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Currently, there is no cure for Alzheimer’s disease (AD) in humans; treatment is symptomatic only. Aging of the population, together with an unhealthy diet and lifestyle, contribute to the steady, global increase of AD patients. This increase creates significant health, societal and economical challenges even for the most developed countries. AD progresses from an asymptomatic stage to a progressively worsening cognitive impairment. The AD cognitive impairment is underpinned by progressive memory impairment, an increasing inability to recall recent events, to execute recently planned actions, and to learn. These changes prevent the AD patient from leading an independent and fulfilling life. Nanotechnology (NT) enables a new, alternative pathway for development of AD treatment interventions. At present, the NT treatments for attenuation of AD memory impairment are at the animal model stage. Over the past four years, there has been a steady increase in publications of AD animal models with a wide variety of original NT treatment interventions, able to attenuate memory impairment. NT therapy development, in animal models of AD, is faced with the twin challenges of the nature of AD, a chronic impairment, unique to human, of the tau protein and A β peptides that regulate several key physiological brain processes, and the incomplete understanding of AD′s aetiology. This paper reviews the state-of-the-art in NT based treatments for AD memory impairment in animal models and discusses the future work for translation to the successful treatment of AD cognitive impairment in human.

Made available in DSpace on 2021-06-25T11:13:10Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-03-01 The aim of the present study was to investigate the effect of shrinking and no shrinking dental filling materials combination in posterior restorations under the combined effects of polymerization shrinkage and occlusal load by means of 3D Finite Elements Analysis. Six computer-generated and restored class I or class II cavities models of a lower molar were designed in the CAD software and evaluated according to the cavity and restorative procedure. Different shrinking and no shrinking adhesive materials combination with diverse Young’s modulus were considered. A food bolus was modeled on the occlusal surface replicating the chewing load using static linear analyses Polymerization shrinkage was simulated for the shrinking different restorative materials. The maximum principal stress was selected as analysis criteria. All models exhibited higher stresses along the dentine restoration interfaces with different magnitude and a similar stress trend along enamel restoration interface. Stress values up to 22 MPa and 19 MPa were recorded in the enamel and restoration, respectively. The use of elastic not shrinking material layer in combination with bulk fill composite reduced the stress magnitude in dentine and enamel to replace dental tissues. Class I and class II posterior cavities adhesively restored with shrinking filling material’s combination showed the most unfavorable stress concentrations and the multilayer technique is a promising restorative alternative in posterior adhesive restorations when deep dentin and enamel volumes are missing. School of Dentistry University of Naples Federico II, via S. Pansini 5 Department of Dental Materials and Prosthodontics Institute of Science and Technology São Paulo State University-UNESP Fraunhofer JL IDEAS Department of Industrial Engineering University of Naples Federico II Endodontic Clinical Section School of Dentistry Department of Biomedical and Neuromotor Sciences University of Bologna-Alma Mater Studiorum School of Dentistry University of Taubaté–UNITAU, Taubaté Department of Dental Materials and Prosthodontics Institute of Science and Technology São Paulo State University-UNESP

Sports performance is primarily perceived to be associated with elite sport, where athletes strive for a place on the podium, with the most prestigious result probably being an Olympic gold medal [...]

The aim of this study was to explore the underlying age-related differences in dynamic motor control during different step ascent conditions using muscle synergy analysis. Eleven older women (67.0 y &plusmn, 2.5) and ten young women (22.5 y &plusmn, 1.6) performed stepping in forward and lateral directions at step heights of 10, 20 and 30 cm. Surface electromyography was obtained from 10 lower limb and torso muscles. Non-negative matrix factorization was used to identify sets of (n) synergies across age groups and stepping conditions. In addition, variance accounted for (VAF) by the detected number of synergies was compared to assess complexity of motor control. Finally, correlation coefficients of muscle weightings and between-subject variability of the temporal activation patterns were calculated and compared between age groups and stepping conditions. Four synergies accounted for &gt, 85% VAF across age groups and stepping conditions. Age and step height showed a significant negative correlation with VAF during forward stepping but not lateral stepping, with lower VAF indicating higher synergy complexity. Muscle weightings showed higher similarity across step heights in older compared to young women. Neuromuscular control of young and community-dwelling older women could not be differentiated based on the number of synergies extracted. Additional analyses of synergy structure and complexity revealed subtle age- and step-height-related differences, indicating that older women rely on more complex neuromuscular control strategies.

Biological membranes are composed of isotropic and anisotropic curved nanodomains. Anisotropic membrane components, such as Bin/Amphiphysin/Rvs (BAR) superfamily protein domains, could trigger/facilitate the growth of membrane tubular protrusions, while isotropic curved nanodomains may induce undulated (necklace-like) membrane protrusions. We review the role of isotropic and anisotropic membrane nanodomains in stability of tubular and undulated membrane structures generated or stabilized by cyto- or membrane-skeleton. We also describe the theory of spontaneous self-assembly of isotropic curved membrane nanodomains and derive the critical concentration above which the spontaneous necklace-like membrane protrusion growth is favorable. We show that the actin cytoskeleton growth inside the vesicle or cell can change its equilibrium shape, induce higher degree of segregation of membrane nanodomains or even alter the average orientation angle of anisotropic nanodomains such as BAR domains. These effects may indicate whether the actin cytoskeleton role is only to stabilize membrane protrusions or to generate them by stretching the vesicle membrane. Furthermore, we demonstrate that by taking into account the in-plane orientational ordering of anisotropic membrane nanodomains, direct interactions between them and the extrinsic (deviatoric) curvature elasticity, it is possible to explain the experimentally observed stability of oblate (discocyte) shapes of red blood cells in a broad interval of cell reduced volume. Finally, we present results of numerical calculations and Monte-Carlo simulations which indicate that the active forces of membrane skeleton and cytoskeleton applied to plasma membrane may considerably influence cell shape and membrane budding.

The hamstrings are biarticular muscle group that plays an important role in the occupational performance of military personnel. The single leg hamstring bridge test (SLHBT) could be a good test to screen military personnel performance. The aims of our study were to assess the reproducibility of the SLHBT in the military population and to use receiver operating curve (ROC) analysis to examine the ability of the SLHBT to discriminate between soldiers with poor and good baseline fitness. A cross-sectional study was performed on 201 male members of the Slovenian Armed Forces (SAF). They undertook army physical fitness testing (APFT) and functional physical fitness testing (FPFT), which included the SLHBT. The SLHBT showed acceptable reproducibility in a military setting and had moderate predictive validity to discriminate between soldiers with poor and good overall physical fitness performance using a cut-off value of 20 repetitions. In conclusion, the SLHBT could be a good candidate test for the military population as the ROC analysis showed the ability of the SLHBT to discriminate between soldiers with poor and good baseline fitness. The SLHBT represents a simple and affordable test that can be used to evaluate performance and form preventive guidelines for military personnel.

The new Coronavirus disease (COVID-19) has seriously affected the world. By the end of November 2020, the global number of new coronavirus cases had already exceeded 60 million and the number of deaths 1,410,378 according to information from the World Health Organization (WHO). To limit the spread of the disease, mandatory face-mask rules are now becoming common in public settings around the world. Additionally, many public service providers require customers to wear face-masks in accordance with predefined rules (e.g., covering both mouth and nose) when using public services. These developments inspired research into automatic (computer-vision-based) techniques for face-mask detection that can help monitor public behavior and contribute towards constraining the COVID-19 pandemic. Although existing research in this area resulted in efficient techniques for face-mask detection, these usually operate under the assumption that modern face detectors provide perfect detection performance (even for masked faces) and that the main goal of the techniques is to detect the presence of face-masks only. In this study, we revisit these common assumptions and explore the following research questions: (i) How well do existing face detectors perform with masked-face images? (ii) Is it possible to detect a proper (regulation-compliant) placement of facial masks? and (iii) How useful are existing face-mask detection techniques for monitoring applications during the COVID-19 pandemic? To answer these and related questions we conduct a comprehensive experimental evaluation of several recent face detectors for their performance with masked-face images. Furthermore, we investigate the usefulness of multiple off-the-shelf deep-learning models for recognizing correct face-mask placement. Finally, we design a complete pipeline for recognizing whether face-masks are worn correctly or not and compare the performance of the pipeline with standard face-mask detection models from the literature. To facilitate the study, we compile a large dataset of facial images from the publicly available MAFA and Wider Face datasets and annotate it with compliant and non-compliant labels. The annotation dataset, called Face-Mask-Label Dataset (FMLD), is made publicly available to the research community.

Due to increasing competition in the global market and to meet the need for rapid changes in product variability, it is necessary to introduce self-configurable and smart solutions within the entire process chain, including manual assembly to ensure the more efficient and ergonomic performance of the manual assembly process. This paper presents a smart assembly system including newly developed smart manual assembly workstation controlled by a smart algorithm. The smart assembly workstation is self-configurable according to the anthropometry of the individual worker, the complexity of the assembly process, the product characteristics, and the product structure. The results obtained by a case study show that is possible to organize manual assembly process with rapid adaptation of the smart assembly system to new products and workers characteristics, to achieve ergonomic working conditions through Digital Human Modelling (DHM), to minimize assembly time, and to prevent error during the assembly process. The proposed system supports the manual assembly process redesign to ensure a better working environment and aims to have an important value for applying the smart algorithms to manual assembly workstations in human-centered manufacturing systems.

Accidents in port areas are generally relatively minor given the lower prevailing speeds, but dangerous cargo terminals located in the vicinity of populated areas present some risk of accidents with catastrophic consequences. The maritime risk assessment frameworks have been developed in many ports, but few include studies incorporating collisions between sailing and moored ships. This paper presents the risk assessment framework for such accidents. Moreover, it presents the important role of harbour regulations in the navigation risk management process within the port area. Today&rsquo, s port regulations are created mostly based on the good practice of pilots and other experts, whereas quantitative methods are used less frequently. The intention of the presented case study was to demonstrate how quantitative risk assessment may be used in port policy development, which is why the method created is general and may be used in any terminal with dangerous cargo. The multi-stage method consists of several steps that make up a complex methodology, consisting of expert study, real-time simulation&mdash, a simulation of a collision in port is presented&mdash, and analytical-empirical calculations for consequence assessment. The case studies of the developed method are presented based on two real accidents, one in the Police port along the Świnoujście-Szczecin waterway, and the second in the Port of Koper in Slovenia. The results of this study present the parameters of the ship&rsquo, s safe approach to the terminal area, such as velocity and approaching angle. These parameters are used to calculate the impact forces in the case of a collision between a moored and passing ship and its consequences on ship integrity as well as on mooring arrangement. Based on probability and consequences, the risk is evaluated and discussed in the sense of port safety. The presented method could be used as the framework for risk assessment of collisions in a port area, particularly when dealing with dangerous cargo or sensitive vessels such as cruise ships.

Bark as a sawmilling residue can be used for producing value-added chemicals and materials. This study investigated the use of partially liquefied bark (PLB) for producing particleboard with or without synthetic adhesives. Maritime pine (Pinus pinaster Ait.) bark was partially liquefied in the presence of ethylene glycol and sulfuric acid. Four types of particleboard panels were prepared with a PLB content of 4.7%, 9.1%, 20%, and 33.3%, respectively. Another five types of particleboard panels were manufactured by using similar amounts of PLB and 10 wt.% of melamine&ndash, urea&ndash, formaldehyde (MUF) adhesives. Characterization of bark and solid residues of PLB was performed by Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), and automated vapor sorption (AVS). Mechanical and physical properties of the particleboard were tested according to the European standards EN 310 for determining modulus of elasticity and bending strength, EN 317 for determining thickness swelling after immersion in water, and EN 319 for determining internal bond strength. The results showed that the increase in PLB content improved the mechanical strength for the non-MUF boards, and the MUF-bonded boards with up to 20% of PLB met the requirements for interior uses in dry conditions according to EN 312. The non-MUF boards containing 33.3% of PLB and the MUF-bonded boards showed comparable thickness swelling and water absorption levels compared to the reference board.

We present the development and evaluation of a gamified rhythmic dictation application for music theory learning. The application was developed as a web application in the existing Troubadour platform for music ear training. The focus of the developed application was on user experience and engagement. With regards to the former, we developed a responsive and intuitive user interface, for the latter, we included several gamification elements and assessed the impact on the students&rsquo, engagement. We report on students&rsquo, experience analysis done through questionnaires and background data collected through the platform. We evaluated the rhythmic dictation application with the conservatory-level music theory students through A/B testing in order to independently evaluate the application&rsquo, s impact. The results show a significant impact of the application on the students&rsquo, exam scores.

THz time-domain spectroscopy (TDS) is a promising tool for quality control purposes in industrial applications, but the high cost and the relatively large laser sources still make it difficult to use the full potential of the technology for a decent price. In this work, a THz TDS system, which uses a commercially available Fabry&ndash, Perot laser diode emitting at 1550 nm, is presented. By dispersion compensation, pulses with a duration of 544 fs were generated, resulting in THz radiation with a bandwidth of 1.4 THz and a peak dynamic range of 56 dB with state-of-the-art ErAs:In(Al)GaAs photoconducting antennas. These results are compared with those of a conventional and expensive fiber laser system with a 90 fs pulse duration.

High temperature effect on cement-based composites, such as concrete or mortars, represents one of the most important damaging process that may drastically affect the mechanical and durability characteristics of structures. In this paper, the results of an experimental campaign on cement mortars submitted to high temperatures are reported and discussed. Particularly, two mixtures (i.e., Normal (MNS) and High Strength Mortar (MHS)) having different water-to-binder ratios were designed and evaluated in order to investigate the incidence of both the mortar composition and the effects of thermal treatments on their physical and mechanical properties. Mortar specimens were thermally treated in an electrical furnace, being submitted to the action of temperatures ranging from 100 to 600 &deg, C. After that and for each mortar quality and considered temperature, including the room temperature case of 20 &deg, C, water absorption was measured by following a capillary water absorption test. Furthermore, uniaxial compression, splitting tensile and three-points bending tests were performed under residual conditions. A comparative analysis of the progressive damage caused by temperature on physical and mechanical properties of the considered mortars types is presented. On one hand, increasing temperatures produced increasing water absorption coefficients, evidencing the effect of thermal damages which may cause an increase in the mortars accessible porosity. However, under these circumstances, the internal porosity structure of lower w/b ratio mixtures results much more thermally-damaged than those of MNS. On the other hand, strengths suffered a progressive degradation due to temperature rises. While at low to medium temperatures, strength loss resulted similar for both mortar types, at higher temperature, MNS presented a relatively greater strength loss than that of MHS. The action of temperature also caused in all cases a decrease of Young&rsquo, s Modulus and an increase in the strain corresponding to peak load. However, MHS showed a much more brittle behavior in comparison with that of MNS, for all temperature cases. Finally, the obtained results demonstrated that mortar quality cannot be neglected when the action of temperature is considered, being the final material performance dependent on the physical properties which, in turn, mainly depend on the mixture proportioning.

Composite materials are becoming more popular in technological applications due to the significant weight savings and strength offered by these materials compared to metallic materials. In many of these practical situations, the structures suffer from drop-impact loads. Materials and structures significantly change their behavior when submitted to impact loading conditions compared to quasi-static loading. The present work is devoted to investigating the thermal process in carbon-fiber-reinforced polymers (CFRP) subjected to a drop test. A novel drop-weight impact test experiment is performed to evaluate parameters specific to 3D composite materials. A strain gauge rosette and infrared thermography are employed to record the kinematic and thermal fields on the composites&rsquo, surfaces. This technique is nondestructive and offers an extensive full-field investigation of a material&rsquo, s response. The combination of strain and infrared thermography data allows a comprehensive analysis of thermoelastic effects in CFRP when subjected to impacts. The experimental results are validated using numerical analysis by developing a MATLAB&reg, code to analyze whether the coupled heat and wave equation phenomenon exists in a two-dimensional polar coordinate system by discretizing through a forward-time central-space (FTCS) finite-difference method (FDM). The results show the coupling has no significant impact as the waves generated due to impact disappears in 0.015 s. In contrast, heat diffusion happens for over a one-second period. This study demonstrates that the heat equation alone governs the CFRP heat flow process, and the thermoelastic effect is negligible for the specific drop-weight impact load.

This study aimed to examine the reliability, validity, and usefulness of the smartphone-based application, My Jump 2, against Optojump in recreationally active adults. Participants (18 women, 28.9 &plusmn, 5.6 years, and 26 men, 30.1 &plusmn, 10.6 years) completed squat jumps (SJ), counter-movement jumps (CMJ), and CMJ with arm swing (CMJAS) on Optojump and were simultaneously recorded using My Jump 2. To evaluate concurrent validity, jump height, calculated from flight time attained from each device, was compared for each jump type. Test-retest reliability was determined by replicating data analysis of My Jump 2 recordings on two occasions separated by two weeks. High test-retest reliability (Intraclass correlation coefficient (ICC) &gt, 0.93) was observed for all measures in both male and female athletes. Very large correlations were observed between the My Jump 2 app and Optojump for SJ (r = 0.95, p = 0.001), CMJ (r = 0.98, p = 0.001), and CMJAS (r = 0.98, p = 0.001) in male athletes. Similar results were obtained for female recreational athletes for all jumps (r &gt, 0.94, p = 0.001). The study results suggest that My Jump 2 is a valid, reliable, and useful tool for measuring vertical jump in recreationally active adults. Therefore, due to its simplicity and practicality, it can be used by practitioners, coaches, and recreationally-active adults to measure vertical jump performance with a simple test as SJ, CMJ, and CMJAS.

EpCAM, a carcinoma cell-surface marker protein and a therapeutic target, has been primarily addressed as a cell adhesion molecule. With regard to recent discoveries of its role in signaling with implications in cell proliferation and differentiation, and findings contradicting a direct role in mediating adhesion contacts, we provide a comprehensive and updated overview on the available structural data on EpCAM and interpret it in the light of recent reports on its function. First, we describe the structure of extracellular part of EpCAM, both as a subunit and part of a cis-dimer which, according to several experimental observations, represents a biologically relevant oligomeric state. Next, we provide a thorough evaluation of reports on EpCAM as a homophilic cell adhesion molecule with a structure-based explanation why direct EpCAM participation in cell–cell contacts is highly unlikely. Finally, we review the signaling aspect of EpCAM with focus on accessibility of signaling-associated cleavage sites.

Polypropylene (PP) and polyethylene (PE) foils, previously activated by ultraviolet (UV)/ozone, were functionalized using chitosan-extract nanoparticle dispersions. A solution of macromolecular chitosan was applied onto foils as a first layer, followed by the deposition of various extracts encapsulated into chitosan nanoparticles, which were attached as an upper layer. Functionalized foils were analyzed from a bioactive point of view, i.e., regarding antimicrobial and antioxidant activity. Desorption kinetics were also studied. Moreover, barrier properties were examined, as the most important parameter influencing antimicrobial and antioxidant activity. Finally, all these properties were correlated with different surface parameters, determined previously, in order to understand if there is any direct correlation between surface elemental composition, surface charge, contact angle, or morphology and a specific bioactive property. It was shown that great bioactive properties were introduced due to the additive effect of antimicrobial chitosan and antioxidative plant extracts. Moreover, oxygen permeability decreased significantly, and the migration of polyphenols and chitosan from the foil surface was below the OML (overall migration limit), which is very important for food industry applications. Furthermore, surface properties of foils influence to some extent the desired bioactivity.

Viroids are small non-capsidated, single-stranded, covalently-closed circular noncoding RNA replicons of 239&ndash, 401 nucleotides that exploit host factors for their replication, and some cause disease in several economically important crop plants, while others appear to be benign. The proposed mechanisms of viroid pathogenesis include direct interaction of the genomic viroid RNA with host factors and post-transcriptional or transcriptional gene silencing via viroid-derived small RNAs (vd-sRNAs) generated by the host defensive machinery. Humulus lupulus (hop) plants are hosts to several viroids among which Hop latent viroid (HLVd) and Citrus bark cracking viroid (CBCVd) are attractive model systems for the study of viroid-host interactions due to the symptomless infection of the former and severe symptoms induced by the latter in this indicator host. To better understand their interactions with hop plant, a comparative transcriptomic analysis based on RNA sequencing (RNA-seq) was performed to reveal the transcriptional alterations induced as a result of single HLVd and CBCVd infection in hop. Additionally, the effect of HLVd on the aggressiveness of CBCVd that underlies severe stunting in hop in a mixed infection was studied by transcriptomic analysis. Our analysis revealed that CBCVd infection resulted in dynamic changes in the activity of genes as compared to single HLVd infection and their mixed infection. The differentially expressed genes that are involved in defense, phytohormone signaling, photosynthesis and chloroplasts, RNA regulation, processing and binding, protein metabolism and modification, and other mechanisms were more modulated in the CBCVd infection of hop. Nevertheless, Gene Ontology (GO) classification and pathway enrichment analysis showed that the expression of genes involved in the proteolysis mechanism is more active in a mixed infection as compared to a single one, suggesting co-infecting viroids may result in interference with host factors more prominently. Collectively, our results provide a deep transcriptome of hop and insight into complex single HLVd, CBCVd, and their coinfection in hop-plant interactions

In this paper we perform a comparative analysis of three models for a feature representation of text documents in the context of document classification. In particular, we consider the most often used family of bag-of-words models, the recently proposed continuous space models word2vec and doc2vec, and the model based on the representation of text documents as language networks. While the bag-of-word models have been extensively used for the document classification task, the performance of the other two models for the same task have not been well understood. This is especially true for the network-based models that have been rarely considered for the representation of text documents for classification. In this study, we measure the performance of the document classifiers trained using the method of random forests for features generated with the three models and their variants. Multi-objective rankings are proposed as the framework for multi-criteria comparative analysis of the results. Finally, the results of the empirical comparison show that the commonly used bag-of-words model has a performance comparable to the one obtained by the emerging continuous-space model of doc2vec. In particular, the low-dimensional variants of doc2vec generating up to 75 features are among the top-performing document representation models. The results finally point out that doc2vec shows a superior performance in the tasks of classifying large documents.

In this diagnostic test validation study, we assessed the clinical accuracy and HPV genotyping performance of the INNO-LiPA HPV Genotyping Extra II (INNO-LiPA) within the VALGENT-3 framework. VALGENT is designed to assess the analytical and clinical performance of HPV tests with genotyping capacity. The VALGENT-3 panel comprised 1300 consecutive cervical cell specimens enriched with 300 samples with abnormal cytology obtained from women attending the Slovenian cervical cancer screening programme. The INNO-LiPA allows type-specific detection of 32 HPV types, however, for the clinical accuracy assessment, we considered it as high-risk (hr)HPV positive when at least one of the following HPV types was present: HPV16, HPV18, HPV31, HPV33, HPV35, HPV39, HPV45, HPV51, HPV52, HPV56, HPV58, HPV59, and HPV68. Clinical accuracy for detection of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) was compared between INNO-LiPA and Hybrid Capture 2 (HC2), which is a standard comparator test for HPV tests used in cervical cancer screening. In addition, hrHPV and type-specific detection HPV types were compared between INNO-LiPA and Linear Array HPV Genotyping Test (Linear Array). The prevalence of hrHPV determined by INNO-LiPA was 17.1% (95% CI, 15.0&ndash, 19.2%) in the screening population. HrHPV testing with INNO-LiPA had a sensitivity for CIN2+ of 96.9% (95% CI, 92.1&ndash, 99.1%) which was non-inferior to HC2 (relative sensitivity of 1.01, 95% CI, 0.97&ndash, 1.04, pn.inf = 0.0002) and a specificity for &le, CIN1 of 85.3% (95% CI, 83.2&ndash, 87.3%) which was inferior to HC2 (relative specificity of 0.95, 95% CI, 0.93&ndash, 0.97, pn.inf = 0.9998). Genotyping agreement between INNO-LiPA and Linear Array was excellent for hrHPV, HPV16, HPV18, HPV35, HPV45, HPV58 and HPV59, but good or fair for other HPV types. To conclude, INNO-LiPA demonstrated non-inferior clinical sensitivity but lower specificity compared to HC2 in addition to excellent concordance compared to Linear Array for hrHPV and some genotypes.

Although the central nervous system (CNS) consists of highly heterogeneous populations of neurones and glial cells, clustered into diverse anatomical regions with specific functions, there are some conditions, including alertness, awareness and attention that require simultaneous, coordinated and spatially homogeneous activity within a large area of the brain. During such events, the brain, representing only about two percent of body mass, but consuming one fifth of body glucose at rest, needs additional energy to be produced. How simultaneous energy procurement in a relatively extended area of the brain takes place is poorly understood. This mechanism is likely to be impaired in neurodegeneration, for example in Alzheimer’s disease, the hallmark of which is brain hypometabolism. Astrocytes, the main neural cell type producing and storing glycogen, a form of energy in the brain, also hold the key to metabolic and homeostatic support in the central nervous system and are impaired in neurodegeneration, contributing to the slow decline of excitation-energy coupling in the brain. Many mechanisms are affected, including cell-to-cell signalling. An important question is how changes in cellular signalling, a process taking place in a rather short time domain, contribute to the neurodegeneration that develops over decades. In this review we focus initially on the slow dynamics of Alzheimer’s disease, and on the activity of locus coeruleus, a brainstem nucleus involved in arousal. Subsequently, we overview much faster processes of vesicle traffic and cytosolic calcium dynamics, both of which shape the signalling landscape of astrocyte-neurone communication in health and neurodegeneration.

This paper presents a compositional hierarchical model for pattern discovery in symbolic music. The model can be regarded as a deep architecture with a transparent structure. It can learn a set of repeated patterns within individual works or larger corpora in an unsupervised manner, relying on statistics of pattern occurrences, and robustly infer the learned patterns in new, unknown works. A learned model contains representations of patterns on different layers, from the simple short structures on lower layers to the longer and more complex music structures on higher layers. A pattern selection procedure can be used to extract the most frequent patterns from the model. We evaluate the model on the publicly available JKU Patterns Datasets and compare the results to other approaches.

Amyotrophic lateral sclerosis (ALS) is a complex multi-system neurodegenerative disorder with currently limited diagnostic and no therapeutic options. Despite the intense efforts no clinically applicable biomarkers for ALS are yet established. Most current research is thus focused, in particular, in identifying potential non-invasive circulating biomarkers for more rapid and accurate diagnosis and monitoring of the disease. In this review, we have focused on messenger RNA (mRNA), non-coding RNAs (lncRNAs), micro RNAs (miRNAs) and circular RNA (circRNAs) as potential biomarkers for ALS in peripheral blood serum, plasma and cells. The most promising miRNAs include miR-206, miR-133b, miR-27a, mi-338-3p, miR-183, miR-451, let-7 and miR-125b. To test clinical potential of this miRNA panel, a useful approach may be to perform such analysis on larger multi-center scale using similar experimental design. However, other types of RNAs (lncRNAs, circRNAs and mRNAs) that, together with miRNAs, represent RNA networks, have not been yet extensively studied in blood samples of patients with ALS. Additional research has to be done in order to find robust circulating biomarkers and therapeutic targets that will distinguish key RNA interactions in specific ALS-types to facilitate diagnosis, predict progression and design therapy.

Adenosine diphosphate ribosylation (ADP-ribosylation, ADPr), the addition of ADP-ribose moieties onto proteins and nucleic acids, is a highly conserved modification involved in a wide range of cellular functions, from viral defence, DNA damage response (DDR), metabolism, carcinogenesis and neurobiology. Here we study MACROD1 and MACROD2 (mono-ADP-ribosylhydrolases 1 and 2), two of the least well-understood ADPr-mono-hydrolases. MACROD1 has been reported to be largely localized to the mitochondria, while the MACROD2 genomic locus has been associated with various neurological conditions such as autism, attention deficit hyperactivity disorder (ADHD) and schizophrenia, yet the potential significance of disrupting these proteins in the context of mammalian behaviour is unknown. Therefore, here we analysed both Macrod1 and Macrod2 gene knockout (KO) mouse models in a battery of well-defined, spontaneous behavioural testing paradigms. Loss of Macrod1 resulted in a female-specific motor-coordination defect, whereas Macrod2 disruption was associated with hyperactivity that became more pronounced with age, in combination with a bradykinesia-like gait. These data reveal new insights into the importance of ADPr-mono-hydrolases in aspects of behaviour associated with both mitochondrial and neuropsychiatric disorders.

Coronavirus disease 2019 (COVID-19) has spread rapidly worldwide. This study aimed to assess and predict the incidence of COVID-19 in Thailand, including the preparation and evaluation of intervention strategies. An SEIR (susceptible, exposed, infected, recovered) model was implemented with model parameters estimated using the Bayesian approach. The model&rsquo, s projections showed that the highest daily reported incidence of COVID-19 would be approximately 140 cases (95% credible interval, CrI: 83&ndash, 170 cases) by the end of March 2020. After Thailand declared an emergency decree, the numbers of new cases and case fatalities decreased, with no new imported cases. According to the model&rsquo, s predictions, the incidence would be zero at the end of June if non-pharmaceutical interventions (NPIs) were strictly and widely implemented. These stringent NPIs reduced the effective reproductive number (Rt) to 0.73 per day (95% CrI: 0.53&ndash, 0.93) during April and May. Sensitivity analysis showed that contact rate, hand washing, and face mask wearing effectiveness were the parameters that most influenced the number of reported daily new cases. Our evaluation shows that Thailand&rsquo, s intervention strategies have been highly effective in mitigating disease propagation. Continuing with these strict disease prevention behaviors could minimize the risk of a new COVID-19 outbreak in Thailand.

Since invasive alien species are one of the main causes of biodiversity loss in the region and thus of changes in ecosystem services, it is important to find the best possible solution for their removal from nature and the best practice for their usability. The aim of the study was to investigate their properties as components of wood-plastic composites and to investigate the properties of the wood-plastic composites produced. The overall objective was to test the potential of available alien plant species as raw material for the manufacture of products. This would contribute to sustainability and give them a better chance of ending their life cycle. One of the possible solutions on a large scale is to use alien wood species for the production of wood plastic composites (WPC). Five invasive alien hardwood species have been used in combination with polyethylene powder (PE) and maleic anhydride grafted polyethylene (MAPE) to produce various flat pressed WPC boards. Microstructural analyses (confocal laser scanning microscopy and scanning electron microscopy) and mechanical tests (flexural strength, tensile strength) were performed. Furthermore, measurements of density, thickness swelling, water absorption and dimensional stability during heating and cooling were carried out. Comparisons were made between the properties of six WPC boards (five alien wood species and mixed boards). The results showed that the differences between different invasive alien wood species were less obvious in mechanical properties, while the differences in sorption properties and dimensional stability were more significant. The analyses of the WPC structure showed a good penetration of the polymer into the lumens of the wood cells and a fine internal structure without voids. These are crucial conditions to obtain a good, mechanically strong and water-resistant material.

The cellular signalling process is a highly complex mechanism, involving multiple players, which together orchestrate the cell’s response to environmental changes and perturbations. Given the multitude of genes that participate in the process of cellular signalling, its study in a genome-wide manner has proven challenging. Recent advances in gene editing technologies, including clustered regularly-interspaced short palindromic repeats/Cas9 (CRISPR/Cas9) approaches, have opened new opportunities to investigate global regulatory signalling programs of cells in an unbiased manner. In this review, we focus on how the application of pooled genetic screening approaches using the CRISPR/Cas9 system has contributed to a systematic understanding of cellular signalling processes in normal and disease contexts.

Cold atmospheric pressure plasma (CAP) is a novel non-thermal technology that is gaining increasing importance as a decontamination method. Stainless steel is a widespread food contact surface used in food-processing environments. In this study, for the first time, a low-voltage piezoelectric CAP device that uses ambient air was assessed for its antimicrobial efficiency against Salmonella and Listeria monocytogenes. These inoculated on stainless steel at different exposure times (0–300 s), two different distances (10 and 20 mm), and two different cleanliness levels (clean and protein-soiled). Two inactivation models were compared to study the inactivation kinetics of the pathogens. The results showed that CAP treatment effectively reduced L. monocytogenes and Salmonella levels. The Weibull + tail model showed better goodness of fit than the Weibull model. Protein-soiled coupons showed a protective effect to cold plasma inactivation achieving lower reductions compared to clean stainless-steel coupons for both L. monocytogenes and Salmonella. Longer distances from the plasma source decreased the decontamination efficiency of CAP, however, the difference in pathogen reduction was less pronounced at longer exposure times. This study demonstrates the capacity of a low-voltage piezoelectric CAP device to effectively reduce the levels of both foodborne pathogens on stainless-steel surfaces and the potential to adopt this technology by the food industry as a disinfection process of surfaces to reduce cross-contamination and thus increase safety.

Background. The molecular profiling of complex microbial communities has become the basis for examining the relationship between the microbiome composition, structure and metabolic functions of those communities. Microbial community structure can be partially assessed with “universal” PCR targeting taxonomic or functional gene markers. Increasingly, shotgun metagenomic DNA sequencing is providing more quantitative insight into microbiomes. However, both amplicon-based and shotgun sequencing approaches have shortcomings that limit the ability to study microbiome dynamics. Methods. We present a novel, amplicon-free, hybridization-based method (CaptureSeq) for profiling complex microbial communities using probes based on the chaperonin-60 gene. Molecular profiles of a commercially available synthetic microbial community standard were compared using CaptureSeq, whole metagenome sequencing, and 16S universal target amplification. Profiles were also generated for natural ecosystems including antibiotic-amended soils, manure storage tanks, and an agricultural reservoir. Results. The CaptureSeq method generated a microbial profile that encompassed all of the bacteria and eukaryotes in the panel with greater reproducibility and more accurate representation of high G/C content microorganisms compared to 16S amplification. In the natural ecosystems, CaptureSeq provided a much greater depth of coverage and sensitivity of detection compared to shotgun sequencing without prior selection. The resulting community profiles provided quantitatively reliable information about all three domains of life (Bacteria, Archaea, and Eukarya) in the different ecosystems. The applications of CaptureSeq will facilitate accurate studies of host-microbiome interactions for environmental, crop, animal and human health. Conclusions: cpn60-based hybridization enriched for taxonomically informative DNA sequences from complex mixtures. In synthetic and natural microbial ecosystems, CaptureSeq provided sequences from prokaryotes and eukaryotes simultaneously, with quantitatively reliable read abundances. CaptureSeq provides an alternative to PCR amplification of taxonomic markers with deep community coverage while minimizing amplification biases.

Resonance frequency analysis (RFA) is the most extended method for measuring implant stability. The implant stability quotient (ISQ) is the measure obtained by different RFA devices, however, inter- and intra-rater reliability and agreement of these instruments remain unknown. Thirty implants were placed in three different pig mandibles. ISQ was measured parallel and perpendicular (lingual) to the peg axis with Osstell® Beacon, Penguin® and MegaISQ® by two different investigators and furthermore, one performed a test-retest. Intraclass correlation coefficient was calculated to assess the intra- and inter-rater reliability. Pearson correlation coefficient was used to assess the agreement. Intraclass correlation coefficients ranged from 0.20 to 0.65 for the Osstell® Beacon, 0.57 to 0.86 for the Penguin®, and −0.01 to 0.60 for the MegaISQ®. The highest ISQ values were obtained using Penguin® (66.3) in a parallel measurement, the lowest, using the MegaISQ® (60.1) in a parallel measurement. The highest correlation values with the other devices were obtained by MegaISQ® in a parallel measurement. Osstell® Beacon and MegaISQ® showed lower reliability than Penguin®. Osstell® had good agreement for measuring ISQ both in parallel and perpendicular, and MegaISQ® had the best agreement for measuring ISQ in parallel.

Saccharomyces cerevisiae is the most commonly used yeast in wine, beer, and bread fermentations. However, Torulaspora delbrueckii has attracted interest in recent years due to its properties, ranging from its ability to produce flavor- and aroma-enhanced wine to its ability to survive longer in frozen dough. In this work, publicly available genomes of T. delbrueckii were explored and their annotation was improved. A total of 32 proteins were additionally annotated for the first time in the type strain CBS1146, in comparison with the previous annotation available. In addition, the annotation of the remaining three T. delbrueckii strains was performed for the first time. eggNOG-mapper was used to perform the functional annotation of the deduced T. delbrueckii coding genes, offering insights into its biological significance, and revealing 24 clusters of orthologous groups (COGs), which were gathered in three main functional categories: information storage and processing (28% of the proteins), cellular processing and signaling (27%), and metabolism (23%). Small intraspecies variability was found when considering the functional annotation of the four available T. delbrueckii genomes. A comparative study was also conducted between the T. delbrueckii genome and those from 386 fungal species, revealing a high number of homologous genes with species from the Zygotorulaspora and Zygosaccharomyces genera, but also with Lachancea and S. cerevisiae. Lastly, the phylogenetic placement of T. delbrueckii was clarified using the core homologs that were found across 204 common protein sequences of 386 fungal species and strains., This work was supported by the UID/BIA/04050/2013 (POCI-01-0145-FEDER-007569) and UID/BIA/04050/2019 strategic programs and by the project PTDC/BIA-MIC/32059/2017 (TODOMICS: Omics approaches towards the industrial exploitation of Torulaspora delbrueckii: Elucidation of the molecular basis underlying complex cellular traits), which is funded by national funds through the FCT-Fundação para a Ciência e Tecnologia and by the ERDF- European Regional Development Fund through the COMPETE2020–Programa Operacional Competitividade e Internacionalização (POCI) and Sistema de Apoio à Investigação Científica e Tecnológica (SAICT).

Type-2 diabetes mellitus (T2DM) is a major systemic disease which involves impaired pancreatic function and currently affects half a billion people worldwide. Diet is considered the cornerstone to reduce incidence and prevalence of this disease. Algae contains fiber, polyphenols, ω-3 PUFAs, and bioactive molecules with potential antidiabetic activity. This review delves into the applications of algae and their components in T2DM, as well as to ascertain the mechanism involved (e.g., glucose absorption, lipids metabolism, antioxidant properties, etc.). PubMed, and Google Scholar databases were used. Papers in which whole alga, algal extracts, or their isolated compounds were studied in in vitro conditions, T2DM experimental models, and humans were selected and discussed. This review also focuses on meat matrices or protein concentrate-based products in which different types of alga were included, aimed to modulate carbohydrate digestion and absorption, blood glucose, gastrointestinal neurohormones secretion, glycosylation products, and insulin resistance. As microbiota dysbiosis in T2DM and metabolic alterations in different organs are related, the review also delves on the effects of several bioactive algal compounds on the colon/microbiota-liver-pancreas-brain axis. As the responses to therapeutic diets vary dramatically among individuals due to genetic components, it seems a priority to identify major gene polymorphisms affecting potential positive effects of algal compounds on T2DM treatment.

The main objective was to determine the chemical, phytochemical, fatty acid and mineral profiles of three commercially relevant brown macroalgae (Laminaria digitata, Laminaria hyperborea and Ascophyllum nodosum) collected each season for two years off the west coast of Ireland. All the chemical, phytochemical, fatty acid and minerals analysed varied significantly depending on the macroalgal species, season and year of collection. Overall, the protein contents of macroalgae were negatively correlated with carbohydrate content. Protein (2–11%) was at its highest during winter and/or spring, decreasing to a minimum during summer and/or autumn. The three macroalgal species analysed in this study had clearly differentiated fatty acid profiles. The concentration of fatty acids was higher in A. nodosum compared with both Laminaria species. The mineral profile of the three macroalgal species was rich in essential metals, particularly Ca, Mg and P, while the levels of I were approximately 9- to 10-fold higher in both Laminaria spp. compared with A. nodosum. The levels of toxic metals (Cd, Hg and Pb) in all the macroalgal species studied were low in the current study, while the levels of total As were high (49–64 mg/kg DW macroalgae) compared with previous reports.

Oral mucositis is an acute side effect of radiation therapy that is especially common with head and neck cancer treatment. In recent years, several studies have revealed the predisposing factors for mucositis, leading to the pre-treatment of patients to deter the development of opportunistic oral fungal infections. Although many clinical protocols already advise the use of probiotics to counteract inflammation and fungal colonization, preclinical studies are needed to better delineate the mechanisms by which a host may acquire benefits via co-evolution with oral microbiota, probiotics, and fungal commensals, such as Candida albicans, especially during acute inflammation. Here, we review the current understanding of radiation therapy-dependent oral mucositis in terms of pathology, prevention, treatment, and related opportunistic infections, with a final focus on the oral microbiome and how it may be important for future therapy.

Cardiovascular diseases continue to be the leading cause of death worldwide, with ischemic heart disease as the most significant contributor. Pharmacological and surgical interventions have improved clinical outcomes, but are unable to ameliorate advanced stages of end-heart failure. Successful preclinical studies of new therapeutic modalities aimed at revascularization have shown short lasting to no effects in the clinical practice. This lack of success may be attributed to current challenges in patient selection, endpoint measurements, comorbidities, and delivery systems. Although challenges remain, the field of therapeutic angiogenesis is evolving, as novel strategies and bioengineering approaches emerge to optimize delivery and efficacy. Here, we describe the structure, vascularization, and regulation of the vascular system with particular attention to the endothelium. We proceed to discuss preclinical and clinical findings and present challenges and future prospects in the field.

The pressurized liquid extraction (PLE) technique was used, for the first time, to obtain protein extracts with antioxidant activity from side streams (muscle, heads, viscera, skin, and tailfins) of gilthead sea bream (Sparus aurata) in order to give added value to these underutilized matrices. Extraction conditions previously optimized for sea bass (Dicentrarchus labrax) side streams were applied. Protein recovery percentages were 22% (muscle), 33% (heads), 78% (viscera), 24% (skin), and 26% (tailfins), which represented an increase of 1.2–4.5-fold compared to control samples (extraction by stirring). The SDS-PAGE profiles revealed that PLE-assisted extraction influenced protein molecular weight distribution of the obtained extracts. PLE conditions also allowed increasing the antioxidant capacity measured by both Trolox equivalent antioxidant capacity (TEAC, 1.3–2.4 fold) and oxygen radical absorbance capacity (ORAC, 1.9–6.4) assays for all fish extracts. Inductively coupled plasma mass spectrometry (ICP-MS) and high-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry (LC-ESI-qTOF-MS) were used to investigate the presence of toxic metals and mycotoxins in sea bream side streams. The levels of As, Hg, Cd, and Pb were below those established by authorities for fish muscle for human consumption (except for Cd in viscera samples). Through a nontargeted screening approach, no mycotoxins or related metabolites were detected for all sea bream side streams. This study contributes to the research on the valorization of fish processing side streams using environmentally friendly technology.

The conserved nuclease-helicase DNA2 has been linked to mitochondrial myopathy, Seckel syndrome, and cancer. Across species, the protein is indispensable for cell proliferation. On the molecular level, DNA2 has been implicated in DNA double-strand break (DSB) repair, checkpoint activation, Okazaki fragment processing (OFP), and telomere homeostasis. More recently, a critical contribution of DNA2 to the replication stress response and recovery of stalled DNA replication forks (RFs) has emerged. Here, we review the available functional and phenotypic data and propose that the major cellular defects associated with DNA2 dysfunction, and the links that exist with human disease, can be rationalized through the fundamental importance of DNA2-dependent RF recovery to genome duplication. Being a crucial player at stalled RFs, DNA2 is a promising target for anti-cancer therapy aimed at eliminating cancer cells by replication-stress overload.

The development of the Artemis programme with the goal of returning to the moon is spurring technology advances that will eventually take humans to Mars and herald a new era of interplanetary space travel. However, long-term space travel poses unique challenges including exposure to ionising radiation from galactic cosmic rays and potential solar particle events, exposure to microgravity and specific nutritional challenges arising from earth independent exploration. Ionising radiation is one of the major obstacles facing future space travel as it can generate oxidative stress and directly damage cellular structures such as DNA, in turn causing genomic instability, telomere shortening, extracellular-matrix remodelling and persistent inflammation. In the gastrointestinal tract (GIT) this can lead to leaky gut syndrome, perforations and motility issues, which impact GIT functionality and affect nutritional status. While current countermeasures such as shielding from the spacecraft can attenuate harmful biological effects, they produce harmful secondary particles that contribute to radiation exposure. We hypothesised that induction of a torpor-like state would confer a radioprotective effect given the evidence that hibernation extends survival times in irradiated squirrels compared to active controls. To test this hypothesis, a torpor-like state was induced in zebrafish using melatonin treatment and reduced temperature, and radiation exposure was administered twice over the course of 10 days. The protective effects of induced-torpor were assessed via RNA sequencing and qPCR of mRNA extracted from the GIT. Pathway and network analysis were performed on the transcriptomic data to characterise the genomic signatures in radiation, torpor and torpor + radiation groups. Phenotypic analyses revealed that melatonin and reduced temperature successfully induced a torpor-like state in zebrafish as shown by decreased metabolism and activity levels. Genomic analyses indicated that low dose radiation caused DNA damage and oxidative stress triggering a stress response, including steroidal signalling and changes to metabolism, and cell cycle arrest. Torpor attenuated the stress response through an increase in pro-survival signals, reduced oxidative stress via the oxygen effect and detection and removal of misfolded proteins. This proof-of-concept model provides compelling initial evidence for utilizing an induced torpor-like state as a potential countermeasure for radiation exposure.

Five macrolichens of different thallus morphology from Antarctica (King George Island) were used for this ecophysiological study. The effect of thallus desiccation on primary photosynthetic processes was examined. We investigated the lichens’ responses to the relative water content (RWC) in their thalli during the transition from a wet (RWC of 100%) to a dry state (RWC of 0%). The slow Kautsky kinetics of chlorophyll fluorescence (ChlF) that was recorded during controlled dehydration (RWC decreased from 100 to 0%) and supplemented with a quenching analysis revealed a polyphasic species-specific response of variable fluorescence. The changes in ChlF at a steady state (Fs), potential and effective quantum yields of photosystem II (FV/FM, ΦPSII), and nonphotochemical quenching (NPQ) reflected a desiccation-induced inhibition of the photosynthetic processes. The dehydration-dependent fall in FV/FM and ΦPSII was species-specific, starting at an RWC range of 22–32%. The critical RWC for ΦPSII was below 5%. The changes indicated the involvement of protective mechanisms in the chloroplastic apparatus of lichen photobionts at RWCs of below 20%. In both the wet and dry states, the spectral reflectance curves (SRC) (wavelength 400–800 nm) and indices (NDVI, PRI) of the studied lichen species were measured. Black Himantormia lugubris showed no difference in the SRCs between wet and dry state. Other lichens showed a higher reflectance in the dry state compared to the wet state. The lichen morphology and anatomy data, together with the ChlF and spectral reflectance data, are discussed in relation to its potential for ecophysiological studies in Antarctic lichens.

Brivaracetam (BRV) is recognized as a novel third-generation antiepileptic drug approved for the treatment of epilepsy. Emerging evidence has demonstrated that it has potentially better efficacy and tolerability than its analog, Levetiracetam (LEV). This, however, cannot be explained by their common synaptic vesicle-binding mechanism. Whether BRV can affect different ionic currents and concert these effects to alter neuronal excitability remains unclear. With the aid of patch clamp technology, we found that BRV concentration dependently inhibited the depolarization-induced M-type K+ current (IK(M)), decreased the delayed-rectifier K+ current (IK(DR)), and decreased the hyperpolarization-activated cation current in GH3 neurons. However, it had a concentration-dependent inhibition on voltage-gated Na+ current (INa). Under an inside-out patch configuration, a bath application of BRV increased the open probability of large-conductance Ca2+-activated K+ channels. Furthermore, in mHippoE-14 hippocampal neurons, the whole-cell INa was effectively depressed by BRV. In simulated modeling of hippocampal neurons, BRV was observed to reduce the firing of the action potentials (APs) concurrently with decreases in the AP amplitude. In animal models, BRV ameliorated acute seizures in both OD-1 and lithium-pilocarpine epilepsy models. However, LEV had effects in the latter only. Collectively, our study demonstrated BRV’s multiple ionic mechanism in electrically excitable cells and a potential concerted effect on neuronal excitability and hyperexcitability disorders.

Tropomyosin is a two-chain coiled coil protein, which together with the troponin complex controls interactions of actin with myosin in a Ca2+-dependent manner. In fast skeletal muscle, the contractile actin filaments are regulated by tropomyosin isoforms Tpm1.1 and Tpm2.2, which form homo- and heterodimers. Mutations in the TPM2 gene encoding isoform Tpm2.2 are linked to distal arthrogryposis and congenital myopathy—skeletal muscle diseases characterized by hyper- and hypocontractile phenotypes, respectively. In this work, in vitro functional assays were used to elucidate the molecular mechanisms of mutations Q93H and E97K in TPM2. Both mutations tended to decrease actin affinity of homo-and heterodimers in the absence and presence of troponin and Ca2+, although the effect of Q93H was stronger. Changes in susceptibility of tropomyosin to trypsin digestion suggested that the mutations diversified dynamics of tropomyosin homo- and heterodimers on the filament. The presence of Q93H in homo- and heterodimers strongly decreased activation of the actomyosin ATPase and reduced sensitivity of the thin filament to [Ca2+]. In contrast, the presence of E97K caused hyperactivation of the ATPase and increased sensitivity to [Ca2+]. In conclusion, the hypo- and hypercontractile phenotypes associated with mutations Q93H and E97K in Tpm2.2 are caused by defects in Ca2+-dependent regulation of actin–myosin interactions.

Alterations in mitochondrial function and morphology are associated with many human diseases, including cancer and neurodegenerative diseases. Mitochondrial impairment is linked to Parkinson’s disease (PD) pathogenesis, and alterations in mitochondrial dynamics are seen in PD models. In particular, α-synuclein (αS) abnormalities are often associated with pathological changes to mitochondria. However, the relationship between αS pathology and mitochondrial dynamics remains poorly defined. Herein, we examined a mouse model of α-synucleinopathy for αS pathology-linked alterations in mitochondrial dynamics in vivo. We show that α-synucleinopathy in a transgenic (Tg) mouse model expressing familial PD-linked mutant A53T human αS (TgA53T) is associated with a decrease in Drp1 localization and activity in the mitochondria. In addition, we show that the loss of Drp1 function in the mitochondria is associated with two distinct phenotypes of enlarged neuronal mitochondria. Mitochondrial enlargement was only present in diseased animals and, apart from Drp1, other proteins involved in mitochondrial dynamics are unlikely to cause these changes, as their levels remained mostly unchanged. Further, the levels of Mfn1, a protein that facilitates mitochondrial fusion, was decreased nonspecifically with transgene expression. These results support the view that altered mitochondrial dynamics are a significant neuropathological factor in α-synucleinopathies.

Several lines of evidence suggest that altered adenosine deaminase (ADA) activity, especially its ADA2 iso-enzyme, is associated with malignant breast cancer (BC) development. Triple-negative breast cancer (TNBC) is currently the most challenging BC subtype due to its metastatic potential and recurrence. Herein, we analyzed the sources of ADA iso-enzymes in TNBC by investigating the effects of cell-to-cell interactions between TNBC cells, macrophages, lymphocytes, and endothelial cells. We also examined the potential relationship between ADA activity and cancer progression in TNBC patients. In vitro analyses demonstrated that the interactions of immune and endothelial cells with MDA-MB-231 triple negative BC cells modulated their extracellular adenosine metabolism pattern. However, they caused an increase in the ADA1 activity, and did not alter ADA2 activity in cancer cells. In turn, the co-culture of MDA-MB-231 cells with THP-1 monocyte/macrophages, Jurkat cells, and human lung microvascular endothelial cells (HULEC) caused the increase in ADA2 activity on THP-1 cells and ADA1 activity on Jurkat cells and HULEC. Clinical sample analysis revealed that TNBC patients had higher plasma ADA2 activities and lower ADA1/ADA2 ratio at advanced stages of cancer development than in the initial stages, while patients with hormone receptor positive, HER2 negative (HR+HER2-), and triple positive (HR+HER2+) breast cancers at the same stages showed opposite trends. TNBC patients also demonstrated positive associations between plasma ADA2 activity and pro-tumor M2 macrophage markers, as well as between ADA1 activity and endothelial dysfunction or inflammatory parameters. The analysis of TNBC patients, at 6 and 12 months following cancer treatment, did not showed significant changes in plasma ADA activities and macrophage polarization markers, which may be the cause of their therapeutic failure. We conclude that alterations in both ADA iso-enzymes can play a role in breast cancer development and progression by the modulation of extracellular adenosine-dependent pathways. Additionally, the changes in ADA2 activity that may contribute to the differentiation of macrophages into unfavorable pro-tumor M2 phenotype deserve special attention in TNBC.

Estrogen-related receptor α (ERRα), which is overexpressed in a variety of cancers has been considered as an effective target for anticancer therapy. ERRα inverse agonists have been proven to effectively inhibit the migration and invasion of cancer cells. As few crystalline complexes have been reported, molecular dynamics (MD) simulations were carried out in this study to deepen the understanding of the interaction mechanism between inverse agonists and ERRα. The binding free energy was analyzed by the MM-GBSA method. The results show that the total binding free energy was positively correlated with the biological activity of an inverse agonist. The interaction of the inverse agonist with the hydrophobic interlayer composed of Phe328 and Phe495 had an important impact on the biological activity of inverse agonists, which was confirmed by the decomposition of energy on residues. As Glu331 flipped and formed a hydrogen bond with Arg372 in the MD simulation process, the formation of hydrogen bond interaction with Glu331 was not a necessary condition for the compound to act as an inverse agonist. These rules provide guidance for the design of new inverse agonists.

This study aimed to investigate the risk factors for and the outcomes of patients with candidemia caused by non-albicans Candida. Candidemia patients treated at Siriraj Hospital (Bangkok, Thailand) during January 2016 to December 2017 were enrolled. A total of 156 patients (mean age: 65 years, 56.4% male) were included. The most prevalent underlying conditions were diabetes (32.1%), chronic cardiac disease (28.2%), chronic kidney disease (26.9%), and hematologic malignancies (21.2%). Candida species isolated from patient blood were C. tropicalis (49.4%), C. albicans (28.8%), C. glabrata (16.7%), and C. parapsilosis (5.1%). Fluconazole resistance was significantly increased in C. tropicalis (37.8%). No independent risk factors were associated with patients with non-albicans Candida candidemia compared to those with C. albicans candidemia. There was no significant difference in mortality between patients with non-albicans Candida candidemia and patients with C. albicans candidemia (OR: 1.35, 95% CI: 0.64–2.85). When compared with C. albicans candidemia, multivariate analysis revealed chronic liver disease (OR: 11.39, 95% CI: 1.38–94.02), neutropenia (OR: 4.31, 95% CI: 1.34–13.87), and male gender (OR: 2.34, 95% CI: 1.04–5.29) to be independent risk factors for C. tropicalis candidemia. The observed high resistance of C. tropicalis to fluconazole indicates that fluconazole should not be used for empirical antifungal treatment in these patients.

Simple Summary To improve the treatment of patients with kidney disease, new renal replacement therapies are being developed. Prior to their use in humans with end-stage kidney disease (ESKD), these therapies need to be tested in animals with kidney disease. Goats seem particularly suitable because they are docile, have bodyweights comparable to humans and easily accessible neck veins to obtain blood access and tolerate frequent blood sampling, allowing for repeated monitoring. To obtain high blood concentrations of waste solutes that accumulate in patients with kidney disease and allow for the evaluation of solute removal by the new renal replacement therapies, we established kidney failure in five goats by partially blocking the blood supply of the kidneys via radiographic embolization. This resulted in stable moderate kidney disease. The administration of high-dose gentamicin caused a temporary further decline in kidney function. Although the response varied with animal, blood concentrations of waste solutes were representative of those found in ESKD patients. These animals can survive for more than ten months in good condition, allowing for the repetitive testing of new therapies in one animal, and therefore limiting the use of laboratory animals. Abstract A large animal model of (end-stage) kidney disease (ESKD) is needed for the preclinical testing of novel renal replacement therapies. This study aimed to create stable uremia via subtotal renal artery embolization in goats and induce a temporary further decline in kidney function by administration of gentamicin. Renal artery embolization was performed in five Dutch white goats by infusing polyvinyl alcohol particles in branches of the renal artery, aiming for the embolization of ~80% of one kidney and complete embolization of the contralateral kidney. Gentamicin was administered to temporarily further increase the plasma concentrations of uremic toxins. After initial acute kidney injury, urea and creatinine plasma concentrations stabilized 1.5 ± 0.7 months post-embolization and remained elevated (12 ± 1.4 vs. 5.6 ± 0.8 mmol/L and 174 ± 45 vs. 65 ± 5.6 µmol/L, resp.) during follow-up (16 ± 6 months). Gentamicin induced temporary acute-on-chronic kidney injury with a variable increase in plasma concentrations of small solutes (urea 29 ± 15 mmol/L, creatinine 841 ± 584 µmol/L, phosphate 2.2 ± 0.3 mmol/L and potassium 5.0 ± 0.6 mmol/L) and protein-bound uremic toxins representative of patients with ESKD. A uremic goat model characterized by stable moderate uremia was established via subtotal renal artery embolization with the induction of temporary severe acute-on-chronic kidney injury by the administration of gentamicin, allowing preclinical in vivo validation of novel renal replacement technologies.

This article belongs to the Section Applied Industrial Technologies. Comprehensive geriatric assessment (CGA) is a multidimensional and multidisciplinary diagnostic instrument that helps provide personalized care to older adults by evaluating their state of health. This evaluation is based on extensive data collection in order to develop a coordinated plan to maximize overall health with aging. In the social and economic context of growing ageing populations, medical experts can save time and effort if provided with interactive tools to efficiently assist them in doing CGAs, managing either standardized tests or data collection. Recent research proposes the use of social robots as the central part of this optimization of clinicians’ time and effort. This paper presents the first and last steps of the research made around the design and evaluation of the CLARC robot: fieldwork (analysis of needs and practices concerning clinical data management) and field trials (pilot experiment in real-life conditions in a rehab hospital). Based on an extensive literature review of social robotics applications for health and ageing, it discusses the practical and methodological questions raised around how to design and test assistive social robots for clinical routine, and questions the feasibility of an automated CGA procedure. This research was partially funded by the EU ECHORD++ project (FP7-ICT-601116), the TIN2015-65686-C5-1-R Spanish Ministerio de Economia y Competitividad project and FEDER funds, the CSO2017-86747-R Spanish project, the ITERA project (UMA-FEDERJA-074), the ROSI project (AT17_5509_UMA), and by Berger Levrault as part of the company's robotics research delegation to the ActivAgeing Living Lab.

Leucine-rich repeat kinase 2 (LRRK2) is a major causative gene of late-onset familial Parkinson’s disease (PD). The suppression of kinase activity is believed to confer neuroprotection, as most pathogenic variants of LRRK2 associated with PD exhibit increased kinase activity. We herein report a novel LRRK2 variant—p.G2294R—located in the WD40 domain, detected through targeted gene-panel screening in a patient with familial PD. The proband showed late-onset Parkinsonism with dysautonomia and a good response to levodopa, without cognitive decline or psychosis. Cultured cell experiments revealed that p.G2294R is highly destabilized at the protein level. The LRRK2 p.G2294R protein expression was upregulated in the patient’s peripheral blood lymphocytes. However, macrophages differentiated from the same peripheral blood showed decreased LRRK2 protein levels. Moreover, our experiment indicated reduced phagocytic activity in the pathogenic yeasts and α-synuclein fibrils. This PD case presents an example wherein the decrease in LRRK2 activity did not act in a neuroprotective manner. Further investigations are needed in order to elucidate the relationship between LRRK2 expression in the central nervous system and the pathogenesis caused by altered LRRK2 activity.

There exist three main types of endogenous opioid peptides, enkephalins, dynorphins and β-endorphin, all of which are derived from their precursors. These endogenous opioid peptides act through opioid receptors, including mu opioid receptor (MOR), delta opioid receptor (DOR) and kappa opioid receptor (KOR), and play important roles not only in analgesia, but also many other biological processes such as reward, stress response, feeding and emotion. The MOR gene, OPRM1, undergoes extensive alternative pre-mRNA splicing, generating multiple splice variants or isoforms. One type of these splice variants, the full-length 7 transmembrane (TM) Carboxyl (C)-terminal variants, has the same receptor structures but contains different intracellular C-terminal tails. The pharmacological functions of several endogenous opioid peptides through the mouse, rat and human OPRM1 7TM C-terminal variants have been considerably investigated together with various mu opioid ligands. The current review focuses on the studies of these endogenous opioid peptides and summarizes the results from early pharmacological studies, including receptor binding affinity and G protein activation, and recent studies of β-arrestin2 recruitment and biased signaling, aiming to provide new insights into the mechanisms and functions of endogenous opioid peptides, which are mediated through the OPRM1 7TM C-terminal splice variants.

CD9 plays a crucial role in cellular growth, mobility, and signal transduction, as well as in hematological malignancy. In myeloid neoplasms, CD9 is involved in the altered interactions between leukemic and stromal cells. However, apart from its role in CD34+ progenitors and myeloid and megakaryocytic differentiation, its function in normal and leukemic pluripotent cells has not yet been determined. Very small embryonic-like stem cells (VSELs) are promising pluripotent stem cells found in adult tissues that can be developed for safe and efficient regenerative medicine. VSELs express different surface receptors of the highest importance in cell functioning, including CD9, and can be effectively mobilized after organ injury or in leukemic patients. In the present study, we observed that CD9 is among the most expressed receptors in VSELs under steady-state conditions, however, once the VSELs are expanded, CD9+ VSELs decrease and are more apoptotic. CD9– VSELs had no proliferative improvement in vitro compared to those that were CD9+. Interestingly, the addition of SDF-1 induced CD9 expression on the surface of VSELs, as observed by flow cytometry, and improved their migration. In addition, we observed, in the phenotypically identical VSELs present in the peripheral blood of patients with myeloproliferative neoplasms, compared to healthy subjects, a significantly higher number of CD9+ cells. However, in their hematopoietic stem cell (HSC) counterparts, the expression remained comparable. These results indicate that, likewise, in progenitors and mature cells, CD9 may play an important function in normal and malignant VSELs. This could explain the refractoriness observed by some groups of expanded stem cells to repairing efficiently damaged tissue when used as a source in cell therapies. Understanding the function of the CD9 receptor in normal and malignant CD34+ and VSELs, along with its relationship with the CXCR4/SDF-1 pathway, will enable advances in the field of adult pluripotent cell usage in regenerative medicine and in their role in leukemia.