Experimental evidence for temporal uncoupling of brain Aβ deposition and neurodegenerative sequelae

Brain A beta deposition is a key early event in the pathogenesis of Alzheimer ' s disease (AD), but the long presymptomatic phase and poor correlation between A beta deposition and clinical symptoms remain puzzling. To elucidate the dependency of downstream pathologies on A beta, we analyzed the trajectories of cerebral A beta accumulation, A beta seeding activity, and neurofilament light chain (NfL) in the CSF (a biomarker of neurodegeneration) in A beta-precursor protein transgenic mice. We find that A beta deposition increases linearly until it reaches an apparent plateau at a late age, while A beta seeding activity increases more rapidly and reaches a plateau earlier, coinciding with the onset of a robust increase of CSF NfL. Short-term inhibition of A beta generation in amyloid-laden mice reduced A beta deposition and associated glial changes, but failed to reduce A beta seeding activity, and CSF NfL continued to increase although at a slower pace. When short-term or long-term inhibition of A beta generation was started at pre-amyloid stages, CSF NfL did not increase despite some A beta deposition, microglial activation, and robust brain A beta seeding activity. A dissociation of A beta load and CSF NfL trajectories was also found in familial AD, consistent with the view that A beta aggregation is not kinetically coupled to neurotoxicity. Rather, neurodegeneration starts when A beta seeding activity is saturated and before A beta deposition reaches critical (half-maximal) levels, a phenomenon reminiscent of the two pathogenic phases in prion disease. The poor correlation between brain A beta deposition and clinical symptoms in Alzheimer ' s disease remains puzzling. Here, the authors show a temporal dissociation of A beta deposition and neurodegeneration

Oxygen carriers affect kidney immunogenicity during ex-vivo machine perfusion

Normothermic ex-vivo machine perfusion provides a powerful tool to improve donor kidney preservation and a route for the delivery of pharmacological or gene therapeutic interventions prior to transplantation. However, perfusion at normothermic temperatures requires adequate tissue oxygenation to meet the physiological metabolic demand. For this purpose, the addition of appropriate oxygen carriers (OCs) to the perfusion solution is essential to ensure a sufficient oxygen supply and reduce the risk for tissue injury due to hypoxia. It is crucial that the selected OCs preserve the integrity and low immunogenicity of the graft. In this study, the effect of two OCs on the organ's integrity and immunogenicity was evaluated. Porcine kidneys were perfused ex-vivo for four hours using perfusion solutions supplemented with red blood cells (RBCs) as conventional OC, perfluorocarbon (PFC)-based OC, or Hemarina-M101 (M101), a lugworm hemoglobin-based OC named HEMO2life®, recently approved in Europe (i.e., CE obtained in October 2022). Perfusions with all OCs led to decreased lactate levels. Additionally, none of the OCs negatively affected renal morphology as determined by histological analyses. Remarkably, all OCs improved the perfusion solution by reducing the expression of pro-inflammatory mediators (IL-6, IL-8, TNFα) and adhesion molecules (ICAM-1) on both transcript and protein level, suggesting a beneficial effect of the OCs in maintaining the low immunogenicity of the graft. Thus, PFC-based OCs and M101 may constitute a promising alternative to RBCs during normothermic ex-vivo kidney perfusion

Enzymatic Cascade in a Simultaneous, One-Pot Approach with In Situ Product Separation for the Asymmetric Production of (4 S ,5 S )-Octanediol

Stereopure aliphatic diols are an interesting class of compounds because of their potential applications as precursors for chemical catalysts, for high-value polymers, or as precursors for cyclic acetals. We present a simultaneous enzymatic two-step, one-pot cascade for the synthesis of vicinal diols with excellent de and ee values with the exemplary reaction system from butanal to (4S,5S)-octanediol. This reaction is restricted by an unfavorable reaction equilibrium. For an intensification of the reaction toward higher conversions in equilibrium and increased space time yields (STY), aqueous, microaqueous, and biphasic reaction systems for in situ product removal (ISPR) were experimentally investigated and compared. Process concepts for the purification of (4S,5S)-octanediol from each reaction system were developed and assessed in terms of product-specific energy demand. The two-phase reaction system for in situ product removal is favorable for the enzymatic reactions in terms of yield and STY at different time points. In comparison to the aqueous and microaqueous reaction systems, the specific energy demand for (4S,5S)-octanediol recovery is drastically reduced by approximately a factor of seven when performing ISPR using a biphasic system in comparison to an aqueous reaction system

Queer Politics in China: A Conversation with "Western" Activists Working in Beijing

status: publishe

Inklusion im Rahmen von Schule - eine Aufgabe, viele Möglichkeiten. Ein Sammelband von Studierenden der Universität Osnabrück

Seit fast 10 Jahren gilt in Deutschland die UN-Konvention über die Rechte von Menschen mit Behinderungen und somit die Inklusion von Menschen mit Behinderungen in allen Lebensbereichen. Daraus ergibt sich insbesondere für das System Schule eine große Aufgabe, aber auch viele Möglichkeiten für alle Beteiligten. Die von Lehramtsstudierenden der Universität Osnabrück in diesem Band gesammelten Forschungsbeiträge beschäftigen sich empirisch mit der Umsetzung von Inklusion aus der Perspektive unterschiedlicher Akteurinnen und Akteure. Sie sind das Ergebnis eines von Peter große Prues geleiteten inklusionspädagogischen Seminars aus dem Wintersemester 2017/18