Search

Background: Inflammation is a critical component of many disease progressions, such as malignancy, cardiovascular and rheumatic diseases. The inhibition of inflammatory mediators synthesis by modulation of cyclooxygenase (COX) and lipoxygenase (LOX) pathways provides challenging strategy for development of more effective drugs. Objective: The aim of this study was to design dual COX-2 and 5-LOX inhibitors with iron-chelating properties using a combination of ligand-based (three-dimensional quantitative structure-activity relationship (3D-QSAR)) and structure-based (molecular docking) methods. Methods: The 3D-QSAR analysis was applied on a literature dataset consisting of 28 dual COX-2 and 5- LOX inhibitors in Pentacle software. The quality of developed COX-2 and 5-LOX 3D-QSAR models were evaluated by internal and external validation methods. The molecular docking analysis was performed in GOLD software, while selected ADMET properties were predicted in ADMET predictor software. Results: According to the molecular docking studies, the class of sulfohydroxamic acid analogues, previously designed by 3D-QSAR, were clustered as potential dual COX-2 and 5-LOX inhibitors with ironchelating properties. Based on the 3D-QSAR and molecular docking, 1j, 1g and 1l were selected as the most promising dual COX-2 and 5-LOX inhibitors. According to the in silico ADMET predictions, all compounds had ADMET_Risk score less than 7 and CYP_Risk score lower than 2.5. Designed compounds were not estimated as hERG inhibitors and 1j had improved intrinsic solubility (8.704) in comparison to the dataset compounds (0.411-7.946). Conclusion: By combining 3D-QSAR and molecular docking, three compounds (1j, 1g and 1l) were selected as the most promising designed dual COX-2 and 5-LOX inhibitors, for which good activity, as well as favourable ADMET properties and toxicity, are expected.

In a series of three studies, we examined whether third-party observers can detect attraction in others based on subtle nonverbal cues. We employed video segments of dates collected from a speed-dating experiment, in which daters went on a brief (approx. 4 min) blind-date and indicated whether they would like to go on another date with their brief interaction partner or not. We asked participants to view these stimuli and indicate whether or not each couple member is attracted to their partner. Our results show that participants could not reliably detect attraction, and this ability was not influenced by the age of the observer, video segment location (beginning or middle of the date), video duration, or general emotion recognition capacity. Contrary to previous research findings, our findings suggest that third-party observers cannot reliably detect attraction in others. However, there was one exception: Recognition rose above chance level when the daters were both interested in their partners compared to when they were not interested.The online version contains supplementary material available at 10.1007/s12144-022-02927-0.

A THz plasma switch, driven by ultrafast XUV pulses for temporal ovelap in pump–probe experiments, is presented., A simple and robust tool for spatio-temporal overlap of THz and XUV pulses in in-vacuum pump–probe experiments is presented. The technique exploits ultrafast changes of the optical properties in semiconductors (i.e. silicon) driven by ultrashort XUV pulses that are probed by THz pulses. This work demonstrates that this tool can be used for a large range of XUV fluences that are significantly lower than when probing by visible and near-infrared pulses. This tool is mainly targeted at emerging X-ray free-electron laser facilities, but can be utilized also at table-top high-harmonics sources.

Faecal calprotectin (FC) is a known marker of colonic inflammation. There is evidence of elevated FC levels in patients with Helicobacter pylori (HP) infection and in patients with colorectal cancer (CRC). Chronic inflammation and HP have been associated with increased risk for CRC. Aim of this study was to find differences in FC levels in patients with CRC regarding HP infection. Our results confirm the association of chronic colonic inflammation and CRC, but also imply there is an additional effect of HP on colonic inflammation in patients with CRC. Further studies in order to clarify the potential role of FC in patients with HP and CRC are needed.

Objective: Psychological safety is increasingly recognised as central to mental health, wellbeing and post-traumatic growth. To date, there is no psychometrically supported measure of psychological safety combining psychological, physiological and social components. The current research aimed to develop and establish the neuroception of psychological safety scale (NPSS), informed by Polyvagal Theory. Method: The study comprised of three stages: (1) item generation, (2) item reduction, and (3) assessment of factor structure and internal consistency. Exploratory and confirmatory factor analysis was conducted from two samples who completed a survey online (exploratory n = 342, confirmatory n = 455). Results: Initially, 107 items were generated. Item reduction and exploratory factor analysis resulted in a 29-item NPSS with subscales of compassion, social engagement and body sensations. The NPSS was found to have a consistent factor structure and internal consistency. Conclusion: The NPSS is a novel measure of psychological safety which can be used across a range of health and social care settings. This research provides a platform for further work to support and enhance understandings of the science of safety through the measurement of psychological, relational and physiological components of safety. The NPSS will help shape new approaches to evaluating trauma treatments, relational issues and mental health concerns. Research to establish the convergent, discriminant and concurrent validity of the NPSS and to explore its use with diverse community and clinical populations is underway.

Spatial organization and gene expression of mammalian chromosomes are maintained and regulated in conjunction with cell cycle progression. This is perturbed once cells enter senescence and the highly abundant HMGB1 protein is depleted from nuclei to act as an extracellular proinflammatory stimulus. Despite its physiological importance, we know little about the positioning of HMGB1 on chromatin and its nuclear roles. To address this, we mapped HMGB1 binding genome-wide in two primary cell lines. We integrated ChIP-seq and Hi-C with graph theory to uncover clustering of HMGB1-marked topological domains that harbor genes involved in paracrine senescence. Using simplified Cross-Linking and Immuno-Precipitation and functional tests, we show that HMGB1 is also a bona fide RNA-binding protein (RBP) binding hundreds of mRNAs. It presents an interactome rich in RBPs implicated in senescence regulation. The mRNAs of many of these RBPs are directly bound by HMGB1 and regulate availability of SASP-relevant transcripts. Our findings reveal a broader than hitherto assumed role for HMGB1 in coordinating chromatin folding and RNA homeostasis as part of a regulatory loop controlling cell-autonomous and paracrine senescence.