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The optimized formulation, TPIA-W, demonstrates uniform in vitro drug delivery, a PK profile suitable for a once-daily administration, efficacy lasting at least 12 h in a hypoxic challenge model, and a significantly higher cough threshold than the parent drug treprostinil.Gliomas account for most primary Central Nervous System (CNS) neoplasms, characterized by high aggressiveness and low survival rates. Despite the immense research efforts, there is a small improvement in glioma survival rates, mostly attributed to their heterogeneity and complex pathophysiology. Recent data indicate the delicate interplay of genetic and epigenetic mechanisms in regulating gene expression and cell differentiation, pointing towards the pivotal role of bivalent genes. Bivalency refers to a property of chromatin to acquire more than one histone marks during the cell cycle and rapidly transition gene expression from an active to a suppressed transcriptional state. Although first identified in embryonal stem cells, bivalent genes have now been associated with tumorigenesis and cancer progression. Emerging evidence indicates the implication of bivalent gene regulation in glioma heterogeneity and plasticity, mainly involving Homeobox genes, Wingless-Type MMTV Integration Site Family Members, Hedgehog protein, and Solute Carrier Family members. selleck products These genes control a wide variety of cellular functions, including cellular differentiation during early organism development, regulation of cell growth, invasion, migration, angiogenesis, therapy resistance, and apoptosis. In this review, we discuss the implication of bivalent genes in glioma pathogenesis and their potential therapeutic targeting options.Nitric oxide (NO) is a regulator of growth, development, and stress responses in living organisms. Plant nitrate reductases (NR) catalyze the reduction of nitrate to nitrite or, alternatively, to NO. In plants, NO action and its targets remain incompletely understood, and the way NO regulates its own homeostasis remains to be elucidated. A significant transcriptome overlapping between NO-deficient mutant and NO-treated wild type plants suggests that NO could negatively regulate its biosynthesis. A significant increase in NO content was detected in transgenic plants overexpressing NR1 and NR2 proteins. In turn, NR protein and activity as well as NO content, decreased in wild-type plants exposed to a pulse of NO gas. Tag-aided immunopurification procedures followed by tandem mass spectrometry allowed identifying NO-triggered post-translational modifications (PTMs) and ubiquitylation sites in NRs. Nitration of tyrosine residues and S-nitrosation of cysteine residues affected key amino acids involved in binding the essential FAD and molybdenum cofactors. NO-related PTMs were accompanied by ubiquitylation of lysine residues flanking the nitration and S-nitrosation sites. NO-induced PTMs of NRs potentially inhibit their activities and promote their proteasome-mediated degradation. This auto-regulatory feedback loop may control nitrate assimilation to ammonium and nitrite-derived production of NO under complex environmental conditions.In most disciplines of natural sciences and engineering, mathematical and computational modelling are mainstay methods which are usefulness beyond doubt. These disciplines would not have reached today's level of sophistication without an intensive use of mathematical and computational models together with quantitative data. This approach has not been followed in much of molecular biology and biomedicine, however, where qualitative descriptions are accepted as a satisfactory replacement for mathematical rigor and the use of computational models is seen by many as a fringe practice rather than as a powerful scientific method. This position disregards mathematical thinking as having contributed key discoveries in biology for more than a century, e.g., in the connection between genes, inheritance, and evolution or in the mechanisms of enzymatic catalysis. Here, we discuss the role of computational modelling in the arsenal of modern scientific methods in biomedicine. We list frequent misconceptions about mathematical modelling found among biomedical experimentalists and suggest some good practices that can help bridge the cognitive gap between modelers and experimental researchers in biomedicine. This manuscript was written with two readers in mind. Firstly, it is intended for mathematical modelers with a background in physics, mathematics, or engineering who want to jump into biomedicine. We provide them with ideas to motivate the use of mathematical modelling when discussing with experimental partners. Secondly, this is a text for biomedical researchers intrigued with utilizing mathematical modelling to investigate the pathophysiology of human diseases to improve their diagnostics and treatment.Thrombotic events are common complications in COVID-19 patients that include both thrombus formation in large vessels and the microvasculature of the lung and other organs. COVID-19-associated coagulopathy (CAC) and disseminated intravascular coagulation (DIC) have similarities and differences, and whether CAC is a form of DIC is the subject of debate. Reported mechanisms of CAC include activated coagulation, endotheliopathy, up-regulated innate and adaptive immunity, and activated complement system. Although the clinical features and laboratory findings of CAC and DIC seem different, there are fundamental similarities that should be considered. Basically, the pathological findings of COVID-19 fall within the scope of the definition of DIC, i.e., systemic activation of coagulation caused by or resulting from the microvascular damage. Therefore, we suggest that although CAC differs from usual infection-associated DIC, its various features indicate that it can be considered a thrombotic phenotype DIC. This review summarizes the current knowledge about CAC including differences and similarities with sepsis-associated DIC.Differently from alpha- and betaherpesviruses affecting swine, interest in the recently discovered Suid gammaherpesvirus 3, Suid gammaherpesvirus 4, and Suid gammaherpesvirus 5, also known as porcine lymphotropic herpesviruses (PLHV-1, PLHV-2, and PLHV-3), has largely focused on their role as potential zoonotic agents in cases of xenotransplantation. However, their role as primary pathogens of swine or as co-factors for other lymphotropic infections has essentially been neglected. The present study aims at filling this gap, evaluating the association between PLHVs infection and different clinical conditions and/or porcine circovirus (PCV) co-infection. One hundred seventy-six samples were obtained from different animals located in a high-density pig area of Northern Italy in the period 2017-2020. The presence of PLHVs and PCVs was tested and quantified by specific real-time PCR PLHVs were widespread among pigs (PLHV-1, PLHV-2, and PLHV-3 prevalence was 28.97%, 10.79%, and 4.54%, respectively) and detected in all considered tissues and clinical conditions.