Plasma-derived therapeutic proteins are produced through an industrial fractionation process where proteins are purified from individual intermediates, some of which remain unused and are discarded. Relatively few plasma-derived proteins are exploited clinically, with most of available plasma being directed towards the manufacture of immunoglobulin and albumin. Although the plasma proteome provides opportunities to develop novel protein replacement therapies, particularly for rare diseases, the high cost of plasma together with small patient populations impact negatively on the development of plasma-derived orphan drugs. Enabling therapeutics development from unused plasma fractionation intermediates would therefore constitute a substantial innovation. To this objective, we characterized the proteome of unused plasma fractionation intermediates and prioritized proteins for their potential as new candidate therapies for human disease. We selected ceruloplasmin, a plasma ferroxidase, as a potential therapy for aceruloplasminemia, an adult-onset ultra-rare neurological disease caused by iron accumulation as a result of ceruloplasmin mutations. Intraperitoneally administered ceruloplasmin, purified from an unused plasma fractionation intermediate, was able to prevent neurological, hepatic and hematological phenotypes in ceruloplasmin-deficient mice. These data demonstrate the feasibility of transforming industrial waste plasma fraction into a raw material for manufacturing of new candidate proteins for replacement therapies, optimizing plasma use and reducing waste generation.

Background: The lack of disease-modifying drugs is one of the major unmet needs in patients with heart failure (HF). Peptides are highly selective molecules with the potential to act directly on cardiomyocytes. However, a strategy for effective delivery of therapeutics to the heart is lacking. Objectives: In this study, the authors sought to assess tolerability and efficacy of an inhalable lung-to-heart nano-in-micro technology (LungToHeartNIM) for cardiac-specific targeting of a mimetic peptide (MP), a first-in-class for modulating impaired L-type calcium channel (LTCC) trafficking, in a clinically relevant porcine model of HF. Methods: Heart failure with reduced ejection fraction (HFrEF) was induced in Göttingen minipigs by means of tachypacing over 6 weeks. In a setting of overt HFrEF (left ventricular ejection fraction [LVEF] 30% ± 8%), animals were randomized and treatment was started after 4 weeks of tachypacing. HFrEF animals inhaled either a dry powder composed of mannitol-based microparticles embedding biocompatible MP-loaded calcium phosphate nanoparticles (dpCaP-MP) or the LungToHeartNIM only (dpCaP without MP). Efficacy was evaluated with the use of echocardiography, invasive hemodynamics, and biomarker assessment. Results: DpCaP-MP inhalation restored systolic function, as shown by an absolute LVEF increase over the treatment period of 17% ± 6%, while reversing cardiac remodeling and reducing pulmonary congestion. The effect was recapitulated ex vivo in cardiac myofibrils from treated HF animals. The treatment was well tolerated, and no adverse events occurred. Conclusions: The overall tolerability of LungToHeartNIM along with the beneficial effects of the LTCC modulator point toward a game-changing treatment for HFrEF patients, also demonstrating the effective delivery of a therapeutic peptide to the diseased heart.

This article argues for a new way of approaching sustainability, reconsidering its fundamental assumptions. It describes two contrasting stances, namely 'restricted' and 'large-scale' sustainability. Restricted sustainability, i.e. the current dominant approach, focuses mostly on human welfare and is still rooted in a dualistic (man/nature) conception and an underlying sense of separateness. Large-scale sustainability instead centres on the concept of interdependence, seeking to rediscover the multiple patterns of connections that typify the world, and to uphold an overall (thus not only human) enduring welfare. The article also illustrates how knowledge co-production, i.e. a methodology currently employed in sustainability science, can contribute to large-scale sustainability. Such a methodology fosters, in fact, the inclusion of alternative cultural perspectives and knowledge traditions, like Indigenous ones, which can provide insight on the subject. In its last part, the article discusses the relation between knowledge, values, and behaviour, supporting the idea that sustainability science should combine the pursuit of knowledge with ethical engagement and commitment to action. This too would contribute to the development of large-scale sustainability. Indigenous epistemologies are explored in this context, as they provide models of ethically oriented knowledge that should be translated into proper conduct towards the entire community of living beings

Arylalkane-derived prodrugs of arylacetic acids are a small group of substances that have long been known for their anti-inflammatory action. Despite their ease of synthesis and good potential for the development of new potent and safe anti-inflammatory agents, this group of substances has not received much attention from researchers so far. Therefore, representative arylalkane derivatives were investigated through molecular docking techniques to verify the possible hepatic activation mode toward active metabolites by CYP1A2. In this regard, arylalkanoic acid prodrugs were docked with a crystallographic structure of human CYP1A2, in which the enzyme is co-crystallized with the selective competitive inhibitor ?-naphthoflavone BHF. Of note, all the examined compounds proved capable of interacting with the enzyme active site in a manner similar to Nabumetone, thus confirming that a productive metabolic transformation is feasible. On the basis of these findings, it is possible to argue that subtle differences in the way CYP1A2 accommodates the ligands depend on the fine details of their molecular structures. Overall, these data suggest that compounds simply formed by an aromatic moiety bearing an appropriate alkane-derived chain could lead to innovative anti-inflammatory agents.

Background: The role of dietary Glycemic Index (GI), independently of fiber intake, in modulating cardiovascular disease (CVD) risk among non-diabetic individuals has not been fully elucidated. Objective: To evaluate the effects of a low- versus a high-GI diet, based on a Mediterranean dietary pattern, on cardiometabolic risk factors in individuals at high CVD risk, participating in the MEDGI-Carb intervention study. Subjects and methods: 160 individuals, aged 30-69 years, BMI 25-37 kg/m2, with a waist circumference >102 cm (males) or >88 cm (females) and one feature of the metabolic syndrome, participated in a multi-national (Italy, Sweden, USA) randomized controlled parallel group trial. Participants were assigned to a low GI (< 55) or high-GI MedDiet ( > 70) for 12 weeks. The diets were isoenergetic and similar for available carbohydrate (270 g/d) and fiber (35 g/d) content. Fasting metabolic parameters were evaluated in the whole cohort, while an 8-h triglyceride profile (after standard breakfast and lunch) was evaluated only in the Italian cohort. Results: Blood pressure and most fasting metabolic parameters improved at the end of the dietary intervention (time effect, p < 0.05 for all); however, no differences were observed between the low- and the high-GI MedDiet groups (time x group effect; p > 0.05 for all). Conversely, the low-GI diet, compared with high-GI diet, significantly reduced the 8-h triglyceride profile (p < 0.017, time*group effect) that was measured only in the Italian cohort. However, it induced a reduction of plasma triglycerides after lunch (tAUC) that was of only borderline statistically significance (p = 0.065). Conclusions: Consuming a low-GI in comparison with a high-GI MedDiet does not differentially affect the major cardiometabolic risk factors at fasting in individuals at increased cardiometabolic risk. Conversely, it could reduce postprandial plasma triglycerides. Clinical trial registry number: NCT03410719, ( https://clinicaltrials.gov ).

Deep learning architectures suffer from depth-related performance degradation, limiting the effective depth of neural networks. Approaches like ResNet are able to mitigate this, but they do not completely eliminate the problem. We introduce Globally Connected Neural Networks (GloNet), a novel architecture overcoming depth-related issues, designed to be superimposed on any model, enhancing its depth without increasing complexity or reducing performance. With GloNet, the network's head uniformly receives information from all parts of the network, regardless of their level of abstraction. This enables GloNet to self-regulate information flow during training, reducing the influence of less effective deeper layers, and allowing for stable training irrespective of network depth. This paper details GloNet's design, its theoretical basis, and a comparison with existing similar architectures. Experiments show GloNet's self-regulation ability and resilience to depth-related learning challenges, like performance degradation. Our findings suggest GloNet as a strong alternative to traditional architectures like ResNets.

The outbreak of Covid-19 pandemic has sped up many healthcare processes and practices. Both stakeholders and standard organizations and authorities had to quickly implement new guidelines and codes to uniquely identify the disease and all the related healthcare data. The object of this work is to study the impact of the Covid-19 pandemic on clinical coding systems, in terms of updates and introduction of new specific codes for the identification of the SARS-CoV-2 virus, with the aim of allowing a better description of the disease and interoperability of the clinical data. The analysis is focused on ICD, SNOMED CT, LOINC, ATC as coding systems either included into the Italian EHR regulation or widely used internationally. Results show that coding systems that created a plenty of new codes for Covid-19 have: i) a flexible structure; ii) a speed process for updates; iii) a large user community for inputs. Others instead demonstrated in this circumstance that they are limited by hierarchical structures or excessively cumbersome updating processes, which conflict with the flexibility required to standards to represent the evolution of clinical knowledge. This is especially true in exceptional situation like the pandemic one.

Quels sont les processus sociaux et cognitifs activés entre les enfants dans la vie quotidienne d'un service éducatif pour la petite enfance ? Que signifie faire de l'éducation avec de jeunes enfants ? Comment soutenir la socialité et le partage des connaissances entre les jeunes enfants ? Comment promouvoir un contexte social inclusif dans lequel tous les enfants trouvent leur place ? Ces questions, cruciales pour assurer le bien-être et le développement des potentialités des enfants et pour promouvoir l'égalité des chances en matière d'éducation, ont été abordées dans le cadre d'un long projet de recherche-action mené en collaboration entre le groupe de recherche ISTC-CNR - Développement humain et société et le Service Éducation de la Ville de Pistoia, Italie. Cet ouvrage en présente les principaux résultats.

Accurate assessment of the rate and state friction parameters of rocks is essential for producing realistic earthquake rupture scenarios and, in turn, for seismic hazard analysis. Those parameters can be directly measured on samples, or indirectly based on inversion of coseismic or postseismic slip evolution. However, both direct and indirect approaches require assumptions that might bias the results. Aiming to reduce the potential sources of bias, we take advantage of a downscaled analog model reproducing megathrust earthquakes. We couple the simulated annealing algorithm with quasi-dynamic numerical models to retrieve rate and state parameters reproducing the recurrence time, rupture duration and slip of the analog model, in the ensemble. Then, we focus on how the asperity size and the neighboring segments' properties control the seismic cycle characteristics and the corresponding variability of rate and state parameters. We identify a tradeoff between (a-b) of the asperity and (a-b) of neighboring creeping segments, with multiple parameter combinations that allow mimicking the analog model behavior. Tuning of rate and state parameters is required to fit laboratory experiments with different asperity lengths. Poorly constrained frictional properties of neighboring segments are responsible for uncertainties of (a-b) of the asperity in the order of per mille. Roughly one order of magnitude larger uncertainties derive from asperity size. Those results provide a glimpse of the variability that rate and state friction estimates might have when used as a constraint to model fault slip behavior in nature.

Membrane technology is recognized to be unique in many industrial sectors. This technology contributes significantly to sustainable development promoted by the principles of Green Chemistry and Process Intensification Strategy (PI). It has become a successful alternative technology that led to significant benefits concerning the conventional separation techniques, such as ease of processability, flexibility, and small footprints making them the preferred choice in many fields of interest. In this overview, the vision for the future development of membrane operations is evidenced and it is based on the improvement of existing membrane processes for specific applications, such as hydrogen production, food sector, and distillation, by using membrane reactors, bioreactors, and membrane distillation (MD) processes, respectively. Furthermore, to enhance the sustainability throughout the lifecycle of membrane products, the exploitation of new solvents and biopolymers platforms that have great potential to replace hazardous solvents or petroleum-based materials for more sustainable membranes in different geometries is presented and discussed.

Recent progress in developing new vaccination strategies against cancer requires the production of complex and reliable animal models reflecting the complexity of the tumors with their microenvironment. Mice can be considered a good source due to low cost and ease of being genetically modified, inoculated with tumor cell lines or treated by chemicals to induce different cancers. Despite significant limitations in modeling human cancer complexity, preclinical trials conducted in mice can efficiently contribute to understand molecular mechanisms of cancer, to closely resemble and follow carcinogenesis steps impossible to study into humans, and to test new anticancer therapies. In this chapter, we generally describe the different mouse models developed for cancer vaccines' preclinical trials. A particular focus is dedicated to a chemically-induced colorectal cancer model in use in our laboratories.

Efficacy of novel cancer immunization protocols could be tested in cell line-derived xenograft tumor models (CDX), which are based on the implantation of human tumor cell lines into mice for the development of different tumors by numerous means, such as subcutaneous implantation and orthotopic, venial, or peritoneal injections. However, the disadvantages of this model are the biological alteration of the derived cells or the inability of the cell lines to accurately reflect the complexity of tumor heterogeneity. Therefore, syngeneic mouse models, which offer a relatively simple grafting technique, preservation of lineage hierarchy, and the ability to generate tumors in as little as 2-8 weeks, are being used to study potential future applications in medical treatment, particularly immunotherapies. Here, we describe a B16.F10 C57Bl/6 mouse melanoma model we selected for therapeutic studies employing IL-2 and IL-12 immunization protocols. Procedure of tumor cells inoculation and melanoma development in mice is described in detail, as first and necessary set-up for successful immunization experiments.

The chapter deals with the different treatment technologies that can be used to purify waters contaminated by As. It begins with a short summary of the conventional As removal methods (not based on the use of membranes) and then focuses on the last development in As removal by membrane technology, with the details of the research works reported in the literature and future perspectives.

Indoor positioning is a thriving research area which is slowly gaining market momentum. Its applications are mostly customised, ad hoc installations; ubiquitous applications analogous to GNSS for outdoors are not available because of the lack of generic platforms, widely accepted standards and interoperability protocols. In this context, the Indoor Positioning and Indoor Navigation (IPIN) competition is the only long-term, technically sound initiative to monitor the state of the art of real systems by measuring their performance in a realistic environment. Most competing systems are pedestrian-oriented and based on the use of smartphones, but several competing Tracks were set up, enabling comparison of an array of technologies. The two IPIN competitions described here include only off-site Tracks. In contrast with on-site Tracks where competitors bring their systems on site -- which were impossible to organise during 2021 and 2022 -- in off-site Tracks competitors download pre-recorded data from multiple sensors and process them using the EvaalAPI, a real-time, web-based emulation interface. As usual with IPIN competitions, Tracks were compliant with the EvAAL framework, ensuring consistency of the measurement procedure and reliability of results. The main contribution of this work is to show a compilation of possible indoor positioning scenarios and different indoor positioning solutions to the same problem.

Introduction: Neutralizing antibodies (NAbs) are an important specific defence against viral infections, as these antibodies bind to specific receptor(s) and block the viral entry. NAbs assessments are therefore useful in determining individual or herd immunity to SARS-CoV-2. This study aims to deepen the investigation by assessing the positivity rate of neutralizing anti-spike antibodies to understand the real protection of the studied population against SARS-CoV-2. Methods: This study involved 260 plasma samples from a larger cohort of 2,700 asymptomatic volunteer donors, enrolled between August and October 2021 in health facilities of N'Djamena. In this study four different kits and techniques including the pseudotype assay have been used and compared with detect the SARS-CoV-2 antibodies. Pseudotyped vesicular stomatitis virus (VSV), was used both the identify and measure the NAbs that to evaluate the performance of two cheaper and easy to use commercial kits, specific for the detection of receptor-binding domain antibodies (anti-RBD) against the SARS-CoV-2 spike protein. Results: The VSV spike neutralization assay showed that 59.0% (n = 59) samples were positive for NAbs with titers ranging from 1:10 to 1:4800. While 23 out the 41 negative NAbs samples were detected positive using anti-RBD (Abbott) test. Furthermore, a direct and significant strong correlation was found between NAbs and anti-RBD, specifically with Abbott kit. Taken together, the Roche and Abbott methods indicated agreement at the high concentrations of antibodies with the VSV-pseudovirus method. Abbott and Roche indicated a good sensitivity, but the Abbott system test appeared to have better specificity than the Roche test. Conclusion: Our findings indicated a high presence of NAbs against SARS-CoV-2 spike protein among asymptomatic individuals in N'Djamena. This could be one of the reasons for the low severity of Covid-19 observed in this area, given the key role of NAbs in blocking SARS-CoV-2 infection.

In border areas, time and space are constantly suspended from the usual rules along a liminal pathway transforming status and identity. In order to understand how different regimes of mobility and reception influence the experience of time and the subjective actions of both asylum seekers arriving via the so-called Balkan route and Ukrainian refugees fleeing from the war, the paper puts forward an analysis of the multiple scales of migration and reception policies as historically situated practices. How and to what extent has the increasing role of the humanitarian regime contributed to improving or worsening the lives of asylum seekers in borderland places where the memory of wars, civil conflicts, and experiences of refoulement is very much alive? Building on a multilocal ethnography of the temporalities of migrants' reception, the paper aims at disentangling the historical layers of hospitality in the northeastern Italian border areas of Trieste and Bolzano and the intersecting forms of (im)mobility at play. By addressing "reception" as an entanglement of spatial and temporal practices carried out by migrants, institutional, and humanitarian actors, we discuss not only how time reduces the existence of asylum seekers and Ukrainian refugees to an empty and meaningless human condition by exerting control over the subjective experiences, but also how the migrants' experience of waiting translates into an active state of being with the creative potential to trigger new forms of sociality, solidarity, and senses of belonging.

Planning petrol station replenishment is an important logistics activity for all the major oil companies. The studied Multi-Depot Periodic Petrol Station Replenishment problem derives from a real case in which the company must replenish a set of petrol stations from a set of depots, during a weekly planning horizon. The company must ensure refuelling according to available visiting patterns, which can be different from customer to customer. A visiting pattern predefines how many times (days) the replenishment occurs during a week and in which visiting days a certain amount of fuel must be delivered. To fulfill the weekly demand of each petrol station, one of the available replenishment plans must be selected among a given set of visiting patterns. The aim is to minimize the total distance travelled by the fleet of tank trucks during the entire planning horizon. A matheuristic approach is proposed, based on the cluster-first route-second paradigm, to solve it. The proposed approach is thoroughly tested on a set of realistic random instances. Finally, a weekly large real instance is considered with 194 petrol stations and two depots.

Rapporto tecnico che descrive dei test di trasmissione di segnale via radio. Si è testata la possibilità di inviare da una stazione Master delle correzioni RTCM (Radio Technical Commission for Maritime), ricevute via internet tramite protocollo NTRIP (Networked Transport of RTCM via Internet Protocol), ad una stazione Slave a cui era connesso un ricevitore GNSS U Blox ZED F9P in grado così di ottenere un posizionamento RTK (real time kinematics) in real-time. Sono stati fatti anche test inserendo un Repeater tra il Master e lo Slave, per simulare il caso reale di trasmissione via radio di segnali con ostacoli. La strumentazione utilizzata, il set-up sperimentale e i test effettuati in laboratorio sono descritti in dettaglio nel rapporto tecnico.

The present work delves into innovative methodologies leveraging the widely used BERT model to enhance the population and enrichment of domainoriented controlled vocabularies as Thesauri. Starting from BERT's embeddings, we extracted information from a sample corpus of Cybersecurity related documents and presented a novel Natural Language Processing-inspired pipeline that combines Neural language models, knowledge graph extraction, and natural language inference for identifying implicit relations (adaptable to thesaural relationships) and domain concepts to populate a domain thesaurus. Preliminary results are promising, showing the effectiveness of using the proposed methodology, and thus the applicability of LLMs, BERT in particular, to enrich specialized controlled vocabularies with new knowledge.

Background: The International Classification of Primary Care (ICPC) has represented the international standard reduction for measuring the content of primary care for over 30 years. In the process of its third revision, its authors, the Wonca International Classification Committee (WICC), delegated a major part of the technical work to a purposely formed Consortium. However, in the process of such revision, standard classification principles and rules have been inconsistently applied with the result that ICPC-3 has been published with major errors and an inconsistent structure. Objectives: To formally describe and critically appraise the revision process of ICPC-3. Methods: The formal review of ICPC-3 performed by an expert group within WICC and commissioned by the Executive Council of Wonca Europe is presented in abridged form. Results: ICPC-3 as currently presented introduces major departures from formal classification principles and rules, besides other major errors and inconsistencies, all of which are listed and described. Conclusion: Major changes in ICPC-3 defy categorisation and conceptualisation standards. ICPC-3 now represents an untested departure from international standard presentations, without a formal academic base. The direct inclusion of measures of functioning in a classification of reasons for encounter and health problems fails to address the dichotomy of these domains, the boundaries of and relationships between which are not satisfactorily resolved by the system. Analysis of ICPC-3 data will require the development and implementation of alternative, as yet undefined, models of the relationships between disease and health. By including different domains without resolving ambiguity, and by splitting function from other body systems, ICPC-3 becomes an internally fractured instrument.