Differential effects of α4β7 and GPR15 on homing of effector and regulatory T cells from patients with UC to the inflamed gut in vivo

Objective: Gut homing of lymphocytes via adhesion molecules has recently emerged as new target for therapy in inflammatory bowel diseases. We aimed to analyze the in vivo homing of effector (Teff) and regulatory (Treg) T cells to the inflamed gut via α4β7 and GPR15. Design: We assessed the expression of homing receptors on T cells in peripheral blood and inflamed mucosa. We studied the migration pattern and homing of Teff and Treg cells to the inflamed gut using intravital confocal microscopy and FACS in a humanized mouse model in DSS-treated NSG (NOD.Cg-Prkdcscid-Il2rgtm1Wjl/SzJ) mice. Results: Expression of GPR15 and α4β7 was significantly increased on Treg rather than Teff cells in peripheral blood of patients with ulcerative colitis (UC) as compared to Crohn´s disease and controls. In vivo analysis in a humanized mouse model showed augmented gut homing of UC Treg cells as compared to controls. Moreover, suppression of UC (but not control) Teff and Treg cell homing was noted upon treatment with the α4β7 antibody vedolizumab. In contrast, siRNA blockade of GPR15 had only effects on homing of Teff cells but did not affect Treg homing in UC. Clinical vedolizumab treatment was associated with marked expansion of UC Treg cells in peripheral blood. Conclusion: α4β7 rather than GPR15 is crucial for increased colonic homing of UC Treg cells in vivo, while both receptors control UC Teff homing. Vedolizumab treatment impairs homing of UC Treg cells leading to their accumulation in peripheral blood with subsequent suppression of systemic effector T cell expansion

Generation of Intense Phase-Stable Femtosecond Hard X-ray Pulse Pairs

Coherent nonlinear spectroscopies and imaging in the X-ray domain provide direct insight into the coupled motions of electrons and nuclei with resolution on the electronic length and time scale. The experimental realization of such techniques will strongly benefit from access to intense, coherent pairs of femtosecond X-ray pulses. We have observed phase-stable X-ray pulse pairs containing more thank 3 x 10e7 photons at 5.9 keV (2.1 Angstrom) with about 1 fs duration and 2-5 fs separation. The highly directional pulse pairs are manifested by interference fringes in the superfluorescent and seeded stimulated manganese K-alpha emission induced by an X-ray free-electron laser. The fringes constitute the time-frequency X-ray analogue of the Young double-slit interference allowing for frequency-domain X-ray measurements with attosecond time resolution.Comment: 39 pages, 13 figures, to be publishe

Propagation and Scattering of High-Intensity X-Ray Pulses in Dense Atomic Gases and Plasmas

Nonlinear spectroscopy in the x-ray domain is a promising technique to explore the dynamicsof elementary excitations in matter. X-rays provide an element specificity that allows themto target individual chemical elements, making them a great tool to study complex molecules.The recent advancement of x-ray free electron lasers (XFELs) allows to investigate non-linearprocesses in the x-ray domain for the first time. XFELs provide short femtosecond x-ray pulseswith peak powers that exceed previous generation synchrotron x-ray sources by more than nineorders of magnitude. This thesis focuses on the theoretical description of stimulated emissionprocesses in the x-ray regime in atomic gases. These processes form the basis for more complexschemes in molecules and provide a proof of principle for nonlinear x-ray spectroscopy. Thethesis also includes results from two experimental campaigns at the Linac Coherent LightSource and presents the first experimental demonstration of stimulated x-ray Raman scattering.Focusing an x-ray free electron laser beam into an elongated neon gas target generates anintense stimulated x-ray emission beam in forward direction. If the incoming x-rays havea photon energy above the neon K edge, they can efficiently photo-ionize 1s electrons andgenerate short-lived core excited states. The core-excited states decay mostly via Auger decaybut have a small probability to emit a spontaneous x-ray photon. The spontaneous emissionemitted in forward direction can stimulate x-ray emission along the medium and generate ahighly directional and intense x-ray laser pulse.If the photon energy of the incoming x-rays however is below the ionization edge in the regionof the pre-edge resonance the incoming x-rays can be inelastically scattered. This spontaneousx-ray Raman scattering process has a very low probability, but the spontaneously scatteredphotons in the beginning of the medium can stimulate Raman scattering along the medium.The scattering signal can thus be amplified by several orders of magnitude.To study stimulated x-ray emission a generalized one-dimensional Maxwell-Bloch model isdeveloped. The radiation is propagated through the medium with the help of the Maxwellequations and the radiation is coupled to the atomic system via the polarization. The atomicsystem is treated in the density matrix formalism and the time evolution of the coherencesdetermine the polarization of the medium

Very large-scale diffraction investigations enabled by a matrix-multiplication facilitated radial and azimuthal integration algorithm : MatFRAIA

As synchrotron facilities continue to generate increasingly brilliant X-rays and detector speeds increase, swift data reduction from the collected area detector images to more workable 1D diffractograms becomes of increasing importance. This work reports an integration algorithm that can integrate diffractograms in real time on modern laptops and can reach 10 kHz integration speeds on modern workstations using an efficient pixel-splitting and parallelization scheme. This algorithm is limited not by the computation of the integration itself but is rather bottlenecked by the speed of the data transfer to the processor, the data decompression and/or the saving of results. The algorithm and its implementation is described while the performance is investigated on 2D scanning X-ray diffraction/fluorescence data collected at the interface between an implant and forming bone

Teacher’s Affective Attitude and its Effect on their Organizational Commitment

The study investigated the affective attitude of teachers and its effect on their organizational commitment. This study made use of a descriptive correlation design of research that utilized validated questionnaires as primary data gathering tools. The results were quantified using a five-point Likert scale and were analyzed by its weighted mean and regression analysis was used to establish the correlation. The teachers' description of their productive attitude in terms of the eleven sub-constructs was found to be very positive. While the story of the level of teachers' organization commitment was found to be high in terms of practical and continuance engagement and very high in terms of normative commitment. The result of the regression analysis revealed that all the eleven variables of teachers' attitude influence their level of involvement to a varying extent. Results of the study of variance showed an F ratio of 27.73 with a p-value of .000, an amount much lower than the level of significance set at .05. Based on the findings, the following conclusions were drawn: a.) A very positive and caring attitude was shown by the teachers in their teaching practices; b.) Teachers' approval of the organization's goals and values was very evident as demonstrated by the kind of support they extend to the school in terms of affective, continuance, and normative commitment; c.) The null hypothesis, which states that teachers' emotional attitude does not exert significant influence on the level of organizational commitment was rejected in favor of the research hypothesis; and, d.) The best predictor of the teachers' organizational commitment was the attitude towards students' autonomy, followed by an approach towards classroom management