Distinguishing between Charge-Transfer Mechanisms at Organic/Inorganic Interfaces Employing Hybrid Functionals

When modeling inorganic/organic interfaces with density functional theory (DFT), the outcome often depends on the chosen functional. Hybrid functionals, which employ a fraction of Hartree–Fock exchange α, tend to give better results than the more commonly applied semilocal functionals, because they remove or at least mitigate the unphysical electron self-interaction. However, the choice of α is not straightforward, as its effect on observables depends on the physical properties of the investigated system, such as the size of the molecule and the polarizability of the substrate. In this contribution, we demonstrate this impact exemplarily for tetrafluoro-1,4-benzoquinone on semiconducting (copper-I-oxide Cu₂O) and metallic (Cu) substrates and explore how the simulated charge transfer depends on α. We determine the value α* that marks the transition point between spurious over-localization and over-delocalization of charges. This allows us to shed light on the interplay between the value of α* and the physical properties of the interface. We find that on the inert semiconducting substrate, α* strongly depends on surface screening. Furthermore, α has a significant impact on the amount of charge transfer and, in particular, the charge localization. Conversely, for the adsorption on Cu, α affects only the amount of transferred charge, but not its localization, which is a consequence of strong hybridization. Finally, we discuss limitations to the predictive power of DFT for modeling charge transfer at inorganic/organic interfaces and explain why the choice of a “correct” amount of Hartree–Fock exchange is difficult, if not impossible. However, we argue why simulations still provide valuable insights into the charge-transfer mechanism at organic/inorganic interfaces and describe how α can be chosen sensibly to simulate any given system

The role of Tyk2 in type I interferon signalling

Die Signaltransduktionskaskade der Janus kinases und signal transducers and activators of transcription (Jak/Stat) stellt eine schnelle Übertragung von Signalen ausgehend von Zelloberflächenrezeptoren zu Zielgenen sicher. Sie ist an zahlreichen Prozessen, wie zum Beispiel während der Entwicklung, des Wachstums und der Immunantwort, beteiligt. Die Jak tyrosine kinase 2 (Tyk2) ist unter anderem in die Signaltransduktion von Typ I Interferonen (IFNα/β) und IL-12 involviert, wo es für die vollständige Aktivierung der Stats notwendig ist. Tyk2-defiziente Mäuse sind einerseits anfälliger auf verschiedenste Pathogene, andererseits resistent gegen Lipopolysaccharid- (LPS-) induzierten Endotoxinschock. Peritoneale Makrophagen weisen in Abwesenheit von Tyk2 eine reduzierte Expression von IFNβ, IFNα-4 und inducible nitric oxide synthase (iNOS) nach LPS Behandlung auf. Der globale Einfluss der Tyk2-Defizienz auf die transkriptionelle Antwort peritonealer Makrophagen auf LPS-Behandlung wurde mittels Microarray-Technologie analysiert. Unter der Verwendung von reverser Transkription (RT) gekoppelt mit quantitativer real-time PCR (qPCR) konnten wir die Microarray-Daten bezüglich der reduzierten Expression von IFNβ und IFN-stimulierten Genen (ISG) verifizieren. Darüber hinaus wurden sechs weitere Gene gefunden, die bis jetzt nicht als LPS- oder IFN-reguliert bekannt waren und die eine Tyk2-abhängige Genregulation aufwiesen. Während einer vorangegangenen Studie hatte sich gezeigt, dass octamer-binding factor 6 (Oct-6, alias Pou3f1, SCIP, Tst-1) in Fibroblasten durch IFNβ-Behandlung Tyk2-abhängig induzierbar war. Dieser Transkriptionsfaktor zählt zu der Familie der Pit-Oct-Unc- (POU-) Domäne-enthaltenden Proteine und wurde bis jetzt nur im Zusammenhang mit Prozessen während der Entwicklung, nicht aber in Verbindung mit Abläufen im Immunsystem, beschrieben. Wir konnten zum ersten Mal überhaupt zeigen, dass Oct-6 durch Behandlung mit IFN in Fibroblasten und Makrophagen induziert wird. Außerdem wurde Oct-6 nach poly(I:C)-Behandlung sowie im Zuge von Virusinfektionen produziert, was wiederum abhängig von einem funktionierenden Typ I IFN-Signalweg war. Diese IFN-vermittelte Oct-6 Induktion war weitestgehend von der Jak/Stat-Signaltransduktionskaskade abhängig. Des Weiteren konnten wir belegen, dass Stat1 in Folge von IFN-Behandlung an den Oct-6-Promoter bindet. Die Funktion von Oct-6 im Kontext der angeborenen Immunität wurde in Überexpressions- und Deletionsexperimenten untersucht. Die Überexpression von Oct-6 führte zu einer verlängerten Expression von Typ I IFN mRNAs, allerdings hatte endogenes Oct-6 keinen Einfluß darauf. Dass Oct-6 eine Rolle im Zuge einer Immunantwort spielt, wurde gezeigt, indem die Antworten von WT und Oct-6-defizienten Makrophagen auf poly(I:C)-Behandlung mittels Microarrays und RT-qPCR verglichen wurden. Um die Rolle des neuen ISG Oct-6 im Zuge der angeborenen Immunität vollständig zu erfassen, sind weitere, detailliertere Analysen notwendig.The Janus kinase / signal transducer and activator of transcription (Jak/Stat) signalling cascade provides a fast way to transmit signals from cell surface receptors to target genes and is involved in numerous pathways including development, growth and immunity. The Jak tyrosine kinase 2 (Tyk2) is amongst others involved in type I interferon (IFNα/β) and IL-12 signalling, where it is required for full activation of Stats. Mice deficient for Tyk2 on the one hand show increased susceptibility to a number of pathogens, but on the other hand are resistant to e.g. lipopolysaccharide- (LPS-) induced shock. In the absence of Tyk2, peritoneal macrophages (PMs) show reduced expression of IFNβ, IFNα-4 and inducible nitric oxide synthase (iNOS) after LPS treatment. The global impact of the absence of Tyk2 on the transcriptional response of PMs to LPS treatment was analysed in a whole genome microarray experiment. By reverse-transcription (RT) quantitative real-time PCR (qPCR) we could confirm the microarray data with respect to reduced expression levels of IFNβ and IFN-stimulated genes (ISGs) in the absence of Tyk2 as compared to WT. In addition, six genes, that had so far not been described to be regulated in response to LPS or IFN treatment, were found to be induced/repressed after LPS treatment in a Tyk2-dependent manner. Within another expression profiling experiment, octamer-binding factor 6 (Oct-6; also known as Pou3f1, SCIP or Tst-1) was found to be induced in response to IFNβ in a Tyk2-dependent manner in fibroblasts. This transcription factor belongs to the family of Pit-Oct-Unc- (POU)- domain containing proteins and has been mainly described to be involved in developmental processes, but has not been related to immunity yet. We showed for the first time that Oct-6 is expressed in murine fibroblasts and macrophages after stimulation with IFNs. Oct-6 was also induced in response to poly(I:C) treatment and during viral infections, both in a strictly type I IFN-dependent manner. IFN-mediated induction of Oct-6 was largely dependent on the Jak/Stat signalling pathway and we could demonstrate Stat1 binding to the Oct-6 promoter in response to IFN treatment. With respect to the role of Oct-6, overexpression of Oct-6 resulted in prolonged expression of type I IFN mRNAs, but endogenous levels of Oct-6 did not impact on IFNα/β expression. However, we could demonstrate that endogenous Oct-6 is involved in regulating transcriptional responses to poly(I:C) treatment using microarray and RT-qPCR methods comparing the transcriptomes of WT and Oct-6-deficient macrophages. More detailed analyses will be required to fully elucidate the role of the novel ISG Oct-6 in innate immunity

Unlocking longevity: the role of telomeres and its targeting interventions

Average life expectancy has been steadily increasing in developed countries worldwide. These demographic changes are associated with an ever-growing social and economic strain to healthcare systems as well as society. The aging process typically manifests as a decline in physiological and cognitive functions, accompanied by a rise in chronic diseases. Consequently, strategies that both mitigate age-related diseases and promote healthy aging are urgently needed. Telomere attrition, characterized by the shortening of telomeres with each cell division, paradoxically serves as both a protective mechanism and a contributor to tissue degeneration and age-related ailments. Based on the essential role of telomere biology in aging, research efforts aim to develop approaches designed to counteract telomere attrition, aiming to delay or reduce age-related diseases. In this review, telomere biology and its role in aging and age-related diseases is summarized along with recent approaches to interfere with telomere shortening aiming at well- and healthy-aging as well as longevity. As aging research enters a new era, this review emphasizes telomere-targeting therapeutics, including telomerase activators and tankyrase inhibitors, while also exploring the effects of antioxidative and anti-inflammatory agents, along with indirectly related approaches like statins

The Union Tin Member of the Rooiberg Group : geodynamic implications for the Bushveld Large Igneous Province, South Africa

Funding: The support of the DSI-NRF Centre of Excellence (CoE) for Integrated Mineral and Energy Resource Analysis (DSI-NRF CIMERA) towards this research is acknowledged.The Union Tin Member, comprising a succession of pyroclastic and shale-dominated sedimentary rocks associated with the 2.05 billion-year-old Bushveld Large Igneous Province (LIP), is well-exposed particularly in the Union Sn field located 150 km north of Pretoria, South Africa. The Union Tin Member is a laterally extensive (>200 km-wide) marker horizon situated between the rhyolitic Kwaggasnek and Schrikkloof formations of the Rooiberg Group. The shale unit exhibits low total organic carbon (TOC) contents (168 ± 70 ppm) along with a narrow range of δ13C values (−27.7 ± 1.7 ‰) and δ15N values mostly around 0 ‰, resembling characteristics typical of marine shales. These siliciclastic sedimentary rocks were deposited in a shallow-marine sedimentary environment subjected to sea-level fluctuations, suggesting widespread submergence of the Kaapvaal Craton despite ongoing LIP magmatism. The whole-rock compositions, particularly rare earth elements (REE), Th, Sc, Zr, Ni, V and TiO2, indicate a provenance dominated by the underlying Rooiberg Group, which may also include the Paleoproterozoic Transvaal Supergroup, Archean tonalite-trondhjemite-granodiorite (TTG) suites and greenstones. Variable enrichments of the shale in Sn, Li, Cs, W and U are primarily associated with chlorite, sericite, illite and hematite. Notably, the rhyolites, immediately underlying and overlying the Union Tin Member, are similarly altered to a mineral assemblage dominated by the Fe-Al-Mg-bearing phases with relative enrichments especially in Sn. Alteration is linked to large-scale Sn-bearing hydrothermal fluids derived from the Lebowa Granite Suite. The periodic emplacement of extensive volcanic rocks of the Rooiberg Group is likely to have resulted in a downsagged >200 km-wide basin underlain by the Transvaal Supergroup. The deposition of the Union Tin Member within this basin could potentially represent the surface expression of a deep-seated, exceptionally large magma reservoir suggested to have contributed to the formation of the entire Bushveld LIP.Peer reviewe

Magnetic configurations of open-shell molecules on metals: The case of CuPc and CoPc on silver

For nanostructured interfaces between open-shell molecules and metal surfaces that involve charge transfer upon adsorption, the investigation of molecular magnetic properties is an interesting yet difficult task, because in principle different magnetic configurations with distinct properties can be found. Here, we study the magnetic properties of CuPc-Ag and CoPc-Ag interfaces, which constitute interesting test cases because charge is transferred to the initially open-shell Pc molecules upon adsorption. Using hybrid density functional theory, we examine the stability of the various magnetic configurations occurring at these nanoscale interfaces, as well as for the corresponding gas-phase anions, and compare our findings to those of previous experimental studies. For CuPc-Ag, we identify a high-spin triplet configuration as the most likely configuration at the interface, whereas for CoPc-Ag a quenching of the total magnetic moment is found. Interestingly, such quenching is consistent with two distinctly different interfacial electronic configurations. These important differences in the magnetic properties of CuPc and CoPc on Ag are rationalized by variations in the interaction of their central metal atoms with the substrate. Our work facilitates a deeper understanding of the magnetic configuration and interlinked electronic-structure properties of molecule-metal interfaces. Furthermore, it highlights the necessity of an appropriate choice of methodology in tandem with a detailed evaluation of the different emerging magnetic properties

Octamer-binding factor 6 (Oct-6/Pou3f1) is induced by interferon and contributes to dsRNA-mediated transcriptional responses

<p>Abstract</p> <p>Background</p> <p>Octamer-binding factor 6 (Oct-6, Pou3f1, SCIP, Tst-1) is a transcription factor of the Pit-Oct-Unc (POU) family. POU proteins regulate key developmental processes and have been identified from a diverse range of species. Oct-6 expression is described to be confined to the developing brain, Schwann cells, oligodendrocyte precursors, testes, and skin. Its function is primarily characterised in Schwann cells, where it is required for correctly timed transition to the myelinating state. In the present study, we report that Oct-6 is an interferon (IFN)-inducible protein and show for the first time expression in murine fibroblasts and macrophages.</p> <p>Results</p> <p>Oct-6 was induced by type I and type II IFN, but not by interleukin-6. Induction of Oct-6 after IFNβ treatment was mainly dependent on signal transducer and activator of transcription 1 (Stat1) and partially on tyrosine kinase 2 (Tyk2). Chromatin immunopreciptitation experiments revealed binding of Stat1 to the Oct-6 promoter in a region around 500 bp upstream of the transcription start site, a region different from the downstream regulatory element involved in Schwann cell-specific Oct-6 expression. Oct-6 was also induced by dsRNA treatment and during viral infections, in both cases <it>via </it>autocrine/paracrine actions of IFNα/β. Using microarray and RT-qPCR, we furthermore show that Oct-6 is involved in the regulation of transcriptional responses to dsRNA, in particular in the gene regulation of serine/threonine protein kinase 40 (<it>Stk40</it>) and U7 snRNA-associated Sm-like protein Lsm10 (<it>Lsm10)</it>.</p> <p>Conclusion</p> <p>Our data show that Oct-6 expression is not as restricted as previously assumed. Induction of Oct-6 by IFNs and viruses in at least two different cell types, and involvement of Oct-6 in gene regulation after dsRNA treatment, suggest novel functions of Oct-6 in innate immune responses.</p

Transcriptome analysis reveals a major impact of JAK protein tyrosine kinase 2 (Tyk2) on the expression of interferon-responsive and metabolic genes

<p>Abstract</p> <p>Background</p> <p>Tyrosine kinase 2 (Tyk2), a central component of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling, has major effects on innate immunity and inflammation. Mice lacking Tyk2 are resistant to endotoxin shock induced by lipopolysaccharide (LPS), and Tyk2 deficient macrophages fail to efficiently induce interferon α/β after LPS treatment. However, how Tyk2 globally regulates transcription of downstream target genes remains unknown. Here we examine the regulatory role of Tyk2 in basal and inflammatory transcription by comparing gene expression profiles of peritoneal macrophages from Tyk2 mutant and wildtype control mice that were either kept untreated or exposed to LPS for six hours.</p> <p>Results</p> <p>Untreated Tyk2-deficient macrophages exhibited reduced expression of immune response genes relative to wildtype, in particular those that contain interferon response elements (IRF/ISRE), whereas metabolic genes showed higher expression. Upon LPS challenge, IFN-inducible genes (including those with an IRF/ISRE transcription factor binding-site) were strongly upregulated in both Tyk2 mutant and wildtype cells and reached similar expression levels. In contrast, metabolic gene expression was strongly decreased in wildtype cells upon LPS treatment, while in Tyk2 mutant cells the expression of these genes remained relatively unchanged, which exaggerated differences already present at the basal level. We also identified several 5'UR transcription factor binding-sites and 3'UTR regulatory elements that were differentially induced between Tyk2 deficient and wildtype macrophages and that have not previously been implicated in immunity.</p> <p>Conclusions</p> <p>Although Tyk2 is essential for the full LPS response, its function is mainly required for baseline expression but not LPS-induced upregulation of IFN-inducible genes. Moreover, Tyk2 function is critical for the downregulation of metabolic genes upon immune challenge, in particular genes involved in lipid metabolism. Together, our findings suggest an important regulatory role for Tyk2 in modulating the relationship between immunity and metabolism.</p

Association between intraoperative hypotension and postoperative nausea and vomiting: a retrospective cohort study

Objective Postoperative nausea and vomiting (PONV) occurs in up to 30% of patients and its pathophysiology and mechanisms have not been completely described. Hypotension and a decrease in cardiac output are suspected to induce nausea. The hypothesis that intraoperative hypotension might influence the incidence of PONV was investigated. Material and methods The study was conducted as a retrospective large single center cohort study. The incidence of PONV was investigated until discharge from post anesthesia care unit (PACU). Surgical patients with general anesthesia during a 2-year period between 2018 and 2019 at a university hospital in Germany were included. Groups were defined based on the lowest documented mean arterial pressure (MAP) with group H50: MAP <50mmHg; group H60: MAP <60mmHg; group H70: MAP <70mmHg, and group H0: no MAP <70mmHg. Decreases of MAP in the different groups were related to PONV. Propensity-score matching was carried out to control for overlapping risk factors. Results In the 2-year period 18.674 patients fit the inclusion criteria. The overall incidence of PONV was 11%. Patients with hypotension had a significantly increased incidence of PONV (H0 vs. H50: 11.0% vs.17.4%, Risk Ratio (RR): 1.285 (99%CI: 1.102–1.498), p < 0.001; H0 vs. H60: 10.4% vs. 13.5%, RR: 1.1852 (99%CI: 1.0665–1.3172), p < 0.001; H0 vs. H70: 9.4% vs. 11.2%, RR: 1.1236 (99%CI: 1.013 − 1.2454); p = 0.0027). Conclusion The study demonstrates an association between intraoperative hypotension and early PONV. A more severe decrease of MAP had a pronounced effect