The ontogeny and regulation of human natural killer cells

Natural Killer (NK) cells are members of the innate lymphoid cell (ILC) family and take part in the detection and eradication of virus-infected and transformed cells. In this thesis, together with my colleagues I have investigated how NK cells and other ILCs develop and function during human fetal development, how NK cells are functionally regulated (educated) via the activating receptor KIR2DS1, and how NK cells in our body are affected during the early phase of an acute viral infection. Little is known about the ontogeny of NK cells and other ILCs in fetal development. The characterization of ILCs has been hampered by their overlapping surface phenotypes. In contrast, ILC transcription factor expression is more specific, and by combining multicolor flow cytometry analysis of transcription factors and surface markers expressed by different fetal ILC subsets, we were able to study and model their development and differentiation. All ILC subsets were detected as early as gestational week six, and their distribution varied depending on both tissue and gestational age. Moreover, putative precursors of NK cells were identified as cells that sequentially lost CD34 and acquired CD122, Eomes, CD94/NKG2A, T-bet, and CD16. In addition putative CD34+ progenitors of RORγt+ ILCs were identified. In the second trimester of fetal development, analysis of mature fetal NK cell subsets revealed that stage 4 and stage 5 NK cells differed in frequency in fetal organs, and the highest NK cell frequency was found in the fetal liver and lung. The vast majority of fetal NK cells were NKG2A+, and fetal lung NK cells also frequently expressed killercell immunoglobulin-like receptors (KIR). Interestingly, while NKG2A educated fetal NK cells similar to adult NK cells, KIR expression on fetal NK cells was linked to hyporesponsiveness, thus contrasting education of NK cells after birth. Nevertheless, fetal NK cells were highly responsive to cytokines, as well as to antibody-coated target cells, suggesting they may take part in fetal immune responses against in utero infections, while remaining tolerant to maternal cells crossing the placenta. While it is established that NK cells in adults are educated via inhibitory KIRs, it is not known how activating KIRs such as KIR2DS1 affects NK cells. By combining antibodies against four inhibitory KIRs, NKG2A, and KIR2DS1, we were able to interrogate the regulation of NK cells by KIR2DS1. We found that KIR2DS1 singlepositive NK cells exist in vivo, and that the presence of the ligand for KIR2DS1, HLAC2, resulted in hyporesponsiveness of such NK cells, thus ensuring self-tolerance. Our findings represent the first identification of NK cell education via activating KIR. The human NK cell response to viral infections is not well understood. To this end we employed the live attenuated yellow fever vaccine 17D as an in vivo model of an acute viral infection. Our results show that the vaccine primed NK cells, and that less differentiated CD57- NK cells dominated the response, which peaked at day 6-10 post vaccination. Moreover, KIR expression on NK cells did not affect their response to the vaccine, indicating that NK cells expressing self-KIR and non-self KIR contributed equally to the NK cell response to the vaccination

Estimation of efficiency of the use of financial resources on enterprises

Стаття присвячена дослідженню теоретичних та практичних питань аналітичного забезпечення управління використанням фінансових ресурсів підприємств. Запропоновані комплексні показники оцінки даного процесуThe article is devoted to research of theoretical and practical questions of the analytical providing of management the use of financial resources of enterprises. The complex indexes of estimation of this process are offere

Human white adipose tissue vasculature contains endothelial colony-forming cells with robust in vivo vasculogenic potential

Epub ahead of print.-- The final publication is available at link.springer.comBlood-derived endothelial colony-forming cells (ECFCs) have robust vasculogenic potential that can be exploited to bioengineer long-lasting human vascular networks in vivo. However, circulating ECFCs are exceedingly rare in adult peripheral blood. Because the mechanism by which ECFCs are mobilized into circulation is currently unknown, the reliability of peripheral blood as a clinical source of ECFCs remains a concern. Thus, there is a need to find alternative sources of autologous ECFCs. Here we aimed to determine whether ECFCs reside in the vasculature of human white adipose tissue (WAT) and to evaluate if WAT-derived ECFCs (watECFCs) have equal clinical potential to blood-derived ECFCs. We isolated the complete endothelial cell (EC) population from intact biopsies of normal human subcutaneous WAT by enzymatic digestion and selection of CD31+ cells. Subsequently, we extensively compared WAT-derived EC phenotype and functionality to bonafide ECFCs derived from both umbilical cord blood and adult peripheral blood. We demonstrated that human WAT is indeed a dependable source of ECFCs with indistinguishable properties to adult peripheral blood ECFCs, including hierarchical clonogenic ability, large expansion potential, stable endothelial phenotype, and robust in vivo blood vessel-forming capacity. Considering the unreliability and low rate of occurrence of ECFCs in adult blood and that biopsies of WAT can be obtained with minimal intervention in an ambulatory setting, our results indicate WAT as a more practical alternative to obtain large amounts of readily available autologous ECFCs for future vascular cell therapies.This work was supported by a National Institutes of Health Grant (R00EB009096, J. M.-M).Peer reviewe

Non-LTE line formation for Pr II and Pr III in A and Ap stars

Non-LTE line formation for Pr II and Pr III is considered through a range of effective temperatures between 7250 K and 9500 K. A comprehensive model atom for Pr II/III is based on the measured and the predicted energy levels, in total, 6708 levels of Pr II and Pr III. We describe calculations of the Pr II energy levels and oscillator strengths for the transitions in Pr II and Pr III. The influence of departures from LTE on Pr abundance determinations is evaluated. At Teff >= 8000 K departures from LTE lead to overionization of Pr II and to systematically depleted total absorption in the line and positive abundance corrections. At the lower temperatures, different lines of Pr II may be either weakened or amplified depending on the line strength. The non-LTE effects strengthen the Pr III lines and lead to negative abundance corrections. Non-LTE corrections grow with effective temperature for the Pr II lines, and, in contrast, they decline for the Pr III lines. The Pr II/III model atom is applied to determine the Pr abundance in the atmosphere of the roAp star HD 24712 from the lines of two ionization stages. In the chemically uniform atmosphere with [Pr/H] = 3, the departures from LTE may explain only small part (0.3 dex) of the difference between the LTE abundances derived from the Pr II and Pr III lines (2 dex). We find that the lines of both ionization stages are described for the vertical distribution of the praseodymium where the Pr enriched layer with [Pr/H] > 4 exists in the outer atmosphere at log tau_5000 < -4. The departures from LTE for Pr II/III are strong in the stratified atmosphere and have the opposite sign for the Pr II and Pr III lines. Using the revised partition function of Pr II and experimental transition probabilities, we determine the solar non-LTE abundance of Pr as log (Pr/H) = -11.15\pm0.08.Comment: 17 pages, 4 tables, 11 figures, accepted for publication in A&

Systematic review: early infant feeding and the prevention of coeliac disease.

BACKGROUND: PREVENTCD, Prevent Coeliac Disease, is an international project investigating the hypothesis of possible induction of tolerance to gluten in genetically predisposed children through introducing small quantities of gluten during the period of breastfeeding. AIM: To summarise current knowledge on the possible relationship between early feeding practices and the risk of coeliac disease (CD). METHODS: The Cochrane Library, MEDLINE, and EMBASE databases were searched in May 2011, and the search was updated in January 2012, and again in July 2012. RESULTS: Breastfeeding (BF) and CD: some studies show a protective effect of BF, while others show no effect. No studies have shown a long-term preventive effect. BF at the time of gluten introduction and CD: Results from a meta-analysis of five observational case-control studies suggest that BF at gluten introduction is associated with a lower risk of CD compared with formula feeding. It is unclear whether BF provides a permanent protection or only delays the onset of CD. Timing of gluten introduction: The data suggest that both early (≤4 months) and late (≥7 months) introduction of gluten may increase the risk of CD. Amount of gluten at weaning (and later) and CD: One incident case-referent study documented that the introduction of gluten in large amounts compared with small or medium amounts increased the risk of CD. CONCLUSIONS: In the absence of clear evidence, in order to decrease the risk of later coeliac disease, it is reasonable to avoid both early (<4 months) and late (≥7 months) introduction of gluten, and to introduce gluten while the infant is still being breastfed. Future studies may clarify the remaining uncertainties

The breakdown of the municipality as caring platform: lessons for co-design and co-learning in the age of platform capitalism

If municipalities were the caring platforms of the 19-20th century sharing economy, how does care manifest in civic structures of the current period? We consider how platforms - from the local initiatives of communities transforming neighbourhoods, to the city, in the form of the local authority - are involved, trusted and/or relied on in the design of shared services and amenities for the public good. We use contrasting cases of interaction between local government and civil society organisations in Sweden and the UK to explore trends in public service provision. We look at how care can manifest between state and citizens and at the roles that co-design and co-learning play in developing contextually sensitive opportunities for caring platforms. In this way, we seek to learn from platforms in transition about the importance of co-learning in political and structural contexts and make recommendations for the co-design of (digital) platforms to care with and for civil society

Activating KIR2DS4 Is Expressed by Uterine NK Cells and Contributes to Successful Pregnancy

Tissue-specific NK cells are abundant in the pregnant uterus and interact with invading placental trophoblast cells that transform the maternal arteries to increase the fetoplacental blood supply. Genetic case-control studies have implicated killer cell Ig-like receptor (KIR) genes and their $\textit{HLA}$ ligands in pregnancy disorders characterized by failure of trophoblast arterial transformation. Activating $\textit{KIR2DS1}$ or $\textit{KIR2DS5}$ (when located in the centromeric region as in Africans) lower the risk of disorders when there is a fetal $\textit{HLA-C}$ allele carrying a C2 epitope. In this study, we investigated another activating $\textit{KIR, KIR2DS4}$, and provide genetic evidence for a similar effect when carried with $\textit{KIR2DS1. KIR2DS4}$ is expressed by ∼45% of uterine NK (uNK) cells. Similarly to KIR2DS1, triggering of KIR2DS4 on uNK cells led to secretion of GM-CSF and other chemokines, known to promote placental trophoblast invasion. Additionally, XCL1 and CCL1, identified in a screen of 120 different cytokines, were consistently secreted upon activation of KIR2DS4 on uNK cells. Inhibitory $\textit{KIR2DL5A}$, carried in linkage disequilibrium with $\textit{KIR2DS1}$, is expressed by peripheral blood NK cells but not by uNK cells, highlighting the unique phenotype of uNK cells compared with peripheral blood NK cells. That KIR2DS4, KIR2DS1, and some alleles of KIR2DS5 contribute to successful pregnancy suggests that activation of uNK cells by KIR binding to HLA-C is a generic mechanism promoting trophoblast invasion into the decidua.This work was supported by the Wellcome Trust, the Centre for Trophoblast Research, the British Heart Foundation, and the Cambridge Philosophical Society

The Hamburg/ESO R-process Enhanced Star survey (HERES). V. Detailed abundance analysis of the r-process enhanced star HE 2327-5642

We report on a detailed abundance analysis of the strongly r-process enhanced giant star, HE 2327-5642 ([Fe/H] = -2.78, [r/Fe] = +0.99). Determination of stellar parameters and element abundances was based on analysis of high-quality VLT/UVES spectra. The surface gravity was calculated from the NLTE ionization balance between Fe I and Fe II, and Ca I and Ca II. Accurate abundances for a total of 40 elements and for 23 neutron-capture elements beyond Sr and up to Th were determined. The heavy element abundance pattern of HE 2327-5642 is in excellent agreement with those previously derived for other strongly r-process enhanced stars. Elements in the range from Ba to Hf match the scaled Solar r-process pattern very well. No firm conclusion can be drawn with respect to a relationship between the fisrt neutron-capture peak elements, Sr to Pd, in HE 2327-5642 and the Solar r-process, due to the uncertainty of the latter. A clear distinction in Sr/Eu abundance ratios was found between the halo stars with different europium enhancement. The strongly r-process enhanced stars reveal a low Sr/Eu abundance ratio at [Sr/Eu] = -0.92+-0.13, while the stars with 0 < [Eu/Fe] < 1 and [Eu/Fe] < 0 have 0.36 dex and 0.93 dex larger Sr/Eu values, respectively. Radioactive dating for HE 2327-5642 with the observed thorium and rare-earth element abundance pairs results in an average age of 13.3 Gyr, when based on the high-entropy wind calculations, and 5.9 Gyr, when using the Solar r-residuals. HE 2327-5642 is suspected to be radial-velocity variable based on our high-resolution spectra, covering ~4.3 years.Comment: 16 pages, 12 figures, accepted to A&