and may serve as targets of future therapies.
Journal Article
CD4 T cell-intrinsic role for the T helper 17 signature cytokine IL-17
Untoward effector CD4+ T cell responses are kept in check by immune regulatory mechanisms mediated by CD4+ and CD8+ T cells. CD4+ T helper 17 (Th17) cells, characterized by IL-17 production, play important roles in the pathogenesis of autoimmune diseases (such as arthritis, multiple sclerosis, psoriasis, inflammatory bowel disease, among others) and in the host response to infection and cancer. Here, we demonstrate that human CD4+ T cells cells exposed to a Th17-differentiating milieu are significantly more resistant to immune suppression by CD8+ T cells compared to control Th0 cells. This resistance is mediated, in part, through the action of IL-17A, IL-17F, and IL-17AF heterodimer through their receptors (IL-17RA and IL-17RC) on CD4+ T cells themselves, but not through their action on CD8+ T cells or APC. We further show that IL-17 can directly act on non-Th17 effector CD4+ T cells to induce suppressive resistance, and this resistance can be reversed by blockade of IL-1β, IL-6, or STAT3. These studies reveal a role for IL-17 cytokines in mediating CD4-intrinsic immune resistance. The pathways induced in this process may serve as a critical target for future investigation and immunotherapeutic intervention.
Journal Article
Altered expression of SIRPγ on the T-cells of relapsing remitting multiple sclerosis and type 1 diabetes patients could potentiate effector responses from T-cells
Factors regulating self-antigen directed immune-responses in autoimmunity are poorly understood. Signal regulatory protein gamma (SIRPγ) is a human T-cell specific protein with genetic variants associated with type 1 diabetes (T1D). SIRPγ's function in the immune system remains unclear. We show that T1D and relapsing remitting multiple sclerosis (RRMS) subjects have significantly greater frequency of rs2281808 T genetic variant, that correlates with reduced SIRPγ-expression in T-cells. Importantly, reduced SIRPγ-expression in RRMS and T1D subjects was not restricted to T variant, suggesting SIRPγ-expression is also regulated by disease specific factors in autoimmunity. Interestingly, increased frequencies of SIRPγlow T-cells in RRMS and T1D positively correlated with proinflammatory molecules from T-cells. Finally, we show that SIRPγlow T-cells have enhanced pathogenecity in vivo in a GVHD model. These findings suggest that decreased-SIRPγ expression, either determined by genetic variants or through peripherally acquired processes, may have a mechanistic link to autoimmunity through induction of hyperactive T-cells.
Journal Article