bluuebunny/crossref_metadata_2025 huggingface dataset:
Urinary Exosomes Identify Inflammatory Pathways in Vancomycin Associated Acute Kidney Injury
Authors: Awdishu Linda , Le Amy , Amato Jordan , Jani Vidhyut , Bal Soma , Mills Robert , Carrillo-Terrazas Marvic , Gonzalez David , Tolwani Ashita , Acharya Anjali , Cerda Jorge , Joy Melanie , Nicoletti Paola , Macedo Etienne , Vaingankar Sucheta , Mehta Ravindra , RamachandraRao Satish ,   on behalf of the Direct Investigators
Published: March 2021

Background: Vancomycin is commonly used as a first line therapy for gram positive organisms such as methicillin resistant Staphylococcusaureus. Vancomycin-induced acute kidney injury (V-AKI) has been reported in up to 43% of patients, especially in those with higher targeted trough concentrations. The precise mechanism of injury in humans remains elusive, with recent evidence directed towards proximal tubule cell apoptosis. In this study, we investigated the protein contents of urinary exosomes in patients with V-AKI to further elucidate biomarkers of mechanisms of injury and potential responses. Methods: Urine samples from patients with V-AKI who were enrolled in the DIRECT study and matched healthy controls from the UAB-UCSD O’Brien Center Biorepository were included in the analysis. Exosomes were extracted using solvent exclusion principle and polyethylene glycol induced precipitation. Protein identity and quantification was determined by label-free liquid chromatography mass spectrometry (LC/MS). The mean peak serum creatinine was 3.7 ± 1.4 mg/dL and time to kidney injury was 4.0 ± 3.0 days. At discharge, 90% of patients demonstrated partial recovery; 33% experienced full recovery by day 28. Proteomic analyses on five V-AKI and 7 control samples revealed 2009 proteins in all samples and 251 proteins significantly associated with V-AKI (Pi-score > 1). The top discriminatory proteins were complement C3, complement C4, galectin-3-binding protein, fibrinogen, alpha-2 macroglobulin, immunoglobulin heavy constant mu and serotransferrin. Conclusion: Urinary exosomes reveal up-regulation of inflammatory proteins after nephrotoxic injury in V-AKI. Further studies are necessary in a large patient sample to confirm these findings for elucidation of pathophysiologic mechanisms and validation of potential injury biomarkers.
The Glycoprotein/Cytokine Erythropoietin Promotes Rapid Alveolar Ridge Regeneration In Vivo by Promoting New Bone Extracellular Matrix Deposition in Conjunction with Coupled Angiogenesis/Osteogenesis
Authors: Pandya Mirali , Saxon Matthew , Bozanich John , Tillberg Connie , Luan Xianghong , Diekwisch Thomas G.H.
Published: March 2021

The loss of bone following tooth extraction poses a significant clinical problem for maxillofacial esthetics, function, and future implant placement. In the present study, the efficacy of an erythropoietin-impregnated collagen scaffold as an alveolar ridge augmentation material versus a conventional collagen scaffold and a BioOss inorganic bovine bone xenograft was examined. The collagen/Erythropoietin (EPO) scaffold exhibited significantly more rapid and complete osseous regeneration of the alveolar defect when compared to bone xenograft and the collagen membrane alone. The new EPO induced extracellular matrix was rich in Collagen I, Collagen III, Fibronectin (Fn) and E-cadherin, and featured significantly increased levels of the osteogenic transcription factors Runt-related transcription factor 2 (Runx2) and Osterix (Osx). Histomorphometric evaluation revealed a significant two-fold increase in the number of capillaries between the EPO and the BioOss group. Moreover, there was a highly significant 3.5-fold higher level of vascular endothelial growth factor (VEGF) in the collagen/EPO-treated group compared to controls. The significant effect of EPO on VEGF, FN, and RUNX2 upregulation was confirmed in vitro, and VEGF pathway analysis using VEGF inhibitors confirmed that EPO modulated extracellular matrix protein expression through VEGF even in the absence of blood vessels. Together, these data demonstrate the effectiveness of an EPO-impregnated collagen scaffold for bone regeneration as it induces rapid matrix production and osseoinduction adjacent to new capillaries via VEGF.
Differential Methylation in the GSTT1 Regulatory Region in Sudden Unexplained Death and Sudden Unexpected Death in Epilepsy
Authors: Christiansen Steffan Noe , Jacobsen Stine Bøttcher , Andersen Jeppe Dyrberg , Kampmann Marie-Louise , Trudsø Linea Christine , Olsen Kristine Boisen , Tfelt-Hansen Jacob , Banner Jytte , Morling Niels
Published: March 2021

Sudden cardiac death (SCD) is a diagnostic challenge in forensic medicine. In a relatively large proportion of the SCDs, the deaths remain unexplained after autopsy. This challenge is likely caused by unknown disease mechanisms. Changes in DNA methylation have been associated with several heart diseases, but the role of DNA methylation in SCD is unknown. In this study, we investigated DNA methylation in two SCD subtypes, sudden unexplained death (SUD) and sudden unexpected death in epilepsy (SUDEP). We assessed DNA methylation of more than 850,000 positions in cardiac tissue from nine SUD and 14 SUDEP cases using the Illumina Infinium MethylationEPIC BeadChip. In total, six differently methylated regions (DMRs) between the SUD and SUDEP cases were identified. The DMRs were located in proximity to or overlapping genes encoding proteins that are a part of the glutathione S-transferase (GST) superfamily. Whole genome sequencing (WGS) showed that the DNA methylation alterations were not caused by genetic changes, while whole transcriptome sequencing (WTS) showed that DNA methylation was associated with expression levels of the GSTT1 gene. In conclusion, our results indicate that cardiac DNA methylation is similar in SUD and SUDEP, but with regional differential methylation in proximity to GST genes.
Bioprospecting Fluorescent Plant Growth Regulators from Arabidopsis to Vegetable Crops
Authors: Sumalan Radu L. , Halip Liliana , Maffei Massimo E. , Croitor Lilia , Siminel Anatolii V. , Radulov Izidora , Sumalan Renata M. , Crisan Manuela E.
Published: March 2021

The phytohormone auxin is involved in almost every process of a plant’s life, from germination to plant development. Nowadays, auxin research connects synthetic chemistry, plant biology and computational chemistry in order to develop innovative and safe compounds to be used in sustainable agricultural practice. In this framework, we developed new fluorescent compounds, ethanolammonium p-aminobenzoate (HEA-pABA) and p-nitrobenzoate (HEA-pNBA), and investigated their auxin-like behavior on two main commercial vegetables cultivated in Europe, cucumber (Cucumis sativus) and tomato (Solanumlycopersicum), in comparison to the model plant Arabidopsis (Arabidopsis thaliana). Moreover, the binding modes and affinities of two organic salts in relation to the natural auxin indole-3-acetic acid (IAA) into TIR1 auxin receptor were investigated by computational approaches (homology modeling and molecular docking). Both experimental and theoretical results highlight HEA-pABA as a fluorescent compound with auxin-like activity both in Arabidopsis and the commercial cucumber and tomato. Therefore, alkanolammonium benzoates have a great potential as promising sustainable plant growth stimulators to be efficiently used in vegetable crops.
Improving Anti-PD-1/PD-L1 Therapy for Localized Bladder Cancer
Authors: de Jong Florus C. , Rutten Vera C. , Zuiverloon Tahlita C. M. , Theodorescu Dan
Published: March 2021

In high-risk non-muscle invasive bladder cancer (HR-NMIBC), patient outcome is negatively affected by lack of response to Bacillus-Calmette Guérin (BCG) treatment. Lack of response to cisplatin-based neoadjuvant chemotherapy and cisplatin ineligibility reduces successful treatment outcomes in muscle-invasive bladder cancer (MIBC) patients. The effectiveness of PD-1/PD-L1 immune checkpoint inhibitors (ICI) in metastatic disease has stimulated its evaluation as a treatment option in HR-NMIBC and MIBC patients. However, the observed responses, immune-related adverse events and high costs associated with ICI have provided impetus for the development of methods to improve patient stratification, enhance anti-tumorigenic effects and reduce toxicity. Here, we review the challenges and opportunities offered by PD-1/PD-L1 inhibition in HR-NMIBC and MIBC. We highlight the gaps in the field that need to be addressed to improve patient outcome including biomarkers for response stratification and potentially synergistic combination therapy regimens with PD-1/PD-L1 blockade.
Modulation by Ozone Therapy of Oxidative Stress in Chemotherapy-Induced Peripheral Neuropathy: The Background for a Randomized Clinical Trial
Authors: Clavo Bernardino , Martínez-Sánchez Gregorio , Rodríguez-Esparragón Francisco , Rodríguez-Abreu Delvys , Galván Saray , Aguiar-Bujanda David , Díaz-Garrido Juan A. , Cañas Silvia , Torres-Mata Laura B. , Fabelo Himar , Téllez Teresa , Santana-Rodríguez Norberto , Fernández-Pérez Leandro , Marrero-Callico Gustavo
Published: March 2021

(1) Background: Chemotherapy-induced peripheral neuropathy (CIPN) decreases the quality of life of patients and can lead to a dose reduction and/or the interruption of chemotherapy treatment, limiting its effectiveness. Potential pathophysiological mechanisms involved in the pathogenesis of CIPN include chronic oxidative stress and subsequent increase in free radicals and proinflammatory cytokines. Approaches for the treatment of CIPN are highly limited in their number and efficacy, although several antioxidant-based therapies have been tried. On the other hand, ozone therapy can induce an adaptive antioxidant and anti-inflammatory response, which could be potentially useful in the management of CIPN. (2) Methods: The aims of this works are: (a) to summarize the potential mechanisms that could induce CIPN by the most relevant drugs (platinum, taxanes, vinca alkaloids, and bortezomib), with particular focus on the role of oxidative stress; (b) to summarize the current situation of prophylactic and treatment approaches; (c) to describe the action mechanisms of ozone therapy to modify oxidative stress and inflammation with its potential repercussions for CIPN; (d) to describe related experimental and clinical reports with ozone therapy in chemo-induced neurologic symptoms and CIPN; and (e) to show the main details about an ongoing focused clinical trial. (3) Results: A wide background relating to the mechanisms of action and a small number of experimental and clinical reports suggest that ozone therapy could be useful to prevent or improve CIPN. (4) Conclusions: Currently, there are no clinically relevant approaches for the prevention and treatment of stablished CIPN. The potential role of ozone therapy in this syndrome merits further research. Randomized controlled trials are ongoing.
A Novel Computational Approach for the Discovery of Drug Delivery System Candidates for COVID-19
Authors: Cho Taeheum , Han Hyo-Sang , Jeong Junhyuk , Park Eun-Mi , Shim Kyu-Sik
Published: March 2021

In order to treat Coronavirus Disease 2019 (COVID-19), we predicted and implemented a drug delivery system (DDS) that can provide stable drug delivery through a computational approach including a clustering algorithm and the Schrödinger software. Six carrier candidates were derived by the proposed method that could find molecules meeting the predefined conditions using the molecular structure and its functional group positional information. Then, just one compound named glycyrrhizin was selected as a candidate for drug delivery through the Schrödinger software. Using glycyrrhizin, nafamostat mesilate (NM), which is known for its efficacy, was converted into micelle nanoparticles (NPs) to improve drug stability and to effectively treat COVID-19. The spherical particle morphology was confirmed by transmission electron microscopy (TEM), and the particle size and stability of 300–400 nm were evaluated by measuring DLSand the zeta potential. The loading of NM was confirmed to be more than 90% efficient using the UV spectrum.
A Detailed Catalogue of Multi-Omics Methodologies for Identification of Putative Biomarkers and Causal Molecular Networks in Translational Cancer Research
Authors: Vlachavas Efstathios Iason , Bohn Jonas , Ückert Frank , Nürnberg Sylvia
Published: March 2021

Recent advances in sequencing and biotechnological methodologies have led to the generation of large volumes of molecular data of different omics layers, such as genomics, transcriptomics, proteomics and metabolomics. Integration of these data with clinical information provides new opportunities to discover how perturbations in biological processes lead to disease. Using data-driven approaches for the integration and interpretation of multi-omics data could stably identify links between structural and functional information and propose causal molecular networks with potential impact on cancer pathophysiology. This knowledge can then be used to improve disease diagnosis, prognosis, prevention, and therapy. This review will summarize and categorize the most current computational methodologies and tools for integration of distinct molecular layers in the context of translational cancer research and personalized therapy. Additionally, the bioinformatics tools Multi-Omics Factor Analysis (MOFA) and netDX will be tested using omics data from public cancer resources, to assess their overall robustness, provide reproducible workflows for gaining biological knowledge from multi-omics data, and to comprehensively understand the significantly perturbed biological entities in distinct cancer types. We show that the performed supervised and unsupervised analyses result in meaningful and novel findings.
Refining Genotypes and Phenotypes in KCNA2-Related Neurological Disorders
Authors: Döring Jan H. , Schröter Julian , Jüngling Jerome , Biskup Saskia , Klotz Kerstin A. , Bast Thomas , Dietel Tobias , Korenke G. Christoph , Christoph Sophie , Brennenstuhl Heiko , Rubboli Guido , Møller Rikke S. , Lesca Gaetan , Chaix Yves , Kölker Stefan , Hoffmann Georg F. , Lemke Johannes R. , Syrbe Steffen
Published: March 2021

Pathogenic variants in KCNA2, encoding for the voltage-gated potassium channel Kv1.2, have been identified as the cause for an evolving spectrum of neurological disorders. Affected individuals show early-onset developmental and epileptic encephalopathy, intellectual disability, and movement disorders resulting from cerebellar dysfunction. In addition, individuals with a milder course of epilepsy, complicated hereditary spastic paraplegia, and episodic ataxia have been reported. By analyzing phenotypic, functional, and genetic data from published reports and novel cases, we refine and further delineate phenotypic as well as functional subgroups of KCNA2-associated disorders. Carriers of variants, leading to complex and mixed channel dysfunction that are associated with a gain- and loss-of-potassium conductance, more often show early developmental abnormalities and an earlier onset of epilepsy compared to individuals with variants resulting in loss- or gain-of-function. We describe seven additional individuals harboring three known and the novel KCNA2 variants p.(Pro407Ala) and p.(Tyr417Cys). The location of variants reported here highlights the importance of the proline(405)–valine(406)–proline(407) (PVP) motif in transmembrane domain S6 as a mutational hotspot. A novel case of self-limited infantile seizures suggests a continuous clinical spectrum of KCNA2-related disorders. Our study provides further insights into the clinical spectrum, genotype–phenotype correlation, variability, and predicted functional impact of KCNA2 variants.
iPSC-Cardiomyocyte Models of Brugada Syndrome—Achievements, Challenges and Future Perspectives
Authors: Nijak Aleksandra , Saenen Johan , Labro Alain J. , Schepers Dorien , Loeys Bart L. , Alaerts Maaike
Published: March 2021

Brugada syndrome (BrS) is an inherited cardiac arrhythmia that predisposes to ventricular fibrillation and sudden cardiac death. It originates from oligogenic alterations that affect cardiac ion channels or their accessory proteins. The main hurdle for the study of the functional effects of those variants is the need for a specific model that mimics the complex environment of human cardiomyocytes. Traditionally, animal models or transient heterologous expression systems are applied for electrophysiological investigations, each of these models having their limitations. The ability to create induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), providing a source of human patient-specific cells, offers new opportunities in the field of cardiac disease modelling. Contemporary iPSC-CMs constitute the best possible in vitro model to study complex cardiac arrhythmia syndromes such as BrS. To date, thirteen reports on iPSC-CM models for BrS have been published and with this review we provide an overview of the current findings, with a focus on the electrophysiological parameters. We also discuss the methods that are used for cell derivation and data acquisition. In the end, we critically evaluate the knowledge gained by the use of these iPSC-CM models and discuss challenges and future perspectives for iPSC-CMs in the study of BrS and other arrhythmias.
Genetic Cardiomyopathies: The Lesson Learned from hiPSCs
Authors: My Ilaria , Di Pasquale Elisa
Published: March 2021

Genetic cardiomyopathies represent a wide spectrum of inherited diseases and constitute an important cause of morbidity and mortality among young people, which can manifest with heart failure, arrhythmias, and/or sudden cardiac death. Multiple underlying genetic variants and molecular pathways have been discovered in recent years; however, assessing the pathogenicity of new variants often needs in-depth characterization in order to ascertain a causal role in the disease. The application of human induced pluripotent stem cells has greatly helped to advance our knowledge in this field and enabled to obtain numerous in vitro patient-specific cellular models useful to study the underlying molecular mechanisms and test new therapeutic strategies. A milestone in the research of genetically determined heart disease was the introduction of genomic technologies that provided unparalleled opportunities to explore the genetic architecture of cardiomyopathies, thanks to the generation of isogenic pairs. The aim of this review is to provide an overview of the main research that helped elucidate the pathophysiology of the most common genetic cardiomyopathies: hypertrophic, dilated, arrhythmogenic, and left ventricular noncompaction cardiomyopathies. A special focus is provided on the application of gene-editing techniques in understanding key disease characteristics and on the therapeutic approaches that have been tested.
The Pathogenic Role of Interferons in the Hyperinflammatory Response on Adult-Onset Still’s Disease and Macrophage Activation Syndrome: Paving the Way towards New Therapeutic Targets
Authors: Di Cola Ilenia , Ruscitti Piero , Giacomelli Roberto , Cipriani Paola
Published: March 2021

Adult-onset Still’s disease (AOSD) is a systemic inflammatory disorder of unknown aetiology affecting young adults, which is burdened by life-threatening complications, mostly macrophage activation syndrome (MAS). Interferons (IFNs) are signalling molecules that mediate a variety of biological functions from defence against viral infections, to antitumor and immunomodulatory effects. These molecules have been classified into three major types: IFN I, IFN II, IFN III, presenting specific characteristics and functions. In this work, we reviewed the role of IFNs on AOSD and MAS, focusing on their pathogenic role in promoting the hyperinflammatory response and as new possible therapeutic targets. In fact, both preclinical and clinical observations suggested that these molecules could promote the hyperinflammatory response in MAS during AOSD. Furthermore, the positive results of inhibiting IFN-γ in primary hemophagocytic lymphohistiocytosis may provide a solid rationale to arrange further clinical studies, paving the way for reducing the high mortality rate in MAS during AOSD.
Understanding the Adoption of Incentivized Word-of-Mouth in the Online Environment
Authors: Anastasiei Bogdan , Dospinescu Nicoleta , Dospinescu Octavian
Published: March 2021

Nowadays, word-of-mouth is a very important component of e-commerce activity because consumers are very sensitive to other people’s opinions. Depending on the companies’ politics, these opinions can be incentivized or non-incentivized. One of the major dilemmas consists in establishing which kind of word-of-mouth has more influence on customers’ perceptions. The purpose of this study is to assess the relationships between perceived argument quality (PAQ) and perceived source expertise (PSE), on the one hand, and electronic word-of-mouth adoption intention on the other hand, for an incentivized message compared to a non-incentivized message. We processed answers from two different random groups by using adapted PAQ and PSE inventories of questions. The constructs, latent variables and items were analyzed in IBM Amos software, and our findings confirm the hypotheses regarding the relationship between the attributes of the message (argument quality and source expertise) and message credibility. Additionally, we found a significant positive relationship between message credibility and electronic word-of-mouth adoption intention. Our research also explores the moderating role of the message type (incentivized vs. non-incentivized) in the relationships above, and we discovered that the message type significantly moderates the relationship between perceived argument quality and credibility, but the type of message does not moderate the relationship between message credibility and eWOM adoption intention.
Cold-Cured Bisphenolic Epoxy Adhesive Filled with Low Amounts of CaCO3: Effect of the Filler on the Durability to Aqueous Environments
Authors: Rudawska Anna , Frigione Mariaenrica
Published: March 2021

The effects of aging exposures to three non-saline aqueous environments on the compressive mechanical properties of a calcium carbonate-filled bisphenolic epoxy adhesive, cold-cured with the addition of two curing agents suitable for the cure at ambient temperature (i.e., Mannich base and triethylenetetramine), were assessed. The amount of the added filler (CaCO3) varied from 1 to 3 g per 100 g of resin; the immersion times in each of the selected medium varied from 1 to 10 months. It was found that the mechanical properties measured in compression mode on cylindrical specimens of unfilled and CaCO3-loaded epoxy were scarcely influenced by the kind of curing agent employed; only the compressive modulus was limitedly affected by this parameter. Referring to the behavior when aged in water, the CaCO3-filled epoxies displayed noticeable growths in modulus, small reductions in strength, and limited variations in strain, with a certain influence of the exposure time, especially when comparing the properties at the lowest time with those at medium–long times. On the basis of the results of statistical MANOVA analysis, it can be concluded that among the compositional factors (i.e., the type of curing agent employed to cure the epoxy compounds and the micro-filler content), only the amount of CaCO3 filler significantly affects the compressive modulus.
Synthesis, Polymorphism and Thermal Decomposition Process of (n-C4H9)4NRE(BH4)4 for RE = Ho, Tm and Yb
Authors: Wegner Wojciech , Jaroń Tomasz
Published: March 2021

In total, three novel organic derivatives of lanthanide borohydrides, n-But4NRE(BH4)4 (TBAREB), RE = Ho, Tm, Yb, have been prepared utilizing mechanochemical synthesis and purified via solvent extraction. Studies by single crystal and powder X-ray diffraction (SC-XRD and PXRD) revealed that they crystalize in two polymorphic forms, α- and β-TBAREB, adopting monoclinic (P21/c) and orthorhombic (Pnna) unit cells, previously found in TBAYB and TBAScB, respectively. Thermal decomposition of these compounds has been investigated using thermogravimetric analysis and differential scanning calorimetry (TGA/DSC) measurements, along with the analysis of the gaseous products with mass spectrometry (MS) and with analysis of the solid decomposition products with PXRD. TBAHoB and TBAYbB melt around 75 °C, which renders them new ionic liquids with relatively low melting points among borohydrides.
The Oxidation Behaviour and Notch Wear Formation of TiAlN Coated Tools Using Different Oxidation Techniques
Authors: Grzesik Wit , Małecka Joanna
Published: March 2021

This paper proposes a novel approach to assessing oxidation behavior of TiAlN coatings with defined stoichiometry on the rake and flank surfaces. This is based on the multi-parametric comparison of the oxidation effects detected on the coatings’ surfaces resulting from static diffusion couple tests. In this experimental study the diffusion couples consisting of Ti-based and Ni-based alloys and coated TiAlN cutting inserts are tested, respectively. The optimum oxidation temperature was determined by annealing the selected TiAlN coating in a high temperature chamber at temperatures: 700 °C, 800 °C, 900 °C and 1000 °C in air. Concurrently, the mass change and corresponding thickness of the Al2O3 oxidized layer were measured and computed. The comparison of oxides produced covers the surface morphologies, chemical elements and phases which were analyzed by means of SEM (scanning electron microscope), EDS (energy dispersive spectroscopy) and XRD (X-ray diffraction techniques). Additionally, scratch tests were performed to assess the penetration depth down to the substrate and coating failure mechanism after oxidation in diffusion couples. An acceptable similarity of Al2O3 films formed on the TiAlN coating surfaces in diffusion couples and machining processes was established.
Thermodynamic Modelling and Microstructural Study of Z-Phase Formation in a Ta-Alloyed Martensitic Steel
Authors: Riedlsperger Florian , Gsellmann Bernadette , Povoden-Karadeniz Erwin , Tassa Oriana , Matera Susanna , Dománková Mária , Kauffmann Florian , Kozeschnik Ernst , Sonderegger Bernhard
Published: March 2021

A thermokinetic computational framework for precipitate transformation simulations in Ta-containing martensitic Z-steels was developed, including Calphad thermodynamics, diffusion mobility data from the literature, and a kinetic parameter setup that considered precipitation sites, interfacial energies and dislocation density evolution. The thermodynamics of Ta-containing subsystems were assessed by atomic solubility data and enthalpies from the literature as well as from the experimental dissolution temperature of Ta-based Z-phase CrTaN obtained from differential scanning calorimetry. Accompanied by a comprehensive transmission electron microscopy analysis of the microstructure, thermokinetic precipitation simulations with a wide-ranging and well-documented set of input parameters were carried out in MatCalc for one sample alloy. A special focus was placed on modelling the transformation of MX into the Z-phase, which was driven by Cr diffusion. The simulation results showed excellent agreement with experimental data in regard to size, number density and chemical composition of the precipitates, showing the usability of the developed thermokinetic simulation framework.
Functionalization of Polycaprolactone Electrospun Osteoplastic Scaffolds with Fluorapatite and Hydroxyapatite Nanoparticles: Biocompatibility Comparison of Human Versus Mouse Mesenchymal Stem Cells
Authors: Malysheva Khrystyna , Kwaśniak Konrad , Gnilitskyi Iaroslav , Barylyak Adriana , Zinchenko Viktor , Fahmi Amir , Korchynskyi Olexandr , Bobitski Yaroslav
Published: March 2021

A capability for effective tissue reparation is a living requirement for all multicellular organisms. Bone exits as a precisely orchestrated balance of bioactivities of bone forming osteoblasts and bone resorbing osteoclasts. The main feature of osteoblasts is their capability to produce massive extracellular matrix enriched with calcium phosphate minerals. Hydroxyapatite and its composites represent the most common form of bone mineral providing mechanical strength and significant osteoinductive properties. Herein, hydroxyapatite and fluorapatite functionalized composite scaffolds based on electrospun polycaprolactone have been successfully fabricated. Physicochemical properties, biocompatibility and osteoinductivity of generated matrices have been validated. Both the hydroxyapatite and fluorapatite containing polycaprolactone composite scaffolds demonstrated good biocompatibility towards mesenchymal stem cells. Moreover, the presence of both hydroxyapatite and fluorapatite nanoparticles increased scaffolds’ wettability. Furthermore, incorporation of fluorapatite nanoparticles enhanced the ability of the composite scaffolds to interact and support the mesenchymal stem cells attachment to their surfaces as compared to hydroxyapatite enriched composite scaffolds. The study of osteoinductive properties showed the capacity of fluorapatite and hydroxyapatite containing composite scaffolds to potentiate the stimulation of early stages of mesenchymal stem cells’ osteoblast differentiation. Therefore, polycaprolactone based composite scaffolds functionalized with fluorapatite nanoparticles generates a promising platform for future bone tissue engineering applications.
Media for Dimensional Stabilization of Rubber Compounds during Additive Manufacturing and Vulcanization
Authors: Drossel Welf-Guntram , Ihlemann Jörn , Landgraf Ralf , Oelsch Erik , Schmidt Marek
Published: March 2021

The current article proposes a concept for the additive manufacturing of rubber components using extrusion-based 3D printing, in which an additional medium is added to ensure the maintenance of shape within the elastomeric structure during the additive manufacturing process and in the subsequent vulcanization process. Specific requirements for the dimensional stabilization of the media were defined and suitable media were derived. Silicone rubber, molding sand, and plaster were examined in experimental vulcanization tests for their suitability as possible media with regard to shape retention. Selected rubber geometries made of NBR were embedded in these media to undergo the vulcanization process. The results show a significant influence of the media on the heating times. All media were able to ensure that the rubber geometries maintained their shape during vulcanization. Nevertheless, some side effects were found. The silicone rubber did not cure properly around the rubber sample. Therefore, it was difficult to remove it from the rubber after vulcanization. The molding sand caused an increased surface roughness on the rubber. Plaster changed the glossy surfaces at the beginning to a matte one after vulcanization and residuals were difficult to remove. However, all media can serve as stabilization media with specific changes.
Recent Advancements in Nanoparticle-Based Optical Biosensors for Circulating Cancer Biomarkers
Authors: Amri Chaima , Shukla Arvind Kumar , Lee Jin-Ho
Published: March 2021

The effectiveness of cancer treatment strongly depends on the early detection of the disease. Currently, the most common diagnostic method, tissue biopsy, takes time and can be damaging to the patient. Circulating cancer biomarkers such as circulating tumor DNA, micro-RNA (miRNA), tumor proteins, exosomes, and circulating tumor cells have repeatedly demonstrated their viability as targets for minimally invasive cancer detection through liquid biopsies. However, among other things, achieving a great sensitivity of detection is still challenging due to the very low concentration of biomarkers in fluid samples. This review will discuss how the recent advances in nanoparticle-based biosensors are overcoming these practical difficulties. This report will be focusing mainly on optical transduction mechanisms of metal nanoparticles (M-NPs), quantum dots (QDs), and upconversion nanoparticles (UCNPs).
Chemical Structure and Microstructure Characterization of Ladder-Like Silsesquioxanes Derived Porous Silicon Oxycarbide Materials
Authors: Marchewka Jakub , Jeleń Piotr , Rutkowska Izabela , Bezkosty Patryk , Sitarz Maciej
Published: March 2021

The aim of this work was to synthesize porous ceramic materials from the SiOC system by the sol-gel method and the subsequent pyrolysis. The usage of two types of precursors (siloxanes) was determined by Si/C ratio in starting materials. It allows us to control the size of the pores and specific surface area, which are crucial for the potential applications of the final product after thermal processing. Methyltrimethoxysilane and dimethyldiethoxysilane were mixed in three different molar ratios: 4:1, 2:1, and 1:1 to emphasize Si/C ratio impact on silicon oxycarbide glasses properties. Structure and microstructure were examined both for xerogels and obtained silicon oxycarbide materials. Brunauer-Emmett-Teller (BET) analysis was performed to confirm that obtained materials are porous and Si/C ratio in siloxanes precursors affects porosity and specific surface area. This kind of porous ceramics could be potentially applied as gas sensors in high temperatures, catalyst supports, filters, adsorbents, or advanced drug delivery systems.
Universal Adhesive for Fixed Retainer Bonding: In Vitro Evaluation and Randomized Clinical Trial
Authors: Sfondrini Maria Francesca , Gallo Simone , Turcato Benedetta , Montasser Mona A. , Albelasy Nehal Fouad , Vallittu Pekka K. , Gandini Paola , Scribante Andrea
Published: March 2021

This study aims to assess the efficacy of a universal adhesive (Scotchbond Universal, 3M ESPE) (SB) in total-etch mode, compared to a traditional orthodontic primer (Transbond XT Primer, 3M ESPE) (XT Primer), to perform bonding of orthodontic fixed retainers along with the Transbond XT Light Cure Adhesive Paste (3M ESPE). For the in vitro study, a round section wire (Ortosmail Krugg) was bonded using XT Primer for 20 bovine incisors (Group 1) and SB for other 20 (Group 2). Samples were debonded in a universal testing machine applying a tangential force to specimens (crosshead speed of 1 millimeter per minute). Shear bond strength (SBS) and adhesive remnant index (ARI) scores were calculated. For the in vivo study, 100 patients needing upper and lower canine-to-canine fixed retainers after orthodontic treatment were randomly assigned to two groups of 50 participants each, i.e., group 1 (retainer bonding with XT Primer) and group 2 (retainer bonding with SB). Over two years, examinations were carried out monthly, and detachments were registered by considering the teeth and arches affected. In vitro, no statistically significant differences in SBS and ARI scores were demonstrated between the two groups, both showing a mean bond strength of about 12 MPa and major frequency of ARI “2” (>50% remnant adhesive on the enamel). Conversely, a significantly lower failure rate over 2 years was assessed clinically for group 2 in both arches. Independently of the adhesive and arch, incisors reported a significantly higher failure rate than canines. Scotchbond Universal used in total-etch mode could be a valid alternative to the traditional orthodontic Transbond XT Primer.
Convenient Synthesis of Functionalized Unsymmetrical Vinyl Disulfides and Their Inverse Electron-Demand Hetero-Diels-Alder Reaction
Authors: Jędrzejewski Bartosz , Musiejuk Mateusz , Doroszuk Justyna , Witt Dariusz
Published: March 2021

The simple, convenient, and efficient methods for the preparation of unsymmetrical vinyl disulfides with additional functional groups under mild conditions with moderate to high yields were designed. The developed methods include the reaction of S-vinyl phosphorodithioate with thiotosylates or S-vinyl thiotosylate with thiols. The designed methods allow for the synthesis of unsymmetrical vinyl disulfides with additional functionalities such as hydroxy, carboxy, protected amino, or ester groups. Vinyl disulfides reacted with the generated transient o-iminothioquinones in an inverse electron-demand [4+2] cycloaddition to produce benzo[b][1,4]thiazine derivatives.
Alkaline Activity of Portland Cement with Additives of Waste Glass
Authors: Szewczenko Wiktor , Kotsay Galyna
Published: March 2021

The concept of the alkaline activity of powdered materials introduced into cement compositions has been proposed, along with methods for its determination. The possibility of using waste glass as an active additive to Portland cement was evaluated from the standpoint of alkaline activity. Replacing the Portland cement component with glass waste in the form of glass powder at amounts from 1 to 35% made it possible to maintain the cement composition’s alkaline activity at a level that met the standard requirements. The previously unknown effects of mixed alkali in Portland cement in the presence of glass waste are described. Portland cement has a high potassium alkaline activity; however, container glass has a high sodium alkaline activity and a fairly low potassium alkaline activity. When glass waste is introduced into the structure of cement compositions, potassium alkaline activity is reduced.
Quasiperiodic Patterns of the Complex Dimensions of Nonlattice Self-Similar Strings, via the LLL Algorithm
Authors: Lapidus Michel L. , van Frankenhuijsen Machiel , Voskanian Edward K.
Published: March 2021

The Lattice String Approximation algorithm (or LSA algorithm) of M. L. Lapidus and M. van Frankenhuijsen is a procedure that approximates the complex dimensions of a nonlattice self-similar fractal string by the complex dimensions of a lattice self-similar fractal string. The implication of this procedure is that the set of complex dimensions of a nonlattice string has a quasiperiodic pattern. Using the LSA algorithm, together with the multiprecision polynomial solver MPSolve which is due to D. A. Bini, G. Fiorentino and L. Robol, we give a new and significantly more powerful presentation of the quasiperiodic patterns of the sets of complex dimensions of nonlattice self-similar fractal strings. The implementation of this algorithm requires a practical method for generating simultaneous Diophantine approximations, which in some cases we can accomplish by the continued fraction process. Otherwise, as was suggested by Lapidus and van Frankenhuijsen, we use the LLL algorithm of A. K. Lenstra, H. W. Lenstra, and L. Lovász.
Emotion Recognition and Regulation Based on Stacked Sparse Auto-Encoder Network and Personalized Reconfigurable Music
Authors: Li Yinsheng , Zheng Wei
Published: March 2021

Music can regulate and improve the emotions of the brain. Traditional emotional regulation approaches often adopt complete music. As is well-known, complete music may vary in pitch, volume, and other ups and downs. An individual’s emotions may also adopt multiple states, and music preference varies from person to person. Therefore, traditional music regulation methods have problems, such as long duration, variable emotional states, and poor adaptability. In view of these problems, we use different music processing methods and stacked sparse auto-encoder neural networks to identify and regulate the emotional state of the brain in this paper. We construct a multi-channel EEG sensor network, divide brainwave signals and the corresponding music separately, and build a personalized reconfigurable music-EEG library. The 17 features in the EEG signal are extracted as joint features, and the stacked sparse auto-encoder neural network is used to classify the emotions, in order to establish a music emotion evaluation index. According to the goal of emotional regulation, music fragments are selected from the personalized reconfigurable music-EEG library, then reconstructed and combined for emotional adjustment. The results show that, compared with complete music, the reconfigurable combined music was less time-consuming for emotional regulation (76.29% less), and the number of irrelevant emotional states was reduced by 69.92%. In terms of adaptability to different participants, the reconfigurable music improved the recognition rate of emotional states by 31.32%.
General Fractional Integrals and Derivatives with the Sonine Kernels
Authors: Luchko Yuri
Published: March 2021

In this paper, we address the general fractional integrals and derivatives with the Sonine kernels on the spaces of functions with an integrable singularity at the point zero. First, the Sonine kernels and their important special classes and particular cases are discussed. In particular, we introduce a class of the Sonine kernels that possess an integrable singularity of power function type at the point zero. For the general fractional integrals and derivatives with the Sonine kernels from this class, two fundamental theorems of fractional calculus are proved. Then, we construct the n-fold general fractional integrals and derivatives and study their properties.
An Ultra-Low-Power Embedded Processor with Variable Micro-Architecture
Authors: Ma Wenheng , Cheng Qiao , Gao Yudi , Xu Lan , Yu Ningmei
Published: March 2021

Embedded processors are widely used in various systems working on different tasks with different workloads. A more complex micro-architecture leads to better peak performance and worse power consumption. Shutting down the units designed for performance enhancement could improve energy efficiency in low-workload scenarios. In this paper, we evaluated the energy distribution in various embedded processors. According to the analysis, pipeline registers and the dynamic branch predictor, which are employed for better peak performance, have great impacts on energy efficiency. Thus, we proposed an ultra-low-power processor with variable micro-architecture. The processor is based on a 4-stage pipeline core with a Gshare branch predictor, and all units work in high-performance mode. In normal mode, the Gshare predictor is shut down and Always-Not-Taken prediction is used. In low-power mode, some of the pipeline registers are bypassed to avoid unnecessary energy dissipation and improve executing efficiency. A mode register (MR) is designed to indicate current working mode. Switching between different modes is controlled by the software. The proposed core is implemented in 40 nm technology and simulated with the traces of 17 benchmarks in Embench. The average amounts of power consumed by the respective modes are 41.7 μW, 59.7 μW and 71.1 μW. The results show that normal mode (N-mode) and low-power mode (L-mode) consume 16.08% and 41.37% less power than high-performance mode (H-mode) on average. In best case scenarios, they could save 25.36% and 49.30% more power than H-mode. Considering the execution efficiency evaluated by instructions per cycle (IPC), the proposed processor consumes 7.78% or 51.57% less energy for each instruction than the baseline core. The area of the proposed processor is only 7.19% larger than the baseline core, and only 3.08% more power is consumed in H-mode.
CRISPR/Cas9-Mediated Genome Editing in Comfrey (Symphytum officinale) Hairy Roots Results in the Complete Eradication of Pyrrolizidine Alkaloids
Authors: Zakaria Mahmoud M. , Schemmerling Brigitte , Ober Dietrich
Published: March 2021

Comfrey (Symphytum officinale) is a medicinal plant with anti-inflammatory, analgesic, and proliferative properties. However, its pharmaceutical application is hampered by the co-occurrence of toxic pyrrolizidine alkaloids (PAs) in its tissues. Using a CRISPR/Cas9-based approach, we introduced detrimental mutations into the hss gene encoding homospermidine synthase (HSS), the first pathway-specific enzyme of PA biosynthesis. The resulting hairy root (HR) lines were analyzed for the type of gene-editing effect that they exhibited and for their homospermidine and PA content. Inactivation of only one of the two hss alleles resulted in HRs with significantly reduced levels of homospermidine and PAs, whereas no alkaloids were detectable in HRs with two inactivated hss alleles. PAs were detectable once again after the HSS-deficient HRs were fed homospermidine confirming that the inability of these roots to produce PAs was only attributable to the inactivated HSS and not to any unidentified off-target effect of the CRISPR/Cas9 approach. Further analyses showed that PA-free HRs possessed, at least in traces, detectable amounts of homospermidine, and that the PA patterns of manipulated HRs were different from those of control lines. These observations are discussed with regard to the potential use of such a CRISPR/Cas9-mediated approach for the economical exploitation of in vitro systems in a medicinal plant and for further studies of PA biosynthesis in non-model plants.
Anti-Tumor Drug Discovery Based on Natural Product β-Elemene: Anti-Tumor Mechanisms and Structural Modification
Authors: Bai Ziqiang , Yao Chuansheng , Zhu Junlong , Xie Yuanyuan , Ye Xiang-Yang , Bai Renren , Xie Tian
Published: March 2021

Natural products are important sources for drug discovery, especially anti-tumor drugs. β-Elemene, the prominent active ingredient extract from the rhizome of Curcuma wenyujin, is a representative natural product with broad anti-tumor activities. The main molecular mechanism of β-elemene is to inhibit tumor growth and proliferation, induce apoptosis, inhibit tumor cell invasion and metastasis, enhance the sensitivity of chemoradiotherapy, regulate the immune system, and reverse multidrug resistance (MDR). Elemene oral emulsion and elemene injection were approved by the China Food and Drug Administration (CFDA) for the treatment of various cancers and bone metastasis in 1994. However, the lipophilicity and low bioavailability limit its application. To discover better β-elemene-derived anti-tumor drugs with satisfying drug-like properties, researchers have modified its structure under the premise of not damaging the basic scaffold structure. In this review, we comprehensively discuss and summarize the potential anti-tumor mechanisms and the progress of structural modifications of β-elemene.
ICH Guideline for Biopharmaceutics Classification System-Based Biowaiver (M9): Toward Harmonization in Latin American Countries
Authors: Miranda Claudia , Aceituno Alexis , Fernández Mirna , Mendes Gustavo , Rodríguez Yanina , Llauró Verónica , Cabrera-Pérez Miguel Ángel
Published: March 2021

The biopharmaceutical classification system (BCS) is a very important tool to replace the traditional in vivo bioequivalence studies with in vitro dissolution assays during multisource product development. This paper compares the most recent harmonized guideline for biowaivers based on the biopharmaceutics classification system and the BCS regulatory guidelines in Latin America and analyzes the current BCS regulatory requirements and the perspective of the harmonization in the region to develop safe and effective multisource products. Differences and similarities between the official and publicly available BCS guidelines of several Latin American regulatory authorities and the new ICH harmonization guideline were identified and compared. Only Chile, Brazil, Colombia, and Argentina have a more comprehensive BCS guideline, which includes solubility, permeability, and dissolution requirements. Although their regulatory documents have many similarities with the ICH guidelines, there are still major differences in their interpretation and application. This situation is an obstacle to the successful development of safe and effective multisource products in the Latin American region, not only to improve their access to patients at a reasonable cost, but also to develop BCS biowaiver studies that fulfill the quality standards of regulators in developed and emerging markets.