102 research outputs found
MHCII-mediated dialog between group 2 innate lymphoid cells and CD4+ T cells potentiates type 2 immunity and promotes parasitic helminth expulsion
Group 2 innate lymphoid cells (ILC2s) release interleukin-13 (IL-13) during protective immunity to helminth infection and detrimentally during allergy and asthma. Using two mouse models to deplete ILC2s in vivo, we demonstrate that T helper 2 (Th2) cell responses are impaired in the absence of ILC2s. We show that MHCII-expressing ILC2s interact with antigen-specific T cells to instigate a dialog in which IL-2 production from T cells promotes ILC2 proliferation and IL-13 production. Deletion of MHCII renders IL-13-expressing ILC2s incapable of efficiently inducing Nippostrongylus brasiliensis expulsion. Thus, during transition to adaptive T cell-mediated immunity, the ILC2 and T cell crosstalk contributes to their mutual maintenance, expansion and cytokine production. This interaction appears to augment dendritic-cell-induced T cell activation and identifies a previously unappreciated pathway in the regulation of type-2 immunity
A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q- syndrome.
The identification of the genes associated with chromosomal translocation breakpoints has fundamentally changed understanding of the molecular basis of hematological malignancies. By contrast, the study of chromosomal deletions has been hampered by the large number of genes deleted and the complexity of their analysis. We report the generation of a mouse model for human 5q- syndrome using large-scale chromosomal engineering. Haploinsufficiency of the Cd74-Nid67 interval (containing Rps14, encoding the ribosomal protein S14) caused macrocytic anemia, prominent erythroid dysplasia and monolobulated megakaryocytes in the bone marrow. These effects were associated with defective bone marrow progenitor development, the appearance of bone marrow cells expressing high amounts of the tumor suppressor p53 and increased bone marrow cell apoptosis. Notably, intercrossing with p53-deficient mice completely rescued the progenitor cell defect, restoring common myeloid progenitor and megakaryocytic-erythroid progenitor, granulocyte-monocyte progenitor and hematopoietic stem cell bone marrow populations. This mouse model suggests that a p53-dependent mechanism underlies the pathophysiology of the 5q- syndrome
Runs of homozygosity in killer whale genomes provide a global record of demographic histories
Runs of homozygosity (ROH) occur when offspring inherit haplotypes that are identical by descent from each parent. Length distributions of ROH are informative about population history; specifically, the probability of inbreeding mediated by mating system and/or population demography. Here, we investigated whether variation in killer whale (Orcinus orca) demographic history is reflected in genome-wide heterozygosity and ROH length distributions, using a global data set of 26 genomes representative of geographic and ecotypic variation in this species, and two F1 admixed individuals with Pacific-Atlantic parentage. We first reconstructed demographic history for each population as changes in effective population size through time using the pairwise sequential Markovian coalescent (PSMC) method. We found a subset of populations declined in effective population size during the Late Pleistocene, while others had more stable demography. Genomes inferred to have undergone ancestral declines in effective population size, were autozygous at hundreds of short ROH (\u3c1 \u3eMb), reflecting high background relatedness due to coalescence of haplotypes deep within the pedigree. In contrast, longer and therefore younger ROH (\u3e1.5 Mb) were found in low latitude populations, and populations of known conservation concern. These include a Scottish killer whale, for which 37.8% of the autosomes were comprised of ROH \u3e1.5 Mb in length. The fate of this population, in which only two adult males have been sighted in the past five years, and zero fecundity over the last two decades, may be inextricably linked to its demographic history and consequential inbreeding depression
Present and Future CP Measurements
We review theoretical and experimental results on CP violation summarizing
the discussions in the working group on CP violation at the UK phenomenology
workshop 2000 in Durham.Comment: 104 pages, Latex, to appear in Journal of Physics
Blocking IL-25 signalling protects against gut inflammation in a type-2 model of colitis by suppressing nuocyte and NKT derived IL-13
Effectiveness and cost-effectiveness of a telehealth intervention to support the management of long-term conditions: study protocol for two linked randomized controlled trials
Background: As the population ages, more people are suffering from long-term health conditions (LTCs). Health
services around the world are exploring new ways of supporting people with LTCs and there is great interest in the
use of telehealth: technologies such as the Internet, telephone and home self-monitoring.
Methods/Design: This study aims to evaluate the effectiveness and cost-effectiveness of a telehealth intervention
delivered by NHS Direct to support patients with LTCs. Two randomized controlled trials will be conducted in parallel,
recruiting patients with two exemplar LTCs: depression or raised cardiovascular disease (CVD) risk. A total of 1,200
patients will be recruited from approximately 42 general practices near Bristol, Sheffield and Southampton, UK.
Participants will be randomly allocated to either usual care (control group) or usual care plus the NHS Direct
Healthlines Service (intervention group). The intervention is based on a conceptual model incorporating promotion of
self-management, optimisation of treatment, coordination of care and engagement of patients and general
practitioners. Participants will be provided with tailored help, combining telephone advice from health information
advisors with support to use a range of online resources. Participants will access the service for 12 months. Outcomes
will be collected at baseline, four, eight and 12 months for the depression trial and baseline, six and 12 months for
the CVD risk trial. The primary outcome will be the proportion of patients responding to treatment, defined in the
depression trial as a PHQ-9 score <10 and an absolute reduction in PHQ-9 ≥5 after 4 months, and in the CVD risk
trial as maintenance or reduction of 10-year CVD risk after 12 months. The study will also assess whether the
intervention is cost-effective from the perspective of the NHS and personal social services. An embedded qualitative
interview study will explore healthcare professionals’ and patients’ views of the intervention.
Discussion: This study evaluates a complex telehealth intervention which combines evidence-based components and
is delivered by an established healthcare organisation. The study will also analyse health economic information. In
doing so, the study hopes to address some of the limitations of previous research by demonstrating the effectiveness
and cost-effectiveness of a real world telehealth interventio
A highly sensitive method for analyzing marker phytoplankton pigments: Ultra-high-performance liquid chromatography-tandem triple quadrupole mass spectrometry
The NEWMEDS rodent touchscreen test battery for cognition relevant to schizophrenia.
RATIONALE: The NEWMEDS initiative (Novel Methods leading to New Medications in Depression and Schizophrenia, http://www.newmeds-europe.com ) is a large industrial-academic collaborative project aimed at developing new methods for drug discovery for schizophrenia. As part of this project, Work package 2 (WP02) has developed and validated a comprehensive battery of novel touchscreen tasks for rats and mice for assessing cognitive domains relevant to schizophrenia. OBJECTIVES: This article provides a review of the touchscreen battery of tasks for rats and mice for assessing cognitive domains relevant to schizophrenia and highlights validation data presented in several primary articles in this issue and elsewhere. METHODS: The battery consists of the five-choice serial reaction time task and a novel rodent continuous performance task for measuring attention, a three-stimulus visual reversal and the serial visual reversal task for measuring cognitive flexibility, novel non-matching to sample-based tasks for measuring spatial working memory and paired-associates learning for measuring long-term memory. RESULTS: The rodent (i.e. both rats and mice) touchscreen operant chamber and battery has high translational value across species due to its emphasis on construct as well as face validity. In addition, it offers cognitive profiling of models of diseases with cognitive symptoms (not limited to schizophrenia) through a battery approach, whereby multiple cognitive constructs can be measured using the same apparatus, enabling comparisons of performance across tasks. CONCLUSION: This battery of tests constitutes an extensive tool package for both model characterisation and pre-clinical drug discovery.This work was supported by the Innovative Medicine Initiative Joint Undertaking under grant agreement no. 115008 of which resources are composed of EFPIA in-kind contribution and financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013). The authors thank Charlotte Oomen for valuable comments on the manuscript.This is the author accepted manuscript. The final version is available from Springer via http://dx.doi.org/10.1007/s00213-015-4007-
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