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.     

Visual search tree profiling

Understanding how the search space is explored for a given constraint problem – and how it changes for different models, solvers or search strategies – is crucial for efficient solving. Yet programmers often have to rely on the crude aggregate measures of the search that are provided by solvers, or on visualisation tools that can show the search tree, but do not offer sophisticated ways to navigate and analyse it, particularly for large trees. We present an architecture for profiling a constraint programming search that is based on a lightweight instrumentation of the solver. The architecture combines a visualisation of the search tree with various tools for convenient navigation and analysis of the search. These include identifying repeated subtrees, high-level abstraction and navigation of the tree, and the comparison of two search trees. The resulting system is akin to a traditional program profiler, which helps the user to focus on the parts of the execution where an improvement to their program would have the greatest effect.     

Knowledge base support for dynamic information system management

Enterprise activities are governed by regulations and laws that are multiple, heterogeneous and not always easy to understand. The arising and/or the modification of these regulations and laws can cause a significant impact in the business context, especially in terms of enterprise information systems adaptation. Currently, there are many methodological and technological tools that facilitate the application of regulations and procedures, but they are not integrated enough to ensure a complete problem management. Therefore, they are not sufficient to support organizations and companies in the management of their business processes. In this paper we propose a methodological and technological solution, able to model, manage, execute and monitor business processes of complex domains. The system allows both the design of an information system and its prototyping as a web application, by the extension of an appropriately selected Business Process Management suite. During both the design and the usage phases of the prototyped information system, it is possible to interface with a knowledge base that contains information about regulations and aspects that characterize the enterprise (organizational chart, tasks, etc.).     

Portability of executable service-oriented processes: metrics and validation

A key promise of process languages based on open standards, such as the Web Services Business Process Execution Language, is the avoidance of vendor lock-in through the portability of processes among runtime environments. Despite the fact that today various runtimes claim to support this language, every runtime implements a different subset, thus hampering portability and locking in their users. It is our intention to improve this situation by enabling the measurement of the portability of executable service-oriented processes. This helps developers to assess their implementations and to decide if it is feasible to invest in the effort of porting a process to another runtime. In this paper, we define several software quality metrics that quantify the degree of portability of an executable, service-oriented process from different viewpoints. When integrated into a development environment, such metrics can help to improve the portability of the outcome. We validate the metrics theoretically with respect to measurement theory and construct validity using two validation frameworks. The validation is complemented with an empirical evaluation of the metrics using a large set of processes coming from several process libraries.