Synthese, Ringöffnungs- und Deoxygenierungsreaktionen von Oxaphosphiran-Metallkomplexen

Im Fokus der vorliegenden Arbeit stand zunächst Studien zur Synthese neuer Oxaphosphirankomplexe der Metalle der 6. Gruppe sowie die Erweiterung der Li/Cl-Phosphinidenoidkomplexroute durch Einbeziehung der Metallkomplexe des Mangans und Eisens. Darüber hinaus wurden an einigen ausgewählten Oxaphosphirankomplexen detaillierte Untersuchungen zur Reaktivität gegenüber Brønsted-Säuren und Lewis-sauren Titankomplexen durchgeführt und deren Reaktionsverläufe teilweise durch theoretische Studien gestützt. Im ersten Teil der Arbeit wurden neue Oxaphosphirankomplexe mit unterschiedlichen Substituenten am Phosphoratom durch Reaktion transient gebildeter Li/Cl-Phosphinidenoidkomplexe mit verschiedenen Aldehyden und Ketonen synthetisiert. Unter gleichen Reaktionsbedingungen konnten so auch erstmals P-Cp*-substituierte Spirooxaphosphirankomplexe dargestellt und umfassend charakterisiert werden. Die durch den Spiroring hervorgerufene Erhöhung der Ringspannungsenergie des Oxaphosphiranringes wurde in einer Kooperation mit A. Espinosa mittels quantenchemischer Berechnungen abgeschätzt.  Interessanterweise führte die Reaktion von [W(CO)5Cp*PCl2] mit einem Überschuss an Cyclopentanon in THF nicht nur zum gewünschten Spirooxaphosphirankomplex, sondern auch zu einem neuartigen Phosphinitokomplex, der im Laufe der Zeit dimerisiert, was durch NMR, IR und ESI-MS belegt werden konnte. Im zweiten Teil der vorliegenden Arbeit lag der Schwerpunkt auf Studien zur Reaktivität von Oxaphosphirankomplexen gegenüber Brønsted-Säuren und Lewis-sauren Titankomplexen. So konnten durch Umsetzung der P-Cp*-substituierten Verbindungen mit HBF4 und HCl, gezielt erstmalig bicyclische P-X-funktionale 1,3-Oxaphospholankomplexe dargestellt werden. Als Lewis-saure Titankomplexe wurden in situ erzeugtes TiCpCl2, [TiCp2Cl]2, Ti[N(SiMe3)2]3 und Ti[N(tBu)-3,5-Me2C6H3]3 verwendet. Deoxygenierungsreaktionen von Oxaphosphirankomplexen mit TiCpCl2 und [TiCp2Cl]2 lieferten eine neue Syntheseroute von diastereomeren Phosphaalkenkomplexen. Um einen Einblick in die Titan(III)-induzierten Ringöffnungsreaktionen zu bekommen, wurden DFT-Rechnungen von Neese durchgeführt. Die oben beschriebene reduktive Ringöffnungs-/Deoxygenierungsreaktion konnte durch Verwendung von TiCp2(btmsa) (btmsa = bis(trimethylsilyl)acetylen) methodisch erweitert werden. Durch thermische Reaktionen ließen sich Phosphaalkenkomplexe, z. T. stereoselektiv, herstellen. Weiteres Erwärmen der Reaktionslösung führte zur Bildung eines neuartigen P,C-Käfigkomplexes.Synthesis, ring opening and deoxygenation reactions of oxaphosphirane metal complexes In the framework of this thesis miscellaneous studies on the synthesis of transition metal coordinated oxaphosphirane complexes of the group 6 metals as well as of manganese and of iron using the Li/Cl phosphidenoid complex route were carried out. In addition, the reactivity of selected oxaphosphirane complexes towards Brønsted acids and Lewis-acidic titanium complexes were studied and their reaction pathways partially supported by theoretical calculations. In the first part the focus was placed on the synthesis of oxaphosphirane metal complexes with different substituents on phosphorus via treatment of transiently formed Li/Cl phosphidenoid complexes with diverse aldehyds and ketones. Under the same conditions first P-Cp* substituted spirooxaphosphirane metal complexes were synthesized. All complexes were fully characterized. Additionally quantum chemical calculations of the spiro ring strain energy of these complexes were done by A. ESPINOSA. Interestingly, the reaction of [W(CO)5Cp*PCl2] with cyclopentanone in THF gave the spiro compound as well a phosphinito complex, which dimerized over time. Both complexes were characterized by NMR, IR and ESI-MS. The second part of this thesis focused on studies on the reactivity of oxaphosphirane complexes under treatment with BRØNSTED acids or Lewis-acidic titanium compounds. From reactions of P-Cp*-substituted oxaphosphirane complexes with HBF4 and HCl gas bicyclic P-X-functional 1,3-oxaphospholane complexes were synthesized via ring opening for the first time. In situ generated TiCpCl2, [TiCp2Cl]2 as well as the steric bulky complexes Ti[N(SiMe3)2]3 and Ti[N(tBu)-3,5-Me2C6H3]3 were used as Lewis-acidic titanium compounds. A new route to synthesize diastereomeric phosphaalkene complexes was found in deoxygenation reactions of oxaphosphirane complexes with TiCpCl2 and [TiCp2Cl]. Theoretical calculations on a P-Cp* substituted example of the reaction pathway were carried out by Neese. The reductive ring opening and deoxygenation reaction described above could be expanded methodically by using TiCp2(btmsa) (btmsa = bis(trimethylsilyl)acetylene). Thermally induced reactions gave the corresponding phosphaalkene complexes, in some cases stereoselectively. Further heating of the reaction mixture led to the formation of a novel P,C-cage compound

Differential expression of ABC transporters and their regulatory genes during lactation and dry period in bovine mammary tissue

ATP-binding cassette (ABC) transporters play a pivotal role in human physiology, and mutations in these genes often result in severe hereditary diseases. ABC transporters are expressed in the bovine mammary gland but their physiological role in this organ remains elusive. Based on findings in the context of human disorders we speculated that candidate ABC transporters are implicated in lipid and cholesterol transport in the mammary gland. Therefore we investigated the expression pattern of selected genes that are associated with sterol transport in lactating and nonlactating mammary glands of dairy cows. mRNA levels from mammary gland biopsies taken during lactation and in the first and second week of the dry period were analysed using quantitative PCR. Five ABC transporter genes, namely ABCA1, ABCA7, ABCG1, ABCG2 and ABCG5, their regulating genes LXRα, PPARγ, SREBP1 and the milk proteins lactoferrin and α-lactalbumin were assessed. A significantly enhanced expression in the dry period was observed for ABCA1 while a significant decrease of expression in this period was detected for ABCA7, ABCG2, SREBP1 and α-lactalbumin. ABCG1, ABCG5, LXRα, PPARγ and lactoferrin expression was not altered between lactation and dry period. These results indicate that candidate ABC transporters involved in lipid and cholesterol transport show differential mRNA expression between lactation and the dry period. This may be due to physiological changes in the mammary gland such as immigration of macrophages or the accumulation of fat due to the loss of liquid in the involuting mammary gland. The current mRNA expression analysis of transporters in the mammary gland is the prerequisite for elucidating novel molecular mechanisms underlying cholesterol and lipid transfer into mil

Online-Bürgerbeteiligung an der Parlamentsarbeit. TAB-Fokus

Online-Bürgerbeteiligung kann dazu dienen, die Beziehungen zwischen Bürgerschaft und Staat zu verbessern sowie Vertrauen und Legitimität zu stärken. Der Bundestag erprobt seit über 10 Jahren unterschiedliche Verfahren der Online-Bürgerbeteiligung. Die Verfahren tragen zur Transparenz der parlamentarischen Arbeit bei und werden von Teilnehmenden wie Außenstehenden positiv bewertet. Die Beteiligung ist meist qualitativ hochwertig, bleibt aber häufig zahlenmäßig hinter den Erwartungen zurück. Eine Ausnahme stellen die E-Petitionen dar, die den höchsten Bekanntheitsgrad der Beteiligungsverfahren erreichen. Für eine Verstetigung und Weiterentwicklung der Online-Bürgerbeteiligung kommen insbesondere konsultative Formate infrage, als Zeitpunkt haben sich frühe Stadien der Meinungsbildung bewährt. In strategischer Hinsicht empfehlen sich eine weiterhin behutsame, sukzessive Entwicklung der Onlinebeteiligungsangebote sowie deren stärker konzeptuelle Einbindung in die parlamentarische Arbeit

A Semiquantitative Non-invasive Measurement of PcomA Patency in C57BL/6 Mice Explains Variance in Ischemic Brain Damage in Filament MCAo

Numerous studies on experimental ischemic stroke use the filament middle cerebral artery occlusion (fMCAo) model in C57BL/6 mice, but lesion sizes in this strain are highly variable. A known contributor is variation in the posterior communicating artery (PcomA) patency. We therefore aimed to provide a semiquantitative non-invasivein vivomethod to routinely assess PcomA patency. We included 43 male C57BL/6 mice from four independent studies using a transient 45 min fMCAo model. Edema-corrected lesion sizes were measured by magnetic resonance (MR) imaging 24 h after reperfusion. Time-of-flight MR angiography was performed 7 days before and 24 h after fMCAo. Scores of PcomA size measured 24 h after, but not scores measured 7 days before fMCAo were negatively correlated with lesion size. Variability in PcomA patency explained 30% of the variance in our cohort (p< 0.0001, coefficient of determinationr(2)= 0.3). In a simulation using parameters typical for experimental stroke research, the power to detect a true effect ofd= 1 between two groups increased by 15% when an according covariate was included in the statistical model. We have demonstrated thatin vivomeasurement of PcomA size is feasible and can lead to increased accuracy in assessing the effect of treatments

The importance of pyramidal tract integrity for cortical plasticity and related functionality in patients with multiple sclerosis

BackgroundCortical plasticity induced by quadripulse stimulation (QPS) has been shown to correlate with cognitive functions in patients with relapsing-remitting multiple sclerosis (RRMS) and to not be reduced compared to healthy controls (HCs).ObjectiveThis study aimed to compare the degree of QPS-induced plasticity between different subtypes of multiple sclerosis (MS) and HCs and to investigate the association of the degree of plasticity with motor and cognitive functions. We expected lower levels of plasticity in patients with progressive MS (PMS) but not RRMS compared to HCs. Furthermore, we expected to find positive correlations with cognitive and motor performance in patients with MS.MethodsQPS-induced plasticity was compared between 34 patients with PMS, 30 patients with RRMS, and 30 HCs using linear mixed-effects models. The degree of QPS-induced cortical plasticity was correlated with various motor and cognitive outcomes.ResultsThere were no differences regarding the degree of QPS-induced cortical plasticity between HCs and patients with RRMS (p = 0.86) and PMS (p = 0.18). However, we only found correlations between the level of induced plasticity and both motor and cognitive functions in patients with intact corticospinal tract integrity. Exploratory analysis revealed significantly reduced QPS-induced plasticity in patients with damage compared to intact corticospinal tract integrity (p &lt; 0.001).ConclusionOur study supports the notion of pyramidal tract integrity being of more relevance for QPS-induced cortical plasticity in MS and related functional significance than the type of disease

Structure and content of the EU-IVDR: current status and implications for pathology

Background Regulation (EU) 2017/746 on in vitro diagnostic medical devices (IVDR) was passed by the European Parliament and the Council of the European Union on 5 April 2017 and came into force on 26 May 2017. A new amending regulation, which introduces a phased implementation of the IVDR with new transitional provisions for certain in vitro diagnostic medical devices (IVDs) and a later date of application of some requirements for in-house devices for healthcare facilities, was adopted on 15 December 2021. The combined use of CE-certified IVDs (CE-IVDs), in-house IVDs (IH-IVDs), and research use only (RUO) devices are a cornerstone of diagnostics in pathology departments and crucial for optimal patient care. The IVDR not only regulates the manufacture and placement on the market of industrially manufactured IVDs, but also imposes conditions on the manufacture and use of IH-IVDs for internal use by healthcare facilities. Objectives Our work provides an overview of the background and structure of the IVDR and identifies core areas that need to be interpreted and fleshed out in the context of the legal framework as well as expert knowledge. Conclusions The gaps and ambiguities in the IVDR crucially require the expertise of professional societies, alliances, and individual stakeholders to successfully facilitate the implementation and use of the IVDR in pathology departments and to avoid aberrant developments

Clinical Post-SARS-CoV-2 Infection Scenarios in Vaccinated and Non-Vaccinated Cancer Patients in Three German Cancer Centers: A Retrospective Analysis.

COVID-19 vaccines have become an integral element in the protection of cancer patients against SARS-CoV-2. To date, there are no direct comparisons of the course of COVID-19 infection in cancer patients between the pre- and post-vaccine era. We analyzed SARS-CoV-2 infections and their impact on cancer in COVID-19 vaccinated and non-vaccinated patients from three German cancer centers. Overall, 133 patients with SARS-CoV-2 were enrolled in pre- and post-vaccine eras: 84 non-vaccinated and 49 vaccinated, respectively. A mild course of COVID-19 was documented more frequently in vaccinated patients (49% vs. 29%), while the frequency of severe and critical courses occurred in approximately one-half of the non-vaccinated patients (22% vs. 42%, p = 0.023). Particularly, patients with hematologic neoplasms benefited from vaccination in this context (p = 0.031). Admissions to intermediate- and intensive-care units and the necessity of non-invasive and invasive respiratory support were reduced by 71% and 50% among vaccinated patients, respectively. The median length of admission was 11 days for non-vaccinated and 5 days for vaccinated patients (p = 0.002). COVID-19 mortality was reduced by 83% in vaccinated patients (p = 0.046). Finally, the median time from SARS-CoV-2 infection to restarting cancer therapy was 12 and 26 days among vaccinated and non-vaccinated groups, respectively (p = 0.002). Although this study does not have enough power to perform multivariate analyses to account for confounders, it provides data on COVID-19 in non-vaccinated and vaccinated cancer patients and illustrates the potential benefits of COVID-19 vaccines for these patients

Prevalence and prognostic value of neurological affections in hospitalized patients with moderate to severe COVID-19 based on objective assessments.

Neurological manifestations of coronavirus disease 2019 (COVID-19) have been frequently described. In this prospective study of hospitalized COVID-19 patients without a history of neurological conditions, we aimed to analyze their prevalence and prognostic value based on established, standardized and objective methods. Patients were investigated using a multimodal electrophysiological approach, accompanied by neuropsychological and neurological examinations. Prevalence rates of central (CNS) and peripheral (PNS) nervous system affections were calculated and the relationship between neurological affections and mortality was analyzed using Firth logistic regression models. 184 patients without a history of neurological diseases could be enrolled. High rates of PNS affections were observed (66% of 138 patients receiving electrophysiological PNS examination). CNS affections were less common but still highly prevalent (33% of 139 examined patients). 63% of patients who underwent neuropsychological testing (n = 155) presented cognitive impairment. Logistic regression models revealed pathology in somatosensory evoked potentials as an independent risk factor of mortality (Odds Ratio: 6.10 [1.01-65.13], p = 0.049). We conclude that hospitalized patients with moderate to severe COVID-19 display high rates of PNS and CNS affection, which can be objectively assessed by electrophysiological examination. Electrophysiological assessment may have a prognostic value and could thus be helpful to identify patients at risk for deterioration