Subtyping and subgrouping: Processes for the prevention and promotion of stereotype change

Two processes of stereotyping, subtyping and subgrouping, are compared. Subtyping occurs when perceivers respond to members of a target group who disconfirm their stereotypes by seeing them as exceptions to the rule and placing them in a separate subcategory apart from members who confirm the stereotype. The more recently defined process of subgrouping refers to the perceiver’s organization of information in terms of clusters of individuals based on their similarities and differences; subgroups can include confirmers and disconfirmers. We consider how subtypes and subgroups are defined, operationalized, and measured, their consequences for stereotype change, and the role of typicality. It is concluded that the clearest difference between subtyping and subgrouping is in terms of their consequences (subtyping leads to the preservation and subgrouping to differentiation of the stereotype). There are, however, some similarities between the processes, and attention is drawn to what future research is required, both to deepen our knowledge of each process and clarify their distinction. Stereotypes are a type of schema or knowledg

Reversing the defective induction of IL-10–secreting regulatory T cells in glucocorticoid-resistant asthma patients

We previously reported that human CD4(+) Tregs secrete high levels of IL-10 when stimulated in the presence of dexamethasone and calcitriol (vitamin D3). We now show that following stimulation by allergen, IL-10–secreting Tregs inhibit cytokine secretion by allergen-specific Th2 cells in an IL-10–dependent manner. A proportion of patients with severe asthma fail to demonstrate clinical improvement upon glucocorticoid therapy, and their asthma is characterized as glucocorticoid resistant (SR, abbreviation derived from “steroid resistant”). Dexamethasone does not enhance secretion of IL-10 by their CD4(+) T cells. Addition of vitamin D3 with dexamethasone to cultures of SR CD4(+) T cells enhanced IL-10 synthesis to levels observed in cells from glucocorticoid-sensitive patients cultured with dexamethasone alone. Furthermore, pretreatment with IL-10 fully restored IL-10 synthesis in these cells in response to dexamethasone. Vitamin D3 significantly overcame the inhibition of glucocorticoid-receptor expression by dexamethasone while IL-10 upregulated glucocorticoid-receptor expression by CD4(+) T cells, suggesting potential mechanisms whereby these treatments may overcome poor glucocorticoid responsiveness. We show here that administration of vitamin D3 to healthy individuals and SR asthmatic patients enhanced subsequent responsiveness to dexamethasone for induction of IL-10. This strongly suggests that vitamin D3 could potentially increase the therapeutic response to glucocorticoids in SR patients

ETV6/RUNX1 fusion at diagnosis and relapse: some prognostic indications

This study was undertaken in order to compare the interphase and metaphase cytogenetics of 28 patients with ETV6/RUNX1 positive acute lymphoblastic leukemia, at diagnosis and relapse. The median time to relapse was 26 months. The significant fusion positive population heterogeneity revealed at interphase by a commercial probe for ETV6/RUNX1 fusion has not been described before. Six diagnostic samples had a single abnormal population; others had up to five each, which differed in the numbers of RUNX1 signals, and in the retention or loss of the second ETV6 signal. In contrast, the number of fusion signals was more constant. At relapse, there were fewer populations; the largest or unique clone was sometimes a re-emergence of a minor, diagnostic one, with a retained copy of ETV6 and the most RUNX1 signals. Abnormal, fusion negative clones were identified in bone marrow samples at extra-medullary relapse. Variant three or four-way translocations, which involved chromosomes 12 and 21, were prominent among the complex rearrangements revealed by metaphase FISH. The frequency of their occurrence at diagnosis and reappearance at relapse, sometimes accompanied by minor clonal evolution, was another new observation. Other recurrent cytogenetic features included a second copy of the fusion signal in six cases, partial duplication of the long arm of the X chromosome in two cases, and trisomy 10 in three cases. In comparing our data with previously reported cases, a picture is beginning to emerge of certain diagnostic features, which may provide circumstantial evidence of an increased risk of relapse

The role of 1α,25-dihydroxyvitamin D3 and cytokines in the promotion of distinct Foxp3+ and IL-10+ CD4+ T cells

1α,25-Dihydroxyvitamin D3 (1α25VitD3) has potent immunomodulatory properties. We have previously demonstrated that 1α25VitD3 promotes human and murine IL-10-secreting CD4+ T cells. Because of the clinical relevance of this observation, we characterized these cells further and investigated their relationship with Foxp3+ regulatory T (Treg) cells. 1α25VitD3 increased the frequency of both Foxp3+ and IL-10+ CD4+T cells in vitro. However, Foxp3 was increased at high concentrations of 1α25VitD3 and IL-10 at more moderate levels, with little coexpression of these molecules. The Foxp3+ and IL-10+ T-cell populations showed comparable suppressive activity. We demonstrate that the enhancement of Foxp3 expression by 1α25VitD3 is impaired by IL-10. 1α25VitD3 enables the selective expansion of Foxp3+ Treg cells over their Foxp3− T-cell counterparts. Equally, 1α25VitD3 maintains Foxp3+ expression by sorted populations of human and murine Treg cells upon in vitro culture. A positive in vivo correlation between vitamin D status and CD4+Foxp3+ T cells in the airways was observed in a severe pediatric asthma cohort, supporting the in vitro observations. In summary, we provide evidence that 1α25VitD3 enhances the frequency of both IL-10+ and Foxp3+ Treg cells. In a translational setting, these data suggest that 1α25VitD3, over a broad concentration range, will be effective in enhancing the frequency of Treg cells

Ligation of TLR9 induced on human IL-10–secreting Tregs by 1α,25-dihydroxyvitamin D3 abrogates regulatory function

Signaling through the TLR family of molecular pattern recognition receptors has been implicated in the induction of innate and adaptive immune responses. A role for TLR signaling in the maintenance and/or regulation of Treg function has been proposed, however its functional relevance remains unclear. Here we have shown that TLR9 is highly expressed by human Treg secreting the antiinflammatory cytokine IL-10 induced following stimulation of blood and tissue CD3+ T cells in the presence of 1α,25-dihydroxyvitamin D3 (1α25VitD3), the active form of Vitamin D, with or without the glucocorticoid dexamethasone. By contrast, TLR9 was not highly expressed by naturally occurring CD4+CD25+ Treg or by Th1 and Th2 effector cells. Induction of TLR9, but not other TLRs, was IL-10 dependent and primarily regulated by 1α25VitD3 in vitro. Furthermore, ingestion of calcitriol (1α25VitD3) by human volunteers led to an increase of both IL-10 and TLR9 expression by CD3+CD4+ T cells analyzed directly ex vivo. Stimulation of 1α25VitD3-induced IL-10–secreting Treg with TLR9 agonists, CpG oligonucleotides, resulted in decreased IL-10 and IFN-γ synthesis and a concurrent loss of regulatory function, but, unexpectedly, increased IL-4 synthesis. We therefore suggest that TLR9 could be used to monitor and potentially modulate the function of 1α25VitD3-induced IL-10–secreting Treg in vivo, and that this has implications in cancer therapy and vaccine design

Outcome heterogeneity in childhood high-hyperdiploid acute lymphoblastic leukemia

High hyperdiploidy (HeH) (51 to 65 chromosomes) is found in one third of children with acute lymphoblastic leukemia and is associated with a good prognosis. Cytogenetic features may further refine this prognosis and identify patients with a poor outcome. We examined the effect of sex, age, individual trisomies, modal number, and structural abnormalities on survival among 700 children with HeH. Univariate analysis showed that age. sex, +4, +10, +18, and a high modal number were associated with survival. Multivariate analysis however, revealed that only age, sex, +4, and +18 were independent indicators. Hazard scores for predicting relapse and mortality were constructed. Three risk groups with 5-year event-free survival (EFS) rates of 86%, 75%, and 50% (P < .0001) were identified. The high-risk group comprised boys older than 9 years, boys aged 1 through 9 years without +18, and girls older than 9 years without +18, while girls aged 1 through 9 years with +18 had the best EFS. In terms of mortality, those younger than age 10 years with both +4 and +18 had an improved survival (96% vs 84% at 5 years, P < .0001). These findings confirm that the outcome of children with HeH is heterogeneous and that specific trisomies can identify patients with the greatest and least risk of treatment failur

The Climate Domesday Book

The Climate Domesday Book includes contributions from climate-conscious writers, artists, research scientists, designers and activists from Australia and the UK. The book is a speculative design, intended to provoke public thought and action on the climate emergency and to explore new ways of communicating through design and technology. It demonstrates how design research can bring together diverse disciplinary perspectives, to re-present and amplify a plurality of voices from across temporal and geographic zones. As a speculative design with multi-modal forms of communication (writing, talking, reading, listening, watching), its final manifestation is intended to show the power of human ingenuity and common cause. It is a book as a curated event; as a programme; as a protest; as a survey of ideas. It owes its coming into being to 1960’s counterculture, to the grand ideas of R.Buckminster Fuller and to the electric information age books of Marshall McLuhan, Jerome Agel and Quentin Fiore. In the creation of an experimental hybrid print-digital book on a topic as essential as the future of energy and the planet, design research becomes more than assembling and packaging (a ‘first order’ concern) but an uncertain, collaborative, and activist mode of knowledge-making (a ‘fourth order’).1 It attempts to make sense of a complex challenge (saving planetary species from extinction), invites dialogue between readers and writers and – eventually – stimulate action. It is a speculative design that provides space for contemplation, for inspiration, for engaging the pragmatic and the imaginary. “But it’s just a book. How can a book make a difference?” To which we would respond: “What world-changing events in the world have not been book-inspired?” We want it to be the first book of many: for others to take our technology, our designs and our ideas and make their own Climate Domesday Book in their city. Our Book-of-the-Future is a book, podcast, music video, poem, a window onto ground-breaking science, a manifesto-in-the-making, a clarion call, a gallery-within-a-gallery, a cultural census, a design of possibilities. It is more than a work of art. It is a design with purpose