bluuebunny/crossref_metadata_2025 huggingface dataset:
An Insight into Giant Cell Arteritis Pathogenesis: Evidence for Oxidative Stress and SIRT1 Downregulation
Authors: Ianni Alessandro , Kumari Poonam , Tarighi Shahriar , Argento Flavia Rita , Fini Eleonora , Emmi Giacomo , Bettiol Alessandra , Braun Thomas , Prisco Domenico , Fiorillo Claudia , Becatti Matteo
Published: June 2021

Giant cell arteritis (GCA), medium and large vessel granulomatous vasculitis affecting the elderly, is characterized by a multitude of vascular complications, including venous thrombosis, myocardial infraction and stroke. The formation of granulomatous infiltrates and the enhanced accumulation of proinflammatory cytokines are typical features of this condition. The GCA pathogenesis remains largely unknown, but recent studies have suggested the involvement of oxidative stress, mainly sustained by an enhanced reactive oxygen species (ROS) production by immature neutrophils. On this basis, in the present study, we intended to evaluate, in GCA patients, the presence of systemic oxidative stress and possible alterations in the expression level of nuclear sirtuins, enzymes involved in the inhibition of inflammation and oxidative stress. Thirty GCA patients were included in the study and compared to 30 healthy controls in terms of leukocyte ROS production, oxidative stress and SIRT1 expression. Our results clearly indicated a significant increase (p < 0.05) both in the ROS levels in the leukocyte fractions and plasma oxidative stress markers (lipid peroxidation and total antioxidant capacity) in the GCA patients compared to the healthy controls. In PBMCs from the GCA patients, a significant decrease in SIRT1 expression (p < 0.05) but not in SIRT6 and SIRT7 expression was found. Taken together, our preliminary findings indicate that, in GCA patients, plasma oxidative stress is paralleled by a reduced SIRT1 expression in PBMC. Further studies are needed to highlight if and how these alterations contribute to GCA pathogenesis.
NADPH Oxidases (NOX): An Overview from Discovery, Molecular Mechanisms to Physiology and Pathology
Authors: Vermot Annelise , Petit-Härtlein Isabelle , Smith Susan M. E. , Fieschi Franck
Published: June 2021

The reactive oxygen species (ROS)-producing enzyme NADPH oxidase (NOX) was first identified in the membrane of phagocytic cells. For many years, its only known role was in immune defense, where its ROS production leads to the destruction of pathogens by the immune cells. NOX from phagocytes catalyzes, via one-electron trans-membrane transfer to molecular oxygen, the production of the superoxide anion. Over the years, six human homologs of the catalytic subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the NOX2/gp91phox component present in the phagocyte NADPH oxidase assembly itself, the homologs are now referred to as the NOX family of NADPH oxidases. NOX are complex multidomain proteins with varying requirements for assembly with combinations of other proteins for activity. The recent structural insights acquired on both prokaryotic and eukaryotic NOX open new perspectives for the understanding of the molecular mechanisms inherent to NOX regulation and ROS production (superoxide or hydrogen peroxide). This new structural information will certainly inform new investigations of human disease. As specialized ROS producers, NOX enzymes participate in numerous crucial physiological processes, including host defense, the post-translational processing of proteins, cellular signaling, regulation of gene expression, and cell differentiation. These diversities of physiological context will be discussed in this review. We also discuss NOX misregulation, which can contribute to a wide range of severe pathologies, such as atherosclerosis, hypertension, diabetic nephropathy, lung fibrosis, cancer, or neurodegenerative diseases, giving this family of membrane proteins a strong therapeutic interest.
Safety Assessment for Upper Part of Floating Crane Considering Minimum Luffing Angle
Authors: Lee Min-Woo , Lee Ji-Hyun , Lee Yeon-Seung , Park Hyun-Jin , Lee Tak-Kee
Published: June 2021

Floating cranes are used for the construction and installation work of harbors, various heavy industries, and offshore structures. In the case of floating cranes that need to move around the work site, their navigation can be constrained due to marine bridges. In some cases, the clearance under the bridge between the water surface and the bottom of the marine bridge may be too low, and floating cranes cannot pass under the marine bridge. In this study, the height of the marine bridges and the boom height of the floating cranes considering the minimum luffing angle were investigated. Through minimizing the boom luffing angle of the floating crane by the height of back tower, a floating crane with improved mobility through marine bridges was developed. A structural analysis model was produced to check whether the developed crane design satisfies the design criteria obeying the KR, DNVGL, and ABS rules, including luffing condition as a special consideration. As a result of the structural analyses, structural safety was validated for the service, stowage, and luffing conditions in terms of combined stresses, displacements, and buckling.
Joint Properties of Aluminum Alloy and Galvanized Steel by AC Pulse MIG Braze Welding
Authors: Ro Chan-Seung , Kim Kyoung-Hak , Bang Hee-Seon , Yoon Hye-Seul
Published: June 2021

In response to global environment and fuel efficiency regulations aiming to reduce CO2 emissions, multi-material structures that use lightweight materials are currently being developed to realize the weight reduction of vehicles in automotive manufacturing. The dissimilar welding of aluminum alloy to steel has great importance, but it is still challenging due to their widely varying thermo-physical properties and the formation of intermetallic compounds. This study aimed to investigate the effect of process parameters on the wettability, mechanical properties, and microstructure in AC Pulse MIG welded joints of AA6061-T6 and galvanized steel sheets. A parametric study on torch aiming position and welding current with EN ratio variation was performed to optimize the process parameters. The result showed that the amount of metal deposition increased with EN ratio. When the EN ratio was higher, the wire feeding speed increased and the heat input process lowered. Moreover, the wetting length increased, ranging from 6.6 to 8.4 mm, and the wetting angle increased from 31.2 to 67.6°, respectively. As a result of the tensile shear test, the maximum tensile shear load of dissimilar welded joints produced at 70 A with a 20% EN ratio was approximately 8.8 kN. From the result of scanning electron microscopy with energy-dispersive spectrometry, FeAl3 IMC was observed at the joint interface, and the IMC layer thickness decreased with EN ratio at 70 A.
Bioactivity and Delivery Strategies of Phytochemical Compounds in Bone Tissue Regeneration
Authors: Valentino Anna , Di Cristo Francesca , Bosetti Michela , Amaghnouje Amal , Bousta Dalila , Conte Raffaele , Calarco Anna
Published: June 2021

Plant-derived secondary metabolites represent a reservoir of phytochemicals for regenerative medicine application because of their varied assortment of biological properties including anti-oxidant, anti-inflammatory, antibacterial, and tissue remodeling properties. In addition, bioactive phytochemicals can be easily available, are often more cost-effective in large-scale industrialization, and can be better tolerated compared to conventional treatments mitigating the long-lasting side effects of synthetic compounds. Unfortunately, their poor bioavailability and lack of long-term stability limit their clinical impact. Nanotechnology-based delivery systems can overcome these limitations increasing bioactive molecules’ local effectiveness with reduction of the possible side effects on healthy bone. This review explores new and promising strategies in the area of delivery systems with particular emphasis on solutions that enhance bioavailability and/or health effects of plant-derived phytochemicals such as resveratrol, quercetin, epigallocatechin-3-gallate, and curcumin in bone tissue regeneration.
Prediction of Transcription Factor Binding Sites of SP1 on Human Chromosome1
Authors: Mahmoud Maiada M. , Belal Nahla A. , Youssif Aliaa
Published: June 2021

Transcription factors (TFs) are proteins that control the transcription of a gene from DNA to messenger RNA (mRNA). TFs bind to a specific DNA sequence called a binding site. Transcription factor binding sites have not yet been completely identified, and this is considered to be a challenge that could be approached computationally. This challenge is considered to be a classification problem in machine learning. In this paper, the prediction of transcription factor binding sites of SP1 on human chromosome1 is presented using different classification techniques, and a model using voting is proposed. The highest Area Under the Curve (AUC) achieved is 0.97 using K-Nearest Neighbors (KNN), and 0.95 using the proposed voting technique. However, the proposed voting technique is more efficient with noisy data. This study highlights the applicability of the voting technique for the prediction of binding sites, and highlights the outperformance of KNN on this type of data. The study also highlights the significance of using voting.
Edge-Preserving Image Denoising Based on Lipschitz Estimation
Authors: Jalil Bushra , Jalil Zunera , Fauvet Eric , Laligant Olivier
Published: June 2021

The information transmitted in the form of signals or images is often corrupted with noise. These noise elements can occur due to the relative motion, noisy channels, error in measurements, and environmental conditions (rain, fog, change in illumination, etc.) and result in the degradation of images acquired by a camera. In this paper, we address these issues, focusing mainly on the edges that correspond to the abrupt changes in the signal or images. Preserving these important structures, such as edges or transitions and textures, has significant theoretical importance. These image structures are important, more specifically, for visual perception. The most significant information about the structure of the image or type of the signal is often hidden inside these transitions. Therefore it is necessary to preserve them. This paper introduces a method to reduce noise and to preserve edges while performing Non-Destructive Testing (NDT). The method computes Lipschitz exponents of transitions to identify the level of discontinuity. Continuous wavelet transform-based multi-scale analysis highlights the modulus maxima of the respective transitions. Lipschitz values estimated from these maxima are used as a measure to preserve edges in the presence of noise. Experimental results show that the noisy data sample and smoothness-based heuristic approach in the spatial domain restored noise-free images while preserving edges.
Accurate Algorithms for Spatial Operations on the Spheroid in a Spatial Database Management System
Authors: Martínez-Llario José Carlos , Baselga Sergio , Coll Eloína
Published: June 2021

Some of the most powerful spatial analysis software solutions (Oracle, Google Earth Engine, PostgreSQL + PostGIS, etc.) are currently performing geometric calculations directly on the ellipsoid (a quadratic surface that models the earth shape), with a double purpose: to attain a high degree of accuracy and to allow the full management of large areas of territory (countries or even continents). It is well known that both objectives are impossible to achieve by means of the traditional approach using local mathematical projections and Cartesian coordinates. This paper demonstrates in a quantitative methodological way that most of the spatial analysis software products make important deviations in calculations regarding to geodesics, being the users unaware of the magnitude of these inaccuracies, which can easily reach meters depending on the distance. This is due to the use of ellipsoid calculations in an approximate way (e.g., using a sphere instead of an ellipsoid). This paper presents the implementation of two algorithms that solve with high accuracy (less than 100 nm) and efficiently (few iterations) two basic geometric calculations on the ellipsoid that are essential to build more complex spatial operators: the intersection of two geodesics and the minimum distance from a point to a geodesic.
Nonlinear and Linear Equation of Gas Diffusion in Coal—Theory and Applications
Authors: Gawor Marek , Skoczylas Norbert , Pajdak Anna , Kudasik Mateusz
Published: June 2021

The authors derived the analytical solution to diffusion equations. The solution requires linearization of diffusion equations, as well as developing the obtained expression into a series. In particular, the result of the first procedure is highly deviated from the exact solution. The authors conducted a sorption experiment and then, in relation to the registered kinetics of the diffusion of CO2 inside hard coal grains, approximated the linear solution and the numerical nonlinear solution by means of the least squares method. As confirmed by the lower value of the sum of deviation squares, it can be clearly demonstrated that the nonlinear equation represents the actual measurement more accurately.
Radiation and Multiple Slip Effects on Magnetohydrodynamic Bioconvection Flow of Micropolar Based Nanofluid over a Stretching Surface
Authors: Abdal Sohaib , Alhumade Hesham , Siddique Imran , Alam Mohammad Mahtab , Ahmad Irfan , Hussain Sajjad
Published: June 2021

Our aim in this article is to study the radiation and multiple slip effects on magnetohydrodynamic bioconvection flow of micropolar based nanofluid over a stretching surface. In addition, a steering mechanism of making improvements to the Brownian motion and thermophoresis motion of nanoparticles is integrated. The numerical solution of 2-dimensional laminar bioconvective boundary layer flow of micropolar based nanofluids is presented. The basic formulation as partial differential equations is transmuted into ordinary differential equations with the help of suitable similarity transformations. Which are then solved by using the Runge–Kutta method of fourth-order with shooting technique. Some important and relevant characteristics of physical quantities are evaluated via inclusive numerical computations. The influence of vital parameters such as buoyancy parameter λ, bioconvection Rayleigh number Rb, the material parameter K are examined. This investigation showed that with the increment in material parameter, micro rotation and velocity profile increases. In addition, the temperature rises due to the enhancement in Nb (Brownian motion) and Nt (thermophoresis parameter).
An Investigation of Particle Swarm Optimization Topologies in Structural Damage Detection
Authors: Li Xiao-Lin , Serra Roger , Olivier Julien
Published: June 2021

In the past few decades, vibration-based structural damage detection (SDD) has attracted widespread attention. Using the response data of engineering structures, the researchers have developed many methods for damage localization and quantification. Adopting meta-heuristic algorithms, in which particle swarm optimization (PSO) is the most widely used, is a popular approach. Various PSO variants have also been proposed for improving its performance in SDD, and they are generally based on the Global topology. However, in addition to the Global topology, other topologies are also developed in the related literature to enhance the performance of the PSO algorithm. The effects of PSO topologies depend significantly on the studied problems. Therefore, in this article, we conduct a performance investigation of eight PSO topologies in SDD. The success rate and mean iterations that are obtained from the numerical simulations are considered as the evaluation indexes. Furthermore, the average rank and Bonferroni-Dunn’s test are further utilized to perform the statistic analysis. From these analysis results, the Four Clusters are shown to be the more favorable PSO topologies in SDD.
Banana Puree Lactic Fermentation: The Role of Ripeness, Heat Treatment, and Ascorbic Acid
Authors: Gallo Marianna , Passannanti Francesca , Schiattarella Paola , Esposito Angela , Colucci Cante Rosa , Nigro Federica , Budelli Andrea , Nigro Roberto
Published: June 2021

Banana puree, due to its nutritional composition, is a good substrate for fermentation in the development of probiotic products. The production of banana puree mainly consists of three phases, i.e., raw material pretreatment, heat treatment, and the addition of anti-browning agents. In this study, we conducted three experimental protocols to evaluate the effect of ripeness grade, heat treatment, and ascorbic acid addition on fermentation performance. At the end of each protocol, the substrate was subjected to the fermentation process (37 °C, 48 h), and then measurements of pH reduction, microbial growth, and lactic acid production were used as markers in the analysis of fermentation performance. Ripe bananas produced better results than unripe bananas whose fermentation appeared to be inhibited. Therefore, ripe bananas were used to test the effect of two different heat treatments (sterilization (121 °C, 20 min) versus tyndallization (70 °C, 30 min; 37 °C, 30 min; 70 °C, 30 min)) on banana puree fermentation, and no significant differences were observed. Finally, 500 or 1000 ppm of ascorbic acid, normally used as an anti-browning agent, was added to ripe tyndallized bananas. No differences in fermentation results were observed between the two tested conditions, though values obtained for growth and lactic acid production were significantly lower than those from fermentation of banana puree without ascorbic acid.
A Modified Quad Q Network Algorithm for Predicting Resource Management
Authors: Kim Yeonggwang , Park Jaehyung , Kim Jinyoung , Yoon Junchurl , Lee Sangjoon , Kim Jinsul
Published: June 2021

As the resource management systems continues to grow, the resource distribution system is expected to expand steadily. The demand response system enables producers to reduce the consumption costs of an enterprise during fluctuating periods in order balance the supply grid and resell the remaining resources of the product to generate revenue. Q-learning, a reinforcement learning algorithm based on a resource distribution compensation mechanism, is used to make optimal decisions to schedule the operation of smart factory appliances. In this paper, we proposed an effective resource management system for enterprise demand response using a Quad Q Network algorithm. The proposed algorithm is based on a Deep Q Network algorithm that directly integrates supply-demand inputs into control logic and employs fuzzy inference as a reward mechanism. In addition to using uses the Compare Optimizer method to reduce the loss value of the proposed Q Network Algorithm, Quad Q Network also maintains a high accuracy with fewer epochs. The proposed algorithm was applied to market capitalization data obtained from Google and Apple. Also, we verified that the Compare Optimizer used in Quad Q Network derives the minimum loss value through the double operation of Double Q value.
Multiscale Modelling and Mechanical Anisotropy of Periodic Cellular Solids with Rigid-Jointed Truss-Like Microscopic Architecture
Authors: Gasparetto Victor , ElSayed Mostafa
Published: June 2021

This paper investigates the macroscopic anisotropic behavior of periodic cellular solids with rigid-jointed microscopic truss-like architecture. A theoretical matrix-based procedure is presented to calculate the homogenized stiffness and strength properties of the material which is validated experimentally. The procedure consists of four main steps, namely, (i) using classical structural analysis to determine the stiffness properties of a lattice unit cell, (ii) employing the Bloch’s theorem to generate the irreducible representation of the infinite lattice, (iii) resorting to the Cauchy–Born Hypothesis to express the microscopic nodal forces and deformations in terms of a homogeneous macroscopic strain field applied to the lattice, and (iv) employing the Hill–Mandel homogenization principle to obtain the macro-stiffness properties of the lattice topologies. The presented model is used to investigate the anisotropic mechanical behavior of 13 2D periodic cellular solids. The results are documented in three set of charts that show (i) the change of the Young and Shear moduli of the material with respect to their relative density; (ii) the contribution of the bending stiffness of microscopic cell elements to the homogenized macroscopic stiffness of the material; and (iii) polar diagrams of the change of the elastic moduli of the cellular solid in response to direction of macroscopic loading. The three set of charts can be used for design purposes in assemblies involving the honeycomb structures as it may help in selecting the best lattice topology for a given functional stiffness and strength requirement. The theoretical model was experimentally validated by means of tensile tests performed in additively manufactured Lattice Material (LM) specimens, achieving good agreement between the results. It was observed that the model of rigid-joined LM (RJLM) predicts the homogenized mechanical properties of the LM with higher accuracy compared to those predicted by pin-jointed models.
Revisiting Forest Effects on Winter Air Temperature and Wind Speed—New Open Data and Transfer Functions
Authors: Klein Michael , Garvelmann Jakob , Förster Kristian
Published: June 2021

The diurnal cycle of both air temperature and wind speed is characterized by considerable differences, when comparing open site conditions to forests. In the course of this article, a new two-hourly, open-source dataset, covering a high spatial and temporal variability, is presented and analyzed. It contains air temperature measurements (128 station pairs (open/forest); six winter seasons; six study sites), wind speed measurements (64 station pairs; three winter seasons, four study sites) and related metadata in central Europe. Daily cycles of air temperature and wind speed, as well as further dependencies of the effective Leaf Area Index (effective LAI), the exposure in the context of forest effects, and the distance to the forest edge, are illustrated in this paper. The forest effects on air temperature can be seen particularly with increasing canopy density, in southern exposures, and in the late winter season, while wind speed depends on multiple factors such as effective LAI or the distance to the forest edge. New transfer functions, developed using linear and non-linear regression analysis, in a leave-one-out cross-validation, improve certain efficiency criteria (NSME; r2; RMSE; MAE) compared to existing transfer functions. The dataset enables multiple purposes and capabilities due to its diversity and sample size.
Pannonian Basin Nocturnal Boundary Layer and Fog Formation: Role of Topography
Authors: Cuxart Joan , Telisman Prtenjak Maja , Matjacic Blazenka
Published: June 2021

Under high-pressure systems, the nocturnal atmospheric boundary layer in the Pannonian Basin is influenced by gravity flows generated at the mountain ranges and along the valleys, determining the variability of wind and temperature at a local scale and the presence of fog. The mechanisms at the mountain foothills are explored at Zagreb Airport using data from a sodar and high-resolution WRF-ARW numerical simulations, allowing identification of how the downslope flows from the nearby Medvednica mountain range condition the temperature inversion and the visibility at night and early morning. These flows may progress tens of kilometres away from the mountain ranges, merging with valley flows and converging in the central areas of the basin. The ECMWF model outputs allow us to explore the mesoscale structures generated in form of low-level jets, how they interact when they meet, and what is the effect of the synoptic pressure field over eastern Europe, to illustrate the formation of a basin-wide cold air pool and the generation of fog in winter.
From the Matrix to the Nucleus and Back: Mechanobiology in the Light of Health, Pathologies, and Regeneration of Oral Periodontal Tissues
Authors: Dieterle Martin Philipp , Husari Ayman , Steinberg Thorsten , Wang Xiaoling , Ramminger Imke , Tomakidi Pascal
Published: June 2021

Among oral tissues, the periodontium is permanently subjected to mechanical forces resulting from chewing, mastication, or orthodontic appliances. Molecularly, these movements induce a series of subsequent signaling processes, which are embedded in the biological concept of cellular mechanotransduction (MT). Cell and tissue structures, ranging from the extracellular matrix (ECM) to the plasma membrane, the cytosol and the nucleus, are involved in MT. Dysregulation of the diverse, fine-tuned interaction of molecular players responsible for transmitting biophysical environmental information into the cell’s inner milieu can lead to and promote serious diseases, such as periodontitis or oral squamous cell carcinoma (OSCC). Therefore, periodontal integrity and regeneration is highly dependent on the proper integration and regulation of mechanobiological signals in the context of cell behavior. Recent experimental findings have increased the understanding of classical cellular mechanosensing mechanisms by both integrating exogenic factors such as bacterial gingipain proteases and newly discovered cell-inherent functions of mechanoresponsive co-transcriptional regulators such as the Yes-associated protein 1 (YAP1) or the nuclear cytoskeleton. Regarding periodontal MT research, this review offers insights into the current trends and open aspects. Concerning oral regenerative medicine or weakening of periodontal tissue diseases, perspectives on future applications of mechanobiological principles are discussed.
Innate Immune Response to Fasting and Refeeding in the Zebrafish Kidney
Authors: Liao Zongzhen , Lin Dihang , Jia Jirong , Cai Ran , Yu Yang , Li Wensheng
Published: June 2021

Animals acquire nutrients and energy through feeding to achieve a balance between growth and organismal health. When there is a change in nutrient acquisition, the state of growth changes and may also cause changes in the intrinsic immune system. Compensatory growth (CG), a specific growth phenomenon, involves the question of whether changes in growth can be accompanied by changes in innate immunity. The zebrafish (Danio rerio), a well-known fish model organism, can serve as a suitable model. In this study, the zebrafish underwent 3 weeks of fasting and refeeding for 3 to 7 day periods. It was found that CG could be achieved in zebrafish. Zebrafish susceptibility to Streptococcus agalactiae increased after starvation. In addition, the amount of melano-macrophage centers increased after fasting and the proportion of injured tubules increased after refeeding for 3 and 5 days, respectively. Furthermore, the kidneys of zebrafish suffering from starvation were under oxidative stress, and the activity of several antioxidant enzymes increased after starvation, including catalase, glutathione peroxidases and superoxide dismutase. Innate immune parameters were influenced by starvation. Additionally, the activity of alkaline phosphatase and lysozyme increased after starvation. The mRNA expression of immune-related genes like il-1β was elevated to a different extent after fasting with or without lipopolysaccharides (LPS) challenge. This study showed that the function of the innate immune system in zebrafish could be influenced by nutrition status.
Parallel and Sequential Pathways of Molecular Recognition of a Tandem-Repeat Protein and Its Intrinsically Disordered Binding Partner
Authors: Smith Ben M. , Rowling Pamela J. E. , Dobson Christopher M. , Itzhaki Laura S.
Published: June 2021

The Wnt signalling pathway plays an important role in cell proliferation, differentiation, and fate decisions in embryonic development and the maintenance of adult tissues. The twelve armadillo (ARM) repeat-containing protein β-catenin acts as the signal transducer in this pathway. Here, we investigated the interaction between β-catenin and the intrinsically disordered transcription factor TCF7L2, comprising a very long nanomolar-affinity interface of approximately 4800 Å2 that spans ten of the twelve ARM repeats of β-catenin. First, a fluorescence reporter system for the interaction was engineered and used to determine the kinetic rate constants for the association and dissociation. The association kinetics of TCF7L2 and β-catenin were monophasic and rapid (7.3 ± 0.1 × 107 M−1·s−1), whereas dissociation was biphasic and slow (5.7 ± 0.4 × 10−4 s−1, 15.2 ± 2.8 × 10−4 s−1). This reporter system was then combined with site-directed mutagenesis to investigate the striking variability in the conformation adopted by TCF7L2 in the three different crystal structures of the TCF7L2–β-catenin complex. We found that the mutation had very little effect on the association kinetics, indicating that most interactions form after the rate-limiting barrier for association. Mutations of the N- and C-terminal subdomains of TCF7L2 that adopt relatively fixed conformations in the crystal structures had large effects on the dissociation kinetics, whereas the mutation of the labile sub-domain connecting them had negligible effect. These results point to a two-site avidity mechanism of binding with the linker region forming a “fuzzy” complex involving transient contacts that are not site-specific. Strikingly, the two mutations in the N-terminal subdomain that had the largest effects on the dissociation kinetics showed two additional phases, indicating partial flux through an alternative dissociation pathway that is inaccessible to the wild type. The results presented here provide insights into the kinetics of the molecular recognition of a long intrinsically disordered region with an elongated repeat-protein surface, a process found to involve parallel routes with sequential steps in each.
Genetic Variants in Patients with Multiple Head and Neck Paragangliomas: Dilemma in Management
Authors: Guha Anasuya , Vicha Ales , Zelinka Tomas , Musil Zdenek , Chovanec Martin
Published: June 2021

Multiple head and neck paragangliomas (HNPGLs) are neuroendocrine tumors of a mostly benign nature that can be associated with a syndrome, precipitated by the presence of a germline mutation. Familial forms of the disease are usually seen with mutations of SDHx genes, especially the SDHD gene. SDHB mutations are predisposed to malignant tumors. We found 6 patients with multiple tumors amongst 30 patients with HNPGLs during the period of 2016 to 2021. We discuss the phenotypic and genetic patterns in our patients with multiple HNPGLs and explore the management possibilities related to the disease. Fifty percent of our patients had incidental findings of HNPGLs. Twenty-one biochemically silent tumors were found. Four patients had germline mutations, and only one had a positive family history. Three out of five underwent surgery without permanent complications. Preventative measures (genetic counselling and tumor surveillance) represent the gold standard in effectively controlling the disease in index patients and their relatives. In terms of treatment, apart from surgical and radiotherapeutic interventions, new therapeutic measures such as gene targeted therapy have contributed very sparsely. With the lack of standardized protocols, management of patients with multiple HNPGLs still remains very challenging, especially in those with sporadic or malignant forms of the disease.
Activin-A Induces Early Differential Gene Expression Exclusively in Periodontal Ligament Fibroblasts from Fibrodysplasia Ossificans Progressiva Patients
Authors: Schoenmaker Ton , Mokry Michal , Micha Dimitra , Netelenbos Coen , Bravenboer Nathalie , Gilijamse Marjolijn , Eekhoff E. Marelise W. , de Vries Teun J.
Published: June 2021

Fibrodysplasia Ossificans Progressiva (FOP) is a rare genetic disease characterized by heterotopic ossification (HO). It is caused by mutations in the Activin receptor type 1 (ACVR1) gene, resulting in enhanced responsiveness to ligands, specifically to Activin-A. Though it has been shown that capturing Activin-A protects against heterotopic ossification in animal models, the exact underlying mechanisms at the gene expression level causing ACVR1 R206H-mediated ossifications and progression are thus far unknown. We investigated the early transcriptomic changes induced by Activin-A of healthy control and patient-derived periodontal ligament fibroblasts (PLF) isolated from extracted teeth by RNA sequencing analysis. To study early differences in response to Activin-A, periodontal ligament fibroblasts from six control teeth and from six FOP patient teeth were cultured for 24 h without and with 50 ng/mL Activin-A and analyzed with RNA sequencing. Pathway analysis on genes upregulated by Activin-A in FOP cells showed an association with pathways involved in, among others, Activin, TGFβ, and BMP signaling. Differential gene expression induced by Activin-A was exclusively seen in the FOP cells. Median centered supervised gene expression analysis showed distinct clusters of up- and downregulated genes in the FOP cultures after stimulation with Activin-A. The upregulated genes with high fold changes like SHOC2, TTC1, PAPSS2, DOCK7, and LOX are all associated with bone metabolism. Our open-ended approach to investigating the early effect of Activin-A on gene expression in control and FOP PLF shows that the molecule exclusively induces differential gene expression in FOP cells and not in control cells.
Advances in Electrochemical and Acoustic Aptamer-Based Biosensors and Immunosensors in Diagnostics of Leukemia
Authors: Hianik Tibor
Published: June 2021

Early diagnostics of leukemia is crucial for successful therapy of this disease. Therefore, development of rapid, sensitive, and easy-to-use methods for detection of this disease is of increased interest. Biosensor technology is challenged for this purpose. This review includes a brief description of the methods used in current clinical diagnostics of leukemia and provides recent achievements in sensor technology based on immuno- and DNA aptamer-based electrochemical and acoustic biosensors. The comparative analysis of immuno- and aptamer-based sensors shows a significant advantage of DNA aptasensors over immunosensors in the detection of cancer cells. The acoustic technique is of comparable sensitivity with those based on electrochemical methods; moreover, it is label-free and provides straightforward evaluation of the signal. Several examples of sensor development are provided and discussed.
The Home Learning Environment of Primary School Children with Down Syndrome and Those with Williams Syndrome
Authors: Ranzato Erica , Tolmie Andrew , Van Herwegen Jo
Published: June 2021

Background and aims: Research on typically developing (TD) populations has shown that the home learning environment plays a significant role in cognitive development and learning, but very little is known about the home learning environment of children with Down syndrome (DS) or children with Williams syndrome (WS). The present study examined and compared, for the first time, the home learning environment of children diagnosed with DS and children diagnosed with WS to investigate whether different cognitive profiles were reflected in their home literacy and number experiences. Methods and procedures: Quantitative and qualitative data were collected through a web-based survey from 58 parents and one foster parent of primary school children with DS (n = 35) and WS (n = 24) mostly based in the UK. The survey targeted the children’s general level of functioning and academic skills; type, format, and frequency of home learning activities; parents’ expectations for their child’s academic outcomes; parents’ attitudes towards literacy and mathematics; children’s interest towards mathematics; and the use of technology to support home learning activities. Outcomes and results: Our results showed that, overall, the home learning environment of children with DS and children with WS were similar but changed based on the child’s cognitive profile. Comparative analyses showed that parents of children with DS engaged more often in activities supporting counting than parents of children with WS, despite both groups reporting difficulties with this skill. Moreover, our results indicated that literacy-based activities occurred more often than mathematics-based activities and that the home numeracy environment was characterized by activities supporting different mathematical skills such as counting, arithmetic, and numeracy. Parents in both groups engaged with their child in both formal and informal literacy and mathematics-based activities, but informal activities occurred more often when supporting counting and number recognition skills. Conclusions and implications: The current study provides evidence that the home learning environment of children with DS and children with WS include different literacy- and mathematics-based activities and that the home learning environment changes on the basis of the child’s strengths and weaknesses. The findings are discussed in relation to previous studies and the impact on parental interventions.
Circulating Tumor Cells from Enumeration to Analysis: Current Challenges and Future Opportunities
Authors: Yang Yu-Ping , Giret Teresa M. , Cote Richard J.
Published: June 2021

Circulating tumor cells (CTCs) have been recognized as a major contributor to distant metastasis. Their unique role as metastatic seeds renders them a potential marker in the circulation for early cancer diagnosis and prognosis as well as monitoring of therapeutic response. In the past decade, researchers mainly focused on the development of isolation techniques for improving the recovery rate and purity of CTCs. These developed techniques have significantly increased the detection sensitivity and enumeration accuracy of CTCs. Currently, significant efforts have been made toward comprehensive molecular characterization, ex vivo expansion of CTCs, and understanding the interactions between CTCs and their associated cells (e.g., immune cells and stromal cells) in the circulation. In this review, we briefly summarize existing CTC isolation technologies and specifically focus on advances in downstream analysis of CTCs and their potential applications in precision medicine. We also discuss the current challenges and future opportunities in their clinical utilization.
Who’s Driving? Switch of Drivers in Immunotherapy-Treated Progressing Sinonasal Melanoma
Authors: Freiberger Sandra N. , Turko Patrick , Hüllner Martin , Dummer Reinhard , Morand Grégoire B. , Levesque Mitchell P. , Holzmann David , Rupp Niels J.
Published: June 2021

Mucosal melanoma can be driven by various driver mutations in genes such as NRAS, KIT, or KRAS. However, some cases present with only weak drivers, or lacking known oncogenic drivers, suggesting immunotherapy over targeted therapy. While resistance mechanisms to immunotherapy in cutaneous melanoma have been uncovered, including alterations in JAK1/2, B2M, or STK11, a switch of oncogenic drivers under immunotherapy has not yet been observed. We report three cases of metastatic sinonasal melanoma that switched oncogenic drivers from KRAS, KIT, or no driver to NRAS during or after immunotherapy, thereby showing progressive disease. One of the cases presented with three spatially separate driver mutations in the primary tumor, whereas the NRAS clone persisted under immunotherapy. In comparison, three different control cases receiving radiotherapy only did not show a change of the detectable molecular drivers in their respective recurrences or metastases. In summary, these data provide an important rationale for longitudinal molecular testing, based on evidence for an unforeseen recurrent event of molecular driver switch to NRAS in progressing sinonasal melanoma. These findings provide the basis for further studies on a potential causal relation of emerging NRAS mutant clones and immunotherapy.
Prognostic Implications of MRI Melanin Quantification and Cytogenetic Abnormalities in Liver Metastases of Uveal Melanoma
Authors: Ramtohul Toulsie , Ait Rais Khadija , Gardrat Sophie , Barnhill Raymond , Román-Román Sergio , Cassoux Nathalie , Rodrigues Manuel , Mariani Pascale , De Koning Leanne , Pierron Gaëlle , Servois Vincent
Published: June 2021

To evaluate the prognostic implications of melanin quantification assessed by magnetic resonance imaging (MRI) with respect to the clinical, pathological, and genetic features of liver metastases of uveal melanoma (LMUM). This single-center retrospective cohort study included 63 patients eligible for margin-free resection of LMUM between 2007 and 2018. Comparative genomic hybridization of resected liver metastases on microarrays was performed for genetic risk classification. Metastases exhibiting monosomy 3 with any type of gain of chromosome 8 (M3/8g) were considered high-genetic-risk. MRI melanin quantification using the mean T1 signal (mT1s) in liver metastases was assessed quantitatively on preoperative imaging examination and compared to that of gross pathological evaluation. The association between MRI melanin quantification and overall survival (OS) was assessed by multivariate analysis using the Cox proportional hazards model. Gross pathological assessment of melanin content and MRI melanin quantification were strongly correlated (r = 0.8, p < 0.001). Independent prognostic factors associated with OS were disease-free interval ≤ 24 months (HR = 3.1; 95% CI, 1.6–6.0; p < 0.001), high-genetic-risk (HR = 2.2; 95% CI, 1.1–4.8; p = 0.04), mT1s > 1.1 (HR = 2.3; 95% CI, 1.2–4.7; p = 0.019), and complete hepatic resection (HR = 0.3; 95% CI, 0.2–0.7; p = 0.004). In patients with high-genetic-risk, mT1s showed a significant association with OS (HR = 3.7; 95% CI, 1.5–9.3; p = 0.006). The median OS was 17.5 months vs. 27 months for >1.1 and ≤1.1 mT1s tumors, respectively (p = 0.003). We showed that the level of pigmentation in M3/8g LMUM identified two subsets that were correlated with distinct clinical outcomes.
Magnetic Nanostructures as Emerging Therapeutic Tools to Boost Anti-Tumour Immunity
Authors: Persano Stefano , Das Pradip , Pellegrino Teresa
Published: June 2021

Cancer immunotherapy has shown remarkable results in various cancer types through a range of immunotherapeutic approaches, including chimeric antigen receptor-T cell (CAR-T) therapy, immune checkpoint blockade (ICB), and therapeutic vaccines. Despite the enormous potential of cancer immunotherapy, its application in various clinical settings has been limited by immune evasion and immune suppressive mechanisms occurring locally or systemically, low durable response rates, and severe side effects. In the last decades, the rapid advancement of nanotechnology has been aiming at the development of novel synthetic nanocarriers enabling precise and enhanced delivery of immunotherapeutics, while improving drug stability and effectiveness. Magnetic nanostructured formulations are particularly intriguing because of their easy surface functionalization, low cost, and robust manufacturing procedures, together with their suitability for the implementation of magnetically-guided and heat-based therapeutic strategies. Here, we summarize and discuss the unique features of magnetic-based nanostructures, which can be opportunely designed to potentiate classic immunotherapies, such as therapeutic vaccines, ICB, adoptive cell therapy (ACT), and in situ vaccination. Finally, we focus on how multifunctional magnetic delivery systems can facilitate the anti-tumour therapies relying on multiple immunotherapies and/or other therapeutic modalities. Combinatorial magnetic-based therapies are indeed offering the possibility to overcome current challenges in cancer immunotherapy.
Detection of EGFR Mutations in Plasma cfDNA and Paired CTCs of NSCLC Patients before and after Osimertinib Therapy Using Crystal Digital PCR
Authors: Ntzifa Aliki , Kotsakis Athanasios , Georgoulias Vassilis , Lianidou Evi
Published: June 2021

Circulating tumor DNA (ctDNA) analysis has clinical utility in EGFR mutant NSCLC. Circulating tumor cells (CTCs) consist a unique source of information at the cellular level. Digital PCR (dPCR) is a valuable tool for accurate and valid analysis of gene mutations in liquid biopsy analysis. In the present study we detected EGFR mutations in ctDNA and paired CTCs under osimertinib therapy at two time points using crystal dPCR and the naica® system (Stilla Technologies). We quantified mutation allele frequencies (MAF) of EGFR mutations in 91 plasma cfDNA samples of 48 EGFR mutant NSCLC patients and in 64 matched CTC-derived genomic DNA samples, and the FDA-cleared cobas® EGFR mutation test in 80 identical plasma samples. Direct comparison between crystal dPCR and the cobas EGFR assay revealed a high concordance for all EGFR mutations. Our comparison of crystal dPCR results in ctDNA with the corresponding primary tissue has shown a strong correlation. EGFR mutations analysis in paired CTC-derived gDNA revealed a high heterogeneity. Crystal dPCR offers the unique advantages of high analytical sensitivity, precision, and accuracy for detecting and quantifying multiple EGFR mutations in plasma cfDNA and CTCs of NSCLC patients.
Insight into Codon Utilization Pattern of Tumor Suppressor Gene EPB41L3 from Different Mammalian Species Indicates Dominant Role of Selection Force
Authors: Kumar Utsang , Khandia Rekha , Singhal Shailja , Puranik Nidhi , Tripathi Meghna , Pateriya Atul Kumar , Khan Raju , Emran Talha Bin , Dhama Kuldeep , Munjal Ashok , Alqahtani Taha , Alqahtani Ali M.
Published: June 2021

Uneven codon usage within genes as well as among genomes is a usual phenomenon across organisms. It plays a significant role in the translational efficiency and evolution of a particular gene. EPB41L3 is a tumor suppressor protein-coding gene, and in the present study, the pattern of codon usage was envisaged. The full-length sequences of the EPB41L3 gene for the human, brown rat, domesticated cattle, and Sumatran orangutan available at the NCBI were retrieved and utilized to analyze CUB patterns across the selected mammalian species. Compositional properties, dinucleotide abundance, and parity analysis showed the dominance of A and G whilst RSCU analysis indicated the dominance of G/C-ending codons. The neutrality plot plotted between GC12 and GC3 to determine the variation between the mutation pressure and natural selection indicated the dominance of selection pressure (R = 0.926; p < 0.00001) over the three codon positions across the gene. The result is in concordance with the codon adaptation index analysis and the ENc-GC3 plot analysis, as well as the translational selection index (P2). Overall selection pressure is the dominant pressure acting during the evolution of the EPB41L3 gene.
Promoting Effect of Copper Loading and Mesoporosity on Cu-MOR in the Carbonylation of Dimethyl Ether to Methyl Acetate
Authors: Poreddy Raju , Mossin Susanne , Jensen Anker Degn , Riisager Anders
Published: June 2021

Cu-mordenite (Cu-MOR) catalysts with different copper loadings were prepared, characterized and examined in continuous, gas-flow synthesis of methyl acetate (MA) by dimethyl ether (DME) carbonylation. Improved activity and selectivity were observed for Cu-MOR catalysts with up to 1 wt% Cu and X-ray photoelectron spectroscopy (XPS), electron paramagnetic resonance (EPR) spectroscopy and temperature-programmed reduction with hydrogen (H2-TPR) were used to elucidate the state of copper in the catalysts. Moreover, mesoporous MOR catalysts (RHMs) were prepared by mild stepwise recrystallization with X-ray powder diffraction (XRPD) and ammonia temperature-programmed desorption (NH3-TPD) demonstrating the retained MOR structure and the acid property of the catalysts, respectively. The RHM catalysts showed improved lifetime compared to pristine MOR giving a yield up to 78% MA with 93% selectivity after 5 h on stream (GHSV = 6711 h−1). Under identical reaction conditions, 1 wt% Cu-RHM catalysts had an even higher catalytic activity and durability resulting in a MA yield of 90% with 97% selectivity for 7–8 h of operation as well as a lower coke formation.