Radio loud AGN and the L_X - \sigma relation of galaxy groups and clusters

We use the ROSAT All-Sky Survey to study the X-ray properties of a sample of 625 groups and clusters of galaxies selected from the Sloan Digital Sky Survey. We stack clusters with similar velocity dispersions and investigate whether their average X-ray luminosities and surface brightness profiles vary with the radio activity level of their central galaxies. We find that at a given value of $\sigma$, clusters with a central radio AGN have more concentrated X-ray surface brightness profiles, larger central galaxy masses, and higher X-ray luminosities than clusters with radio-quiet central galaxies. The enhancement in X-ray luminosity is more than a factor of two, is detected with better than 6$\sigma$ significance, and cannot be explained by X-ray emission from the radio AGN itself. This difference is largely due to a subpopulation of radio-quiet, high velocity dispersion clusters with low mass central galaxies. These clusters are underluminous at X-ray wavelengths when compared to otherwise similar clusters where the central galaxy is radio-loud, more massive, or both.Comment: Section 5.2 is updated, more discussion on the dependence of L_X - \sigma relation on the stellar mass of BCG

Hematopoietic development and immunological tolerance

The immune system can discriminate between self and non-self, thus assuring clearance of infections by both innate and adaptive effector cells without auto-aggression, thus, establishing tolerance. Projects discussed within this thesis focus on hematopoiesis with special emphasis on T cell development and acquisition of self-tolerance. A multitude of signals derived from cell-cell interactions and/or cytokine signaling determine the first developmental steps of HSCÕs differentiating towards the lymphoid lineage. Instructive cytokine signaling that drives cells into differentiation towards the next progenitor stage or a specified cell type by actively switching genes on or off is rarely known. Our data from project I, introduces FLT3L as a cytokine with such an effect. In vivo administration of FLT3L promotes expansion of progenitors with combined myeloid and lymphoid potential. To investigate further the role of FLT3L in hematopoietic development, we generated transgenic mice expressing high levels of human FLT3L. FLT3L transgenic mice displayed a dramatic expansion of dendritic and myeloid cells, leading to splenomegaly and blood leukocytosis. Bone marrow myeloid and lymphoid progenitors were significantly increased in numbers but retained their developmental potential. Furthermore, transgenic mice developed anemia together with a reduction in platelet numbers. FLT3L was shown to rapidly reduce erythrocyte numbers when injected into wild-type mice, indicating a direct negative role of the cytokine on erythropoiesis. We conclude that FLT3L acts on multipotent progenitors in an instructive way, inducing their development into myeloid/lymphoid lineages while suppressing their megakaryocyte/erythrocyte potential. The aim of project II was to set up an in vitro T cell culture system which is not based on OP9-DL1 or OP9-DL4 stromal cell lines for studying early T cell development prior to T cell selection. Notch-ligand expression by OP9 stromal cells may vary; thus, reproducibility of culture conditions has been proven difficult. To address timing, durability and reversibility of Notch signaling effects on hematopoietic precursors, the Òplastic thymusÓ in vitro culture system was developed. To provide precursors with an adequate signal, a DLL4-Fc fusion protein is immobilized at the surface of cell culture flasks. The Fc-part of the fusion molecule is fixed to the surface by means of a monoclonal IgG anti-Fc antibody, thus directing the orientation of DLL4 towards the cells. We have studied the ability of surface-bound DLL4-Fc to induce prolonged and extensive expansion of ex vivo isolated Sca1+ c-kit+ fetal liver or adult BM haematopoietic progentiors (LSKÕs). Functionality of in vitro generated pro T cells could be demonstrated by transplantation experiments. ÒPlastic thymusÓ derived pro T cells could be shown to reconstitute the thymus of irradiated CD3-/-, preTalpha-/- or WT mice and generate a functional peripheral T cell compartment of both CD8+ and CD4+ antigen reactive T cells. Autoimmune diseases develop when self-specific T cells that escaped negative selection initiate a harmful immune response against self. In project III, by establishing a double transgenic mouse system in which different amounts of a cell-surface neo-self antigen are expressed under the CD11c promoter, we demonstrate that antigen dose dramatically influences T cell tolerance mechanisms. Moderate antigen expression favors the development of antigen-specific regulatory T cells and the establishment of a tolerogenic environment. In marked contrast, high dose of antigen expression results in very stringent negative selection, in poor development of antigen-specific regulatory T cells and the early onset of anemia and splenomegaly and the late development of arthritis and high titers of IgG auto-antibodies. Disease is initiated by autoreactive T cells, which escape negative selection by expressing a second T cell receptor with a different specificity or an altered affinity. Transfer of antigen-specific regulatory T cells ameliorates the early onset signs of disease but does not prevent the development of long-term chronic pathologies. Some signs of potential autoimmunity, such as the presence of anti-nuclear antibodies (ANA), become more prevalent with age. In most cases, these elderly people remain healthy. In project IV we have investigated whether the same holds true for inbred strains of mice. We found, that when they reach the age of 12 months, almost all mice of the C57BL/6 (B6) strain spontaneously produce high titers of IgG ANA. At this time, large numbers of germinal centers are present in the spleen, IgG deposition can be found in kidney glomeruli and lymphocyte infiltrates are found in the salivary glands. Despite all these signs of a potential autoimmune response, the mice remain healthy. In contrast to B6 mice, DBA/2 mice do not produce IgG ANAÕs at that age. The F1 hybrids of these two strains (BDF1), show an intermediate incidence and lower titers of IgG ANA, pointing out the importance of genetic background and suggesting a mechanism of suppression of ANA production in DBA/2 mice. The production of ANA is CD4 T cell dependent, since B6 mice deficient for MHC class II do not produce IgG ANAÕs upon ageing. Experiments with irradiated bone marrow chimeras clearly show that ANA production is not determined by age related changes in radiosensitive, hematopoietic precursor cells, and that the CD4 T cells that promote ANA production is radioresistent. Thymectomy of young adult B6 mice leads to premature alterations in T cell homeostasis and ANA production, mimicking the conditions observed in old mice. Our findings indicate that a disturbed T cell homeostasis is closely associated with and likely to drive the onset of some autoimmune features

Persisting inter‐limb differences in patients following total hip arthroplasty four to five years after surgery? : a preliminary cross‐sectional study

Background: Total hip arthroplasty (THA) is an effective procedure for patients with end-stage hip osteoarthritis. However, whether or not pre-operatively existing functional deficits are persisting several years post-surgery in the affected limb has not been thoroughly researched. Therefore, the primary aim of this preliminary study was to include patients four to five years after undergoing THA and to investigate potential differences between the operated and non-operated leg in hip strength, range of motion (ROM), balance, and gait. The secondary aim was to compare these values from the operated leg of the patients to those of the legs of healthy subjects. Methods: Sixteen patients (age: 65.20 ± 5.32 years) following unilateral THA (post-operation time: 4.7 ± 0.7 years) and ten, healthy, age-matched control subjects (age: 60.85 ± 7.57 years) were examined for maximum isometric hip muscle strength, active ROM of the hip joint, balance and gait on both limbs. Paired t-tests were used to assess the inter-limb differences in the THA group. Analyses of covariance (ANCOVA) were performed to compare groups, using age as a covariate. Results: The analysis of inter-limb differences in patients following THA revealed significant deficits on the operated side for hip abduction strength (p = 0.02), for hip flexion ROM (p < 0.01) and for balance in terms of the length of center of pressure (COP) (p = 0.04). Compared to values of the control subjects, the patients demonstrated significantly reduced hip strength in flexion, extension and abduction (p < 0.05) on the operated leg as well as reduced ROM measures in hip flexion, extension and abduction (p < 0.05). Conclusions: The first results of this explorative study indicated that inter-limb differences as well as reduced hip strength and hip ROM compared with control subjects were still present four to five years after THA. These persisting asymmetries and deficits in patients following THA may be one explanation for the decrease in healthrelated quality of life (HRQoL) seen in patients over the years after surgery. Further studies are required to replicate these findings with a larger sample size.OVGU-Publikationsfonds 202

Persisting inter‐limb differences in patients following total hip arthroplasty four to five years after surgery? A preliminary cross‐sectional study

Background!#!Total hip arthroplasty (THA) is an effective procedure for patients with end-stage hip osteoarthritis. However, whether or not pre-operatively existing functional deficits are persisting several years post-surgery in the affected limb has not been thoroughly researched. Therefore, the primary aim of this preliminary study was to include patients four to five years after undergoing THA and to investigate potential differences between the operated and non-operated leg in hip strength, range of motion (ROM), balance, and gait. The secondary aim was to compare these values from the operated leg of the patients to those of the legs of healthy subjects.!##!Methods!#!Sixteen patients (age: 65.20 ± 5.32 years) following unilateral THA (post-operation time: 4.7 ± 0.7 years) and ten, healthy, age-matched control subjects (age: 60.85 ± 7.57 years) were examined for maximum isometric hip muscle strength, active ROM of the hip joint, balance and gait on both limbs. Paired t-tests were used to assess the inter-limb differences in the THA group. Analyses of covariance (ANCOVA) were performed to compare groups, using age as a covariate.!##!Results!#!The analysis of inter-limb differences in patients following THA revealed significant deficits on the operated side for hip abduction strength (p = 0.02), for hip flexion ROM (p &amp;lt; 0.01) and for balance in terms of the length of center of pressure (COP) (p = 0.04). Compared to values of the control subjects, the patients demonstrated significantly reduced hip strength in flexion, extension and abduction (p &amp;lt; 0.05) on the operated leg as well as reduced ROM measures in hip flexion, extension and abduction (p &amp;lt; 0.05).!##!Conclusions!#!The first results of this explorative study indicated that inter-limb differences as well as reduced hip strength and hip ROM compared with control subjects were still present four to five years after THA. These persisting asymmetries and deficits in patients following THA may be one explanation for the decrease in health-related quality of life (HRQoL) seen in patients over the years after surgery. Further studies are required to replicate these findings with a larger sample size.!##!Trial registration!#!DRKS, DRKS00016945. Registered 12 March 2019 - Retrospectively registered

A stromal cell free culture system generates mouse pro-t cells that can reconstitute t-cell compartments in vivo

T-cell lymphopenia following BM transplantation or diseases such as AIDS result in immunodeficiency. Novel approaches to ameliorate this situation are urgently required. Herein, we describe a novel stromal cell free culture system in which Lineage(-)Sca1(+)c-kit(+) BM hematopoietic progenitors very efficiently differentiate into pro-T cells. This culture system consists of plate-bound Delta-like 4 Notch ligand and the cytokines SCF and IL-7. The pro-T cells developing in these cultures express CD25, CD117, and partially CD44; express cytoplasmic CD3 epsilon; and have their TCR locus partially D-J rearranged. They could be expanded for over 3 months and used to reconstitute the T-cell compartments of sublethally irradiated T-cell-deficient CD3 epsilon(-/-) mice or lethally irradiated WT mice. Pro-T cells generated in this system could partially correct the T-cell lymphopenia of pre-T-/- mice. However, reconstituted CD3 epsilon(-/-) mice suffered from a wasting disease that was prevented by co-injection of purified CD4(+) CD25(high) WT Treg cells. In a T-cell-sufficient or T-lymphopenic setting, the development of disease was not observed. Thus, this in vitro culture system represents a powerful tool to generate large numbers of pro-T cells for transplantation and possibly with clinical applications

Immuno-LipoTRAIL: Targeted Delivery of TRAIL-Functionalized Liposomal Nanoparticles

The TNF-related apoptosis-inducing ligand (TRAIL) is a powerful inducer of apoptosis in tumor cells; however, clinical studies with recombinant soluble TRAIL were rather disappointing. Here, we developed TRAIL-functionalized liposomes (LipoTRAIL, LT) to mimic membrane-displayed TRAIL for efficient activation of death receptors DR4 and DR5 and enhanced induction of apoptosis, which were combined with an anti-EGFR single-chain Fv fragment (scFv) for targeted delivery to EGFR-positive tumor cells. These immuno-LipoTRAILs (ILTs) bound specifically to EGFR-expressing cells (Colo205) and exhibited increased cytotoxicity compared with that of nontargeted LTs. Compared to that of the soluble TRAIL, the plasma half-life of the functionalized liposomes was strongly extended, and increased antitumor activity of LT and ILT was demonstrated in a xenograft tumor model. Thus, we established a multifunctional liposomal TRAIL formulation (ILT) with improved pharmacokinetic and pharmacodynamic behavior, characterized by targeted delivery and increased induction of apoptosis due to multivalent TRAIL presentation