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During COVID-19 pandemic, international pharmaceutical companies put effort to build global manufacturing networks for vaccines. Soberana Plus vaccine, a recombinant protein based vaccine (RBD dimer), with the trade name of PastoCovac Plus in Iran, is based on a protein subunit platform in Cuba and completed preclinical and toxicological assessments. This study aimed at presenting the steps of vaccine technology transfer from Cuba to Iran. This study provides the first practical comparability results in Iran to ensure the quality, safety and efficacy of a protein subunit vaccine against COVID-19 after a successful technology transfer from Cuba. PastoCovac Plus was transferred to Iran at the formulation stage. The assessment of the active ingredient pharmaceutical (API) was achieved through physicochemical and clinical data collection and tests to assure if there was any adverse impact on the vaccination results. In order to assess the quality of the vaccine product after technology transfer, we sought different properties including regulatory features, physicochemical quality, vaccine potency and stability as well as its immunogenicity and safety. Following the evaluation of the clinical quality attributes (CQAs) based on the standard protocols, the results showed that the two vaccines are highly similar and comparable, with no considerable effect on safety or efficacy profiles. The CQAs were all in the acceptance limits in terms of safety and efficacy as well as clinical evaluation results. The immunogenicity evaluation also confirmed no significant differences between the vaccines regarding reinfection (P = 0.199) or vaccine breakthrough (P = 0.176). Furthermore, the level of anti-spike and neutralizing antibodies in the both vaccine groups was not significantly different indicating the equality of performance between the two vaccines. According to the results of the quality and clinical assessment of this study, we achieved an acceptable quality attributes and acceptant limits in terms of safety and efficacy of the vaccines pre and post technology transfer. [ABSTRACT FROM AUTHOR]

Pertussis vaccines have been very effective in controlling whooping-cough epidemics but are ineffective in controlling circulation in older children and adults, thus facilitating the onset of future outbreaks. Antibodies against the lipopolysaccharide could reduce the carriage of the bacteria, its circulation, and transmission. The oligosaccharide fragments from the lipopolysaccharide may become a potential complement to existing vaccines in the form of protein glycoconjugates. An important step in the development of this type of vaccine is defining the minimal oligosaccharide epitope recognized by B. pertussis anti-lipopolysaccharide antibodies. This paper describes the complete synthesis of oligosaccharides containing two to five monosaccharide units corresponding to the pentasaccharide at the nonreducing end of the lipooligosaccharide and their recognition by mice and rabbit antibodies elicited against whole-cell B. pertussis. For the first time, we report that the terminal disaccharide, α-D-GlcNAcp-(1 → 4)-(2,3-di-NAc)-D-ManAp acid is the minimal structure recognized by antibodies induced by B. pertussis. [ABSTRACT FROM AUTHOR]

Biomechanical analysis of the human spine is crucial to understanding injury patterns. Motion capture technology has gained attention due to its non-invasive nature. Nevertheless, traditional motion capture studies consider the spine a single rigid segment, although its alignment changes during movement. Moreover, guidelines that indicate where markers should be placed for a specific exercise do not exist. This study aims to review the methods used to assess spine biomechanics using motion capture systems to determine the marker sets used, the protocols used, the resulting parameters, the analysed activities, and the characteristics of the studied populations. PRISMA guidelines were used to perform a Scoping Review using SCOPUS and Web of Science databases. Fifty-six journal and conference articles from 1997 to 2023 were considered for the analysis. This review showed that Plug-in-Gait is the most used marker set. The lumbar spine is the segment that generates the most interest because of its high mobility and function as a weight supporter. Furthermore, angular position and velocity are the most common outcomes when studying the spine. Walking, standing, and range of movement were the most studied activities compared to sports and work-related activities. Male and female participants were recruited similarly across all included articles. This review presents the motion capture techniques and measurement outcomes of biomechanical studies of the human spine, to help standardize the field. This work also discusses trends in marker sets, study outcomes, studied segments and segmentation approaches. [ABSTRACT FROM AUTHOR]

Patulin is a mycotoxin whose presence in apple-derived products and fruit juices is legally regulated, being its maximum limits established in the legislation of multiple countries. However, the management of contaminated batches is still an issue for producers. This investigation aims to evaluate ultraviolet light (254 nm, UV-C254nm) irradiation to find solutions that can be applied at different stages of the apple juice production chain. In this regard, 8.8 (UV-1) and 35.1 (UV-2) kJ m−2 treatments inactivated spores of Penicillium expansum CMP-1 on the surface of apples. Although the same treatments applied to wounded apples (either before the infection or after the infection, immediately or when the lesion had appeared) did not show any effect on the growth rate of P. expansum during storage (up to 14 days, at 4 or 25 °C), they reduced patulin content per lesion size in apples treated after the infection had occurred (patulin decreased from 2.24 (control) to 0.65 µg kg−1 cm−2 (UV-2 treated apples)). Additionally, the treatment of juice with patulin with ultraviolet light up to 450.6 kJ m−2 resulted in more than 98 % reduction of patulin. Degradation products of patulin after UV-C254nm treatments were tentatively identified by HPLC–MS, and toxicity and biological activities were assessed in silico, and results indicated that such products did not pose an increased risk when compared to patulin. [ABSTRACT FROM AUTHOR]

Relaxation Runge–Kutta methods reproduce a fully discrete dissipation (or conservation) of entropy for entropy stable semi-discretizations of nonlinear conservation laws. In this paper we derive the discrete adjoint of relaxation Runge–Kutta schemes, which are applicable to discretize-then-optimize approaches for optimal control problems. Furthermore, we prove that the derived discrete relaxation Runge–Kutta adjoint preserves time-symmetry when applied to linear skew-symmetric systems of ODEs. Numerical experiments verify these theoretical results while demonstrating the importance of appropriately treating the relaxation parameter when computing the discrete adjoint. [ABSTRACT FROM AUTHOR]

The aging of alcoholic beverages in wood barrels is a very common practice that allows the improvement of the organoleptic characteristics of the products. Although oak wood is most usually used for manufacturing barrels, the new trends based on accelerated aging processes by using wood chips have encouraged the study of other wood species that could confer its specific characteristics for obtaining differentiated beverages. In this work, three Mediterranean wood species, olive tree (Olea europaea L.), almond tree (Prunus dulcis (Mill.) D.A.Webb) and common grape vine (Vitis vinífera L. (White Grenache)), as well as the usual French oak (Quercus petraea (Matt) Liebl.) were macerated in alcohol–water solution to determine optimal extraction conditions, evaluating the polyphenol extraction, color parameters and organoleptic characteristics. To do that, a central composite design was applied to each wood species considering the toasting level, the dose of chips and alcoholic strength of the extracting solution. In addition, a kinetics study was carried out. From the results, it can be suggested that the optimum conditions for the accelerated aging (based on polyphenol extraction) are a high toasting level of chips, a dose of 18 g/L and macerating in an alcoholic solution of 60% v/v, for a minimum period of 70 days. Sensory analysis showed that the organoleptic characteristics of almond and vine wood are similar to those of French oak, except for the vanilla parameter (higher in both wood species compared to oak), and that the vine wood also presents a more smoky character. Olive wood differs from other wood species due to a greater fruit and floral character, and organoleptic characteristics less associated with oak wood. [ABSTRACT FROM AUTHOR]

Self-adaptive systems (SASs) are increasingly leveraging autonomy in their decision-making to manage uncertainty in their operating environments. A key problem with SASs is ensuring their requirements remain satisfied as they adapt. The trade-off analysis of the non-functional requirements (NFRs) is key to establish balance among them. Further, when performing the trade-offs it is necessary to know the importance of each NFR to be able to resolve conflicts among them. Such trade-off analyses are often built upon optimisation methods, including decision analysis and utility theory. A problem with these techniques is that they use a single-scalar utility value to represent the overall combined priority for all the NFRs. However, this combined scalar priority value may hide information about the impacts of the environmental contexts on the individual NFRs' priorities, which may change over time. Hence, there is a need for support for runtime, autonomous reasoning about the separate priority values for each NFR, while using the knowledge acquired based on evidence collected. In this paper, we propose Pri-AwaRE, a self-adaptive architecture that makes use of Multi-Reward Partially Observable Markov Decision Process (MR-POMDP) to perform decision-making for SASs while offering awareness of NFRs' priorities. MR-POMDP is used as a priority-aware runtime specification model to support runtime reasoning and autonomous tuning of the distinct priority values of NFRs using a vector-valued reward function. We also evaluate the usefulness of our Pri-AwaRE approach by applying it to two substantial example applications from the networking and IoT domains. [ABSTRACT FROM AUTHOR]

Testing Neanderthal behavioural hypotheses requires a spatial–temporal resolution to the level of a human single occupation episode. Yet, most of the behavioural data on Neanderthals has been obtained from coarsely dated, time-averaged contexts affected by the archaeological palimpsest effect and a diversity of postdepositional processes. This implies that time-resolved Neanderthal behaviour remains largely unknown. In this study, we performed archaeostratigraphic analysis on stratigraphic units ive, ivf, ivg, va, vb and vc from Abric del Pastor (Alcoi, Iberian Peninsula). Further, we isolated the archaeological remains associated with the resulting archaeostratigraphic unit and applied raw material, technological, use-wear, archaeozoological and spatial analyses. Our results show a low-density accumulation of remains from flintknapping, flint tool-use and animal processing around a hearth. These data provide a time-resolved human dimension to previous high-resolution environmental and pyrotechnological data on the same hearth, representing the first comprehensive characterisation of a Neanderthal single occupation episode. Our integrated, multidisciplinary method also contributes to advance our understanding of archaeological record formation processes. [ABSTRACT FROM AUTHOR]

The problem of mitigating uncertainty in self-adaptation has driven much of the research proposed in the area of software engineering for self-adaptive systems in the last decade. Although many solutions have already been proposed, most of them tend to tackle specific types, sources, and dimensions of uncertainty (e.g., in goals, resources, adaptation functions) in isolation. A special concern are the aspects associated with uncertainty modeling in an integrated fashion. Different uncertainties are rarely independent and often compound, affecting the satisfaction of goals and other system properties in subtle and often unpredictable ways. Hence, there is still limited understanding about the specific ways in which uncertainties from various sources interact and ultimately affect the properties of self-adaptive, software-intensive systems. In this SoSym expert voice, we introduce the Uncertainty Interaction Problem as a way to better qualify the scope of the challenges with respect to representing different types of uncertainty while capturing their interaction in models employed to reason about self-adaptation. We contribute a characterization of the problem and discuss its relevance in the context of case studies taken from two representative application domains. We posit that the Uncertainty Interaction Problem should drive future research in software engineering for autonomous and self-adaptive systems, and therefore, contribute to evolving uncertainty modeling towards holistic approaches that would enable the construction of more resilient self-adaptive systems. [ABSTRACT FROM AUTHOR]

Modern software systems are increasingly expected to show higher degrees of autonomy and self-management to cope with uncertain and diverse situations. As a consequence, autonomous systems can exhibit unexpected and surprising behaviours. This is exacerbated due to the ubiquity and complexity of Artificial Intelligence (AI)-based systems. This is the case of Reinforcement Learning (RL), where autonomous agents learn through trial-and-error how to find good solutions to a problem. Thus, the underlying decision-making criteria may become opaque to users that interact with the system and who may require explanations about the system's reasoning. Available work for eXplainable Reinforcement Learning (XRL) offers different trade-offs: e.g. for runtime explanations, the approaches are model-specific or can only analyse results after-the-fact. Different from these approaches, this paper aims to provide an online model-agnostic approach for XRL towards trustworthy and understandable AI. We present ETeMoX, an architecture based on temporal models to keep track of the decision-making processes of RL systems. In cases where the resources are limited (e.g. storage capacity or time to response), the architecture also integrates complex event processing, an event-driven approach, for detecting matches to event patterns that need to be stored, instead of keeping the entire history. The approach is applied to a mobile communications case study that uses RL for its decision-making. In order to test the generalisability of our approach, three variants of the underlying RL algorithms are used: Q-Learning, SARSA and DQN. The encouraging results show that using the proposed configurable architecture, RL developers are able to obtain explanations about the evolution of a metric, relationships between metrics, and were able to track situations of interest happening over time windows. [ABSTRACT FROM AUTHOR]

High-order entropy-stable discontinuous Galerkin (DG) methods for nonlinear conservation laws reproduce a discrete entropy inequality by combining entropy conservative finite volume fluxes with summation-by-parts (SBP) discretization matrices. In the DG context, on tensor product (quadrilateral and hexahedral) elements, SBP matrices are typically constructed by collocating at Lobatto quadrature points. Recent work has extended the construction of entropy-stable DG schemes to collocation at more accurate Gauss quadrature points (Chan et al. in SIAM J Sci Comput 41(5):A2938–A2966, 2019). In this work, we extend entropy-stable Gauss collocation schemes to non-conforming meshes. Entropy-stable DG schemes require computing entropy conservative numerical fluxes between volume and surface quadrature nodes. On conforming tensor product meshes where volume and surface nodes are aligned, flux evaluations are required only between “lines” of nodes. However, on non-conforming meshes, volume and surface nodes are no longer aligned, resulting in a larger number of flux evaluations. We reduce this expense by introducing an entropy-stable mortar-based treatment of non-conforming interfaces via a face-local correction term, and provide necessary conditions for high-order accuracy. Numerical experiments for the compressible Euler equations in two and three dimensions confirm the stability and accuracy of this approach. [ABSTRACT FROM AUTHOR]

Summary: Lactoferrin has gained extensive attention due to its ample biological properties. In this study, recombinant human lactoferrin carrying humanized glycosylation (rhLf-h-glycan) expressed in the yeast Pichia pastoris SuperMan5, which is genetically glycoengineered to efficiently produce functional humanized glycoproteins inclosing (Man)5(GlcNAc)2 Asn-linked glycans, was analyzed, inspecting its potential toxicity against cancer cells. The live-cell differential nuclear staining assay was used to quantify the rhLf-h-glycan cytotoxicity, which was examined in four human cell lines: acute lymphoblastic leukemia (ALL) CCRF-CEM, T-cell lymphoblastic lymphoma SUP-T1, cervical adenocarcinoma HeLa, and as control, non-cancerous Hs27 cells. The defined CC50 values of rhLf-h-glycan in CCRF-CEM, SUP-T1, HeLa, and Hs27 cells were 144.45 ± 4.44, 548.47 ± 64.41, 350 ± 14.82, and 3359.07 ± 164 µg/mL, respectively. The rhLf-h-glycan exhibited a favorable selective cytotoxicity index (SCI), preferentially killing cancer cells: 23.25 for CCRF-CEM, 9.59 for HeLa, and 6.12 for SUP-T1, as compared with Hs27 cells. Also, rhLf-h-glycan showed significant antiproliferative activity (P < 0.0001) at 24, 48, and 72 h of incubation on CCRF-CEM cells. Additionally, it was observed via fluorescent staining and confocal microscopy that rhLf-h-glycan elicited apoptosis-associated morphological changes, such as blebbing, nuclear fragmentation, chromatin condensation, and apoptotic bodies in ALL cells. Furthermore, rhLf-h-glycan-treated HeLa cells revealed shrinkage of the microfilament structures, generating a speckled/punctuated pattern and also caused PARP-1 cleavage, a hallmark of apoptosis. Moreover, in ALL cells, rhLf-h-glycan altered cell cycle progression inducing the G2/M phase arrest, and caused apoptotic DNA fragmentation. Overall, our findings revealed that rhLf-h-glycan has potential as an anticancer agent and therefore deserves further in vivo evaluation. [ABSTRACT FROM AUTHOR]

Background: Increased expression of the progesterone receptor membrane component 1 (PGRMC1) has been linked to multiple cancers, including breast cancer. Despite being a regulatory receptor and a potential therapeutic target, the oncogenic potential of PGRMC1 has not been studied.Methods: The impact of PGRMC1 on breast cancer growth and progression was studied following chemical inhibition and alteration of PGRMC1 expression, and evaluated by using online-based gene expression datasets of human breast cancer tissue. MTS, flow cytometry, qPCR, Western blotting, confocal microscopy and phosphoproteome analysis were performed.Results: We observed higher PGRMC1 levels in both ER-positive ZR-75-1 and TNBC MDA-MB-468 cells. Both chemical inhibition and silencing decreased cell proliferation, induced cell-cycle arrest, promoted apoptosis and reduced the migratory and invasive capabilities of ZR-75-1 and MDA-MB-468 cells. Further, phosphoproteome analysis demonstrated an overall decrease in activation of proteins involved in PI3K/AKT/mTOR and EGFR signalling pathways. In contrast, overexpression of PGRMC1 in non-malignant MCF10A cells resulted in increased cell proliferation, and enhanced activity of PI3K/AKT/mTOR and EGFR signalling pathways.Conclusions: Our data demonstrate that PGRMC1 plays a prominent role in regulating the growth of cancer cells by altering the PI3K/AKT/mTOR and EGFR signalling mechanisms in both ER-positive and TNBC cells. [ABSTRACT FROM AUTHOR]

Modeling is requiring increasingly larger efforts while becoming indispensable given the complexity of the problems we are solving. Modelers face high cognitive load to understand a multitude of complex abstractions and their relationships. There is an urgent need to better support tool builders to ultimately provide modelers with intelligent modeling assistance that learns from previous modeling experiences, automatically derives modeling knowledge, and provides context-aware assistance. However, current intelligent modeling assistants (IMAs) lack adaptability and flexibility for tool builders, and do not facilitate understanding the differences and commonalities of IMAs for modelers. Such a patchwork of limited IMAs is a lost opportunity to provide modelers with better support for the creative and rigorous aspects of software engineering. In this expert voice, we present a conceptual reference framework (RF-IMA) and its properties to identify the foundations for intelligent modeling assistance. For tool builders, RF-IMA aims to help build IMAs more systematically. For modelers, RF-IMA aims to facilitate comprehension, comparison, and integration of IMAs, and ultimately to provide more intelligent support. We envision a momentum in the modeling community that leads to the implementation of RF-IMA and consequently future IMAs. We identify open challenges that need to be addressed to realize the opportunities provided by intelligent modeling assistance. [ABSTRACT FROM AUTHOR]

Background: Small intestinal bacterial overgrowth (SIBO) affects up to 60% of patients with systemic sclerosis (SSc), and it improves with antibiotics. The addition of probiotics could lead to better results.Aims: To evaluate the efficacy and safety of Saccharomyces boulardii (SB) versus metronidazole (M) versus M + SB for 2 months, to reduce gastrointestinal symptoms and SIBO assessed with hydrogen breath test in SSc.Methods: An open pilot clinical trial performed in forty patients with SIBO and SSc (ACR-EULAR 2013) who signed informed consent. Three groups were assigned: M, SB, and M + SB, for 2 months. Hydrogen was measured in parts per million with a hydrogen breath test to evaluate SIBO. The National Institutes of Health Patient-Reported Outcomes Measurement Information System (NIH-PROMIS) questionnaire was applied to quantify gastrointestinal symptoms with a raw score of eight symptoms. This study is registered in ClinicalTrials.gov with the following ID: NCT03692299.Results: Baseline characteristics were similar between groups. The average age was 53.2 ± 9.3 years, and the evolution of SSc was 13.5 (1-34) years. After 2 months of treatment, SIBO was eradicated in 55% of the M + SB group: 33% of SB, and 25% of M. The SB and M + SB groups had decreased diarrhea, abdominal pain, and gas/bloating/flatulence, but M remained unchanged. Reductions in expired hydrogen at 45 to 60 min were as follows: M + SB 48% and 44%, M 18% and 20%, and SB 53% and 60% at the first and second months, respectively (p < 0.01). Adverse effects were epigastric burning and constipation in M (53%) and M + SB (36%), and flatulence/diarrhea in SB (22%).Conclusions: Metronidazole treatment is partially effective in SIBO, but S. boulardii in monotherapy or in combination improves the gastrointestinal outcomes in SSc. [ABSTRACT FROM AUTHOR]

Two procedures for the definition of an autotuning algorithm for event-based proportional-integral (PI) control systems are proposed in this contribution. Firstly, a method for the identification of the most common transfer functions used for tuning PI controllers is explained. The rationale of the identification method is based on the limit cycles that the event-based sampler and a convenient tuning of the PI controller can produce in the closed loop. The identification method is designed for controller tuning, that is, fitting the behaviour of the process in the range of frequencies between ω-180° and ω-135°. Secondly, a new method for tuning the event-based PI controller is explained. The main control objective of the new tuning rule is to generate a set of parameters that introduces the process in a limit cycle at a user-specified inter-event time. However, by introducing an oscillation margin in the tuning rule, the method generalizes to produce controller parameters that avoid limit cycles with a certain robustness margin. Simulations demonstrate the effectiveness of the tuning rule to force the system to oscillate at a specified frequency as a consequence of the events triggered by the event-based sampler. [ABSTRACT FROM AUTHOR]

More than a decade ago, the research topic models@run.time was coined. Since then, the research area has received increasing attention. Given the prolific results during these years, the current outcomes need to be sorted and classified. Furthermore, many gaps need to be categorized in order to further develop the research topic by experts of the research area but also newcomers. Accordingly, the paper discusses the principles and requirements of models@run.time and the state of the art of the research line. To make the discussion more concrete, a taxonomy is defined and used to compare the main approaches and research outcomes in the area during the last decade and including ancestor research initiatives. We identified and classified 275 papers on models@run.time, which allowed us to identify the underlying research gaps and to elaborate on the corresponding research challenges. Finally, we also facilitate sustainability of the survey over time by offering tool support to add, correct and visualize data. [ABSTRACT FROM AUTHOR]

In this work, we compare the effect of the addition during fermentation of both sodium bentonite and sodium-activated bentonite on the protein content, protein stability, lees volume, and aroma compounds of a Sauvignon blanc wine. Protein unstable Sauvignon blanc juices were vinified with or without bentonite added at three different stages: before fermentation, early during fermentation, and towards the end of fermentation. Different addition doses of bentonite were used ( X, X − 0.1, X − 0.2 g/L) according to protein instability of the grape juice ( X = 1.7 and 2.7 g/L to sodium bentonite and sodium-activated bentonite, respectively). The wines stabilized with sodium-activated bentonite presented a higher content of volatile compounds and a lower volume of lees were produced than those treated with sodium bentonite, an effect that was greater when the fining treatment was done before the start of the fermentation. [ABSTRACT FROM AUTHOR]

The production of spirits by distillation of wine, fruit wines, and grape pomace is normally carried out using classic copper Charentais alembic or batch distillation columns. An alternative to these classic systems, however, is a rectification packed column equipped with an internal partial condenser which allows for easy control of the internal reflux by manipulating the flow of cooling water of the partial condenser. This paper outlines an experimental study which explores the ability of variable reflux distillation policies in packed columns to tailor the chemical composition of the distillate. The results showed that a high reflux rate at the beginning of the distillation is a good option to reduce the impact of unpleasant compounds in the heart cut. Using this strategy, 40 % less head compounds were recovered in the heart cut, reducing their sensorial impact by 70 %. In addition, 50 % less acetic acid was recovered in the heart cuts. High reflux rates during the heart cut distillation reduce the concentration of higher alcohols; nevertheless, this strategy must be applied for longer periods than those used in our study to significantly alter the composition of the heart cuts. [ABSTRACT FROM AUTHOR]

This paper describes the development of a motivating and innovative multi-robot formation control platform for laboratory experiments with mobile robots. The platform is composed of two components: a simulator and an environment to experiment with low cost wheeled mobile robots. The environment constitutes a ready to use test tool that provides to engineering students the opportunity to simulate and test many different formation and cooperation control strategies with a real system. Currently the platform is used in the Systems and Control Engineering Master program offered by the National University of Distance Education (UNED) and the Complutense University of Madrid (UCM) in Spain. The use of the platform exposes students to hands-on laboratory sessions, contributing to their development as engineers. [ABSTRACT FROM AUTHOR]