The amino-terminal region of Tyk2 sustains the level of interferon alpha receptor 1, a component of the interferon alpha/beta receptor

Tyk2 belongs to the Janus kinase (JAK) family of receptor associated tyrosine kinases, characterized by a large N-terminal region, a kinase-like domain and a tyrosine kinase domain. It was previously shown that Tyk2 contributes to interferon-alpha (IFN-alpha) signaling not only catalytically, but also as an essential intracellular component of the receptor complex, being required for high affinity binding of IFN-alpha. For this function the tyrosine kinase domain was found to be dispensable. Here, it is shown that mutant cells lacking Tyk2 have significantly reduced IFN-alpha receptor 1 (IFNAR1) protein level, whereas the mRNA level is unaltered. Expression of the N-terminal region of Tyk2 in these cells reconstituted wild-type IFNAR1 level, but did not restore the binding activity of the receptor. Studies of mutant Tyk2 forms deleted at the N terminus indicated that the integrity of the N-terminal region is required to sustain IFNAR1. These studies also showed that the N-terminal region does not directly modulate the basal autophosphorylation activity of Tyk2, but it is required for efficient in vitro IFNAR1 phosphorylation and for rendering the enzyme activatable by IFN-alpha. Overall, these results indicate that distinct Tyk2 domains provide different functions to the receptor complex: the N-terminal region sustains IFNAR1 level, whereas the kinase-like domain provides a function toward high affinity ligand binding.     

A logic of argumentation for specification and verification of abstract argumentation frameworks

In this paper, we propose a logic of argumentation for the specification and verification (LA4SV) of requirements on Dung??s abstract argumentation frameworks. We distinguish three kinds of decision problems for argumentation verification, called extension verification, framework verification, and specification verification respectively. For example, given a political requirement like ??if the argument to increase taxes is accepted, then the argument to increase services must be accepted too,?? we can either verify an extension of acceptable arguments, or all extensions of an argumentation framework, or all extensions of all argumentation frameworks satisfying a framework specification. We introduce the logic of argumentation verification to specify such requirements, and we represent the three verification problems of argumentation as model checking and theorem proving properties of the logic. Moreover, we recast the logic of argumentation verification in a modal framework, in order to express multiple extensions, and properties like transitivity and reflexivity of the attack relation. Finally, we introduce a logic of meta-argumentation where abstract argumentation is used to reason about abstract argumentation itself. We define the logic of meta-argumentation using the fibring methodology in such a way to represent attack relations not only among arguments but also among attacks. We show how to use this logic to verify the requirements of argumentation frameworks where higher-order attacks are allowed [A preliminary version of the logic of argumentation compliance was called the logic of abstract argumentation?(2005).]     

The Landscape of microRNAs in βCell: Between Phenotype Maintenance and Protection

Diabetes mellitus is a group of heterogeneous metabolic disorders characterized by chronic hyperglycaemia mainly due to pancreatic β cell death and/or dysfunction, caused by several types of stress such as glucotoxicity, lipotoxicity and inflammation. Different patho-physiological mechanisms driving β cell response to these stresses are tightly regulated by microRNAs (miRNAs), a class of negative regulators of gene expression, involved in pathogenic mechanisms occurring in diabetes and in its complications. In this review, we aim to shed light on the most important miRNAs regulating the maintenance and the robustness of β cell identity, as well as on those miRNAs involved in the pathogenesis of the two main forms of diabetes mellitus, i.e., type 1 and type 2 diabetes. Additionally, we acknowledge that the understanding of miRNAs-regulated molecular mechanisms is fundamental in order to develop specific and effective strategies based on miRNAs as therapeutic targets, employing innovative molecules.     

Refining Genotypes and Phenotypes in KCNA2-Related Neurological Disorders

Pathogenic variants in KCNA2, encoding for the voltage-gated potassium channel K_v1.2, have been identified as the cause for an evolving spectrum of neurological disorders. Affected individuals show early-onset developmental and epileptic encephalopathy, intellectual disability, and movement disorders resulting from cerebellar dysfunction. In addition, individuals with a milder course of epilepsy, complicated hereditary spastic paraplegia, and episodic ataxia have been reported. By analyzing phenotypic, functional, and genetic data from published reports and novel cases, we refine and further delineate phenotypic as well as functional subgroups of KCNA2-associated disorders. Carriers of variants, leading to complex and mixed channel dysfunction that are associated with a gain- and loss-of-potassium conductance, more often show early developmental abnormalities and an earlier onset of epilepsy compared to individuals with variants resulting in loss- or gain-of-function. We describe seven additional individuals harboring three known and the novel KCNA2 variants p.(Pro407Ala) and p.(Tyr417Cys). The location of variants reported here highlights the importance of the proline(405)–valine(406)–proline(407) (PVP) motif in transmembrane domain S6 as a mutational hotspot. A novel case of self-limited infantile seizures suggests a continuous clinical spectrum of KCNA2-related disorders. Our study provides further insights into the clinical spectrum, genotype–phenotype correlation, variability, and predicted functional impact of KCNA2 variants.     

SUL-151 Decreases Airway Neutrophilia as a Prophylactic and Therapeutic Treatment in Mice after Cigarette Smoke Exposure

Chronic obstructive pulmonary disease (COPD) caused by cigarette smoke (CS) is featured by oxidative stress and chronic inflammation. Due to the poor efficacy of standard glucocorticoid therapy, new treatments are required. Here, we investigated whether the novel compound SUL-151 with mitoprotective properties can be used as a prophylactic and therapeutic treatment in a murine CS-induced inflammation model. SUL-151 (4 mg/kg), budesonide (500 μg/kg), or vehicle were administered via oropharyngeal instillation in this prophylactic and therapeutic treatment setting. The number of immune cells was determined in the bronchoalveolar lavage fluid (BALF). Oxidative stress response, mitochondrial adenosine triphosphate (ATP) production, and mitophagy-related proteins were measured in lung homogenates. SUL-151 significantly decreased more than 70% and 50% of CS-induced neutrophils in BALF after prophylactic and therapeutic administration, while budesonide showed no significant reduction in neutrophils. Moreover, SUL-151 prevented the CS-induced decrease in ATP and mitochondrial mtDNA and an increase in putative protein kinase 1 expression in the lung homogenates. The concentration of SUL-151 was significantly correlated with malondialdehyde level and radical scavenging activity in the lungs. SUL-151 inhibited the increased pulmonary inflammation and mitochondrial dysfunction in this CS-induced inflammation model, which implied that SUL-151 might be a promising candidate for COPD treatment.     

Esterification of acrylic acid with methanol by reactive chromatography: Experiments and simulations

The esterification of acrylic acid with methanol using Amberlyst 15 as a stationary phase has been investigated using a chromatographic reactor. Several experimental runs at various operating conditions have been conducted on a batch column. A classical reactive chromatography model including lumped kinetics, a linear driving force transport model and a heterogeneous kinetic model for the catalytic reaction has been developed. The additional dispersion of concentration fronts due to density gradient effects has been accounted for in the model. The model parameters have been determined in a fast and reliable way by directly fitting the batch column experiments. In general, a good agreement between experimental and calculated results is obtained. The evaluation of the covariance of the fitted model parameters reveals important insights about the system behavior.Based on the detailed batch column model, a complete model of a simulated-moving-bed reactor has been implemented and its optimal point of operation for the synthesis of methyl acrylate from acrylic acid has been determined. Particularly when considering the low-operating temperature, we can regard this process as a possible competition for current technologies.     

Electrochemical anticorrosion performance evaluation of Al2O3 coatings deposited by MOCVD on an industrial brass substrate

Alumina (Al₂O₃) coatings of different thickness were deposited on OT59 brass substrate (BS) using the metal organic chemical vapour deposition (MOCVD) technique to evaluate the corrosion performance by EIS measurements. The used precursor was dimethyl-aluminium-isopropoxide. Electrochemical characterizations of the deposited films were performed in a standard very aggressive acidic solution (aerated 1N H₂SO₄ at 25 °C up to 168 h of immersion time) by means of direct current method (Tafel curves) and electrochemical impedance spectroscopy (EIS). The Rutherford backscattering spectroscopy (RBS) indicated that the films are very pure with the correct Al₂O₃ stoichiometry, while the IR absorption spectra showed that the films did not contain any OH groups. The surface film morphology was investigated by atomic force microscopy (AFM) and displayed a globular texture. The films were very smooth, with a maximum root mean square roughness, for example, of 14 nm for a 0.96 μm thick coating. The EIS data confirmed, as expected, that a 2.40 μm Al₂O₃ layer ensures the best corrosion protection after 168 h of immersion in the very acidic environment used.     

Improved bibliographic reference parsing based on repeated patterns

Parsing details like author names and titles out of bibliographic references of scientific publications is an important issue that has received considerable attention recently. However, most existing techniques are tailored to the highly standardized reference styles used in the last two to three decades. They do not perform well with the wide variety of reference styles used in older, historic publications. Thus, they are of limited use when creating comprehensive bibliographies covering both historic and contemporary scientific publications. This paper presents a generic approach to bibliographic reference parsing, named RefParse, which is independent of any specific reference style. Its core feature is an inference mechanism that exploits the regularities inherent in any list of references to deduce its format. In addition, our approach learns names of authors, journals, and publishers to increase the accuracy in scenarios where human users double check parsing results to increase data quality. Our evaluation shows that our approach performs comparably to existing ones with contemporary reference lists and also works well with older ones.     

Reaction engineering studies in a polytropic fixed-bed reactor over a highly active and selective catalyst for oxidative methane coupling

The oxidative coupling of methane (OCM) was carried out in a polytropic fixed-bed reactor applying a Zr/La/Sr catalyst developed by the Neste company. Over this catalyst the OCM reaction follows a complex reaction scheme which includes primary parallel reaction steps to CO, CO₂ and C₂H₆ and consecutive reactions of ethane to ethylene or CO_x. Yield of higher hydrocarbons C₂₊ obtained with this catalyst strongly depended on reaction conditions, i.e. low partial pressures of methane and oxygen obtained by diluting the feed gas with nitrogen and high reaction temperatures promoted C₂₊ selectivity and yield. The maximum yield amounted to 21.4% (20 Vol.-% CH₄, 9 Vol.-% O₂, 71 Vol.-% N₂, T = 860°C; X_CH4 = 41.8%, S = 52.5%). This result belongs to the highest yields reported in the open literature.     

N2O catalytic decomposition over various spinel-type oxides

Various spinel-type catalysts AB₂O₄ (where A = Mg, Ca, Mn, Co, Ni, Cu, Cr, Fe, Zn and B = Cr, Fe, Co) were prepared and characterized by XRD, BET, TEM and FESEM-EDS. The performance of these catalysts towards the decomposition of N₂O to N₂ and O₂ was evaluated in a temperature programmed reaction (TPR) apparatus in the absence and the presence of oxygen. Spinel-type oxides containing Co at the B site were found to provide the best activity. The half conversion temperature of nitrous oxide over the MgCo₂O₄ catalyst was 440 °C and 470 °C in the absence and presence of oxygen, respectively (GHSV = 80,000 h⁻¹).

On the grounds of temperature programmed oxygen desorption (TPD) analyses as well as of reactive runs, the prevalent activity of the MgCo₂O₄ catalyst could be explained by its higher concentration of suprafacial, weakly chemisorbed oxygen species, whose related vacancies contribute actively to nitrous oxide catalytic decomposition. This indicates the way for the development of new, more active catalysts, possibly capable of delivering at low temperatures amounts of these oxygen species even higher than those characteristic of MgCo₂O₄.