Deriving session and union types for objects

Guaranteeing that the parties of a network application respect a given protocol is a crucial issue. Session types offer a method for abstracting and validating structured communication sequences (sessions). Object-oriented programming is an established paradigm for large scale applications. Union types, which behave as the least common supertypes of a set of classes, allow the implementation of unrelated classes with similar interfaces without additional programming. We have previously developed an integration of the features above into a class-based core language for building network applications, and this successfully amalgamated sessions and methods so that data can be exchanged flexibly according to communication protocols (session types). The first aim of the work reported in this paper is to provide a full proof of the type safety property for that core language by renewing syntax, typing and semantics. In this way, static typechecking guarantees that after a session has started, computation cannot get stuck on a communication deadlock. The second aim is to define a constraint-based type system that reconstructs the appropriate session types of session declarations instead of assuming that session types are explicitly given by the programmer. Such an algorithm can save programming work, and automatically presents an abstract view of the communications of the session

Dexamethasone nano-embedded sodium hyaluronate microparticles for treatment of COVID-19 acute respiratory distress syndrome

Dexamethasone (DX) is a synthetic glucocorticoid employed in a wide range of diseases asimmunosuppressant. Recent studies reported that DX could be administered orally or intravenouslyfor the treatment of acute respiratory distress syndrome in patients with COVID-19 phase-3infection caused by an overreaction of their immune system, reducing 28-day mortality in patientsmechanically ventilated or receiving oxygen [1]. Nevertheless, the long-term systemicadministration of dexamethasone led to severe side effects, highlighting the urgent need of newstrategies for its delivery [2][3]. The aim of this work was to develop a new formulation for inhalationbased on DX-nanoparticles. High molecular weight sodium hyaluronate (HA, 750 kDa) was employedto coat DX nanoparticles to exploit HA targeting to CD44 receptors on pulmonary macrophages andits anti-inflammatory effects[4]. DX-nanoparticles were obtained by anti-solvent precipitation usingwater as anti-solvent dripped into an alcoholic solution of drug. The suspension was spray-dried toobtain a dry powder. Size distribution and morphology of microparticles were investigated by laserdiffraction and scanning electron microscopy. Nanoparticle characteristics and composition wereassessed after powder redispersion in physiological medium by dynamic light scattering and X-rayscattering techniques. Results revealed the release of quite polydisperse nanoparticles (PdI = 0.3-0.4) with size around 290 nm in water and 180 nm in phosphate buffer. SAXS results showednanoparticles with a DX-rich crystalline core stabilized in solution by the presence of a shell of HAchains partially embedded in the core. After particle redispersion in water the aerodynamicbehavior of the obtained suspension was assessed in vitro using a device for aerosol therapyobtaining a Fine Particle Fraction of 87.5 +- 0.7% while the Emitted Fraction was 26.4 +-2.9%. Thelatter figure represents a limit that may be overcome by nebulizing directly the nanosuspension inthe pipe of a ventilator.Fil: Laura Bertocchi. Università di Parma; Italia. Departamento de Alimentos y Drogas ; Universita Degli Studi Di Parma;Fil: Cámara, Candelaria Inés. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; ArgentinaFil: Laura F. Cantú. Universita Degli Studi Di Milano. Dipartimento Di Beitecnologe Mediche E Medicina Traslazionale.; ItaliaFil: Elena Del Favero. Universita Degli Studi Di Milano. Dipartimento Di Beitecnologe Mediche E Medicina Traslazionale.; ItaliaFil: Ruggero Bettini. Departamento de Alimentos y Drogas ; Universita Degli Studi Di Parma;20th Advanced Course in Pharmaceutical TechnologyItaliaAssociazione Docenti e Ricercatori Italiani di Tecnologie e Legislazione Farmaceutich

Mutational Analysis of c-KIT and PDGFRA in Canine Gastrointestinal Stromal Tumors (GISTs)

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the canine gastrointestinal tract and are diagnosed by the immunohistochemical expression of the receptor tyrosine kinase (RTK) KIT. Activating mutations of the proto-oncogenes c-KIT and PDGFRA drive GIST oncogenesis and are used to predict the response to RTK-inhibitors in human oncology. Currently, the frequency and significance of these mutations in canine GIST have not been adequately explored. Therefore, we investigated the mutational status of c-KIT (exons 9, 11 and 13) and PDGFRA (exons 12 and 18) genes by PCR followed by fragment analysis for c-KIT deletions and PCR followed by screening with DHPLC and direct sequencing confirmation for single nucleotide variations in 17 formalin-fixed paraffin-embedded canine GISTs confirmed by KIT immunopositivity. c-KIT mutations were detected in 47% of cases, with a mutation detection rate significantly higher (p = 0.0004, Fisher's exact test) and always involving exon 11. A PDGFRA gene mutation (exon 18) was identified in one case. Even if follow-up data were not available for all cases, four cases with documented abdominal metastases displayed c-KIT mutations. These data confirm that c-KIT exon 11 mutations occur frequently in canine GISTs, and identify the presence of a PDGFRA mutation similar to human GISTs. This study also suggests a potential association of c-KIT mutation with more aggressive biological behavior

Anhedonia in schizophrenia: The role of subjective experiences

Background High levels of anhedonia have been found in patients with schizophrenia; specifically they report higher levels of social anhedonia rather than physical anhedonia, and further, in the anticipatory rather than consummatory facets of pleasure. Nonetheless, contrasting results emerged regarding the underlying mechanisms of this deficit. Basic Symptoms (BS) disturb subjective experiences present for most of the illness' course; this impacts patients' daily lives leading to a loss of the ability to organize the experience of the self and the world in a fluid and automatic way. Considering the role played by negative emotions in the subjective evaluation of anhedonia, the aim of the study is to clarify the role of BS in the assessment of anhedonia in a sample of patients with schizophrenia (n = 53) compared with healthy controls (n = 46). Methods Participants completed a self-administered trait questionnaire evaluating social anhedonia (Revised-Social Anhedonia Scale), physical anhedonia (Physical Anhedonia Scale), and the consummatory and anticipatory pleasure experiences (Temporal Experience of Pleasure Scale). BS were evaluated with the Frankfurter Beschwerde-Frageboden (FBF) whereas psychopathology was assessed with the Positive and Negative Syndromes Scale. Results Patients scored higher than healthy controls in social, physical and anticipatory anhedonia, but not in consummatory anhedonia and these relationships were mediated by the FBF. Basic Symptoms of Memory, Overstimulation and Lack of Automatism were related to some facets of anhedonia, independently from depressive symptoms. Conclusions We hypothesize that a subjective cognitive deficit and a reduced ability in information processing, could prevent patients from retaining a positive experience from past pleasant activities. Therefore the lack of pleasure would be, at least in part, related to an avoidance of potentially stressful new scenarios

The "Obsessive Paradox": The Complex Relationship Between Cognitive and Obsessive Dimensions in Schizophrenia

The objective of the study was to investigate the relationship between cognitive functions and obsessive-compulsive dimension in schizophrenia and a possible moderating effect of schizophrenia symptom dimensions on this association. Sixty-one schizophrenia patients were administered the Positive and Negative Syndrome Scale, the Yale-Brown Obsessive-Compulsive Scale (YBOCS), and the Matrics Consensus Cognitive Battery. A U-shaped curve described a gradual transition from an inverse association to a positive relationship between YBOCS and processing speed scores, along a severity gradient of obsessive dimension. This effect ("the obsessive paradox") was not moderated by other symptom dimensions. The present study suggests that severe obsessive-compulsive symptoms may participate to counterbalance processing speed impairment independently from other symptom dimensions. These results highlight the complexity of the relationship between cognitive and obsessive dimensions in schizophrenia

Hyaluronic acid—dexamethasone nanoparticles for local adjunct therapy of lung inflammation

The delivery of a dexamethasone formulation directly into the lung appears as an appro-priate strategy to strengthen the systemic administration, reducing the dosage in the treatment of lung severe inflammations. For this purpose, a hyaluronic acid-dexamethasone formulation was developed, affording an inhalable reconstituted nanosuspension suitable to be aerosolized. The physico-chemical and biopharmaceutical properties of the formulation were tested: size, stability, loading of the spray-dried dry powder, reconstitution capability upon redispersion in aqueous me-dia. Detailed structural insights on nanoparticles after reconstitution were obtained by light and X-ray scattering techniques. (1) The size of the nanoparticles, around 200 nm, is in the proper range for a possible engulfment by macrophages. (2) Their structure is of the core-shell type, hosting dex-amethasone nanocrystals inside and carrying hyaluronic acid chains on the surface. This specific structure allows for nanosuspension stability and provides nanoparticles with muco-inert proper-ties. (3) The nanosuspension can be efficiently aerosolized, allowing for a high drug fraction poten-tially reaching the deep lung. Thus, this formulation represents a promising tool for the lung administration via nebulization directly in the pipe of ventilators, to be used as such or as adjunct therapy for severe lung inflammation.Fil: Cámara, Candelaria Inés. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Físico-química de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Investigaciones en Físico-química de Córdoba; ArgentinaFil: Bertocchi, Laura. Departamento de Alimentos y Drogas ; Universita Degli Studi Di Parma;Fil: Ricci, Caterina. Universita Degli Studi Di Milano. Dipartimento Di Beitecnologe Mediche E Medicina Traslazionale.; ItaliaFil: Bassi, Rosaria. Universita Degli Studi Di Milano. Dipartimento Di Beitecnologe Mediche E Medicina Traslazionale.; ItaliaFil: Bianchera, Annalisa. Departamento de Alimentos y Drogas ; Universita Degli Studi Di Parma;Fil: Cantú, Laura F.. Universita Degli Studi Di Milano. Dipartimento Di Beitecnologe Mediche E Medicina Traslazionale.; ItaliaFil: Ruggero, Bettini. Departamento de Alimentos y Drogas ; Universita Degli Studi Di Parma;Fil: Del Favero, Elena. Universita Degli Studi Di Milano. Dipartimento Di Beitecnologe Mediche E Medicina Traslazionale.; Itali

Nano-adjuvanted dry powder vaccine for the mucosal immunization against airways pathogens

Nasal vaccination has been shown to provide optimal protection against respiratory pathogens. However, mucosal vaccination requires the implementation of specific immunization strategies to improve its effectiveness. Nanotechnology appears a key approach to improve the effectiveness of mucosal vaccines, since several nanomaterials provide mucoadhesion, enhance mucosal permeability, control antigen release and possess adjuvant properties. Mycoplasma hyopneumoniae is the main causative agent of enzootic pneumonia in pigs, a respiratory disease responsible for considerable economic losses in the pig farming worldwide. The present work developed, characterized, and tested in vivo an innovative dry powder nasal vaccine, obtained from the deposition on a solid carrier of an inactivated antigen and a chitosan-coated nanoemulsion, as an adjuvant. The nanoemulsion was obtained through a low-energy emulsification technique, a method that allowed to achieve nano droplets in the order of 200 nm. The oil phase selected was alpha-tocopherol, sunflower oil, and poly(ethylene glycol) hydroxystearate used as non-ionic tensioactive. The aqueous phase contained chitosan, which provides a positive charge to the emulsion, conferring mucoadhesive properties and favoring interactions with inactivated M. hyopneumoniae. Finally, the nanoemulsion was layered with a mild and scalable process onto a suitable solid carrier (i.e., lactose, mannitol, or calcium carbonate) to be transformed into a solid dosage form for administration as dry powder. In the experimental study, the nasal vaccine formulation with calcium carbonate was administered to piglets and compared to intramuscular administration of a commercial vaccine and of the dry powder without antigen, aimed at evaluating the ability of IN vaccination to elicit an in vivo local immune response and a systemic immune response. Intranasal vaccination was characterized by a significantly higher immune response in the nasal mucosa at 7 days post-vaccination, elicited comparable levels of Mycoplasma-specific IFN-gamma secreting cells and comparable, if not higher, responsiveness of B cells expressing IgA and IgG in peripheral blood mononuclear cells, with those detected upon a conventional intramuscular immunization. In conclusion, this study illustrates a simple and effective strategy for the development of a dry powder vaccine formulation for nasal administration which could be used as alternative to current parenteral commercial vaccines

Agrobacterium rhizogenes rolB gene affects photosynthesis and chlorophyll content in transgenic tomato (Solanum lycopersicum L.) plants

Insertion of Agrobacterium rhizogenes rolB gene into plant genome affects plant development, hormone balance and defence. However, beside the current research, the overall transcriptional response and gene expression of rolB as a modulator in plant is unknown. Transformed rolB tomato plant (Solanum lycopersicum L.) cultivar Tondino has been used to investigate the differential expression profile. Tomato is a well-known model organism both at the genetic and molecular level, and one of the most important commercial food crops in the world. Through the construction and characterization of a cDNA subtracted library, we have investigated the differential gene expression between transgenic clones of rolB and control tomato and have evaluated genes specifically transcribed in transgenic rolB plants. Among the selected genes, five genes encoding for chlorophyll a/b binding protein, carbonic anhydrase, cytochrome b6/f complex Fe-S subunit, potassium efflux antiporter 3, and chloroplast small heat-shock protein, all involved in chloroplast function, were identified. Measurement of photosynthesis efficiency by the level of three different photosynthetic parameters (Fv/Fm, rETR, NPQ) showed rolB significant increase in non-photochemical quenching and a, b chlorophyll content. Our results point to highlight the role of rolB on plant fitness by improving photosynthesis

Nationwide consensus on the clinical management of treatment-resistant depression in Italy: a Delphi panel

Background: Treatment-resistant depression (TRD) is defined by the European Medicines Agency as a lack of clinically meaningful improvement after treatment, with at least two different antidepressants. Individual, familiar, and socio-economic burden of TRD is huge. Given the lack of clear guidelines, the large variability of TRD approaches across different countries and the availability of new medications to meet the need of effective and rapid acting therapeutic strategies, it is important to understand the consensus regarding the clinical characteristics and treatment pathways of patients with TRD in Italian routine clinical practice, particularly in view of the recent availability of esketamine nasal spray. Methods: A Delphi questionnaire with 17 statements (with a 7 points Likert scale for agreement) was administered via a customized web-based platform to Italian psychiatrists with at least 5 years of experience and specific expertise in the field of depression. In the second-round physicians were asked to answer the same statements considering the interquartile range of each question as an index of their colleagues' responses. Stata 16.1 software was used for the analyses. Results: Sixty panellists, representative of the Italian territory, answered the questionnaire at the first round. For 8/17 statements more than 75% of panellists reached agreement and a high consensus as they assigned similar scores; for 4 statements the panellists assigned similar scores but in the middle of the Likert scale showing a moderate agreement with the statement, while for 5 statements there was indecision in the agreement and low consensus with the statement. Conclusions: This Delphi Panel showed that there is a wide heterogeneity in Italy in the management of TRD patients, and a compelling need of standardised strategies and treatments specifically approved for TRD. A high level of consensus and agreement was obtained about the importance of adding lithium and/or antipsychotics as augmentation therapies and in the meantime about the need for long-term maintenance therapy. A high level of consensus and agreement was equally reached for the identification of esketamine nasal spray as the best option for TRD patients and for the possibility to administrate without difficulties esketamine in a community outpatient setting, highlighting the benefit of an appropriate educational support for patients