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ObjectivesRheumatic immune-related adverse events (irAE) such as (poly)arthritis in patients undergoing immune checkpoint inhibitor (ICI) treatment pose a major clinical challenge. ICI therapy improves CD8+T cell (CD8) function, but CD8 contributes to chronic inflammation in autoimmune arthritis (AA). Thus, we investigated whether immune functional and metabolic changes in CD8 explain the development of musculoskeletal irAE in ICI-treated patients.MethodsPeripheral CD8 obtained from ICI-treated patients with and without arthritis irAEs and from AA patients with and without a history of malignancy were stimulated in media containing13C-labelled glucose with and without tofacitinib or infliximab. Changes in metabolism, immune-mediator release, expression of effector cell-surface molecules and inhibition of tumour cell growth were quantified.ResultsCD8 from patients with irAE showed significantly lower frequency and expression of cell-surface molecule characteristic for activation, effector-functions, homing, exhaustion and apoptosis and reduced release of cytotoxic and proinflammatory immune mediators compared with CD8 from ICI patients who did not develop irAE. This was accompanied by a higher glycolytic rate and ATP production. Gene-expression analysis of pre-ICI-treated CD8 revealed several differentially expressed transcripts in patients who later developed arthritis irAEs. In vitro tofacitinib or infliximab treatment did not significantly change the immune-metabolic profile nor the capacity to release cytolytic mediators that inhibit the growth of the human lung cancer cell line H838.ConclusionsOur study shows that CD8 from ICI-treated patients who develop a musculoskeletal irAE has a distinct immune-effector and metabolic profile from those that remain irAE free. This specific irAE profile overlaps with the one observed in CD8 from AA patients and may prove useful for novel therapeutic strategies to manage ICI-induced irAEs.

The present work describes the reaction of triplet dioxygen with the porphyrinogenic calix[4]pyrrolato aluminates to alkylperoxido aluminates in high selectivity. Multiconfigurational quantum chemical computations disclose the mechanism for this spin‐forbidden process. Despite a negligible spin–orbit coupling constant, the intersystem crossing (ISC) is facilitated by singlet and triplet state degeneracy and spin–vibronic coupling. The formed peroxides are stable toward external substrates but undergo an unprecedented oxidative pyrrole α‐cleavage by ligand aromatization/dearomatization‐initiated O−O σ‐bond scission. A detailed comparison of the calix[4]pyrrolato aluminates with dioxygen‐related enzymology provides insights into the ISC of metal‐ or cofactor‐free enzymes. It substantiates the importance of structural constraint and element–ligand cooperativity for the functions of aerobic life., The reaction of triplet dioxygen with closed shell molecules is formally spin‐forbidden. Nature overcomes this prohibition by a variety of enzymes. The surprising reactivity of calix[4]pyrrolato aluminate with O2 is described and the spin‐inversion process is analyzed. The square‐planar aluminates transpire as enzyme models that substantiate the critical role of metal–ligand cooperativity and structural constraint for the functions of aerobic life.

ObjectivesRA CD8+ T-cells (CD8) maintain their effector pro-inflammatory phenotype by changing their metabolism towards aerobic glycolysis. However, their massive energetic and biosynthetic needs may require additional substrates to furnish this high demand. Since systemic alterations in lipid metabolism have been reported in RA patients, we explored the role of fatty acid (FA) metabolism in CD8 to identify potential targets to curb their pro-inflammatory potential.MethodsThe expression of FA metabolism-related genes was analyzed for total and CD8-subsets from RA patients and healthy controls (CNT). Peripheral-blood CD8 were isolated from RA, PsA, SpA patients under different therapies (DMARD, biologicals, JAK-inhibitors) and CNT and were TCR-stimulated with or without FA metabolism inhibitors. We quantified the expression of the main FA transporters, lipid uptake, intracellular content of (un-)saturated FA, cytokine production, activation, proliferation, and capacity to inhibit tumor cell growth.ResultsThe CD8 gene expression profile of FA metabolism-related genes was significantly different between untreated RA patients and CNT. RA patients with a good clinical response after 6 months MTX therapy significantly increased the expression of FA metabolism-related genes. Cell-surface expression of FA transporters FABP4 and GPR84 and FA-uptake was higher in effector and memory CD8 of RA patients than for CNT. In vitro blockade of FA metabolism significantly impaired CD8 effector functions.ConclusionsRA CD8 present an altered FA-metabolism which can be potential therapeutic targets to control their pro-inflammatory profile, especially by targeting the transport and oxidation of free FAs which are abundant in the serum and synovial fluid of patients.

8-Nitro-4H-benzo[e][1,3]thiazinones (BTZs) are potent in vitro antimycobacterial agents. New chemical transformations, viz. dearomatization and decarbonylation, of two BTZs and their influence on the compounds' antimycobacterial properties are described. Reactions of 8-nitro-2-(piperidin-1-yl)-6-(trifluoromethyl)-4H-benzo[e][1,3]thiazin-4-one and the clinical drug candidate BTZ043 with the Grignard reagent CH

Spontaneous correlated activity is a universal hallmark of immature neural circuits. However, the cellular dynamics and intrinsic mechanisms underlying network burstiness in the intact developing brain are largely unknown. Here, we use two-photon Ca2+ imaging to comprehensively map the developmental trajectories of spontaneous network activity in the hippocampal area CA1 of mice in vivo. We unexpectedly find that network burstiness peaks after the developmental emergence of effective synaptic inhibition in the second postnatal week. We demonstrate that the enhanced network burstiness reflects an increased functional coupling of individual neurons to local population activity. However, pairwise neuronal correlations are low, and network bursts (NBs) recruit CA1 pyramidal cells in a virtually random manner. Using a dynamic systems modeling approach, we reconcile these experimental findings and identify network bi-stability as a potential regime underlying network burstiness at this age. Our analyses reveal an important role of synaptic input characteristics and network instability dynamics for NB generation. Collectively, our data suggest a mechanism, whereby developing CA1 performs extensive input-discrimination learning prior to the onset of environmental exploration.

Zusammenfassung Zusammenfassung Der Aufsatz gibt einen Überblick über den Verlauf der Covid-19-Pandemie in Hessen, stellt die zentralen Instrumente der Krisenbewältigung durch das Hessische Ministerium für Soziales und Integration (HMSI) im stationären Bereich vor, wirft einen Blick auf die während der Pandemie neu entwickelten Möglichkeiten zur Pandemiebewältigung und zieht ein erstes Fazit. Demnach sind die zentrale Steuerung, die Vorhaltung einer Vernetzungsstruktur sowie eine stringente Planung sowie eine gute Personalausstattung und vernünftige Arbeitsbedingungen die zentralen Erfolgsfaktoren für die Krisenbewältigung. Der Fokus des Aufsatzes liegt dabei auf der Krisenbewältigung und Patientensteuerung im stationären Bereich.

Nach nahezu allen einschlägigen Gesetzesbegründungen der letzten Jahre sollen die gesundheitsrelevanten Vorhaben fast ausnahmslos einer Verbesserung der Versorgungsqualität und der Stärkung des Wettbewerbs zwischen den Krankenkassen dienen. Insbesondere das „Faire Kassenwettbewerb-Gesetz“ spricht dem Wettbewerb zwischen Krankenkassen eine tragende Funktion zu. Doch welcher Wettbewerb ist hier adressiert und wie kongruent sind die programmatischen Zuschreibungen mit der gesundheitspolitischen Gesetzgebung der Großen Koalition? Der Beitrag widmet sich der Frage des wettbewerblichen Status Quo sowie dessen Perspektiven im Rahmen der aktuellen politischen Verfasstheit unter Berücksichtigung technologischer Entwicklungen.

C8H16Cl3NO2, monoclinic, P21 (no. 4), a = 9.1804(5), Å, b = 19.4133(10) Å, c = 13.9191(7) Å, β = 90.593(3)°, V = 2480.6(2) Å3, Z = 8, R gt(F) = 0.0605, wR ref(F 2) = 0.1387, T = 296(2) K.

In this talk, we will summarize the key parameters for combining multilayer optics and microfocus tubes to achieve collimated or focused X-ray sources with high brilliance. The main part of the talk will explain the application-dependent design and capabilities of our newly developed custom metal-ceramic tubes and how to match them with our advanced multilayer optics. Stand-alone custom tubes and optics made possible by the advanced knowledge of the two centerpieces of the source will also be covered. Applications include crystallography, detector calibration, or as a tool at synchrotrons during downtime or con-struction periods.

Spontaneous correlated activity is a universal hallmark of immature neural circuits. However, the cellular dynamics and intrinsic mechanisms underlying network burstiness in the intact developing brain are largely unknown. Here, we use two-photon Ca2+ imaging to comprehensively map the developmental trajectories of spontaneous network activity in hippocampal area CA1 in vivo. We unexpectedly find that network burstiness peaks after the developmental emergence of effective synaptic inhibition in the second postnatal week. We demonstrate that the enhanced network burstiness reflects an increased functional coupling of individual neurons to local population activity. However, pairwise neuronal correlations are low, and network bursts (NBs) recruit CA1 pyramidal cells in a virtually random manner. Using a dynamic systems modeling approach, we reconcile these experimental findings and identify network bi-stability as a potential regime underlying network burstiness at this age. Our analyses reveal an important role of synaptic input characteristics and network instability dynamics for NB generation. Collectively, our data suggest a mechanism, whereby developing CA1 performs extensive input-discrimination learning prior to the onset of environmental exploration.

Mechanically interlocked structures, such as catenanes and rotaxanes, are fascinating synthetic targets and some are used for molecular switches and machines. Today, the vast majority of catenated structures are built upon macrocycles and only a very few examples of three-dimensional shape-persistent organic cages forming such structures have been reported. However, the catenation in all these cases was based on a thermodynamically favoured π–π-stacking under certain reaction conditions. Here, we show that catenane formation can be induced by adding methoxy or thiomethyl groups to one of the precursors during the synthesis of chiral [8 + 12] imine cubes, giving dimeric and trimeric catenated organic cages. To elucidate the underlying driving forces, we reacted 11 differently 1,4-disubstituted terephthaldehydes with a chiral triamino tribenzotriquinacene under various conditions to study whether monomeric cages or catenated cage dimers are the preferred products. We find that catenation is mainly directed by weak interactions derived from the substituents rather than by π-stacking.

NKCC1 is the primary transporter mediating chloride uptake in immature principal neurons, but its role in the development of in vivo network dynamics and cognitive abilities remains unknown. Here, we address the function of NKCC1 in developing mice using electrophysiological, optical, and behavioral approaches. We report that NKCC1 deletion from telencephalic glutamatergic neurons decreases in vitro excitatory actions of gamma-aminobutyric acid (GABA) and impairs neuronal synchrony in neonatal hippocampal brain slices. In vivo, it has a minor impact on correlated spontaneous activity in the hippocampus and does not affect network activity in the intact visual cortex. Moreover, long-term effects of the developmental NKCC1 deletion on synaptic maturation, network dynamics, and behavioral performance are subtle. Our data reveal a neural network function of NKCC1 in hippocampal glutamatergic neurons in vivo, but challenge the hypothesis that NKCC1 is essential for major aspects of hippocampal development.

NKCC1 is the primary transporter mediating chloride uptake in immature principal neurons, but its role in the development of in vivo network dynamics and cognitive abilities remains unknown. Here, we address the function of NKCC1 in developing mice using electrophysiological, optical and behavioral approaches. We report that NKCC1 deletion from telencephalic glutamatergic neurons decreases in-vitro excitatory GABA actions and impairs neuronal synchrony in neonatal hippocampal brain slices. In vivo, it has a minor impact on correlated spontaneous activity in the hippocampus and does not affect network activity in the intact visual cortex. Moreover, long-term effects of the developmental NKCC1 deletion on synaptic maturation, network dynamics and behavioral performance are subtle. Our data reveal a neural network function of depolarizing GABA in the hippocampus in vivo, but challenge the hypothesis that NKCC1 is essential for major aspects of hippocampal development.

Hintergrund Die SARS-CoV-2/COVID-19-Pandemie erfordert eine schnelle Umstrukturierung der Abläufe in den Krankenhäusern. Die Einrichtung von COVID-Schwerpunktversorgungszentren erfordert auch für die chirurgische Fachrichtung eine Vorbereitung auf die anfallenden Notfalleingriffe bei infizierten Patienten oder Patienten mit unklarem Infektionsstatus. Hier erfolgt eine Zusammenfassung der Evidenz zu Standards bei der persönlichen Schutzausrüstung (PSA) für die Mitarbeitenden in den zentralen Notaufnahmen und im Operationsbereich sowie Umstrukturierungsmaßnahmen für die Abläufe im Operationsbereich in einem COVID-plus-Bereich. Methoden Systematische Literaturrecherche. Ergebnisse Die Dunkelziffer an unerkannten Infizierten und potenziellen Überträgern von SARS-CoV-2/COVID-19 ist hoch. Patienten mit unklarem Infektionsstatus oder dringendem Verdacht auf eine Infektion sollten bis zum Beweis des Gegenteils als infektiös eingestuft werden. Dem Infektionsschutz von Mitarbeitenden in den Gesundheitsberufen kommt eine besondere Bedeutung zu. Die Ausstattung mit adäquater PSA in einer risikostratifizierten Form kann den Erfolg zur Bekämpfung der Pandemie wesentlich beeinflussen. Die meisten Operationen sind als aerosolbildende Prozeduren einzuschätzen und erfordern einen maximalen Schutz der direkt am Patienten arbeitenden Mitarbeitenden. Auf zwingend einzuhaltende hygienische Vorgaben zum Kontaminationsschutz ist bei den Umstrukturierungen im Operationsbereich und auf den Transportwegen zwischen den Stationen besonderes Augenmerk zu legen. Schlussfolgerung Die richtige PSA unter Berücksichtigung des Arbeitsschutzes hilft, Mitarbeitende nachhaltig vor Infektionen zu schützen. Umstrukturierungsmaßnahmen im OP sind bei potenziell aerosolbildenden Prozeduren bei Infizierten oder Patienten mit unklarem Infektionsstatus dringend indiziert. Die aktuelle dynamische Situation erfordert ein hohes Maß an Flexibilität, Neubewertung und Anpassung der Maßnahmen in kurzen Intervallen.

A concise synthetic route towards a new family of phosphorus‐containing polycyclic aromatic hydrocarbons starting from the versatile acridophosphine has been established. The structural and optoelectronic properties of these compounds were efficiently modulated through derivatization of the phosphorus center. X‐ray crystallographic analysis, UV/Vis spectroscopic, and electrochemical studies supported by DFT calculations identified the considerable potential of these scaffolds for the development of organophosphorus functional materials with tailored properties upon further functionalization., Phosphorus in place: A new family of phosphorus‐containing polycyclic scaffolds was realized through a concise synthetic route. The impact of the phosphorus functionalization on the structural, electrochemical, and photophysical properties was investigated both in experiment and theory to reveal the highly tunable nature of these compounds.

The SARS-CoV-2 pandemic poses major challenges for the entire medical care system. Especially in university institutions as maximum care providers, a higher exposure to potentially infectious patients or actual COVID-19 patients is to be expected. In a short period of time, an operational concept had to be developed regarding the current hygiene recommendations of the Robert Koch Institute (RKI), the leading medical societies and the internal hospital hygiene plan. Here, patient safety and employee protection are equally important.In cooperation with the Institute for Medical Microbiology and Hospital Hygiene and the occupational medical service, interventions were defined to develop solutions to minimize the COVID-19 transmission risk for examiners and patients despite limited diagnostic and equipment resources. For this purpose, an operational concept was developed, consisting of various individual actions, e. g. the reduction of outpatient treatment to emergencies, life-threatening diseases and urgent aftercare, a double triage of patients and the introduction of treatment teams.The newly developed operational concept was successfully implemented within a few days. After the initial rollout and several "hygiene inspections" only minor improvements to the concept were necessary. All measures were documented in the internal quality handbook and are accessible to all employees. Since the SARS-CoV-2 pandemic is a dynamic process with regular changes in the development and information status, the operational concept is regularly reviewed for validity and adjusted as necessary.Die SARS-CoV-2-Pandemie stellt das gesamte medizinische Versorgungssystem vor große Herausforderungen. Gerade in universitären Einrichtungen als Maximalversorger ist eine höhere Exposition zu potenziell infektiösen Patienten oder tatsächlichen COVID-19-Kranken zu erwarten. Es musste kurzfristig ein Betriebskonzept entwickelt werden, das den aktuellen Hygiene-Empfehlungen des Robert Koch-Instituts (RKI), den Empfehlungen der führenden Fachgesellschaften und dem daraus abgeleiteten internen Hygieneplan entsprach. Hierbei sind die Patientensicherheit und der Mitarbeiterschutz gleichermaßen zu beachten.In Zusammenarbeit mit dem Institut für Medizinische Mikrobiologie und Krankenhaushygiene sowie dem Betriebsärztlichen Dienst wurden Maßnahmen festgelegt, um trotz begrenzter diagnostischer und Ausrüstungsressourcen Lösungen zu erarbeiten, um die COVID-19-Übertragungsgefahr für Untersucher und Patienten zu minimieren. Hierzu wurde ein Betriebskonzept erarbeitet, das aus verschiedenen Einzelmaßnahmen bestand, wie z. B. der Reduktion der ambulanten Patientenbehandlung auf Notfälle, lebensbedrohliche Erkrankungen und dringliche Nachsorgen, eine Doppeltriage von Patienten sowie die Einführung von Behandlungsteams.Das neue erarbeitete Betriebskonzept konnte erfolgreich innerhalb weniger Tage umgesetzt werden. Nach ersten Erfahrungen aus dem Realbetrieb und mehreren „Hygienebegehungen“ waren lediglich geringfügige Nachbesserungen des Konzeptes erforderlich. Alle Maßnahmen wurden schriftlich im klinikinternen Qualitätshandbuch dokumentiert und sind allen Mitarbeitern zugänglich. Da es sich bei der SARS-CoV-2-Pandemie um einen dynamischen Prozess mit regelmäßiger Änderung des Entwicklungs- und Informationsstandes handelt, wird das Betriebskonzept regelmäßig neu auf Gültigkeit überprüft und ggf. angepasst.