Circulating Histones Induce Inflammatory Responses in Monocytes: Effects of Heparins as Histone-Neutralizing Agents

Background The formation and release of Extracellular Traps (ETs), characterizing the mechanism of ETosis, represents both a cellular death mechanism and an additional immune system pathway against infections. The uncontrolled occurrence of this process results in an excessive release of these ETs, which can have dangerous effects on the host. The core of these structures is made up of extracellular DNA that is connected to various nuclear, cytosolic, and granular proteins. The biomolecular characterization of ET revealed that histones, in particular, can promote and/or amplify hyperinflammatory response, coagulation cascade, endothelial dysfunction, and eventually multi-organ failure. On these bases, extracellular histones could become potential biomarkers and predictive laboratory tools for numerous human diseases, including cancer, thrombosis, autoimmune disorders, systemic lupus erythematosus, Sepsis, and COVID-19 infection. The discovery of therapeutic approaches aimed at the neutralization and inhibition of extracellular histones activity could improve the clinical course and outcomes of these pathologies. Experimental Objectives and Approaches This project was designed to I) investigate the ability of histones to alter monocyte morphology and functions, promoting the onset of a pro-inflammatory phenotype, and II) to evaluate the ability of heparin variants to limit the histone-induced inflammatory profiles. To this end, we used an ex vivo human whole-blood experimental model. We used histones as inflammatory triggers and tested their ability to promote the release of a wide panel of inflammatory mediators, and how this could be inhibited by using four commercially available anticoagulant drugs (Enoxaparin, Unfractionated Heparin, Sulodexide, and Fondaparinux). Furtherly, we explored the impact of extracellular histones on the cytomorphological features of human monocytes by evaluating the alterations of MDW (Monocyte Distribution Width), a hematological laboratory parameter associated with monocytic heterogeneity in response to massive inflammatory stimulation. Results Our studies demonstrated the direct role of histones as contributing agents in the initiation of cytokine storm, as found in vivo in some severe human disorders such as Sepsis and COVID -19. Besides, we observed that heparin variants (Enoxaparin, Unfractionated Heparin, Sulodexide, and Fondaparinux) have different inhibiting effects on histone-Induced Inflammation, thus representing potential candidates to limit their harmful effects. Finally, the most intriguing and innovative discovery is that histones can act as MDW modifiers, by altering circulating monocyte volume, cytoplasmic granularity and vacuolization, and nuclear structure, all alterations that are generally found in viral and classical septic patients but never referred to histones, to date. Final Considerations Taken together all these findings highlight the dangerous effect of circulating histones, suggesting that a greater understanding of their biomolecular mechanisms of action, as well as their neutralization, might have a positive impact on the outcomes of many life-threatening clinical disorders.Background The formation and release of Extracellular Traps (ETs), characterizing the mechanism of ETosis, represents both a cellular death mechanism and an additional immune system pathway against infections. The uncontrolled occurrence of this process results in an excessive release of these ETs, which can have dangerous effects on the host. The core of these structures is made up of extracellular DNA that is connected to various nuclear, cytosolic, and granular proteins. The biomolecular characterization of ET revealed that histones, in particular, can promote and/or amplify hyperinflammatory response, coagulation cascade, endothelial dysfunction, and eventually multi-organ failure. On these bases, extracellular histones could become potential biomarkers and predictive laboratory tools for numerous human diseases, including cancer, thrombosis, autoimmune disorders, systemic lupus erythematosus, Sepsis, and COVID-19 infection. The discovery of therapeutic approaches aimed at the neutralization and inhibition of extracellular histones activity could improve the clinical course and outcomes of these pathologies. Experimental Objectives and Approaches This project was designed to I) investigate the ability of histones to alter monocyte morphology and functions, promoting the onset of a pro-inflammatory phenotype, and II) to evaluate the ability of heparin variants to limit the histone-induced inflammatory profiles. To this end, we used an ex vivo human whole-blood experimental model. We used histones as inflammatory triggers and tested their ability to promote the release of a wide panel of inflammatory mediators, and how this could be inhibited by using four commercially available anticoagulant drugs (Enoxaparin, Unfractionated Heparin, Sulodexide, and Fondaparinux). Furtherly, we explored the impact of extracellular histones on the cytomorphological features of human monocytes by evaluating the alterations of MDW (Monocyte Distribution Width), a hematological laboratory parameter associated with monocytic heterogeneity in response to massive inflammatory stimulation. Results Our studies demonstrated the direct role of histones as contributing agents in the initiation of cytokine storm, as found in vivo in some severe human disorders such as Sepsis and COVID -19. Besides, we observed that heparin variants (Enoxaparin, Unfractionated Heparin, Sulodexide, and Fondaparinux) have different inhibiting effects on histone-Induced Inflammation, thus representing potential candidates to limit their harmful effects. Finally, the most intriguing and innovative discovery is that histones can act as MDW modifiers, by altering circulating monocyte volume, cytoplasmic granularity and vacuolization, and nuclear structure, all alterations that are generally found in viral and classical septic patients but never referred to histones, to date. Final Considerations Taken together all these findings highlight the dangerous effect of circulating histones, suggesting that a greater understanding of their biomolecular mechanisms of action, as well as their neutralization, might have a positive impact on the outcomes of many life-threatening clinical disorders

Stratigraphic variations control deformation patterns in evaporite basins : Messinian examples, onshore and offshore Sicily (Italy)

Acknowledgements and Funding We are grateful to Ente Minerario Siciliano and Italkali for the provision of extensive subsurface data from Realmonte, Corvillo and Mandre areas. We thank F. Peel and an anonymous referee for comments. Seismic reflection data are available for inspection and interpretation at the Virtual Seismic Atlas (www. seismicatlas.org). R.M. acknowledges a MIUR Cofin-PRIN 2010–2011 grant.Peer reviewedPublisher PD

Syn-kinematic sedimentary systems as constraints on the structural response of thrust belts : re-examining the structural style of the Maghrebian thrust belt of Eastern Sicily

We are indebted to the generosity of the late Fabio Lentini. While he may not have agreed with our findings, he nevertheless openly and cheerfully shared his mapping and insight of Sicilian geology. This work also builds upon many years’ collaboration between us, initiated by the late Mario Grasso (the Pantagruelian Master of Speranza et alii, 2018). The mapping of Lentini, Grasso and colleagues represents a remarkable resource for future geologists. We dedicate this contribution to their memory. We thank Sveva Corrado and an anonymous referee for constructive comments on an earlier draft of this paper. Butler’s Sicilian field research has been variously funded by the UK’s Natural Environment Research Council and the Royal Society. Maniscalco acknowledges “Fondi per la Ricerca di AteneoPiano per la Ricerca 2016/2018”. Pinter was supported through a PhD grant funded by the BG Group (now Shell) and Brazil’s National Council for Scientific and Technological Development (CNPq).Peer reviewedPublisher PD

Tracking sand-fairways through a deformed turbidite system : the Numidian (Miocene) of Central Sicily, Italy

The research presented here is funded by BG Group in partnership with CNPq-Brazil (National Council for Scientific and Technological Development). Rosanna Maniscalco acknowledges a FIR 2014 grant awarded from the University of Catania. We thank Christian Haug Eide, David Hodgson and Enrico Tavarnelli for constructive and thorough reviews on an earlier draft that have greatly improved this contribution.Peer reviewedPublisher PD

Do Circulating Histones Represent the Missing Link among COVID-19 Infection and Multiorgan Injuries, Microvascular Coagulopathy and Systemic Hyperinflammation?

none5no: Several studies shed light on the interplay among inflammation, thrombosis, multi-organ failures and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Increasing levels of both free and/or circulating histones have been associated to coronavirus disease 2019 (COVID-19), enhancing the risk of heart attack and stroke with coagulopathy and systemic hyperinflammation. In this view, by considering both the biological and clinical rationale, circulating histones may be relevant as diagnostic biomarkers for stratifying COVID-19 patients at higher risk for viral sepsis, and as predictive laboratory medicine tool for targeted therapies.openLigi, Daniela; Maniscalco, Rosanna; Plebani, Mario; Lippi, Giuseppe; Mannello, FerdinandoLigi, Daniela; Maniscalco, Rosanna; Plebani, Mario; Lippi, Giuseppe; Mannello, Ferdinand

Deep-water sand-fairway mapping as a tool for tectonic restoration : decoding Miocene central Mediterranean palaeogeography using the Numidian turbidites of southern Italy

The research presented here was funded by BG-Shell in partnership with CNPq-Brazil (National Council for Scientific and Technological Development). Rosanna Maniscalco acknowledges a Piano Triennale della Ricerca 2016-2018 grant awarded from the University of Catania.Peer reviewedPublisher PD

The Estimation of Lava Flow Temperatures Using Landsat Night-Time Images: Case Studies from Eruptions of Mt. Etna and Stromboli (Sicily, Italy), Kīlauea (Hawaii Island), and Eyjafjallajökull and Holuhraun (Iceland)

Using satellite-based remote sensing to investigate volcanic eruptions is a common approach for preliminary research, chiefly because a great amount of freely available data can be effectively accessed. Here, Landsat 4-5TM, 7ETM+, and 8OLI night-time satellite images are used to estimate lava flow temperatures and radiation heat fluxes from selected volcanic eruptions worldwide. After retrieving the spectral radiance, the pixel values were transformed into temperatures using the calculated calibration constants. Results showed that the TIR and SWIR bands were saturated and unable to detect temperatures over the active lava flows. However, temperatures were effectively detected over the active lava flows in the range ~500–1060 ◦C applying the NIR-, red-, green- or blue-band. Application of the panchromatic band with 15 m resolution also revealed details of lava flow morphology. The calculated radiant heat flux for the lava flows accords with increasing cooling either with slope or with distance from the vent

Paleomagnetic Evidence for 25–15 Ma Crust Fragmentation of North Indochina (23–26°N): Consequence of Collision With Greater India NE Corner?

AbstractThe Cenozoic deformation of SE Asia is classically related to India‐Asia collision and Tibet Plateau rise, supposedly resulting in the southeastward drift of lithospheric blocks bounded by strike‐slip faults with displacements in the order of 1,000 km. Here we report on the paleomagnetism of 44 Triassic‐Cretaceous red bed sites from the northern Simao, Chuandian, and Lanping "blocks," along both sides of the Ailao Shan‐Red River shear zone (north Indochina). In the Simao domain, remagnetization predates folding and subsequent 48–70° clockwise rotation of three 2–5 km wide subblocks separated by two unrotated blocks. A primary magnetization component from the Lanping domain center suggests variably clockwise rotated (up to 95° ± 24°) sites, interrupted by a 2–6 km wide block that is rotated counterclockwise by 27° ± 6°. Thus, the Lanping and Simao "blocks" are far from being rigid, being made of a mosaic of independently deforming subblocks, whose kinematics and association with documented tectonics are speculative. It is unclear whether both folding and widespread remagnetization were synchronous or diachronous across north Indochina, but (considering previously published results) strike‐slip activity along major shear zones, remagnetization, rotations, and crustal shortening overlapped within the 32–15 Ma time window, thus were likely genetically related. As opposed to previous models, we suggest that in early to mid‐Cenozoic times, north Indochina was under the influence of oblique Neo‐Tethys subduction. Collision between the NE corner of Greater India and Indochina at ~30 Ma yielded ENE‐WSW shortening and strike‐slip reactivation of preexisting faults, in turn fragmenting the crust into small, independently rotating, blocks

The Numidian of Sicily revisited : a thrust-influenced confined turbidite system

The research presented here is funded by BG Group in partnership with CNPq-Brazil (National Council for Scientific and Technological Development). Rosanna Maniscalco acknowledges a FIR 2014 grant awarded by the University of Catania, Sicily. Patricia Pinter thanks Prof. Karin Goldberg for helpful discussions in the field and Thisiane dos Santos, Francesca Porro and Dario La Camiola for extensive field assistance. Finally we thank Simon Lomas and the anonymous reviewers for their constructive comments that helped us to improve this paper.Peer reviewedPublisher PD

Recent Updates and Advances in the Use of Glycated Albumin for the Diagnosis and Monitoring of Diabetes and Renal, Cerebro- and Cardio-Metabolic Diseases

Diabetes mellitus is a heterogeneous and dysmetabolic chronic disease in which the laboratory plays a fundamental role, from diagnosis to monitoring therapy and studying complications. Early diagnosis and good glycemic control should start as early as possible to delay and prevent metabolic and cardio-vascular complications secondary to this disease. Glycated hemoglobin is currently used as the reference parameter. The accuracy of the glycated hemoglobin dosage may be compromised in subjects suffering from chronic renal failure and terminal nephropathy, affected by the reduction in the survival of erythrocytes, with consequent decrease in the time available for glucose to attach to the hemoglobin. In the presence of these renal comorbidities as well as hemoglobinopathies and pregnancy, glycated hemoglobin is not reliable. In such conditions, dosage of glycated albumin can help. Glycated albumin is not only useful for short-term diagnosis and monitoring but predicts the risk of diabetes, even in the presence of euglycemia. This protein is modified in subjects who do not yet have a glycemic alteration but, as a predictive factor, heralds the risk of diabetic disease. This review summarizes the importance of glycated albumin as a biomarker for predicting and stratifying the cardiovascular risk linked to multiorgan metabolic alterations