Efficient Delivery of MicroRNA and AntimiRNA Molecules Using an Argininocalix[4]arene Macrocycle

MicroRNAs (miRNAs) are short non-coding RNA molecules acting as gene regulators by repressing translation or by inducing degradation of the target RNA transcripts. Altered expression of miRNAs may be involved in the pathogenesis of many severe human diseases, opening new avenues in the field of therapeutic strategies, i.e., miRNA targeting or miRNA mimicking. In this context, the efficient and non-toxic delivery of premiRNA and antimiRNA molecules might be of great interest. The aim of the present paper is to determine whether an argininocalix[4]arene is able to efficiently deliver miRNA, premiRNA, and antimiRNA molecules to target cells, preserving their biological activity. This study points out that (1) the toxicity of argininocalix[4]arene 1 is low, and it can be proposed for long-term treatment of target cells, being that this feature is a pre-requisite for the development of therapeutic protocols; (2) the delivery of premiRNA and antimiRNA molecules is efficient, being higher when compared with reference gold standards available; and (3) the biological activity of the premiRNAs and antimiRNAs is maintained. This was demonstrated using the argininocalix[4]arene 1 in miRNA therapeutic approaches performed on three well-described experimental model systems: (1) the induction of apoptosis by antimiR-221 in glioma U251 cells; (2) the induction of apoptosis by premiR-124 in U251 cells; and (3) the inhibition of pro-inflammatory IL-8 and IL-6 genes in cystic fibrosis IB3-1 cells. Our results demonstrate that the argininocalix[4]arene 1 should be considered a very useful delivery system for efficient transfer to target cells of both premiRNA and antimiRNA molecules, preserving their biological activity

Exploring the feasibility of ex-post harmonisation of religiosity items from the European Social Survey and the European Values Study

This paper examines the feasibility of ex-post harmonisation strategies using European Values Study (EVS) Wave 5 (2017–2020) and European Social Survey (ESS) Round 9 (2018–2019) data across 17 countries. The study shows an empirical assessment of the comparability of four items measuring religious behaviours (belonging to a religious denomination at present/in the past, religious services attendance, and praying), captured in both surveys. The novelty of this paper lies in the analytical comparison of religiosity indicators that are rarely assessed from a comparative perspective.The harmonisation strategy was based upon several analytical techniques that seek to determine similarities and differences between the selected items in terms of (a) their validity, by examining their correlations with a set of sociodemographic and substantive correlates, (b) their distributions, supplemented by visual comparisons and relevant statistical tests, and (c) item non-substantive shares. The findings pointed to the most consistency among the partial correlations, where individual religiosity produced the most differences between the surveys. Distributions produced the most discrepancies that also corresponded to less similarity across variable categories as gauged by Duncan’s index. This paper is descriptive and exploratory in its aim. It can be taken as a jumping-off point for future research where the time series of these two surveys, and potentially others, can be examined across aggregate levels (e.g. birth cohorts, countries)

Media response to colon cancer campaigns in Switzerland 2005-2007: regional newspapers are the most reliable among the printed media

<p>Abstract</p> <p>Background</p> <p>Health campaigns are frequently covered by printed media, but coverage is not homogeneous across different types of newspapers. Switzerland as a multilinguistic country with many newspapers offers a good field for study. A better understanding of how printed media report on national campaigns against colon cancer in the three main linguistic regions may help to improve future public health interventions. Therefore, we analyzed articles published between 2005 and 2007 during the campaigns "<it>Darmkrebs-nie</it>?" and "<it>Self-Care</it>" in the German, French and Italian regions of Switzerland.</p> <p>Findings</p> <p>Some 65% of articles reporting on colon cancer were in German, 23% and 12% were in French and Italian respectively. During the campaign, topics linked to colon cancer were increasingly covered by the media. Regional newspapers (66%) reported significantly more about colon cancer and produced the most detailed articles.</p> <p>Both gain- and loss-framed messages have been used by journalists, whereas the campaigns used merely gain-framed messages. Latin (French and Italian) newspapers mixed gain- and loss-framed messages in the same articles, while German articles mainly used a single frame throughout.</p> <p>Conclusions</p> <p>Swiss-German papers reported more about the topic and the reporting was quantitatively and qualitatively more prominent in regional papers. The press followed the campaigns closely only during the period of campaigning, with high coverage. We propose to consider the regional press as an important vehicle of health information. Moreover, slight differences in framing can be observed between German and Latin articles.</p

Custom Made Candy Plug for Distal False Lumen Occlusion in Aortic Dissection: International Experience

Objective: To evaluate early and midterm outcomes of the Candy Plug (CP) technique for distal false lumen (FL) occlusion in thoracic endovascular aortic repair for aortic dissection (AD) in a more real world cohort of patients from an international multicentre registry. Methods: A multicentre retrospective study was conducted of all consecutive patients from the contributing centres with subacute and chronic AD treated with the CP technique from October 2013 to April 2020 at 18 centres. Results: A custom made CP was used in 155 patients (92 males, mean age 62 ± 11 years). Fourteen (9%) presented with ruptured false lumen aneurysms. Technical success was achieved in all patients (100%). Clinical success was achieved in 138 patients (89%). The median hospital stay was 7 days (1 – 77). The 30 day mortality rate was 3% (n = 5). Stroke occurred in four patients (3%). Spinal cord ischaemia occurred in three patients (2%). The 30 day computed tomography angiogram (CTA) confirmed successful CP placement at the intended level in all patients. Early complete FL occlusion was achieved in 120 patients (77%). Early (30 day) CP related re-intervention was required in four patients (3%). The early (30 day) stent graft related re-intervention rate was 8% (n = 12). Follow up CTA was available in 142 patients (92%), with a median follow up of 23 months (6 – 87). Aneurysmal regression was achieved in 68 of 142 patients (47%); the aneurysm diameter remained stable in 69 of 142 patients (49%) and increased in five of 142 patients (4%). A higher rate of early FL occlusion was detected in the largest volume centre patients (50 [88%] vs. 70 [71%] from other centres; p = .019). No other differences in outcome were identified regarding volume of cases or learning curve. Conclusion: This international CP technique experience confirmed its feasibility and low mortality and morbidity rates. Aortic remodelling and false lumen thrombosis rates were high and support the concept of distal FL occlusion in AD using the CP technique

Sleep-Deprivation Regulates α-2 Adrenergic Responses of Rat Hypocretin/Orexin Neurons

We recently demonstrated, in rat brain slices, that the usual excitation by noradrenaline (NA) of hypocretin/orexin (hcrt/orx) neurons was changed to an inhibition following sleep deprivation (SD). Here we describe that in control condition (CC), i.e. following 2 hours of natural sleep in the morning, the α2-adrenergic receptor (α2-AR) agonist, clonidine, had no effect on hcrt/orx neurons, whereas following 2 hours of SD (SDC), it hyperpolarized the neurons by activating G-protein-gated inwardly rectifying potassium (GIRK) channels. Since concentrations of clonidine up to a thousand times (100 µM) higher than those effective in SDC (100 nM), were completely ineffective in CC, a change in the availability of G-proteins is unlikely to explain the difference between the two conditions. To test whether the absence of effect of clonidine in CC could be due to a down-regulation of GIRK channels, we applied baclofen, a GABAB agonist known to also activate GIRK channels, and found that it hyperpolarized hcrt/orx neurons in that condition. Moreover, baclofen occluded the response to clonidine in SDC, indicating that absence of effect of clonidine in CC could not be attributed to down-regulation of GIRK channels. We finally tested whether α2-ARs were still available at the membrane in CC and found that clonidine could reduce calcium currents, indicating that α2-ARs associated with calcium channels remain available in that condition. Taken together, these results suggest that a pool of α2-ARs associated with GIRK channels is normally down-regulated (or desensitized) in hcrt/orx neurons to only become available for their inhibition following sleep deprivation

Inborn errors of OAS-RNase L in SARS-CoV-2-related multisystem inflammatory syndrome in children

Multisystem inflammatory syndrome in children (MIS-C) is a rare and severe condition that follows benign COVID-19. We report autosomal recessive deficiencies of OAS1, OAS2, or RNASEL in five unrelated children with MIS-C. The cytosolic double-stranded RNA (dsRNA)-sensing OAS1 and OAS2 generate 2'-5'-linked oligoadenylates (2-5A) that activate the single-stranded RNA-degrading ribonuclease L (RNase L). Monocytic cell lines and primary myeloid cells with OAS1, OAS2, or RNase L deficiencies produce excessive amounts of inflammatory cytokines upon dsRNA or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) stimulation. Exogenous 2-5A suppresses cytokine production in OAS1-deficient but not RNase L-deficient cells. Cytokine production in RNase L-deficient cells is impaired by MDA5 or RIG-I deficiency and abolished by mitochondrial antiviral-signaling protein (MAVS) deficiency. Recessive OAS-RNase L deficiencies in these patients unleash the production of SARS-CoV-2-triggered, MAVS-mediated inflammatory cytokines by mononuclear phagocytes, thereby underlying MIS-C

Vascular Access Challenges in Thoracic Endovascular Aortic Repair: A Literature Review

BACKGROUND: This review aims to comprehensively summarize access challenges in thoracic endovascular aortic repair (TEVAR) by describing vascular access routes, associated risks, outcomes, and complications. METHODS: A literature search was conducted utilizing the PubMed (Medline), Scopus, and Web of Science databases. Qualitative and quantitative data from selected studies are extracted and discussed according to available standards for narrative reviews. RESULTS: In total, there were 109 eligible studies based on predefined inclusion- and exclusion criteria. There were 39 original articles or reviews and 57 case series or case reports. This article summarizes the evidence from these studies and discusses traditional retrograde access routes and techniques for TEVAR via a femoral or iliac route, with or without the use of conduits. Next, alternative antegrade access routes and techniques via a brachial, axillary, carotid, ascending aorta, transapical, transcaval, or another route are discussed. Vascular access complications are presented with specific attention to the importance of gender and alternative antegrade access routes. CONCLUSIONS: Multiple access routes and techniques are currently available to overcome access challenges associated with TEVAR, based on low grade evidence from heterogeneous studies. Future research that compares different access routes and techniques might help in the development of a tailored access protocol for specific patients with challenging TEVAR access