Interleukin 15 throughout murine natural killer cell biology

Natural killer (NK) cells are innate immune cells that mount responses against virally infected, transformed and allogeneic transplanted cells. Equipped with cytolytic molecules and death receptors, NK cells mediate cytotoxicity against cells expressing low levels of MHC class I (MHC-I) or high levels of stress-induced molecules. NK cells are also immune-modulatory, releasing various cytokines and chemokines as well as kill immature immune cells. A tight regulation is available to endow NK cells with capacity to distinguish self and non-self, while making sure that they are well functional. Numerous extrinsic and intrinsic factors become parts of the regulatory network to control NK cell development, maturation and functional acquisition. Interleukin 15 (IL-15) is an indispensable cytokine throughout NK cell biology. In this thesis, a few novel aspects of IL-15 in NK cell biology under non-inflammatory conditions were reported. In paper I, the importance of IL-15 expressed by dendritic cells (DCs) for NK cell homeostasis, maturation, and functions at steady-state were investigated. In paper II, the coordination of IL-15 with activating signaling DNAX-1-associated receptor (DNAM-1) in controlling the expression of linker for activation of T cells (LAT), an activating signaling molecule, was studied. In paper III, we studied the functional impact of brief contact with IL-15 (“priming”) and its underlying molecular mechanism. Finally, in paper IV, the roles of forkhead box transcription factors of the O class (FOXO) transcription factors in NK cell development in relation to IL-15 receptor (IL-15R) expression and other transcription factors were explored (Figure 1). In summary, we have found that under non-inflammatory conditions, the presence of DCs is required to maintain NK cell homeostasis in regards to apoptosis and proliferation. NK cell maturation and receptor expression were also perturbed upon DC depletion. Importantly, DC derived IL-15 was required for “missing self” reactivity of NK cells in the absence of infection (paper I). At steadystate, the brief contacts with IL-15 are functionally relevant as five-minute treatment with IL-15 augmented degranulation, cytokine production, and calcium flux triggered by activating receptor stimulation, as well as cytotoxicity against YAC1 cells (paper III). Short-time IL-15 stimulation induced phosphorylation of activating signaling molecules, which is Janus Kinase 3 (JAK3) dependent. The functional impact of short time IL-15 stimulation remained up to three hours after IL15 removal. In paper II, IL-15 stimulation was found to induce expression of LAT especially in DNAM-1+ NK cells. The absence of DNAM-1 or its ligand, CD155, reduced LAT expression. The heightened level of LAT expression in DNAM-1+ NK cells endows them with better responsiveness to NK1.1 stimulation, as measured by calcium flux, cytokine production and degranulation. In the last paper, paper IV, mouse models with specific deletion of FOXO1 and FOXO3 in hematopoietic cells (Vav1+iCre FOXO1,3flox/flox) were employed to study the roles of these transcription factors in NK cell development. Upon depletion of FOXO1,3 in Vav1+ cells, NK cell development was blocked at the transition from pre-NK cell progenitors (preNKP) (CD122- or IL15Rβ-) to refined NK cell progenitors (rNKP) (CD122+), resulting in very few committed NK cells in both bone marrow (BM) and spleen. The few NK cells developing in the absence of FOXO1,3 were less mature and display perturbed inhibitory and activating receptor expression. The transplantation experiment demonstrated that the effects of FOXO1,3 on NK cell development, maturation and receptor expression were NK-cell-progenitor intrinsic. The experiment employing RNA sequencing (RNA-seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) revealed a possible mechanism underlying the roles of FOXO1,3 in controlling NK cell development. The expression and/or DNA binding of ETS proto-oncogene 1 (ETS1), transcription factor T cell factor 7 (TCF7), and CD122 were affected in different stages of NK cell development in the absence of FOXO1,3. With the reduction in CD122 (IL-15Rβ), mature NK cells from both BM and spleen displayed an increase rate in undergoing apoptosis. Taken together, FOXO1,3 controlled IL-15R expression on NK progenitors and committed NK cells, which contributes to maintain NK cell population in mice. In summary, we have found that, under non-inflammatory condition, IL-15 regulated NK cell homeostasis and functions, brief contacts with IL-15 were functionally relevant, and the cellular effect was coordinated with DNAM-1 signaling via controlling LAT expression. Lastly, FOXO1,3 were identified as novel transcription factors which control IL-15R expression and NK cell development

Rice market integration in the Mekong river delta : the successful liberalisation of the domestic food market in Vietnam

This article analyses the spatial price differences in the rice market of the Mekong River Delta to assess the impact of the liberalisation policies on its functioning. The results of these policies carried out during the last two decades are impressive. The rice market system in the Delta is competitive. Price patterns strongly cohere and are integrated with the regulated export prices. However, price patterns in other regions and in particular in the North, are only weakly integrated with price patterns in the South. Private traders in the South satisfy local demand and deal with State Owned Enterprises (SOEs) involved in exports and transactions with the North. In the framework of the national food security policy, the state owned food companies subsidise transactions between the South and the North. Therefore, no profitable long distance trade can be established. Moreover, the state owned food companies acquire nearly all licences to export (quota). We conclude that, despite all the dramatic changes, the liberalisation process still faces major challenges.

Are There Delays in Receipt of Treatment Among Appalachian Kentucky Women With Breast Cancer

Background: Women living in rural and under-resourced Appalachian Kentucky may experience delays in receiving cancer treatment yet such delays have not been systematically evaluated. In this analysis, we hypothesize that women diagnosed with breast cancer who live in Appalachian Kentucky would be more likely to have a treatment delay compared to those living in other Kentucky regions and adjusting for individual measures of socioeconomic status. Methods: In this cohort study, women included in the Kentucky Cancer Registry with a diagnosis of an incident, primary breast cancer in the prior 12 months were interviewed by phone (n=1,245; response rate 26.9%). Cox proportional hazards regression analysis was used to estimate rates of any treatment initiation and rates of specific types of first treatment of Appalachian residence relative to non-Appalachian residence after a breast cancer diagnosis. Results: In contrast to our hypothesis, Appalachian women received any first cancer treatment sooner than non-Appalachian women after adjusting for age and stage (adjusted hazard ratio= 1.14; p=0.04). When additionally adjusting for income and health insurance, this association was no longer statistically significant (adjusted hazard ratio=1.11; p=0.14). Among women diagnosed at an earlier stage (n=899), Appalachian residents received first treatment (primarily surgery) sooner than Non-Appalachian women (p=0.05) and among those diagnosed at a later stage (n=346), Appalachian residence received radiation sooner than non-Appalachian residents (p=0.06). There were 2 also no statistical differences in receipt of chemotherapy or hormone therapy between Appalachian and non-Appalachians. Conclusion: Our results indicate for the first time no disparity related to breast cancer diagnosis-treatment intervals in Appalachian Kentucky as compared with the rest of the state

Bright X-ray source from a laser-driven micro-plasma-waveguide

Owing to the rapid progress in laser technology, very high-contrast femtosecond laser pulses of relativistic intensities become available. These pulses allow for interaction with micro-structured solid-density plasma without destroying the structure by parasitic pre-pulses. This opens a new realm of possibilities for laser interaction with micro- and nano-scales photonic materials at the relativistic intensities. Here we demonstrate, for the first time, that when coupling with a readily available 1.8 Joule laser, a micro-plasma-waveguide (MPW) may serve as a novel compact x-ray source. Electrons are extracted from the walls and form a dense self-organized helical bunch inside the channel. These electrons are efficiently accelerated and wiggled by the waveguide modes in the MPW, which results in a bright, well-collimated emission of hard x-rays in the range of 1~100 keV.Comment: 5 pages, 4 figure

Teaching Ways and Learning Ways Revisited

In learning and teaching of languages, numerous theories have been put forward. These theories, normally influenced by developments in the fields of linguistics and psychology, have inspired several approaches to the teaching of second and foreign languages. This paper revisits English language teaching approaches, both traditional and modern, as well as learning styles and teaching styles. Such learning style models as The Myers-Briggs Type Indicator (MBTI); Kolb’s Experiential Learning Model; the Felder-Silverman Learning Styles Model are explored in-depth in this paper. Keywords: teaching approach; learning style; teaching styl