Interfacial supramolecular electrochemistry Cui, Kang; Dorner, Iris; Mertens, Stijn F.L.
Current opinion in electrochemistry,
March 2018, 2018-03-00, Letnik:
8
Journal Article
Recenzirano
•Key principles of self-assembly at electrified solid–liquid interfaces are reviewed.•The effect of the electric field in the double layer on intermolecular and substrate–molecule interactions is ...explained.•The equivalence between the electrochemical interface and the field in an STM configuration is analyzed.
Supramolecular chemistry at solid–liquid interfaces is guided by the interactions between the molecular building blocks, the solid substrate and the liquid phase. At an electrochemical interface (i.e., at the interface between an electronic and ionic conductor), the substrate potential allows modulating many of these interactions, resulting in a high level of control over the supramolecular structures that are formed and their reactivity. In this paper, we review key principles and recent work in this area, and discuss how a standard scanning tunneling microscope setup allows to scale down interfacial supramolecular electrochemistry to the few-molecule level.
We demonstrate how metal UPD may find use as a general tool to determine the collective defect area in hybrids between 2D materials (graphene, hexagonal boron nitride, etc.) and various substrate ...metals. By investigating copper UPD on a monolayer of hexagonal boron nitride (h-BN) on Rh(111), we explore how this process can be used to quantify the defects in the h-BN monolayer which form during its chemical vapor deposition. In addition, the UPD signature allows assessing the potential window of the h-BN/metal hybrid, which is important to explore its functionality under ambient and electrochemical conditions. Importantly, UPD itself does not alter the defect area on repeated cycling. Overpotential deposition, on the other hand, is shown to have significant consequences on the defect area. We show that this non-innocent Cu electrodeposition involves intercalation originating at initial defects, causing irreversible delamination of the h-BN layer; this effect therefore may be used for 2D material nanoengineering.
Interferon lambda (IFNL) is expressed at high levels by intestinal epithelial cells (IECs) and mucosal immune cells in response to infection and inflammation. We investigated whether IFNL might ...contribute to pathogenesis of Crohn’s disease (CD).
We obtained serum samples and terminal ileum biopsies from 47 patients with CD and 16 healthy individuals (controls). We measured levels of IFNL by enzyme-linked immunosorbent assay and immunohistochemistry and location of expression by confocal microscopy. Activation of IFNL signaling via STAT1 was measured in areas of no, mild, moderate, and severe inflammation and correlated with Paneth cell homeostasis and inflammation. IFNL expression and function were studied in wild-type mice and mice with intestinal epithelial cell-specific (ΔIEC) disruption or full-body disruption of specific genes (Mlkl–/–, Stat1ΔIEC, Casp8ΔIEC, Casp8ΔIECRipk3–/–, Casp8ΔIECTnfr–/–, Casp8ΔIECMlkl–/–, and Nod2–/– mice). Some mice were given tail vein injections of a vector encoding a secreted form of IFNL. Intestinal tissues were collected from mice and analyzed by immunohistochemistry and immunoblots. We generated 3-dimensional small intestinal organoids from mice and studied the effects of IFNL and inhibitors of STAT-signaling pathway.
Patients with CD had significant increases in serum and ileal levels of IFNL compared with controls. Levels of IFNL were highest in ileum tissues with severe inflammation. High levels of IFNL associated with a reduced number of Paneth cells and increased cell death at the crypt bottom in inflamed ileum samples. Intestinal tissues from the ileum of wild-type mice injected with a vector expressing IFNL had reduced numbers of Paneth cells. IFNL-induced death of Paneth cells in mice did not occur via apoptosis, but required Mixed Lineage Kinase Domain Like (MLKL) and activation of Signal transducer and activator of transcription 1 (STAT1). In organoids, inhibitors of Janus kinase (JAK) signaling via STAT1 (glucocorticoids, tofacitinib, or filgotinib) reduced expression of proteins that mediate cell death and prevented Paneth cell death.
Levels of IFNL are increased in serum and inflamed ileal tissues from patients with CD and associated with a loss of Paneth cells. Expression of a secreted form of IFNL in mice results in loss of Paneth cells from intestinal tissues, via STAT1 and MLKL, controlled by caspase 8. Strategies to reduce IFNL or block its effects might be developed for treatment of patients with CD affecting the terminal ileum.
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Primary sclerosing cholangitis (PSC), often associated with inflammatory bowel disease (IBD), presents a multifactorial etiology involving genetic, immunological, and environmental factors. Gut ...dysbiosis and bacterial translocation have been implicated in PSC-IBD, yet the precise mechanisms underlying their pathogenesis remain elusive. Here, we describe the role of gut pathobionts in promoting liver inflammation and fibrosis due to the release of bacterial outer membrane vesicles (OMVs).
Preclinical mouse models in addition to ductal organoids were used to acquire mechanistic data. A proof-of-concept study including serum and liver biopsies of a patient cohort of PSC (n=22), PSC-IBD (n=45) and control individuals (n=27) was performed to detect OMVs in the systemic circulation and liver.
In both, preclinical model systems and in human PSC-IBD patients, the translocation of OMVs to the liver correlated with enhanced bacterial sensing and accumulation of the NLRP3 inflammasome. Using ductal organoids, we were able to precisely attribute the pro-inflammatory and pro-fibrogenic properties of OMVs to signaling pathways dependent on TLR4 and NLRP3-GSDMD. The immunostimulatory potential of OMVs could be confirmed in macrophages and hepatic stellate cells. Furthermore, when we administered gut pathobiont-derived OMVs to Mdr2-/- mice, we observed a significant enhancement in liver inflammation and fibrosis. In a translational approach, we substantiated the presence of OMVs in the systemic circulation and hepatic regions of severe fibrosis using a PSC-IBD patient cohort.
This study demonstrates the contribution of gut pathobionts in releasing OMVs that traverse the mucosal barrier, and thus, promote liver inflammation and fibrosis in PSC-IBD. OMVs might represent a critical new environmental factor that interacts with other disease factors to cause inflammation and thus define potential new targets for fibrosis therapy.
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Primary central nervous system (CNS) gliomas can be classified by characteristic genetic alterations. In addition to solid tissue obtained via surgery or biopsy, cell-free DNA (cfDNA) from ...cerebrospinal fluid (CSF) is an alternative source of material for genomic analyses.
We performed targeted next-generation sequencing (NGS) of CSF cfDNA in a representative cohort of 85 patients presenting at two neurooncological centers with suspicion of primary or recurrent glioma. Copy-number variation (CNV) profiles, single nucleotide variants (SNVs), and small insertions/ deletions (indels) were combined into a molecular-guided tumor classification. Comparison with the solid tumor was performed for 38 cases with matching solid tissue available.
Cases were stratified into four groups: glioblastoma (n = 32), other glioma (n = 19), non-malignant (n = 17) and non-diagnostic (n = 17). We introduced a molecular-guided tumor classification, which enabled identification of tumor entities and/ or cancer specific alterations in 75.0 % (n = 24) of glioblastoma and 52.6 % (n = 10) of other glioma cases. The overlap between CSF and matching solid tissue was highest for CNVs (26-48 %) and SNVs at pre-defined gene loci (44 %), followed by SNVs/ indels identified via uninformed variant calling (8-14 %). A molecular-guided tumor classification was possible for 23.5 % (n = 4) of non-diagnostic cases.
We developed a targeted sequencing workflow for CSF cfDNA as well as a strategy for interpretation and reporting of sequencing results based on a molecular-guided tumor classification in glioma.
The aim of this study was to evaluate the safety and efficacy of rituximab (RTX) in a large cohort of patients with rheumatoid arthritis in routine care, and to monitor changes in daily practice ...since the introduction of RTX therapy.
This was a multicentre, prospective, non-interventional study conducted under routine practice conditions in Germany. Efficacy was evaluated using Disease Activity Score in 28 joints (DAS28) and Health Assessment Questionnaire-Disability Index (HAQ-DI). Safety was assessed by recording adverse drug reactions (ADRs). Physician and patient global efficacy and tolerability assessments were also evaluated.
Overall, 2,484 patients (76.7% female, mean age 56.4 years, mean disease duration 11.7 years) received RTX treatment (22.7% monotherapy). The total observation period was approximately six-years (median follow-up 14.7 months). RTX treatment led to improvements in DAS28 and HAQ-DI that were sustained over multiple courses. DAS28 improvements positively correlated with higher rheumatoid factor levels up to 50 IU/ml. Response and tolerability were rated good/very good by the majority of physicians and patients. Mean treatment intervals were 10.5 and 6.8 months for the first and last 400 enrolled patients, respectively. Infections were the most frequently reported ADRs (9.1%; 11.39/100 patient-years); approximately 1% of patients per course discontinued therapy due to ADRs.
Prolonged RTX treatment in routine care is associated with good efficacy and tolerability, as measured by conventional parameters and by physicians' and patients' global assessments. Rheumatoid factor status served as a distinct and quantitative biomarker of RTX responsiveness. With growing experience, physicians repeated treatments earlier in patients with less severe disease activity.
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