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"Truman, Lucy"
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Layla and Dancer
Layla must overcome her cautious nature and take her unicorn Dancer on a dangerous ride to find a cure for the trees dying around Sparkle Lake.
Book
Low-dose IL-2 enhances the generation of IL-10-producing immunoregulatory B cells
Dysfunction of interleukin-10 producing regulatory B cells has been associated with the pathogenesis of autoimmune diseases, but whether regulatory B cells can be therapeutically induced in humans is currently unknown. Here we demonstrate that a subset of activated B cells expresses CD25, and the addition of low-dose recombinant IL-2 to in vitro stimulated peripheral blood and splenic human B cells augments IL-10 secretion. Administration of low dose IL-2, aldesleukin, to patients increases IL-10-producing B cells. Single-cell RNA sequencing of circulating immune cells isolated from low dose IL2-treated patients reveals an increase in plasmablast and plasma cell populations that are enriched for a regulatory B cell gene signature. The transcriptional repressor
BACH2
is significantly down-regulated in plasma cells from IL-2-treated patients, BACH2 binds to the IL-10 gene promoter, and
Bach2
depletion or genetic deficiency increases B cell IL-10, implicating BACH2 suppression as an important mechanism by which IL-2 may promote an immunoregulatory phenotype in B cells.
The dysfunction of IL-10 secreting regulatory B cells has been linked to the pathogenesis of autoimmune disease. Here the authors show that low dose IL-2 therapy can enhance IL-10 production in regulatory B cell populations via the modulation of BACH2.
Journal Article
Isabel and Cloud
Isabel is having trouble getting along with other students, her teacher, and even her unicorn, Cloud, but another threat to Unicorn Academy brings them back together.
Book
SNP in human ARHGEF3 promoter is associated with DNase hypersensitivity, transcript level and platelet function, and Arhgef3 KO mice have increased mean platelet volume
Genome-wide association studies have identified a genetic variant at 3p14.3 (SNP rs1354034) that strongly associates with platelet number and mean platelet volume in humans. While originally proposed to be intronic, analysis of mRNA expression in primary human hematopoietic subpopulations reveals that this SNP is located directly upstream of the predominantly expressed ARHGEF3 isoform in megakaryocytes (MK). We found that ARHGEF3, which encodes a Rho guanine exchange factor, is dramatically upregulated during both human and murine MK maturation. We show that the SNP (rs1354034) is located in a DNase I hypersensitive region in human MKs and is an expression quantitative locus (eQTL) associated with ARHGEF3 expression level in human platelets, suggesting that it may be the causal SNP that accounts for the variations observed in human platelet traits and ARHGEF3 expression. In vitro human platelet activation assays revealed that rs1354034 is highly correlated with human platelet activation by ADP. In order to test whether ARHGEF3 plays a role in MK development and/or platelet function, we developed an Arhgef3 KO/LacZ reporter mouse model. Reflecting changes in gene expression, LacZ expression increases during MK maturation in these mice. Although Arhgef3 KO mice have significantly larger platelets, loss of Arhgef3 does not affect baseline MK or platelets nor does it affect platelet function or platelet recovery in response to antibody-mediated platelet depletion compared to littermate controls. In summary, our data suggest that modulation of ARHGEF3 gene expression in humans with a promoter-localized SNP plays a role in human MKs and human platelet function-a finding resulting from the biological follow-up of human genetic studies. Arhgef3 KO mice partially recapitulate the human phenotype.
Journal Article
Olivia and Snowflake
Olivia hopes to bond with her unicorn, Snowflake, before graduation day, but someone has set out to ruin the graduation ball and a secret Olivia has been keeping may be revealed.
Book
Protocol of the adaptive study of IL-2 dose frequency on regulatory T cells in type 1 diabetes (DILfrequency): a mechanistic, non-randomised, repeat dose, open-label, response-adaptive study
IntroductionType 1 diabetes (T1D) is caused by autoimmune destruction of the insulin-producing β cells in the pancreatic islets, leading to insulinopenia and hyperglycaemia. Genetic analyses indicate that alterations of the interleukin-2 (IL-2) pathway mediating immune activation and tolerance predispose to T1D, specifically the polymorphic expression of the IL-2 receptor-α chain (CD25) on T lymphocytes. Replacement of physiological doses of IL-2 could restore self-tolerance and prevent further autoimmunity by enhancing the function of CD4+ T regulatory cells (Tregs) to limit the activation of auto reactive T effector cells (Teffs). In this experimental medicine study, we use an adaptive trial design to determine the optimal dosing regimen for IL-2 to improve Treg function while limiting activation of Teffs in participants with T1D.Methods and analysisThe Adaptive study of IL-2 dose frequency on Tregs in type 1 diabetes(DILfrequency) is a mechanistic, non-randomised, repeat dose open-label, response-adaptive study of 36 participants with T1D. The objective is to establish the optimal dose and frequency of ultra-low dose IL-2: to increase Treg frequency within the physiological range, to increase CD25 expression on Tregs, without increasing CD4+ Teffs. DILfrequency has an initial learning phase where 12 participants are allocated to six different doses and frequencies followed by an interim statistical analysis. After analysis of the learning phase, the Dose and Frequency Committee will select the optimal targets for Treg frequency, Treg CD25 expression and Teff frequency. Three groups of eight participants will be treated consecutively in the confirming phase. Each dose and frequency selected will be based on statistical analysis of all data collected from the previous groups.EthicsEthical approval for DILfrequency was granted on 12 August 2014.ResultsThe results of this study will be reported, through peer-reviewed journals, conference presentations and an internal organisational report.Trial registration numbersNCT02265809, ISRCTN40319192, CRN17571.
Journal Article
Scarlett and Blaze
\"Magical Sparkle Lake is starting to freeze, and Unicorn Academy might have to close. Can ten-year-old Scarlett and her unicorn Blaze find out who's freezing the lake and save the school?\"-- Provided by publisher.
Book
Rare case of sudden onset sensorineural hearing loss in a patient diagnosed with sarcoidosis
We report the case of a woman in her 30s who was referred to the ear, nose and throat department with sudden onset left-sided sensorineural hearing loss (SNHL), left anterior uveitis and erythematous lower limb lesions with bilateral pitting oedema. Based on her symptoms, an underlying inflammatory systemic disease was suspected. Autoantibodies were negative but an X-ray and high-resolution CT scan of the chest were suggestive of sarcoidosis, which was confirmed on endoscopic bronchial biopsy. Following treatment with a course of oral steroids, the patient’s hearing has improved but she still suffers from episodes of uveitis. While immune-mediated inner ear disorders are a recognised cause of SNHL, sarcoidosis is a very rare cause. This case demonstrates the importance of screening for systemic autoimmune aetiology in SNHL and highlights the importance of an effective multidisciplinary team in the diagnosis and management of these patients.
Journal Article
Sophia and Rainbow
\"After ten-year-old Sophia meets her unicorn, Rainbow, at Lakeside Unicorn Academy, they're away on their first amazing adventure--they must discover who is tampering with the lake that gives unicorns their magic!\"-- Provided by publisher.
Book
Macrophage chemotaxis to apoptotic Burkitt's lymphoma cells in vitro: role of CD14 and CD36
In Burkitt's lymphoma (BL), apoptosis occurs at high frequency alongside uncontrolled proliferation. Macrophages infiltrate these tumours in large numbers and engage in the phagocytic clearance of apoptotic cells
in situ. Here we tested the hypothesis that apoptosis of BL cells may provide a mechanism for recruitment of macrophages to these tumours. We show that monocytes and macrophages, but not neutrophils, preferentially migrated to apoptotic BL cells
in vitro. Transfection of BL cells with the anti-apoptotic gene
bcl-2 both prevented apoptosis and abolished macrophage chemotaxis. Macrophage migration to BL populations correlated well with the number of apoptotic BL cells present (the Pearson correlation
r=0.81,
p<0.0001). Chemoattraction of murine macrophages to apoptotic human BL cells demonstrated that the mechanism was conserved across these species. In an attempt to identify the macrophage receptors involved in this process, we investigated whether CD14 and CD36, two receptors important in the phagocytic clearance of apoptotic cells, were also involved in the chemotactic macrophage response. We found that bone marrow-derived macrophages from CD14
−/− and CD36
−/− mice moved as well as wild-type macrophages in chemotaxis assays towards apoptotic BL cells. Migrating macrophages were found to be up-regulated in their expression of CD14, however, suggesting that, although this receptor does not appear to be required for ‘sensing’ apoptotic cells, it may be up-regulated on the surface of the migrating macrophage in readiness for apoptotic corpse clearance.
Journal Article